Àññîöèàöèè ïîëèìîðôíûõ âàðèàíòîâ ãåíîâ ðåïàðàöèè ÄÍÊ è ìåòàáîëèçìà êñåíîáèîòèêîâ ñ óðîâíåì õðîìîñîìíûõ íàðóøåíèé â ëèìôîöèòàõ åëîâåêà*
|
|
- Ethelbert Corey Heath
- 6 years ago
- Views:
Transcription
1 ÎÐÈÃÈÍÀËÜÍÛÅ ÈÑÑËÅÄÎÂÀÍÈß Àññîöèàöèè ïîëèìîðôíûõ âàðèàíòîâ ãåíîâ ðåïàðàöèè ÄÍÊ è ìåòàáîëèçìà êñåíîáèîòèêîâ ñ óðîâíåì õðîìîñîìíûõ íàðóøåíèé â ëèìôîöèòàõ åëîâåêà* Áàáóøêèíà Í.Ï., Êó åð À.Í., Ëåáåäåâ È.Í., Âàñèëüåâ Ñ.À., Òè ìî øåâ ñêèé Â.À., Áðà ãè íà Å.Þ., Ñó õà íî âà Í.Í., Òîð õî âà Í.Á., ßêîâ ëå âà Þ.Ñ. ÔÃÁÓ «ÍÈÈ ìå äè öèí ñêîé ãå íå òè êè» ÑÎ ÐÀÌÍ, , ã.òîìñê, óë. Íà áå ðåæ íàÿ ð. Óøàé êè, 10, òåë. (3822) , ôàêñ (3822) , e-ma il: nad.ba bus h ki na@med ge ne tics.ru Ïðåäñòàâëåíû äàííûå î àñòîòàõ ïîëèìîðôíûõ âàðèàíòîâ ãåíîâ ñèñòåì ðåïàðàöèè ÄÍÊ (MLH1 (rs ), PMS2 (rs ), XRCC1 (rs25487)), êîíòðîëÿ êëåòî íîãî öèêëà (TP53 (rs )) è äåòîêñèêàöèè êñåíîáèîòèêîâ (Cyp2C19 (rs ), GSTT1 (del) è GSTM1 (del)) ó èíäèâèäîâ ñ íàëè èåì â îðãàíèçìå èíêîðïîðèðîâàííîãî ïëóòîíèÿ-239 è â êîíòðîëü - íîé ãðóïïå, à òàêæå â ïîäãðóïïàõ, õàðàêòåðèçóþùèõñÿ ðàçëè íîé àñòîòîé õðîìîñîìíûõ àíîìàëèé (òðè ãðóïïû ñðàâíåíèÿ: ñ âû - ñîêèì è íèçêèì óðîâíåì àñòîòû õðîìîñîìíûõ àáåððàöèé, àíåóïëîèäèè è ìèêðîÿäåð). Íè ïî îäíîìó èç èññëåäîâàííûõ ëîêóñîâ íå çàðåãèñòðèðîâàíî ñòàòèñòè åñêè çíà èìûõ ðàçëè èé ïî àñòîòàì àëëåëåé è ãåíîòèïîâ ìåæäó ãðóïïîé êîíòðîëÿ è ãðóïïîé ñ íàëè èåì â îðãàíèçìå èíêîðïîðèðîâàííîãî ïëóòîíèÿ-239. Îäíàêî óñòàíîâëåíû ñòàòèñòè åñêè çíà èìûå ðàçëè èÿ â àñòîòàõ ãåíîòèïîâ ïî rs ãåíà MLH1 ìåæäó ïîäãðóïïàìè ñ âûñîêèì è íèçêèì óðîâíåì õðîìîñîìíûõ àáåððàöèé (p=0,047), à òàêæå ïî àñòîòå êîìáèíàöèé ãåíîòèïîâ GSTT1/GSTM1 ìåæäó ïîäãðóïïàìè ñ ðàçíûì óðîâíåì àíåóïëîèäèè (p=0,032). Äëÿ äðóãèõ èññëåäîâàííûõ ëîêóñîâ îòìå åíû íåêîòîðûå ðàçëè èÿ ïî àñòîòàì ãåíîòèïîâ ìåæäó ãðóïïàìè ñ âûñîêîé è íèçêîé àñòîòîé õðîìîñîìíûõ íàðóøåíèé ðàçíûõ òèïîâ, êîòîðûå, îäíàêî, íå äîñòèãàëè óðîâíÿ ñòàòèñòè åñêîé çíà èìîñòè. àñòîòû àëëåëåé ìåæäó ñðàâíèâàåìûìè ãðóïïàìè âàðüèðîâàëè â ìåíüøåé ñòåïåíè; ñòàòèñòè åñêè çíà èìûå ðàçëè èÿ çàðåãèñòðèðîâàíû òîëüêî ìåæäó ïîäãðóïïàìè ñ ðàçíûì óðîâíåì õðîìîñîìíûõ àáåððàöèé (äëÿ rs25487 â ãåíå XRCC1, p=0,039). Êëþ åâûå ñëîâà: èíäèâèäóàëüíàÿ ðàäèî óâñòâèòåëüíîñòü, ïîëèìîðôèçì ãåíîâ, ðåïàðàöèÿ ÄÍÊ, õðîìîñîìíûå àáåððà - öèè, ìèêðîÿäðà Ââåäåíèå Â íàñòîÿùåå âðåìÿ ñóùåñòâîâàíèå ôåíîìåíà èíäèâèäóàëüíîé ðàäèî óâñòâèòåëüíîñòè íè ó êîãî íå âûçûâàåò ñîìíåíèÿ, òàê æå êàê è íàëè èå ãåíåòè åñêîãî êîìïîíåíòà, îêàçûâàþùåãî âëèÿíèå íà ñïîñîáíîñòü îðãàíèçìà âûäåðæèâàòü âîçäåéñòâèå èîíèçèðóþùåãî èçëó åíèÿ. Ýòî ïîäòâåðæäàåòñÿ ñõîäíîé èíäèâèäóàëüíîé ðàäèî óâ - ñòâèòåëüíîñòüþ â ïàðàõ îäíîÿéöåâûõ áëèçíåöîâ, à òàêæå ïîâûøåííîé ðàäèî óâñòâèòåëüíîñòüþ ïàöèåíòîâ ñ íàñëåäñòâåííûìè çàáîëåâàíèÿìè, îáóñëîâëåííûìè ìóòàöèÿìè ãåíîâ ðåïàðàöèè ÄÍÊ. Ïîýòîìó îöåíêà èíäèâè - äóàëüíîé ðàäèî óâñòâèòåëüíîñòè è èçó åíèå îïðåäåëÿþùèõ å ôàêòîðîâ ÿâëÿþòñÿ îäíèìè èç ïðèîðèòåòíûõ íàïðàâëåíèé ñîâðåìåííîé ðàäèîáèîëîãèè. Àêòèâíîå èñïîëüçîâàíèå èîíèçèðóþùèõ èçëó åíèé â ïîâñåäíåâíîé æèçíè (ðåíòãåíîëîãèÿ, ðàäèîòåðàïèÿ, àòîìíàÿ ýëåêòðîýíåðãåòèêà) óâåëè èâàåò òåõíîãåííóþ íàãðóçêó íà åëîâåêà è åãî ñðåäó îáèòàíèÿ. Êîíòàêò ñ èîíèçèðóþùèì èçëó åíèåì ïðîèñõîäèò, ïðåèìóùåñòâåííî, â äèàïàçîíå ìàëûõ äîç, ðåàêöèÿ îðãàíèçìà íà êîòîðûå ìîæåò çàìåòíî âàðüèðîâàòü. Èçâåñòíî, òî ñóùåñòâóþò ðàçëè èÿ ïî ðàäèî óâñòâèòåëüíîñòè ìåæäó âèäàìè, ïîïóëÿöèÿìè, ïîëîâîçðàñòíûìè ãðóïïàìè; ðåàêöèÿ íà ðàäèàöèþ ìîæåò çàâèñåòü îò ôèçèîëîãè åñêîãî ñîñòîÿíèÿ îðãàíèçìîâ, îòëè àòüñÿ ó êëåòîê ðàçíûõ òèïîâ, çàâèñåòü îò ñòàäèè äèôôåðåíöèðîâêè è ñòàäèè êëåòî íîãî öèêëà [36]. Òàêèì îáðàçîì, ïðè ðàâíîì ðàäèàöèîííîì âîçäåéñòâèè ðåàê - öèÿ îðãàíèçìà ìîæåò îòëè àòüñÿ ó ðàçíûõ èíäèâèäîâ. Ïîêà íåò îäíîçíà íûõ ñóæäåíèé î òîì, êàêèå èìåííî ãåíû ÿâëÿþòñÿ êëþ åâûìè â îïðåäåëåíèè èíäèâèäóàëüíîé ðàäèî óâñòâèòåëüíîñòè. Îäíàêî àñòî ê êàíäèäàòíûì îò - íîñÿò ãåíû ðåïàðàöèè ÄÍÊ, êîíòðîëÿ êëåòî íîãî öèêëà, ìåòàáîëèçìà êñåíîáèîòèêîâ è äð. [2]. Â íàñòîÿùåì èññëåäîâàíèè èçó åí ïîëèìîðôèçì ãå - íîâ ñèñòåì ðåïàðàöèè ÄÍÊ (ìèññ-ìàò MLH1 (rs ) è PMS2 (rs ); ýêñöèçèîííîé ðåïàðà - öèè îñíîâàíèé XRCC1 (rs25487)), êîíòðîëÿ êëåòî íî - ãî öèê ëà (TP53 (rs )), äåòîêñèêàöèè êñåíîáèîòè - êîâ (Cyp2C19 (rs ) ïåð âîé ôà çû, GSTT1 (del) è GSTM1 (del) âòî ðîé ôà çû) â ãðóï ïàõ èí äè âè äîâ, ñ îä - íîé ñòîðîíû äèôôåðåíöèðîâàííûõ ïî íàëè èþ/îò - ñóòñòâèþ â îðãàíèçìå èíêîðïîðèðîâàííîãî ïëóòî - íèÿ-239, ñ äðóãîé, õàðàêòåðèçóþùèõñÿ ðàçëè íîé à - ñòîòîé õðîìîñîìíûõ àíîìàëèé. Íà ñòî ÿ ùåå èñ ñëå äî âà íèå âû ïîë íå íî â ðàì êàõ ãî ñó äàð ñò âåí íî ãî êîí ò ðàê òà ¹ ÔÖÏ «Èñ ñëå äî âà íèÿ è ðàç ðà áîò êè ïî ïðè î ðè òåò íûì íà ïðàâ ëå íè ÿì ðàç âè òèÿ íà ó íî-òåõ íî ëî ãè å ñêî ãî êîì ï ëåê ñà Ðîñ ñèè íà ãî äû». ISSN
2 ÎÐÈ ÃÈ ÍÀ ËÜ ÍÛÅ ÈÑ ÑËÅ ÄÎ ÂÀ ÍÈß Ìàòåðèàëû è ìåòîäû Âñå ãî îá ñëå äî âà íî 145 åë., èç íèõ 71 åë. ëè öà ñ íà - ëè èåì â îðãàíèçìå èíêîðïîðèðîâàííîãî ïëóòîíèÿ-239 (àêòèâíîñòü íêè) (ðàáîòíèêè ÎÀÎ «Ñèáèðñêèé õèìè åñêèé êîìáèíàò», ã.ñåâåðñê; äàëåå «Pu»). 74 åë., íå èìåþùèå îòíîøåíèÿ ê ïëóòîíèåâîìó ïðîèçâîäñòâó, ñîñòàâèëè êîíòðîëüíóþ ãðóïïó (äàëåå «Ê») (òàáë. 1). Âñå èíäèâèäû â îáåèõ ãðóïïàõ áûëè ìóæñêîãî ïîëà, ïðåîáëàäàëè ïðåäñòàâèòåëè ðóññêîé íàöèîíàëüíîñòè. Îò êàæäîãî èíäèâèäà ïîëó åíî èíôîðìèðîâàííîå ñîãëàñèå íà ïðîâåäåíèå ãåíåòè åñêîãî èññëåäîâàíèÿ. Êóëüòèâèðîâàíèå ëèìôîöèòîâ ïåðèôåðè åñêîé êðîâè è ïðèãîòîâëåíèå ïðåïàðàòîâ õðîìîñîì äëÿ öèòîãåíåòè åñêîãî àíàëèçà ïðîâîäèëè ñ èñïîëüçîâàíèåì ñòàíäàð - òíûõ ìåòîäîâ [29]. Àíàëèç õðîìîñîìíûõ íàðóøåíèé ïðî - âîäèëñÿ ñ èñïîëüçîâàíèåì êëàññè åñêèõ öèòîãåíåòè åñêèõ (ïðèìåíÿëàñü ðóòèííàÿ îêðàñêà õðîìîñîì ïî Ãèìçà è äèôôåðåíöèàëüíàÿ îêðàñêà õðîìîñîì ïî G-ìåòîäó (Ðîìàíîâñêîãî Ãèìçà)) [29] è ìîëåêóëÿðíî-öèòîãåíåòè- å ñêèõ ìå òî äîâ [12] â ñëó àå ó òà ìèê ðî ÿäåð. Áî ëåå ïî - äðîáíî èñïîëüçîâàííûå ìîëåêóëÿðíî-öèòîãåíåòè åñêèå ìåòîäû îïèñàíû íàìè ðàíåå [4]. Ó êàæäîãî èíäèâèäà ïðîàíàëèçèðîâàíî 300 ðóòèííî îêðàøåííûõ ìåòàôàç è 100 ìåòàôàçíûõ ïëàñòèíîê ñ äèôôåðåíöèàëüíîé îêðàñêîé. àñòîòó àíîìàëüíûõ ñåãðåãàöèîííûõ ñîáûòèé äëÿ êàæäîé ïàðû àíàëèçèðóåìûõ íà îäíîì ïðåïàðàòå õðîìîñîì îöåíèâàëè â 1000 äâóõúÿäåðíûõ êëåòîê, â êîòîðûõ ïðîâîäèëè ó åò ìèêðîÿäåð. ÄÍÊ äëÿ ïðîâåäåíèÿ ìîëåêóëÿðíî-ãåíåòè åñêîãî àíàëèçà âûäåëÿëè èç ëèìôîöèòîâ ïåðèôåðè åñêîé êðîâè ïî ñòàíäàðòíîé ìåòîäèêå ñ ôåíîë-õëîðîôîðìíîé î èñòêîé [3]. Ïîëèìîðôíûå âàðèàíòû ãåíîâ àíàëèçèðîâàëè ñ ïîìîùüþ ÏÖÐ-ÏÄÐÔ. Ñòðóêòóðà ïðàéìåðîâ, òåìïåðàòóðà îòæèãà è ïàòòåðí ðåñòðèêöèè ïðåäñòàâëåíû â òàáë. 2. Ïðîãðàììû àìïëèôèêàöèè âêëþ àëè ñëåäóþùèå áëîêè: ïåðâè íàÿ äåíàòóðàöèÿ â òå åíèå 5 7 ìèí ïðè Ñ, öèêëîâ îòæèãà ïðàéìåðîâ ïðè ñïåöèôè åñêîé äëÿ êàæäîãî snp òåìïåðàòóðå (òàáë. 2), ýëîíãàöèÿ öåïè ïðè 72 Ñ è äåíàòóðàöèÿ ïðè 94 Ñ. Ïðîãðàììû çàâåðøàëà ôèíàëüíàÿ ýëîí ãà öèÿ â òå å íèå 5 10 ìèí ïðè 72 Ñ. Äëÿ îïðå äå ëå íèÿ ãåíîòèïîâ ïðîäóêòû àìïëèôèêàöèè ïîäâåðãàëè ãèäðîëèçó ñïåöèôè åñêîé ýíäîíóêëåàçîé ðåñòðèêöèè (ñîãëàñíî ïðîòîêîëó ôèðìû-ïðîèçâîäèòåëÿ), çàòåì ïðîäóêòû ðåñòðèêöèè ôðàêöèîíèðîâàëè â 3%-íîì àãàðîçíîì ãåëå, îêðàøåííîì áðîìèñòûì ýòèäèåì. Ãåíîòèïèðîâàíèå ïîëèìîðôíûõ âàðèàíòîâ ãåíîâ GSTT1 è GSTM1 ïðîâîäèëè ñ ïîìîùüþ ìóëüòèïëåêñíîé ÏÖÐ. Îòñóòñòâèå ñîîòâåòñòâóþùèõ ôðàãìåí òîâ ðàç ìå ðîì 131 è 114 ï.í. óêà çû âà ëî íà íà ëè èå ãî ìî - çèãîò ïî «íóëåâûì» àëëåëÿì ãåíîâ GSTT1 è GSTM1 ñî îò - âåòñòâåííî. Íàëè èå ýòèõ ôðàãìåíòîâ ñâèäåòåëüñòâîâàëî î íàëè èè íîðìàëüíîé êîïèè ãåíà â ãîìî-, ëèáî ãåòåðîçèãîòíîì ñîñòîÿíèè. Äëÿ âíóòðåííåãî êîíòðîëÿ àìïëèôèêàöèè îïðåäåëÿëè ôðàãìåíò ãåíà ER ðàç ìå ðîì 181 ï.í. Ðàçëè èÿ ïî âåëè èíàì óñðåäí ííûõ çíà åíèé àñòîò õðîìîñîìíûõ íàðóøåíèé ìåæäó ñðàâíèâàåìûìè ãðóïïàìè îöåíèâàëè ñ ïîìîùüþ îäíîôàêòîðíîãî äèñïåðñèîííîãî àíàëèçà. Ñîîòâåòñòâèå ðàñïðåäåëåíèÿ àñòîò ãåíîòèïîâ ðàâíîâåñèþ Õàðäè Âàéíáåðãà ïðîâåðÿëè ñ ïîìîùüþ êðèòåðèÿ 2 ; äëÿ ñðàâíåíèÿ àñòîò ãåíîòèïîâ è àëëåëåé ìåæäó ðàçëè íûìè ãðóïïàìè èñïîëüçîâàëè êðèòåðèé 2 ñ ïî ïðàâ - êîé Éåò ñà íà íå ïðå ðûâ íîñòü è òî íûé òåñò Ôè øå ðà. Ðåçóëüòàòû è îáñóæäåíèå Âàæíûì âîïðîñîì â îöåíêå èíäèâèäóàëüíîé ðàäèî óâñòâèòåëüíîñòè ÿâëÿåòñÿ àíàëèç çàâèñèìîñòè óðîâíÿ õðîìîñîìíûõ íàðóøåíèé â êëåòêàõ åëîâåêà îò íîñèòåëüñòâà ðàçëè íûõ âàðèàíòîâ ãåíîâ, ïðîäóêòû êîòîðûõ ó àñòâóþò â ðåïàðàöèè ÄÍÊ, ìåòàáîëèçìå êñåíîáèîòèêîâ è äðóãèõ ïðîöåññàõ â îðãàíèçìå, ñâÿçàííûõ ñ îòâåòîì íà âîçäåéñòâèå ðàäèàöèè. Ðàíåå íàìè áûë ïðîâåäåí àíàëèç àñòîòû ñòðóêòóðíûõ è èñëîâûõ õðîìîñîìíûõ íàðóøåíèé è ìèêðîÿäåð â ëèìôîöèòàõ ïåðèôåðè åñêîé êðîâè ó èíäèâèäîâ ñ èíêîðïîðèðîâàííûì ïëóòîíèåì è ëèö êîíòðîëüíîé ãðóïïû, íèêîãäà íå êîíòàêòèðîâàâøèõ ñ ðàäèàöèåé â ðàìêàõ ïðîôåññèîíàëüíîé äåÿòåëüíîñòè [4]. Îñíîâíûå ðåçóëüòàòû äàííîãî èññëåäîâàíèÿ ïðåäñòàâëåíû â òàáë. 3. Â ãðóïïå èíäèâèäîâ ñ èíêîðïîðèðîâàííûì ïëóòîíèåì-239 íàáëþäàëàñü ñòàòèñòè åñêè çíà èìî áîëåå âûñîêàÿ àñòîòà àáåððàöèé õðîìîñîìíîãî òèïà ïî ñðàâíåíèþ ñ êîíòðîëüíîé ãðóïïîé. Íàïðîòèâ, àñòîòà àáåððàöèé õðîìàòèäíîãî òèïà íå îòëè àëàñü ñòàòèñòè åñêè çíà èìî ìåæäó îáñëåäîâàííûìè ãðóïïàìè, òî ñîãëàñóåòñÿ ñ èçâåñòíûìè ìåõàíèçìàìè õðîíè åñêîãî âîçäåéñòâèÿ èîíèçèðóþùåãî èçëó åíèÿ. Êðîìå òîãî, óðîâåíü ìèêðîÿäåð, ñîîòâåòñòâóþùèõ îòñòàâøèì ôðàãìåíòàì õðîìîñîì è öåëûì õðîìîñîìàì, ó ðàáîòíèêîâ ïëóòîíèåâîãî ïðîèçâîäñòâà áûë ñòàòèñòè åñêè çíà èìî âûøå, åì â êîíòðîëüíîé ãðóïïå. Íàêîíåö, ñóììàðíàÿ àñòîòà àíåóïëîèäèè ïî øåñòè èññëåäîâàííûì õðîìîñîìàì òàêæå îêàçàëàñü âûøå â ëèìôîöèòàõ ïåðèôåðè åñêîé êðîâè èíäèâèäîâ ñ èíêîðïîðèðîâàííûì ïëóòîíèåì-239 ïî ñðàâíåíèþ ñ êîíòðîëüíîé ãðóïïîé. Õàðàêòåðèñòèêà ñôîðìèðîâàííûõ äëÿ îáñëåäîâàíèÿ ãðóïï èíäèâèäîâ ñ èíêîðïîðèðîâàííûì ïëóòîíèåì è êîíòðîëüíûõ ëèö Òàá ëè öà 1 Ãðóïïà Îáî çíà å íèå ãðóïïû Êîí ò ðî ëü íàÿ ãðóï ïà "Ê" (53,0±9,42) Ëè öà ñ èí êîð ïî ðè ðî âàí íûì ïëó òî íè åì-239 "Pu" 26,5 70 (56,7±9,5) Âîçðàñò, ëåò Àêòèâíîñòü ïëó òî íèÿ, íêè èñ ëî èí äè âè äîâ
3 ÌÅÄÈÖÈÍÑÊÀß ÃÅÍÅÒÈÊÀ ¹4 Ïî ðå çó ëü òà òàì öè òî ãå íå òè å ñêî ãî èñ ñëå äî âà íèÿ áû ëè âû äå ëå íû ïîä ãðóï ïû èí äè âè äîâ ñ ðàç íûì óðîâ - íåì õðîìîñîìíûõ íàðóøåíèé: õðîìîñîìíûõ àáåððàöèé (ÕÀ), àíåóïëîèäèè (Àí), ìèêðîÿäåð (Ìß) (òàáë. 4). Ìåæäó ñôîðìèðîâàííûìè ãðóïïàìè ïðîâîäèëîñü ñðàâíå íèå à ñ òîò ïî ëè ìîð ô íûõ âà ðè àí òîâ ãå íîâ MLH1 (rs ), PMS2 (rs ), XRCC1 (rs25487), TP53 (rs ), Cyp2C19 (rs ), GSTT1 (del) è GSTM1 (del). Íè ïî îäíîìó èç èññëåäîâàííûõ ëîêóñîâ íå óñòàíîâëåíî ñòàòèñòè åñêè çíà èìûõ ðàçëè èé ïî àñòîòàì àëëåëåé è ãåíîòèïîâ ìåæäó ãðóïïîé êîíòðîëÿ è ãðóïïîé èíäèâèäîâ ñ èíêîðïîðèðîâàííûì ïëóòîíèåì-239, òî ïîçâîëèëî íàì â äàëüíåéøåì ôîðìèðîâàòü ïîäãðóïïû ñ ðàçíûì óðîâíåì Ãåí Ïîëèìîð - ôèçì Ëî êà ëè çà - öèÿ â ãå íå Ñòðóê òó ðà ïðàé ìå ðîâ, ïà ðà ìåò ðû ÏÖÐ è ðå ñò ðèê öèè äëÿ îïðå äå ëå íèÿ ãå íî òè ïîâ ïî èñ ñëå äî âàí íûì ìàðê ðàì Ïî ñëå äî âà òå ëü íîñòü ïðàé ìå ðîâ MLH1 rs Ýêçîí 8 F: 5`-ATAGTTTGCTGGTGGAGATA-3` R: 5`-ATGTGATGGAATGATAAACC-3` PMS2 rs Ýêçîí 11 F: 5`-AGAACAAGCCTCACAGCCCA-3` R: 5`-CCGTGTCTGGGATGCTGAAC-3` XRCC1 rs25487 Ýêçîí 10 F: 5'-TTGTGCTTTCTCTGTGTCCA-3' R: 5'-TCCTCCAGCCTTTTCTGATA-3' TP53 rs Ýêçîí 4 F: 5`-TTGCCGTCCCAAGCAATGGATGA-3` R: 5`-TCTGGGAAGGGACAGAAGATGAC-3` Cyp2C19 rs Ýêçîí 5 F: 5`-AATTACAACCAGAGCTTGGC-3` R: 5`-TATCACTTTCCATAAAAGCAAG-3` GSTT1 GSTM1 Ïðîòÿæ ííàÿ äåëåöèÿ 10 òûñ. ï.í. Ïðîòÿæ ííàÿ äåëåöèÿ 10 òûñ. ï.í. F: 5`-GGTCATTCTGAAGGCCAAGG-3` R: 5`-TTTGTGGACTGCTGAGGACG-3` F: 5`-TGCTTCACGTGTTATGGAGGTTC-3` R: 5`-GTTGGGCTCAAATATACGGTGG-3` Òåì ïå ðà òó ðà îò æè ãà ïðàé ìå ðîâ Ìå òîä äå òåê - öèè 56 C ÏÖÐ / ÏÄÐÔ BccI 64 C ÏÖÐ / ÏÄÐÔ Bst MA I 55 C ÏÖÐ / ÏÄÐÔ Msp I 63 C ÏÖÐ / ÏÄÐÔ Bst FN I 60 C ÏÖÐ / ÏÄÐÔ Sma I 65 C 61 C (ãðàäèåíò) Ìóëü òè ïëåê - ñ íàÿ ÏÖÐ In/Del Ïðîäóêòû ãèä ðî ëè çà, ï.í. G: 243 À: T: 243 C: A: 615 G: C: 199 G: A: 169 G: "+": 13 " ": "+": 114 " ": Ïðè ìå à íèå. * äëÿ êîí ñò ðó è ðî âà íèÿ ïî ñëå äî âà òå ëü íî ñòè ïðàé ìå ðîâ èñ ñëå äó å ìûõ îá ëà ñ òåé ãå íîâ èñ ïî ëü çî âà ëàñü ïðîãðàììà Vector NTI Òàá ëè öà 2 Èñ òî - íèê * * * * [8] [32] Òàá ëè öà 3 Ñðåäíèå çíà åíèÿ àñòîòû õðîìîñîìíûõ íàðóøåíèé â èññëåäîâàííûõ ãðóïïàõ (% ± ñò.îøèáêà) Òèï õðîìîñîìíûõ íàðóøåíèé Ãðóï ïà èí äè âè äîâ ñ èí êîð ïî ðè ðî âàí - íûì ïëóòîíèåì-239 Êîí ò ðî ëü íàÿ ãðóïïà Àáåð ðà öèè õðî ìî ñîì íî ãî òè ïà 0,86±0,10* 0,33±0,12 Àáåð ðà öèè õðî ìà òèä íî ãî òè ïà 0,75±0,08 0,55±0,11 Ñóììàðíàÿ àñòîòà àíåóïëîèäèè (õðîìîñîìû 2, 7, 8, 12, X, Y) 1,49±0,30* 0,73±0,23 Ìèê ðî ÿä ðà 0,78±0,07* 0,55±0,04 Ïðè ìå à íèå. * ñòà òè ñòè å ñêè çíà è ìî áî ëåå âû ñî êàÿ à ñ òî òà â ãðóï ïå èí äè âè äîâ ñ èí êîð ïî ðè ðî âàí íûì ïëó òî íè - åì-239 ïî ñðàâíåíèþ ñ êîíòðîëüíîé ãðóïïîé (p<0,05) Ãðóï ïà ñðàâ íå - íèÿ Õàðàêòåðèñòèêà ãðóïï, ñôîðìèðîâàííûõ íà îñíîâå óðîâíÿ õðîìîñîìíûõ íàðóøåíèé â ëèì ôî öè òàõ ïå ðè ôå ðè å ñêîé êðî âè Èñ õîä íûå ãðóï ïû ( èñ ëåí íîñòü) Êðè òå ðèé ôîð ìè ðî âà íèÿ Îáú ì âûáîðêè >ÕÀ "Pu" (15) + "Ê" (2) Óðîâåíü õðîìîñîìíûõ àáåððàöèé 17 <ÕÀ "Pu" (30) + "Ê" (3) âûøå (>) ëè áî íè æå (<) 2,5% 33 >Àí "Pu" (26) + "Ê" (5) Óðî âåíü àíå óï ëî è äèè 10 è 31 <Àí "Ê" (23) âûøå (>) ëè áî íè æå (<) 23 >Ìß "Pu" (26) + "Ê" (16) Óðîâåíü ìèêðîÿäåð âûøå 6 (>) 42 <Ìß "Pu" (12) + "Ê" (25) ëè áî íè æå (<) 37 Ïðè ìå à íèå. "Ê" è "Pu" ñì. òàáë. 1 Òàá ëè öà 4 ISSN
4 ÎÐÈ ÃÈ ÍÀ ËÜ ÍÛÅ ÈÑ ÑËÅ ÄÎ ÂÀ ÍÈß õðîìîñîìíûõ íàðóøåíèé èç îáåèõ èñõîäíûõ ãðóïï (òàáë. 4). Îòêëîíåíèÿ íàáëþäàåìîãî ðàñïðåäåëåíèÿ ãåíîòèïîâ îò îæèäàåìîãî ïðè ðàâíîâåñèè Õàðäè Âàéíáåðãà òå ñ òè ðî âà ëè êàê â èñ õîä íûõ ãðóï ïàõ («Pu» è «Ê»), òàê è â ïîäãðóïïàõ, ðàçëè àþùèõñÿ ïî óðîâíþ õðîìîñîìíûõ íàðóøåíèé. Â èñõîäíûõ ãðóïïàõ ïî âñåì èññëåäîâàííûì ëîêóñàì íàáëþäàëîñü ñîîòâåòñòâèå ðàâíîâåñèþ Õàðäè Âàéíáåðãà (òàáë. 5). Ñîîòâåòñòâèå íàáëþäàåìîãî ðàñïðåäåëåíèÿ ãåíîòèïîâ îæèäàåìîìó áûëî çàðåãèñòðèðîâàíî âî âñåõ ïîäãðóïïàõ ïî èçó åííûì ïîëèìîðôíûì âàðèàíòàì â ãåíàõ CYP2C19, XRCC1 è PMS2, â ïÿ òè èç øåñ òè ïîä ãðóïï ïî ãåíó ÒÐ53 è â òð õ èç øåñ òè ïîä ãðóïï ïî ãå íó MLH1. Â ïîä - ãðóïïàõ ñ âûñîêèìè óðîâíÿìè õðîìîñîìíûõ àáåððàöèé, àíåóïëîèäèè è ìèêðîÿäåð ïî ïîëèìîðôíîìó âàðèàíòó â ãåíå MLH1 è â ïîäãðóïïå ñ âûñîêèì óðîâíåì àíåóïëîèäèè ïî ïîëèìîðôíîìó âàðèàíòó â ãåíå TP53 ðàñïðåäåëåíèå ãåíîòèïîâ îòëè àëîñü îò ðàâíîâåñèÿ Õàðäè Âàéíáåðãà. Âî âñåõ ñëó à ÿõ (è äëÿ ãå íà TP53, è äëÿ ãå íà MLH1) îòêëîíåíèå áûëî îáóñëîâëåíî îòñóòñòâèåì ãîìîçèãîò ïî ðåäêîìó àëëåëþ è èçáûòêîì ãåòåðîçèãîò. Ïðè ýòîì, äëÿ ïîëèìîðôíîãî âàðèàíòà ãåíà MLH1 â ïà ðàõ ñðàâ íå íèé ñ âû ñî êèì è íèçêèì óðîâíåì õðîìîñîìíûõ íàðóøåíèé ñòàòèñòè åñêè çíà èìûå ðàçëè èÿ ïî ðàñïðåäåëåíèþ ãåíîòèïîâ áûëè óñòàíîâëåíû òîëüêî ìåæäó ãðóïïàìè ñ õðîìîñîìíûìè àáåððàöèÿìè âûøå 2,5% è íèæå 2,5%, òî ñîîòâåòñòâóåò ôîíîâîìó óðîâíþ ( 2 =6,097, p=0,047). Ïðåäðàñïîëàãàþùèì ê ïîâûøåííîìó óðîâíþ õðîìîñîìíûõ àáåððàöèé îêà - çàëñÿ ãåòåðîçèãîòíûé ãåíîòèï: OR=4,41 (CI: 1,14 14,29), 2 =3,95, p=0,047. Ìåæäó äðóãèìè ñðàâíèâàåìûìè ïîäãðóïïàìè (ðàçëè àþùèìèñÿ ïî óðîâíþ àíåóïëîèäèè è ìèêðîÿäåð) ïî àñòîòàì ãåíîòèïîâ rs â ãåíå MLH1 íå óñòàíîâëåíî ñòàòèñòè åñêè çíà èìûõ îòëè èé, êàê è ïî èññëåäîâàííîìó ëîêóñó â ãåíå TP53. Âìåñòå ñ òåì, ñèòóàöèÿ ïî «ñìåùåíèþ» ðàñïðåäåëåíèé àñòîò ãåíîòèïîâ (òàáë. 5) â ïîäãðóïïàõ ñ âûñîêèì óðîâíåì õðîìîñîìíûõ íàðóøåíèé íå ìî æåò áûòü ñëó àé íîé, òàê êàê äàí íûå ïîä ãðóï ïû áû ëè ñôîðìèðîâàíû èç äâóõ èñõîäíûõ ãðóïï (êîíòðîëüíîé è ãðóïïû ñ èíêîðïîðèðîâàííûì ïëóòîíèåì-239 òàáë. 5), â êîòîðûõ, ïî âñåì èññëåäîâàííûì ïîëèìîðôíûì âàðèàíòàì íàáëþäàëîñü ñîîòâåòñòâèå ðàâíîâåñèþ Õàðäè-Âàéíáåðãà, à ìåæäó ãðóïïàìè íå áûëî óñòàíîâëåíî ñòàòèñòè åñêè çíà- èìûõ ðàçëè èé ïî àñòîòàì ãåíîòèïîâ. Ïðè ïîïàðíîì ñðàâíåíèè ïîäãðóïï ñ ðàçíûì óðîâíåì õðîìîñîìíûõ íàðóøåíèé, ïîìèìî îòìå åííîãî âûøå ãåíà MLH1, åù òîëüêî â äâóõ ñëó àÿõ âûÿâëåííûå ðàçëè èÿ äîñòèãëè óðîâíÿ ñòàòèñòè åñêîé çíà èìîñòè: äëÿ rs25487 ãåíà XRCC1 ïðè ñðàâ íå íèè ïîä ãðóïï ñ âû ñî êèì è íèç êèì óðîâíåì õðîìîñîìíûõ àáåððàöèé è äëÿ ñî åòàíèé ãåíîòèïîâ GSTT1/GSTM1 ïðè ñðàâ íå íèè ïîä ãðóïï ñ âû ñî êèì è íèçêèì óðîâíåì àíåóïëîèäèè. Îäíàêî â îòäåëüíûõ ïàðàõ ñðàâíåíèé äëÿ âñåõ ëîêóñîâ íàáëþäàëèñü îïðåäåë ííûå îòëè èÿ â õàðàêòåðå ðàñïðåäåëåíèÿ àñòîò ãåíîòèïîâ è àëëåëåé, íå äîñòèãàâøèå, òåì íå ìåíåå, çíà èìîãî óðîâíÿ. Ñëåäóåò îòìåòèòü, òî èñëåííîñòè îáñëåäîâàííûõ ãðóïï íåâåëèêè, òî ìîæåò îòðàæàòüñÿ íà ñòàòèñòè åñêîé çíà èìîñòè ïîëó åííûõ ðåçóëüòàòîâ. Ïî ïîëèìîðôíîìó âàðèàíòó â ãåíå PMS2 ñòàòèñòè åñêè çíà èìûõ ðàçëè èé ïî àñòîòàì àëëåëåé è ãåíîòèïîâ â ïîäãðóïïàõ ñ ðàçíûì óðîâíåì õðîìîñîìíûõ íàðóøåíèé íå çàðåãèñòðèðîâàíî. Âìåñòå ñ òåì, íàáëþäàåòñÿ ñóùåñòâåííîå (â 1,59 ðàçà) ðàçëè èå ïî àñòîòå íîñèòåëüñòâà ãåòåðîçèãîò â ïîäãðóïïàõ ñ âûñîêèì è íèçêèì óðîâíåì õðîìîñîìíûõ àáåððàöèé (35,29 è 56,25% ñîîòâåòñòâåííî) (òàáë. 5). Áåëêè PMS2 è MLH1 ÿâëÿþòñÿ êîìïîíåíòàìè ñèñòå - ìû ïîñò-ðåïëèêàòèâíîé ìèññ-ìàò ðåïàðàöèè (MMR). Îíè îáðàçóþò ãåòåðîäèìåð, íàçûâàåìûé MutL, ôóíêöèîíèðóþùèé ñîâìåñòíî ñ ãåòåðîäèìåðîì MutS èëè MutS ñóáúåäèíèöåé êîìïëåêñà, óçíàþùåãî íàðóøåíèÿ ñïàðèâàíèÿ äâîéíîé ñïèðàëè ÄÍÊ (ìèññ-ìàò è). PMS2 îáëàäàåò ýíäîíóêëåàçíîé àêòèâíîñòüþ, âíîñÿ îäíîöåïî å íûå ðàç ðû âû â íèòü ÄÍÊ ïî êðà ÿì ó à ñò êà ñ ìèññ-ìàò åì. Äåãðàäàöèþ ïîâðåæä ííîãî ó àñòêà îñóùåñòâëÿåò ýêçîíóêëåàçà EXO1. Ïîêàçàíû ôèçè åñêèå âçàèìîäåéñòâèÿ MutL ñ ÄÍÊ-ïîëèìåðàçîé III, òàêæå ïðèâëåêàåìîé ê ïðîöåññó ðåïàðàöèè. Ýíäîíóêëåàçà PMS2 íå ìîæåò ðàçðåçàòü ìåòèëèðîâàííóþ ÄÍÊ, ïîýòîìó òàêèì ïóòåì ìîãóò ðåïàðèðîâàòüñÿ òîëüêî íàðóøåíèÿ, âîçíèêøèå de no vo. Êðîìå òîãî, MutL ÿâëÿåòñÿ àñòüþ BRCA1-àññîöèèðî - âàííîãî êîìïëåêñà, êîíòðîëèðóþùåãî ñòàáèëüíîñòü ãåíîìà BASC (êî òî ðûé ñî äåð æèò áåë êè BRCA1, MSH2, MSH6, MLH1, ATM, BLM, PMS2), à òàê æå áåë êî âî ãî êîìïëåêñà RAD50-MRE11-NBS1. Ýòîò êîìïëåêñ äèíàìè - åí è èçìåíÿåòñÿ êàê íà ïðîòÿæåíèè êëåòî íîãî öèêëà, òàê è â ïðåäåëàõ ñóáêëåòî íûõ äîìåíîâ. MLH1 ìîæåò òàêæå ãåòåðîäèìåðèçîâàòüñÿ ñ MLH3 (MutL ) è èã ðàòü îïðå - äåë ííóþ ðîëü â ìåé î çå. Èç âå ñò íî òàê æå, òî PMS2 âî âëå - åí â ñèãíàëüíûé ïóòü, êîòîðûé ïðè ñèëüíûõ ïîâðåæäåíèÿõ ÄÍÊ âûçûâàåò îñòàíîâêó êëåòî íîãî öèêëà è âåäåò ê àïîï òî çó [19, 28]. Áåë êè PMS2 è MLH1 èã ðà þò âàæ íóþ ðîëü â ïîääåðæàíèè ñòàáèëüíîñòè ãåíîìà [22, 35]. Ìóòà - öèè â ãå íàõ PMS2 è MLH1 ìîãóò ïðèâîäèòü ê íåêîòîðûì íàñëåäñòâåííûì îíêîëîãè åñêèì çàáîëåâàíèÿì, òàêèì êàê ñèíäðîì Ëèí à è ñèíäðîì Òóðêîòà. Áîëüøèíñòâî ñåìåé ñ êëèíè åñêè âåðèôèöèðîâàííûì íàñëåäñòâåííûì íåïîëèïîçíûì êîëîðåêòàëüíûì ðàêîì èìååò ìóòàöèè â ãå íàõ MLH1 è MSH2. Êðîìå òîãî, ìóòàöèè â MLH1 ìî - ãóò âûçâàòü ñèíäðîì Ìüþ Òîððå, ëîáóëÿðíóþ êàðöèíîìó (LCIS), ðàê ýí äî ìåò ðèÿ [9, 20, 34]. Â íà ñòî ÿ ùåì èñ ñëå äî âà íèè äëÿ çà ìå íû â ãå íå XRCC1 (rs25487) òàê æå áû ëà âû ÿâ ëå íà íå êî òî ðàÿ ñïå öè ôè êà â ðàñïðåäåëåíèè àñòîò ãåíîòèïîâ â ðàçíûõ ïîäãðóïïàõ (òàáë. 5): à ñ òî òà ãî ìî çè ãîò íî ãî ãå íî òè ïà ïî ìà æîð íî ìó àë ëå ëþ âà ðü è ðî âà ëà â ïðå äå ëàõ 35 59%, à ãå òå ðî çè ãîò - íî ãî 40 60%. Òåì íå ìå íåå, ìåæ äó ñðàâ íè âà å ìû ìè ïàðàìè ïîäãðóïï ñòàòèñòè åñêè çíà èìûõ ðàçëè èé ïî à ñ òî òàì ãå íî òè ïîâ íå âû ÿâ ëå íî. Ïî à ñ òî òàì àë ëå ëåé ðàçëè èÿ ðåãèñòðèðîâàëèñü òîëüêî ïðè ñðàâíåíèè ïîä - ãðóïï ñ âûñîêèì è íèçêèì óðîâíåì õðîìîñîìíûõ àáåððàöèé: àëëåëü A ÿâëÿåòñÿ ïðåäðàñïîëàãàþùèì ê ôîðìè - ðî âà íèþ ñòðóê òóð íûõ íà ðó øå íèé õðî ìî ñîì (OR=2,82 (CI: 1,05 7,66) 2 =4,26, p=0,039). 22
5 ÌÅÄÈÖÈÍÑÊÀß ÃÅÍÅÒÈÊÀ ¹4 àñòîòû àëëåëåé è ãåíîòèïîâ èçó åííûõ ëîêóñîâ â èññëåäîâàííûõ ãðóïïàõ Ïîëèìîðôèçì Ãðóïïû MLH1 Òàá ëè öà 5 "Pu" "Ê" >ÕÀ <ÕÀ >Àí <Àí >Ìß <Ìß AA 39,44 37,84 23,53 42,42 26,67 35,71 26,19 29,73 AG 53,52 48,65 76,47 42,42 73,33 57,14 64,29 59,46 GG 7,04 13, ,15 0 7,14 9,52 10,81 A 66,2 62,16 61,76 63,64 63,33 63,04 58,33 59,46 ÐÕÂ: 2 (p) 2,725 0,086 6,515 (<0,01) 0,229 2 (p) ãå íî òè ïû 6,097 (0,047) PMS2 10,055 (<0,01) 1,043 4,367 (<0,05) 2,014 CC 21,43 22,22 29,41 18, ,09 28,57 18,92 CT 58, ,29 56,25 46,67 47,82 52,38 48,65 TT 20 27,78 35, ,33 26,09 19,05 32,43 C 50,71 47,22 47,06 46,88 53,33 50,00 54,76 43,24 ÐÕÂ: 2 (p) 2,063 XRCC1 0,001 0,487 1,446 0,536 0,117 0,138 0,003 GG 45,71 35,14 35,29 59,37 43,33 34,78 38,10 56,76 AG 42,86 55,41 41,18 37,5 46,67 60,87 52,38 40,54 AA 11,43 9,46 23,53 3, ,35 9,52 2,7 G 67,14 62,84 55,88 78,13 66,67 65,22 64,23 77,03 ÐÕÂ: 2 (p) 0,058 2,569 0,462 0,302 2 (p) àë ëå ëè 4,259 (0,039) TP53 0,075 (>0,05 2,685 0,832 0,783 GG 57,75 48,65 64,71 48,49 46,67 65,22 61,90 51,35 CG 36,62 44,59 35,29 39,39 53,33 30,43 38,10 43,24 CC 5,63 6, ,12 0 4,35 0 5,41 G 76,06 70,95 82,35 68,18 73,33 80,43 80,95 72,97 ÐÕÂ: 2 (p) 0,002 Cyp2C19 0,494 0,781 0,280 3,967 (<0,05) 0,025 2,325 0,343 GG 77,14 69,86 88,24 68,75 83,33 60,87 63,41 81,08 GA 20 28,77 11,76 28,12 13,33 39,13 34,15 18,92 AA 2,86 1,37 0 3,13 3,34 0 2,44 0 G 87,14 84,25 94,12 82, ,43 80,49 90,54 ÐÕÂ: 2 (p) 0,809 GSTT1/GSTM1 0,512 0,066 0,005 2,017 1,361 0,311 0,404 +/+ 46,48 39,19 47,06 45,46 56,67 30,43 47,62 43,24 +/- 36,62 47,3 47,06 39,39 36,67 43,48 33,33 43,24 -/+ 11,27 4, , ,74 9,52 10,81 -/- 5,63 9,46 5,88 3,03 6,66 4,35 9,52 2,7 GSTT1 "+" 83,1 86,49 94,12 84, ,57 75,00 86,49 GSTM1 "+" 57,75 43,24 47,06 57, ,14 54,05 2 (p) ñî åòàíèÿ ãåíîòèïîâ 8,78 (0,032) Ïðè ìå à íèå. à ñ òî òû ïðè âå äå íû â ïðî öåí òàõ; ÐÕÂ ïî êà çà òå ëè ( 2 è p) îöåí êè ñî îò âåò ñò âèÿ à ñ òîò ãå íî òè ïîâ èñ ñëå - äî âàí íûõ ãðóïï ðàâ íî âå ñèþ Õàð äè Âàé íáåð ãà; ïðè âå äå íû òî ëü êî ñòà òè ñòè å ñêè çíà è ìûå ðàç ëè èÿ, ïî ëó åí íûå ïðè ñðàâ íå íèè à ñ òîò àë ëå ëåé ( 2 (p) àëëåëè) è ãåíîòèïîâ ( 2 (p) ãå íî òè ïû) ìåæ äó ãðóï ïà ìè ISSN
6 ÎÐÈ ÃÈ ÍÀ ËÜ ÍÛÅ ÈÑ ÑËÅ ÄÎ ÂÀ ÍÈß Íå èñê ëþ å íî âëè ÿ íèå ýòîé íóê ëå î òèä íîé çà ìå íû íà ðå ïà ðà öèþ õðî ìî ñîì íûõ àáåð ðà öèé, òî ñî ãëà ñó åò ñÿ ñ äàí íû ìè ëè òå ðà òó ðû. Â ðÿ äå ðà áîò ïî êà çà íî, òî âû ñî - êàÿ àñòîòà àëëåëÿ A àññîöèèðîâàíà ñ ïîâûøåíèåì óðîâíÿ ðàçëè íûõ õðîìîñîìíûõ íàðóøåíèé [14, 18, 23]. Â íàñòîÿ - ùåì èññëåäîâàíèè àñòîòà ðåäêîãî àëëåëÿ A ó èíäèâèäîâ ñ âûñîêèì óðîâíåì õðîìîñîìíûõ àáåððàöèé ñîñòàâëÿåò 44,12%, â òî âðåìÿ êàê â ãðóï ïå ñ íèç êèì óðîâ íåì â äâà ðàçà íèæå (21,88%); â îñòàëüíûõ ãðóïïàõ àñòîòà äàííîãî àëëåëÿ íàõîäèòñÿ â ïðåäåëàõ 23 36%. Áåëîê XRCC1 ïðèíèìàåò ó àñòèå â ýêñöèçèîííîé ðå - ïàðàöèè îñíîâàíèé ÄÍÊ (BER), âçàèìîäåéñòâóÿ ñ äðóãèìè ôåðìåíòàìè ýòîé ñèñòåìû. Ïîëèìîðôèçì â ãåíå XRCC1 ÿâëÿåòñÿ ôàêòîðîì ðèñêà ðàçâèòèÿ ðàçíûõ ôîðì îíêîïàòîëîãèè. Îäíàêî äàæå ïðè ìåòààíàëèçàõ àññîöèàöèè ïîëèìîðôíûõ âàðèàíòîâ ýòîãî ãåíà ñ îíêîëîãè åñêè - ìè çàáîëåâàíèÿìè â îäíèõ ñëó àÿõ ïîäòâåðæäàþòñÿ [17], â äðó ãèõ íåò [16]. Ïî êà çà íî, òî àë ëåëü 399Gln (àë ëåëü A) ãåíà XRCC1 àññîöèèðîâàí ñ âûñîêèì óðîâíåì ìèêðîÿäåð [14] è ïî âû øåí íûì óðîâ íåì ðàç ðû âîâ ÄÍÊ, ò.å. ñíè æå - íèåì ñïîñîáíîñòè ôåðìåíòà ðåïàðèðîâàòü ïîâðåæäåíèÿ ÄÍÊ [18, 23]. Â íàøåì èññëåäîâàíèè íå óñòàíîâëåíî âëèÿíèå äàííîé çàìåíû íà óðîâåíü ìèêðîÿäåð. Ïî SNP rs â ãå íå TP53 â ïîä ãðóï ïàõ ñ âû ñî - êèìè óðîâíÿìè õðîìîñîìíûõ àáåððàöèé, àíåóïëîèäèè, ìèê ðî ÿäåð ãî ìî çè ãî òû ÑÑ íå âû ÿâ ëå íû. Â äðó ãèõ ïîä - ãðóïïàõ èíäèâèäîâ èõ àñòîòà íå ïðåâûøàåò 12,12%. Â ðàç íûõ ïîä ãðóï ïàõ ðàç áðîñ à ñ òîò àëü òåð íà òèâ íûõ ãî - ìî çè ãîò è ãå òî ðî çè ãîò ñî ñòàâ ëÿ åò îêî ëî 20% (òàáë. 5). Ñòàòèñòè åñêè çíà èìûõ ðàçëè èé ìåæäó ñðàâíèâàåìû - ìè ïîä ãðóï ïà ìè íå âû ÿâ ëå íî. Áåëîê p53, êîäèðóåìûé ãåíîì TP53, ÿâëÿåòñÿ îïóõîëåâûì ñóïðåññîðîì, èíäóöèðóþùèì îñòàíîâêó êëåòî íîãî ðîñòà èëè àïîïòîç â çàâèñèìîñòè îò ôèçèîëîãè åñêèõ îáñòî ÿ òåëüñòâ è òè ïà êëå òîê. Êðî ìå òî ãî, îí âî âëå í â êîí ò - ðîëü êëåòî íîãî öèêëà êàê òðàíñ-àêòèâàòîð ìíîæåñòâà ãåíîâ, ó àñòâóþùèõ â êëåòî íîì äåëåíèè, àïîïòîçå è ðåïàðàöèè ÄÍÊ [6]. Êîëè åñòâî p53 âîçðàñòàåò â òðàíñôîðìèðîâàííûõ êëåòêàõ ðàçíûõ òèïîâ. Ãåðìèíàòèâíîå íîñèòåëüñòâî ìó òà öèé â ãå íå ÒP53 â 80% ñëó à åâ ïðè âî äÿò ê ôîð ìè ðî - âàíèþ åòûðåõ òèïîâ ðàêîâûõ íîâîîáðàçîâàíèé: ýòî ðàê ìîëî íîé æåëåçû, ñàðêîìà ìÿãêèõ òêàíåé è êîñòåé, îïóõîëè ãîëîâíîãî ìîçãà è àäðåíîêîðòèêàëüíûå êàðöèíîìû [13, 24, 27]. Íà îñòàâøèåñÿ 20% ïðèõîäèòñÿ ìíîæåñòâî áîëåå ðåä êèõ îïó õî ëåé. Â öå ëîì æå, ïðè ìåð íî â 60% âñåõ ðà êî - âûõ îáðàçîâàíèé âûÿâëÿþòñÿ ìóòàöèè â ãåíå TP53, ïðè âî - äÿùèå ëèáî ê èíàêòèâàöèè ãåíà, ëèáî ê íàðóøåíèþ ôóíêöèé êîäèðóåìîãî èì áåëêà p53. Êîäîí 72 ðàñïîëîæåí â ïðîëèí-áîãàòîì ðåãèîíå áåëêà è çàìåíà àìèíîêèñëîòû ìîæåò ìåíÿòü ñòðóêòóðó SH3-ñâÿçûâàþùåãî äîìåíà [10]. Ýòîò êîäîí ÿâëÿåòñÿ ðåçâû àéíî âàðèàáåëüíûì, â íåì îïèñàíî 5 íåñèíîíèìè íûõ íóêëåîòèäíûõ çàìåí, è òîëüêî çàìåíà Arg (äèêèé òèï) íà Pro ÿâëÿåòñÿ ïîëèìîðôíûì âàðèàíòîì, îñòà ëü íûå (çà ìå íû íà Cys, Gly, His, Leu) ïðåä ñòàâ ëÿ þò ñî - áîé ìóòàöèè [15]. Èìåþòñÿ äàííûå, òî ïîëèìîðôíûé âàðèàíò TP53 Pro72 (ïî ñðàâ íå íèþ ñ äè êèì òè ïîì Arg72) ñíèæàåò àïîïòîòè åñêóþ ôóíêöèþ áåëêà, à òàêæå ñâÿçàí ñ óâåëè åíèåì ðàäèî óâñòâèòåëüíîñòè êëåòêè [10]. Ïî çà ìå íå â ãå íå Cyp2C19 (rs ) â ïîä ãðóï ïàõ ñ íèçêèìè óðîâíÿìè àíåóïëîèäèè è ìèêðîÿäåð, à òàêæå â ïîäãðóïïå ñ âûñîêèì óðîâíåì õðîìîñîìíûõ àáåððàöèé íå áûë çàðåãèñòðèðîâàí ãåíîòèï AA (òàáë. 5). Îäíàêî àñòîòû ãåòåðîçèãîò è àëüòåðíàòèâíûõ ãîìîçèãîò â ýòèõ ãðóïïàõ íåîäèíàêîâû è âàðüèðóþò äëÿ GA îò 11,76% (âûñîêèé óðîâåíü õðîìîñîìíûõ àáåððàöèé) äî 39,13% (íèçêèé óðîâåíü àíåóïëîèäèè). Â ãåíå Cyp2C19 àñòîòà ìàæîðíîãî àëëåëÿ w íàõîäèëàñü â ãðàíèöàõ îò 80,43% (ïîäãðóïïà ñ íèçêèì óðîâíåì àíåóïëîèäèè) äî 94,12% (ïîä - ãðóïïà ñ âûñîêèì óðîâíåì õðîìîñîìíûõ àáåððàöèé). Ñòàòèñòè åñêè çíà èìûå ðàçëè èÿ ìåæäó ñðàâíèâàåìû - ìè ïîäãðóïïàìè íå çàðåãèñòðèðîâàíû. Ãåíû äåòîêñèêàöèè êñåíîáèîòèêîâ, êîòîðûå èãðàþò âàæíóþ ðîëü â èíäèâèäóàëüíîé óâñòâèòåëüíîñòè ê âîçäåéñòâèþ ðàçëè íûõ òîêñè åñêèõ àãåíòîâ îêðóæàþùåé ñðåäû, ïðåäñòàâëÿþò áîëüøîé èíòåðåñ ñ òî êè çðåíèÿ ôåíîìåíà èíäèâèäóàëüíîé ðàäèî óâñòâèòåëüíîñòè. Ãðóïïà ôåðìåíòîâ I ôàçû äåòîêñèêàöèè êñåíîáèîòèêîâ ïðåäñòàâ - ëåíà ñåìåéñòâîì öèòîõðîìîâ Ð-450, êîòîðîå âêëþ àåò â ñå áÿ áî ëåå 60 ãå íîâ [21, 25]. Ôåð ìåíò CYP2C19 ìå òà áî - ëèçèðóåò øèðîêèé ñïåêòð ëåêàðñòâåííûõ ïðåïàðàòîâ [33]. Îñíîâíîé ãåíåòè åñêèé äåôåêò, íàéäåííûé ó òàê íàçûâàåìûõ «ìåäëåííûõ» ìåòàáîëèçåðîâ (S)-ìåôåíèòîèíà ýòî òî êîâàÿ çàìåíà G íà A â ïÿòîì ýêçîíå â ïîëîæåíèè 681 ãåíà CYP2C19 (CYP2C19*2), ïðèâîäÿùàÿ ê ïîÿâëåíèþ àáåððàíòíîãî ñàéòà ñïëàéñèíãà [8]. Ýòîò ïîëèìîðôèçì îáóñëîâëèâàåò íàðóøåíèå ñïîñîáíîñòè öèòîõðîìà Ð450 ìåòàáîëèçèðîâàòü àíòèýïèëåïòè åñêèé ïðåïàðàò (S)-ìå - ôåíèòîèí, îìåïðàçîë, ïðîãóàíèë, íåêîòîðûå áàðáèòóðàòû è ðÿä äðóãèõ ñîåäèíåíèé [31, 38]. Äåëåöèîííûé ãåíîòèï () â ãå íå GSTT1 (òàáë. 5) â ñðàâíèâàåìûõ ïîäãðóïïàõ âñòðå àëñÿ ñ àñòîòàìè â èíòåðâàëå îò 5,88% (ïîäãðóïïà ñ âûñîêèì óðîâíåì õðîìîñîìíûõ àáåððàöèé) äî 25,00% (ïîäãðóïïà ñ âûñîêèì óðîâíåì ìèêðîÿäåð). Ãåíîòèï ñ äåëåöèåé â ãåíå GSTM1 ðåãèñòðèðîâàëñÿ ñ âû ñî êîé à ñ òî òîé (îò 40 äî 57% â ðàç íûõ ïîä ãðóï ïàõ). Ïî ñî åòàíèþ ãåíîòèïîâ GSTT1/GSTM1 ðåäêèìè ÿâëÿþòñÿ «-/+» è «-/-». àñòîòà ñî åòàíèÿ «-/+» âàðüèðóåò îò 0% (â ïîäãðóïïàõ ñ âûñîêèìè óðîâíÿìè õðîìîñîìíûõ àáåððàöèé è àíå óï ëî è äèè) äî 21,74% (â ïîä ãðóï ïå ñ íèç êèì óðîâ íåì àíåóïëîèäèè). àñòîòà ñî åòàíèÿ «-/-» íàõîäèòñÿ â ïåðåäåëàõ 3,03 9,52%. Â áîëüøèíñòâå ñëó àåâ ïðåîáëàäàþùèì ÿâ ëÿ åò ñÿ ñî å òà íèå «+/+» (îò 30,43 äî 56,67%). Ìåæ äó ãðóïïàìè ñ âûñîêèì è íèçêèì óðîâíåì àíåóïëîèäèè âûÿâëÿþòñÿ ñòàòèñòè åñêè çíà èìûå ðàçëè èÿ ïî ãåíîòèïè åñêèì êîìáèíàöèÿì GSTT1/GSTM1: 2 =8,78, p=0,032. Ãëóòàòèîí-S-òðàíñôåðàçû GSTT1 è GSTM1 îòíîñÿòñÿ ê ãðóïïå ôåðìåíòîâ âòîðîé ôàçû áèîòðàíñôîðìàöèè êñåíîáèîòèêîâ, íà êîòîðîé ðàçëè íûìè ãèäðîëàçàìè è òðàíñôåðàçàìè ïðîâîäèòñÿ íåéòðàëèçàöèÿ òîêñè íûõ ïðîäóêòîâ ïåðâîé ôàçû äåòîêñèêàöèè. Ãëóòàòèîí-S-òðàíñôåðàçû èãðàþò îñíîâíóþ ðîëü â îáåñïå åíèè ðåçèñòåíòíîñòè êëåòîê ê ïåðåêèñíîìó îêèñëåíèþ ëèïèäîâ, àëêèëèðîâàíèþ áåë- 24
7 ÌÅÄÈÖÈÍÑÊÀß ÃÅÍÅÒÈÊÀ ¹4 êîâ, íåãàòèâíîìó âîçäåéñòâèþ ñâîáîäíûõ ðàäèêàëîâ, ïðèâîäÿùèõ ê ïðåäîòâðàùåíèþ ïîâðåæäåíèé ÄÍÊ [1]. Ìóòàöèè ãåíîâ ñåìåéñòâà GST âîâëå åíû â ïàòîãåíåç ðàçëè íûõ ôîðì ðàêà è ÿâëÿþòñÿ ôàêòîðàìè ðèñêà ðàçâèòèÿ ðÿäà çàáîëåâàíèé. «Íóëåâûå» ãåíîòèïû GSTM1 èëè GSTT1 (ïîë - íàÿ äåëåöèÿ ãåíà), êàê ïðàâèëî, àññîöèèðîâàíû ñ ïîâûøåííîé àñòîòîé ñåñòðèíñêèõ õðîìàòèäíûõ îáìåíîâ (ÑÕÎ), ïî ñðàâíåíèþ ñ íîðìàëüíûì ãåíîòèïîì ïðè âîçäåéñòâèè òàêèõ õèìè åñêèõ ñîåäèíåíèé, êàê 1,2-ýïîêñè-3-áóòåí è äèýïîêñèáóòàí [11]. «Íóëåâîé» GSTM1 ãå íî - òèï îáóñëîâëèâàåò òàêæå óâåëè åíèå àñòîòû õðîìîñîìíûõ àáåððàöèé õðîìàòèäíîãî òèïà [30]. Ó èíäèâèäîâ ñ ñî åòàíèåì ãîìîçèãîò ïî «íóëåâûì» àëëåëÿì ãåíîâ GSTM1 è GSTT1 îïèñàíà ïîâûøåííàÿ àñòîòà àáåððàöèé õðîìîñîìíîãî òèïà ïðè âîçäåéñòâèè òåõ æå ñîåäèíåíèé. Äëÿ ãîìîçèãîòíûõ ïî «íóëåâîìó» àëëåëþ ãåíîâ GSTM1 è GSTT1 èí äè - âèäîâ ïðè êóðåíèè õàðàêòåðíû ïîâûøåííàÿ àñòîòà õðîìîñîìíûõ àáåððàöèé è âûñîêèé ðèñê ðàçâèòèÿ ðàêà ëåãêîãî [5, 7]. Â òî æå âðåìÿ, â ðÿ äå äðó ãèõ èñ ñëå äî âà íèé îò ìå à - þòñÿ ïðîòèâîïîëîæíûå ðåçóëüòàòû: íå ïîäòâåðæäàþòñÿ àññîöèàöèè ðàññìîòðåííûõ ãåíîòèïîâ ñ õðîìîñîìíûìè àáåððàöèÿìè è ðèñêîì ðàçâèòèÿ êàêîé-ëèáî ôîðìû ðàêà [26, 37], â íåêîòîðûõ èññëåäîâàíèÿõ [39] óêàçûâàåòñÿ äàæå ïðîòåêòèâíàÿ â îòíîøåíèè îíêîïàòîëîãèè ðîëü «íóëåâîãî» ãåíîòèïà ïî GSTM1. Òàêèì îáðàçîì, â õîäå âûïîëíåíèÿ íàñòîÿùåãî èññëåäîâàíèÿ áûëè èçó åíû ïîëèìîðôíûå âàðèàíòû â ñåìè ãåíàõ. Âûáðàííûå äëÿ èññëåäîâàíèÿ ãåíû êîäèðóþò áåëêè, îòíîñÿùèåñÿ ê ñèñòåìàì ðåïàðàöèè ÄÍÊ, ìåòàáîëèçìà êñåíîáèîòèêîâ, ðåãóëÿöèè êëåòî íîãî öèêëà è ïðîëèôåðàöèè. Äëÿ áîëüøèíñòâà èññëåäîâàííûõ ëîêóñîâ íàáëþäàëèñü îòëè èÿ ïî ðàñïðîñòðàí ííîñòè ãåíîòèïîâ ìåæäó ñðàâíèâàåìûìè ïîäãðóïïàìè, ðàçëè àþùèìèñÿ ïî àñòîòå âñòðå àåìîñòè õðîìîñîìíûõ íàðóøåíèé ðàçíûõ òèïîâ. Îäíàêî ñòàòèñòè åñêè çíà èìûå îòëè èÿ áûëè âûÿâëåíû òîëüêî äëÿ ïîëèìîðôíîãî âàðèàíòà â ãåíå MLH1 (ïðè ñðàâ - íåíèè ïîäãðóïï ñ âûñîêèì è íèçêèì óðîâíåì õðîìîñîìíûõ àáåððàöèé), à òàêæå äëÿ êîìáèíàöèé ãåíîòèïîâ GSTT1/GSTM1 (ìåæäó ïîäãðóïïàìè ñ ðàçíûì óðîâíåì àíåóïëîèäèè). àñòîòû àëëåëåé ìåæäó ñðàâíèâàåìûìè ãðóïïàìè âàðüèðóþò â ìåíüøåé ñòåïåíè; ñòàòèñòè åñêè çíà èìûå ðàçëè èÿ çàðåãèñòðèðîâàíû òîëüêî ìåæäó ïîäãðóïïàìè ñ ðàçíûì óðîâíåì õðîìîñîìíûõ àáåððàöèé (ïîëèìîðôíûé âàðèàíò â ãåíå XRCC1). Ñïåöèôèêà ôîðìèðîâàíèÿ âûáîðîê äëÿ íàñòîÿùåãî èññëåäîâàíèÿ, à èìåííî òðóäîåìêîñòü ïðåäâàðèòåëüíîãî äåòàëüíîãî öèòîãåíåòè åñêîãî è ìîëåêóëÿðíî-öèòîãåíåòè- åñêîãî èññëåäîâàíèÿ, îáóñëîâèëà, â êîíå íîì èòîãå, òîò ôàêò, òî áîëüøèíñòâî âûäåëåííûõ ãðóïï ñ ðàçëè íûìè ãåíîòèïàìè îêàçàëèñü ìàëî èñëåííûìè. Ýòî ñóùåñòâåííî ñíèæàåò âåðîÿòíîñòü ïîëó åíèÿ ñòàòèñòè åñêè çíà èìûõ îòëè èé ìåæäó îáñëåäîâàííûìè ãðóïïàìè è íå ïîçâîëÿåò îäíîçíà íî îöåíèòü ðîëü êàê îòäåëüíî âçÿòûõ àëëåëåé è ãåíîòèïîâ, òàê è èõ ñî åòàíèé â ôîðìèðîâàíèè òåõ èëè èíûõ õðîìîñîìíûõ íàðóøåíèé. Òåì íå ìåíåå, ïîëó åííûå äàííûå óêàçûâàþò íà âîçìîæíîñòü âîâëå åíèÿ îòäåëüíûõ ëîêóñîâ ãåíîìà â ôîðìèðîâàíèå èíäèâèäóàëüíîé óâñòâèòåëüíîñòè îðãàíèçìà ê âîçäåéñòâèþ ïëîòíî-èîíèçèðóþùå - ãî èçëó åíèÿ. Äëÿ ïîäòâåðæäåíèÿ ïîëó åííûõ ðåçóëüòàòîâ îá àññîöèàöèè íåêîòîðûõ èçó åííûõ ïîëèìîðôíûõ âàðèàíòîâ ñ óðîâíåì õðîìîñîìíûõ íàðóøåíèé è âûñêàçàííûõ ïðåäïîëîæåíèé î âîçìîæíîé âîâëå ííîñòè äðóãèõ ïîëèìîðôèçìîâ â ðèñê âîçíèêíîâåíèÿ öèòîãåíåòè åñêèõ íàðóøåíèé íåîáõîäèìî ïðîäîëæåíèå èññëåäîâàíèé êàê íà áîëåå îáøèðíûõ âûáîðêàõ, òàê è ó ïðåäñòàâèòåëåé äðóãèõ ýòíè åñêèõ ãðóïï. Ñïèñîê ëèòåðàòóðû 1. Áà ðà íîâ Â.Ñ., Áà ðà íî âà Å.Â., Èâà ùåí êî Ò.Ý. è äð. Ãå íîì å ëî âå êà è ãå íû «ïðåä ðàñ ïî ëî æåí íî ñòè». (Ââå äå íèå â ïðå äèê - òèâíóþ ìåäèöèíó). ÑÏá.: Èíòåðìåäèêà, ñ. 2. Ãîí à ðî âà È.À., Ôðåé äèí Ì.Á., Òà õàó îâ Ð.Ì., Êàð - ïîâ À.Á. Ìî ëå êó ëÿð íî-ãå íå òè å ñêèå ïîä õî äû, ïðè ìå íÿ å ìûå äëÿ îöåí êè âîç äåé ñò âèÿ ðà äè à öèè íà ãå íîì, è èí äè âè äó à ëü íàÿ ðà äèî óâ ñò âè òå ëü íîñòü å ëî âå êà // Ñè áèð ñêèé ìå äè öèí ñêèé æóð íàë ¹5. Ñ Ìà íè à òèñ Ò., Ôðè Ý., Ñýì á ðóê Äæ. Ìî ëå êó ëÿð íîå êëî - íè ðî âà íèå. Ì.: Ìèð, ñ. 4. Òè ìî øåâ ñêèé Â.À., Ëå áå äåâ È.Í., Âà ñè ëü åâ Ñ.À. è äð. Õðî ìî ñîì íûé è öè òî ìíûé àíà ëèç ñî ìà òè å ñêèõ êëå òîê ðà áî - òíè êîâ ðà äèî õè ìè å ñêî ãî ïðî èç âîä ñò âà ñ èí êîð ïî ðè ðî âàí íûì 239 Pu // Ðàäèàöèîííàÿ áèîëîãèÿ. Ðàäèîýêîëîãèÿ Ò. 50, ¹6. Ñ Ab del-rah mad S.Z., Ei-Ze in R.A., Zwis h c hen ber der J.B. As - so ci a ti on of the NAT110 ge no ty pe with in c re a sed chro mo so me aber - ra ti ons and hig her lung can cer risk in ci ga ret te smo kers // Mu tat. Res Vol P An W., Kim J., Ro e der R.G. Or de red co o pe ra ti ve fun c ti ons of PRMT1, p300, and CARM1 in transcriptional activation by p53 // Cell Vol P Con for ti-fro es N., Ei-Ze in., Ab del-rah man S.Z. et al. Pre dis po - sing genes and increased chromosome aberrations in lung cancer cigarette smo kers // Mu tat. Res Vol P De Mo ra is S.M.F., Wil kin son G.R., Bla is dell J. et al. The ma - jor ge ne tic de fect res pon sib le for the po ly mor p hism of S-mep he ny to - in me ta bo lism in hu man // J. Bi ol. Chem Vol ¹22. P De Vos M., Ha y ward B.E, Pic ton S. et al. No vel PMS2 pse u do ge - nes can conceal recessive mutations causing a distinctive childhood cancer syn d ro me // Am. J. Hum. Ge net Vol. 74. P Du mont P, Leu JI, Del la P.A.C. 3 rd et al. The co don 72 po - lymorphic variants of p53 have markedly different apoptotic potenti - al // Nat. Ge net Vol. 33. P Falck G.C., Hir vo nen A., Scsrpa to R. et al. Mic ro nuc lei in blo od lym p ho cy res and ge ne tic po ly mor p hism for GCTM1, GCTT1, and NAT2 in pesticide-exposed greenhouse workers // Mu tat. Res Vol P Fe nech M. Cy to ki ne sis-block mic ro nuc le us as say evol ves in - to a «cy to me» as say of chro mo so mal in s ta bi li ty, mi to tic dys fun c ti on and cell de ath // Mu tat Res Vol P Fre bo urg T., Bar bi er N., Yan Y.-X. et al. Germ-li ne p53 mu - tations in 15 families with Li-Fraumeni syndrome // Am. J. Hum. Ge net Vol. 56. P Gu ven M., Gu ven G.S., Oz E. et al. DNA re pa ir ge ne XRCC1 and XPD polymorphisms and their association with corona - ry ar te ry di se a se risks and mic ro nuc le us fre qu en cy // He art Ves sels Vol. 22. P rot.org/unip rot/p ISSN
8 ÎÐÈ ÃÈ ÍÀ ËÜ ÍÛÅ ÈÑ ÑËÅ ÄÎ ÂÀ ÍÈß 16. Hu Z., Ma H., Chen F. et al. XRCC1 Po ly mor p hisms and can cer risk: A Me ta-ana ly sis of 38 Ca se-con t rol Stu di es // Can cer Epi de mi ol. Bi o mar kers. Prev Vol. 14. P Hung R.J., Hall J., Bren nan P., Bof fet ta P. Ge ne tic po ly mor p - hisms in the ba se ex ci si on re pa ir pat h way and can cer risk: A Hu GE re - vi ew // Am. J. Epi de mi ol Vol P Iar mar co vai G., Sa ri-mi no di er I., Chas po ul F. et al. Risk as - ses sment of wel ders using ana ly sis of eight me tals by ICP-MS in blo - od and uri ne and DNA da ma ge eva lu a ti on by the co met and mic ro - nucleus assays; in?uence of XRCC1 and XRCC3 polymorphisms // Mu ta ge ne sis Vol. 20. P Ka dy rov F.A., Dzan ti ev L., Con s tan tin N., Mod rich P. En - do nuc le o ly tic fun c ti on of Mut Lal p ha in hu man mis match re pa ir. // Cell Vol P Miy a ki M., Nis hio J., Ko nis hi M. et al. Dras tic ge ne tic in s ta - bi li ty of tu mors and nor mal tis su es in Tur cot syn d ro me // On co ge ne Vol. 15. P Ne bert D.V., Gar van M.J. Eco ge ne tics: from bi o lo gy to he - alth // To xi col. In dust. Hlth Vol. 13. P Pan X.-M., Yang W.-Z., Xu G.-H. et al. The as so ci a ti on bet we en MLH1-93G>A polymorphism of DNA mismatch repair and can cer sus cep ti bi li ty: a me ta-ana ly sis // Mu ta ge ne sis Vol. 26. P Qu T, Mo rii E, Obo ki K, Lu Y, Mo ri mo to K. Mic ro nuc lei in EM9 cells ex p res sing po ly mor p hic forms of hu man XRCC1 // Can - cer Lett Vol P Ribeiro R.C., Sandrini F., Figueiredo B. et al. An inherited p53 mutation that contributes in a tissue-specific manner to pediatric ad re nal cor ti cal car ci no ma // Proc. Natl. Acad. Sci. U.S.A Vol. 98. P Ro berts R., Jo y ce P., Ken ne dy M.A. Ra pid and com p re hen - si ve de ter mi na ti on of cy toc h ro me P450 CYP2D6 po or me ta bo li zer ge no ty pes by mul tip lex po ly me ra se cha in re ac ti on // Hum. Mu tat Vol. 16, ¹1. P Rossi A.M., Hansteen I.-L., Skjelbred C.F. et al. Association between frequency of chromosomal aberration and cancer risk is not influenced by genetic polymorphisms in GSTM1 and GSTT1 // Environmen tal He alth Per s pec ti ves Vol P Rut her ford J., Chu C.E., Dud dy P.M. et al. In ves ti ga ti ons on a cli ni cal ly and fun c ti o nal ly unu su al and no vel ger m li ne p53 mu ta ti - on // Br. J. Can cer Vol. 86. P Sacho E.J., Kadyrov F.A., Modrich P. et al. Direct visualization of asymmetric adenine-nucleotide-induced conformational changes in MutL al p ha // Mol Cell Vol. 29. P Sa sa ki M.S., Nor man A. Se lec ti on aga inst chro mo so me aber ra ti ons in hu man lym p ho cy tes // Na tu re Vol P Scatpato R., Hirvonen A., Migliore L. et al. Influence of GSTM1 and GSTT1 polymorphisms on rte frequency of chromosome aberrations in lymphocytes of smokes and pesticide-exposed greenhou se wor kers // Mu tat. Res Vol P Schwab M., Scha ef fe ler E., Klotz U. et al. CYP2C19 po ly mor p - hism is a ma jor pre dic tor of tre at ment fa i lu re in whi te pa ti ents by use of lansoprazole-based quadruple therapy for eradication of Helicobacter pylo ri // Clin. Phar ma col. Ther Vol. 76. P Spur d le A.B., Webb P.M., Pur die D.M. et al. Po ly mor p - hisms at the glu tat hi o ne S-tran s fe ra se GSTM1, GSTT1 and GSTP1 lo ci: risk of ova ri an can cer by his to lo gi cal sub ty pe // Car ci no ge ne sis Vol. 22. P Thum T., Bor lak J. Ge ne ex p res si on in dis tinct re gi ons of the he art // Lan cet Vol P Tro jan J., Ze u zem S., Ran dolph A. et al. Fun c ti o nal ana ly sis of hmlh1 variants and HNPCC-related mutations using a human expression sys tem // Gas t ro en te ro lo gy Vol P van Oers J.M.M., Roa S., Wer ling U. et al. PMS2 en do nuc - lease activity has distinct biological functions and is essential for ge - no me ma in te nan ce // PNAS Vol P Xu B., Kim S., Lim D., Kas tan M.G. Two mo le cu lar ly dis - tinct G2/M checkpoints are induced by ionizing irradiation // Mol. And Cell. Bi ol Vol. 22, ¹4. P Xu X., Wi en c ke J.K., Niu T. et al. Ben ze ne Ex po su re, Glu - tat hi o ne S-tran s fe ra se the ta ho mo zy go us de le ti on, and sis ter chro - ma tid ex c han ges // Am. J. Ind. Med Vol. 33. P Yang H.G., Wong L. P., Lee T. C. et al. Ge ne tic po ly mor p - hism of cy toc h ro me P450 2C19 in he al t hy Ma la y si an sub jects // Br. J. Clin. Phar ma col Vol. 58. ¹3. P Yu K.D., Di G.H., Fan L. et al. A fun c ti o nal po ly mor p hism in the pro mo ter re gi on of GSTM1 im p li es a com p lex ro le for GSTM1 in bre ast can cer // FASEB J Vol. 23. P Associations between polymorphic variants of DNA repair and metabolism of xenobiotics genes and chro mo some ab er ra tion level in hu man lym pho cytes Babushkina N.P., Kucher A.N., Lebedev I.N., Vasilyev S.A., Timoshevsky V.A., Bragina E.Yu., Sukhanova N.N., Torkhova N.B., Yakovleva Yu.S. Institute of Medical Genetics SB RAMS, , Tomsk, Naberezhnaya r.ushaiki, 10, tel. (3822) , fax (3822) , nad.babushkina@medgenetics.ru We pres ent data con cern ing fre quen cies of poly mor phic vari ants of DNA re pair (MLH1 (rs ), PMS2 (rs ), XRCC1 (rs25487)), cell cy cle con trol (TP53 (rs )) and me tab o lism of xenobiotics (Cyp2C19 (rs ), GSTT1 (del) è GSTM1 (del)) genes in co hort of plu to nium work ers and con trol group. Also, sub groups with var i ous lev els of chro mo some ab nor mal i ties are con - sid ered (with high and low lev els of chro mo some ab er ra tions, aneuploidy and micronuclei). There were no sig nif i cant dif fer ences of allele and genotype frequencies between group of plutonium workers and control group. However, significant differences of rs MLH1 genotype frequencies was observed between subgroups with different levels of chromosome aberrations (p=0.047) and GSTT1/GSTM1 ge no type fre quen cies be tween sub groups with high and low lev els of aneuploidy (p=0.032). There were also dif - ferences between subgroups regarding to genotype frequencies at other loci, but insignificant. Allele frequencies differences were registered only in XRCC1 (rs25487) between subgroups with different levels of chromosome aberrations (p=0.039). Key words: individual radiosensitivity, gene polymorphism, DNA repair, chromosome aberrations, micronuclei 26
COHU, INC. Elec tron ics Di vi sion In stal la tion and Op era tion In struc tions
COHU, INC. Elec tron ics Di vi sion In stal la tion and Op era tion In struc tions 2200 SE RIES NTSC/YC, PAL/YC, AND RGB COLOR CAM ERAS This de vice com plies with part 15 of the FCC Rules. Op era tion
More informationJoel Martinson (Choral score) Selah Publishing Co., Inc. Hn. J œ œ œ œ œ œ. j œ. 8 5 Choir: (Women or Men) for review only. ni- mi- pax.
Missa Guadalupe o Martson 10-911 (Choral score) Sah Publishg Co. Inc. Orr rom your avorite aler or at.sahpub.com (Or call 00--1.S. and Cada) This document is provid or revie purposes only. It is illegal
More informationÎïðå äå ëå íèå óðîâ íÿ ñïîí òàí íî ãî è èíäóöèðîâàííîãî àïîïòîçà êëåòîê, ïîëó åííûõ èç îïåðàöèîííîãî ìàòåðèàëà ïðè ëèôòèíãå ëèöà
ÊËÈÍÈ ÅÑÊÈÅ ÈÑÑËÅÄÎÂÀÍÈß Ïà òî ãå íåç. 2016. Ò.14, ¹4. Ñ. 63 68 ÓÄÊ: 617-089.844 Îïðå äå ëå íèå óðîâ íÿ ñïîí òàí íî ãî è èíäóöèðîâàííîãî àïîïòîçà êëåòîê, ïîëó åííûõ èç îïåðàöèîííîãî ìàòåðèàëà ïðè ëèôòèíãå
More informationMAURIZIO MACHELLA Arranger, Interpreter, Publisher
MAURIZIO MACHELLA Arranger, Interpreter, Publisher Italia About the artist Famous musician and organist, known throughout the world. Italian publisher, researcher and organist. Music collaborator with
More informationÁåëêè è ïåïòèäû íåéòðîôèëîâ â ðåãóëÿöèè ñèñòåìû êîìïëåìåíòà
ÎÁÇÎÐÛ Ïà òî ãå íåç. 2017. Ò.15, ¹1. Ñ. 19 23 ÓÄÊ 632.938 Áåëêè è ïåïòèäû íåéòðîôèëîâ â ðåãóëÿöèè ñèñòåìû êîìïëåìåíòà Áåð ëîâ Ì.Í. 1,2, Óì íÿ êî âà Å.Ñ. 1, Êîê ðÿ êîâ Â.Í. 1,2 1 ÔÃÁÍÓ «Èíñòèòóò ýêñïåðèìåíòàëüíîé
More informationPlease note that not all pages are included. This is purposely done in order to protect our property and the work of our esteemed composers.
Please note that not all pages are included. his is purposely done in order to protect our property and the work of our esteemed composers. If you would like to see this work in its entirety, please order
More informationAve Maria. œ œ œ œ œ. œ œ j. j œ. n œ # œ œ. Lord is with. Sol m Gm
2 Based on Luke 1:28, 2 3 Eleazar Cortés cc. y Rick Modlin Keyoard % INTRO/INTERLUDE/INTERLUDIO (q = ca. 90) Do a C VERSES/ESTROS Latin Español. Dios English Hail, 7 #. # ve, rí a, grá ti te sal ve, rí
More informationEU RO PE AN AG RE E MENT
Príloha k čiastke 120 Zbierka zákonov 2004 Strana 5781 K ozná me niu č. 297/2004 Z. z. EU RO PE AN AG RE E MENT ON THE EX CHAN GE OF BLOOD-GROUPING RE A GENTS The sig na to ry go ver nments of the mem
More informationKees Schoonenbeek Arranger, Composer, Director, Publisher, Teacher
Kees choonenbeek rranger, Comoser, Director, ublisher, eacher Netherlands, Dieren bout the artist Kees choonenbeek as born in rnhem, the Netherlands, on October 1 st 1947.He studied the iano at the Conservatory
More informationJean Mouton. (before ) Quis dabit oculis? This edition prepared for The Tallis Scholars. Gimell
Jean Mouton (before 1459 1522) Quis dabit oculis? This edition prepared for The Tallis Scholars Gimell Quis dabit oculis nostris fontem lachrimarum? Et plorabimus die ac nocte coram domino? ritannia, quid
More informationÏÀÒÎËÎÃÈ ÅÑÊÀß ÔÈÇÈÎËÎÃÈß
ÏÎ ÒÎÂÛÉ ÀÄÐÅÑ: 125315, Ìî ñê âà, óë. Áàë òèé ñêàÿ, 8. Ôåäåðàëüíîå ãîñóäàðñòâåííîå áþäæåòíîå ó ðåæäåíèå «ÍÈÈ Îáùåé ïàòîëîãèè è ïàòîôèçèîëîãèè» Ðîñ ñèé ñêîé àêà äå ìèè ìå äè öèí ñêèõ íà óê Ðå äàê öèÿ æóð
More information2017 Tentative Roster
2017 Tentative Roster Seeing your name on this list only means that you were assigned to a DHA in the Application Process & Lottery. To actually be placed into the 2017 Hunt, you are still required to
More informationwhich best answers the question
ÈÏ apple INSTRUCTIONS The following section contains two types of questions: Reading Comprehension and Sentence Completion. Each question is followed by four possible responses. Choose the response which
More informationVENDOR NUMBER CROSS REFERENCE LIST
CROSS REFERENCE LIST 574-S. 839 987 6E-2 912 412 6J-3 E-70 168-M 6K-3 E-70 259-M AFB-2447 S 1731 513 AFB-2448 S 1731 514 AFB-2641 S *1822 052 AFB-2642 S *1822 053 AFB-2650 S *1826 079 AFB-2651 S *1826
More informationA MUSICAL. Preview Only. pizz.
Arranged by ALAN BILLINGSLEY FLUTE CLARINET 1 CLARINET 2 TENOR SAXOPHONE BARITONE SAXOPHONE TRUMPET 1 TRUMPET 2 TROMBONE 1 TROMBONE 2 SOLOS SOPRANO ALTO TENOR BASS PIANO SYNTHESIZER 1 (Strings) SYNTHESIZER
More informationÓÄÊ :66.093:
Õèìèÿ â èíòåðåñàõ óñòîé èâîãî ðàçâèòèÿ 20 (2012) 575 580 575 ÓÄÊ 542.65:66.093:661.887 Ïîëó åíèå öèòðàòà âèñìóòà-êàëèÿ Å. Ñ. ÍÀÉÄÅÍÊÎ, Þ. Ì. ÞÕÈÍ, Ë. È. ÀÔÎÍÈÍÀ, Ê. Á. ÃÅÐÀÑÈÌÎÂ Èíñòèòóò õèìèè òâåðäîãî
More informationTrial Version.
1 2 3 4 5 6 7 8 9 10 11 12 PEGGY O NEIL If her eyes are blue as skies, That s Peg-gy O Neil. If she s smil-ing all the while, That s Peg-gy O Neil. If she walks like a sly lit-tle rogue, If she talks with
More information#21 Stand up and Bless the Lord. œ œ œ œ œ. up high is up. bless bove strength bless. and a - our and. choice; high, ours; dore; heart laud all forth
#21 St up Bless Lord 1 c Ó.. 1. 2. 4. 5. St Though God St up high is up a bless bove strength bless Lord, praise, song, Lord, Ye A And 4 Bb. peo bove His Lord ple sal y bless va God His ing tion a choice;
More informationCOPYRIGHTED MATERIAL. About Reading Pathways
About Reading Pathways Many students need extra help in learning how to track left-to-right with their eyes. These students benefit from reading practice that gradually and systematically builds letters
More informationStalin and the Little Girl
duration: ca. 10 min. q = ca.40 very rubato, esecially silences? 4 > # > Stalin and the Little Girl # AN ICN (or unaccomanied bass-baritone voice) # words & music by William Vollinger (ASCA) 2012 # Gel-ya!
More informationMeet 12 Famous Composers Through Song Arranged, with new Words, by Sally K. Albrecht. Recording Orchestrated by Alan Billingsley and David Hagy
Composer Songs Meet 12 Famous Composers Through Song Arranged, with new Words, by Sally K. Albrecht Recording Orchestrated by Alan Billingsley and David Hagy Teacher s Handbook Title Bio/Song Song Sheet
More informationPus hing and Bra king Aid. Trans la ti on of the ori gi nal user s Ma nu al. V-max
Pus hing and Bra king Aid Trans la ti on of the ori gi nal user s Ma nu al V-max GB CE De cla ra ti on of con for mi ty The com pa ny AAT Al ber An triebs tech nik GmbH he re with de cla res that the pro
More informationAyzehu. by Peter Rothbart (text from the Ethics of the Fathers) Transliteration Pronunciation Guide for Hebrew
2 Ayzehu by Peter Rothbart (text from the Ethics of the Fathers) English Who is wise He who learns from every man. From all my teachers, I gained wisdom. Who is strong He who subdues his evil impulse.
More informationSAMPLE MISSA MARIA MAGDALENA. Kyrie Free and mysterious; molto rubato h = 54 SOLO (SOPRANO 2) SOPRANO ALTO TENOR BASS ORGAN
SOPRANO For Will Dawes and the choir o St Mary Magdalen, Oxord MISSA MARIA MAGDALENA Kyrie Free and mysterious; molto rubato h = (SOPRANO ) calm and distant DAVID ALLEN (b. 198 - ) ALTO TENOR BASS ORGAN
More informationNä Wä Kamali i Hawai i
A note to those who are printing this.pdf file This file was prepared for electronic delivery / reprinting at your desktop. Do print and bind (or hole-punch) to create your own book; print both sides ("duplex"),
More informationPhase Equilibria, Crystallographic and Thermodynamic Data of Binary Alloys
Landolt-Börnstein Numerical Data and Functional Relationships in Science and Technology New Series / Editor in Chief: W. Martienssen Group IV: Physical Chemistry Volume 12 Phase Equilibria, Crystallographic
More informationTESOROS OCULTOS. Treasures Out of Darkness
TESOROS OCULTOS Treasures Out of Darkness Coro al SATB, Cantor, Asblea, (Flauta, Oboe, Trompa en Fa opcionales), Guitarra, Piano SATB Choir, Cantor, Assembly, (optional Flute, Oboe, Horn in F), Guitar,
More informationGIVE ME A CHORAL MEDLEY!
2 PIANO 4 GIVE ME A CHORAL MEDLEY! Grandioso (q = ca. 104) (A Singer s Spoof ) for S.A.T.B. voices and piano with optional SoundTrax CD* molto rit. decresc. 7 Freely (q = ca. 88) f 6 * Also avaible for
More informationSWINGIN WITH THE GERSHWINS! They Can t Take That Away from Me Nice Work If You Can Get It S Wonderful Let s Call the Whole Thing Off They All Laughed
K K PREVIEW 2 PIANO SWINGIN WITH THE GERSHWINS! They Can t Take That Away rom Me Nice Work I You Can Get It S Wonderul Let s Call the Whole Thing O They All Laughed Arranged by MAC HUFF REVIEW PREVIE PART
More informationOn the Common Goods. Dr. Gregory Froelich
[T Aa R V. W. 0: 1 5 Ma 2010, 2:19..] O C G D. G F S. Ta a a a a aa a a. I a a a a Ta a a a, a,, a a a a. T, Ta a a P a, a a aa; a, a a.¹ B a a Ta a a Taa. Ra, S. Ta a a aa a a a a aa a a a a a. Ca a,
More informationCover photo by Malene Thyssen,
Transcriptions by Stephen ucke Tutorial videos for these songs available at www.tradschool.com Cover photo by Malene Thyssen, http://commons.wikimedia.org/wiki/user:malene Contact tradschool@gmail.com
More informationClassroom Cantatas. can ta ta singers. Mather Elementary School. Out of Many We are One
Composed and Performed by Ms. King and Ms. White s 2nd Grade Classes Classroom Cantatas Mather Elementary School Out of Many We are One Cantata Singers, 201 can ta ta singers In Diversity there is Beauty
More informationPreview Only. Legal Use Requires Purchase. LYDIA, THE TATTOOED LADY for T.T.B.B. voices and piano* Music by HAROLD ARLEN Lyric by E. Y.
Arranged by JAY ALTHOUSE LYDIA, THE TATTOOED LADY or voices and piano* Music by HAROLD ARLEN Lyric by E. Y. HARBURG 1 Piccolo Trumpet 1 Trumpet 2 Trombone Baritone Horn Tuba Percussion 1 (S.D./D.) Percussion
More informationCome, Ye Faithful, Raise The Strain Exodus 15 John of Damascus, c Translated by John M. Neale, , alt. Alto
2 Exodus 15 John of Damascus, c. 675 749 Translated by John M. Neale, 1818 1866, alt. Scott Soper INTRO: With joyful intensity ( = ca. 76 ) Keyboard VERSES 1 & 2: Vs. 1 Cantor or unison Choir; Vs. 2 Soprano/Alto
More informationThe Lisbon Carol A/D. œ œ œ œ. J œ œ œ. the of gi ing cre. an kings, from Star. cient yet the and tion - - œ œ œ œ œ. œ œ œ œ œ œ.
Craig Ksbury, riend colleague Piano? 3 4 5? Soprano Al INTRO/INTERLE With oy (h = ca 56)? 5 ß com born gold Rose praise 3 4 5 VERSES Lo! K Ma Morn o save rank o Shar Tri o gi cre an ks, rom Star a cient
More informationMissa Nova. Service music for Christian worship. Composed by. Jeffry Hamilton Steele
Missa Nova Service music for Christn worship Composed by Jeffry Hamilton Steele for Cantor, SATB choir and congregation with classical guitar accompaniment (organ/keyboard optional) 1 3 5 7 11 13 15 Kyrie
More informationle vent gon Perusal only L'aubean
Commissioned by Arts Buau or Continents or Unisong Festival, Ottawa, Canada UNITED IN SONG TOUS UNIS EN CHANSON SSA and piano our hands Fnch translation by Gilles Plante Words and music by Paul Halley
More informationThe Dramatic Publishing Company
This is the supreme theatrical event of the season. The play itself is a flying carpet, gliding us aloft into a land of mystery, splendor and ritual. A nation of birds is in crisis, and urged on by one
More informationCopying is illegal. Review copy only. U j œ. œ œ œ œ œ. œ œ. # œ œ œ œ œ œ œ. ? b. œ œ œ œ œ œ œ œ. œ œ. Nancy M. Raabe
Tad. Pueto Rican; t. Caolyn ennings Solo o Canto Piano 3 Anuncio eely 4 2 4 2 4 2 U U u The Los ma gi who to Beth le hem did go wee the ma gos que lle ga on a Be lén a nun g. g he alds o the com ing o
More informationFifth Grade Music History Video 2
GRADE 5 Lesson 31 Fifth Grade Music History Video 2 Teams present their music history videos. Each team: 1. Presents the piece of music they selected. 2. Describes the music using musical terms for instrumentation,
More informationOpening Processional Hymn: Band and Organ Joy to the World. j œ. is ior. let. King; let sins. nor. grow, rows. œ œ œ. heart floods, room, plains; he
Openg Processional Hymn: B Organ Joy World Watts 1 & 2 4.. m/ /G G7.. G. J. Joy Joy world! earth! Lord Sav ior come; reigns; earth all, re ceive ir songs her Kg; em ploy, Nomore ss sor rows grow, nor thorns
More informationSYMBOL CONVERSION LONG-TERM EQUITY OPTIONS EXPIRING IN JANUARY AND MARCH 2007
Trading Interest Rate Derivatives Trading Equity and Index Derivatives Back-office Futures Back-office - Options Technology Regulation CIRCULAR June 6, 2006 SYMBOL CONVERSION LONG-TERM EQUITY OPTIONS EXPIRING
More informationMISSA PACEM. Penitential Act. heal the con - S, A, Assembly
revie e vi Moderato h = 0 You ere sent Cantor e MISSA ACEM enitential Act to heal con - n trite L Randolph Bain heart: e Lord, have mer - cy Ó S, A, Assemly Sel elec ec Lord, have mer - et, B ec cy Ó 10
More informationELF. A Medley from the Broadway Musical
2 Arranged by ANDY BECK PIANO 4 north that helps us put our best foot forth: If you want to deck the halls for north that helps us put our best foot forth: If you want to deck the halls for PART I PART
More informationTwelve Canons for recorder ensemble page Round. for 3-6 treble recorders
Telve Canons for recorder ensemble page 1 Round for 3-6 treble recorders A round is a type of canon, hich may continue repeating it indefinitely. This round is at maximum a canon in six. A ne part can
More informationBali, last paradise or paradise lost
Bali, last paradise or paradise lost Travelogue Febr-March 2012 Offering to the templel A few weeks on Bali, at the end of the mon soon se a son, is a hot and hu mid ex pe rien ce, but also al lows, next
More informationLagniappe-Potpourri 2019: Audition Selections
Lagniappe-Potpourri 2019: Audition Selections Baritone Why? 'Cause I'm A Guy - I Love You, You re Perfect, Now Change Poisoning Pigeons In The Park - An Evening Wasted with Tom Lehrer Tenor You and Me
More informationThree Latin Prayers. Music by Christopher J. Hoh Traditional texts. Angele Dei prayer to the guardian angel
Three Latin rayers ~ for SSATBB choir, a cappella ~ Angele i prayer to the guardian angel Agimus Tii Gratias prayer of thanks and rememrance Dona Nois acem prayer for peace Music y Christopher J. Hoh Traditional
More informationA Winnie-The-Pooh Christmas Tail (Birthday Tail) Musical Overview Product Code: W03000
A Winnie-The-Pooh Christmas Tail (Birthday Tail) Musical Overview Product Code: W03000 To help you find the perfect musical for your next performance, we have provided this overview of the vocal and orchestral
More informationParis Is So In Love!
Lyrics: Paul James Tempo rubato (h. = c.62) Paris Is So In Love! Gerard: Could it be? p Music: Ben Mason Was it so? Did we real - ly have no-where to go? Life is good What went right? Cer-tain ap - pe-tites
More informationCommunity Worship. Thursday, October 3, 2013 Davis Chapel
Community Worship Thursday, October 3, 2013 avis Chapel Today in Worship aring Chime Kenneth Pettigrew, Miv '16 ntroduction Call to Worship r. Bill J. Leonard Centering * Congregational Singing: "The Trumpets
More informationGLORIOUS FREEDOM (TTB)...
DAY BY DAY (SSA)... 3 GLORIOUS FREEDOM (TTB)... 8 SPEAK TO US, WE PRAY (SAB)... 12 TIS SO SWEET TO TRUST IN JESUS (SSA)... 18 REDEEMED, HOW I LOVE TO PROCLAIM IT (TTB)... 23 COME, THOU FOUNT OF EVERY BLESSING
More informationCotton Patch Gospel Musical Overview Product Code: C05000
Cotton Patch Gospel Musical Overvie Product Code: C05000 To help you find the perfect musical for your next performance, e have provided this overvie of the vocal and orchestral demands for this title
More informationA Girl Born in Afghanistan
GREG BARTHOLOMEW A Girl Born in Aghanistan A setting o excerts rom the Nol Peace Prize Lecture by United Natis Secretary General Koi Annan or unaccoanied mixed choir with iano reducti or rehearsal ly BURKE
More informationTerms and Conditions. By printing the attached sheet music, you acknowledge that you have read and agree to these Terms and Conditions.
Terms and onditions UPT MRH 2016 Thank you or downloading the attached sheet music or irst. We hope that these songs are a source o encouragement or both you and your church. Please note: This download
More informationBook of Psalms ~ Volume 2
Book o Psalms ~ Volume 2 Song Verse Style 1. Psalm 4: Let Your ace Shine On Us 2. Psalm 15: Those Who o Justice 3. Psalm 25: Remember Your Mercies 4. Psalm 32: Turn To You n Times O Trouble 5. Psalm 40:
More informationœ œ œ œ œ œ œ œ œ œ œ œ œ bœ bœ. œ œ œ œ œ œ œ œ œ œ œ!! œ œ œ œ œ œ œ œ œ œ! œ œ bœ . œ œ œ œ œ œ œ œ œ! œ œ œ œ œ! œ œ œ! œ œ œ œ œ D(4-1) D(4-1)
The Emancipation of Metric Displacement Dissonance in Hip-Hop Music Ben Duinker, McGill University benamin.duinker@mail.mcgill.ca Eample 1: ecerpt from Award Tour (A Tribe Called Quest, 199). Bass and
More informationTelex. RadioCom TM. Op er at ing In struc tions FM-1 QSB-1 SMP. Professional Wireless Intercom System Management
Telex Op er at ing In struc tions RadioCom TM FM-1 QSB-1 SMP Professional Wireless Intercom System Management Ta ble of Con tent Section 1 Introduction...1-1 Over all De scrip tion...1-1 Sec tion 2 Sys
More informationFor Review Only. Pangasinan Pronunciation Guide. Consonants are pronounced like the typical Italian ones except: c which is pronounced like k
Pangasinan Pronunciation Guide Consonants are ronounced like the tyical Italian ones excet: c which is ronounced like k n and g when seen together in that order (ng) are considered one consonant and is
More informationDe voted to Prof. Pavel Povinec 65-th an ni ver sary. 241 Am source was used in the test cham ber. The beam was collimated by me chan i cal
Our group is de vel op ing Time Pro jec tion Cham bers (TPC) for sev eral years [1]. Cath - ode pad read-out is of ten used for the sec ond co or di nate mea sure ment. The cath ode to an - ode sig nal
More informationVol.30 No Journal of Chinese Society for Corrosion and Protection Jun Å «: TM501 TG Þ½ : A ÃÝ : Å
3 à ½ Ð Vol. No.3 6 Journal of Chinese Society for Corrosion and Protection Jun. 400 Hz Æ À¹ л 1 Í Ì 1,2 Ï 1 É 2 ÍÊ 2 Î 3 (1. Å» Ê Å 7049 2. Ê»ÒÇ 4111 3. Õ Å» 325603)  : ± Ø Ã Â ASTM Ù ÚÊ À±Ã ±¾Ç Þ 400
More informationAngels We Have Heard On High
Choraegus ShareMusic To use this song your choral music mistry, please follo these structions: 1. Make the numer of copies you need. Ensure that this notice appears on each copy. 2. Send a check or money
More informationMycobacteria Growth Indicator Tube, OADC Enrichment, PANTA Antibiotic Mixture JAA См. глоссарий символов в конце вкладыша.
B BBL Mycobacteria Growth Indicator Tube, OADC Enrichment, PANTA Antibiotic Mixture 8809501JAA См. глоссарий символов в конце вкладыша. (2005/11) U Русский Ïàòåíò ÑØÀ 5 567 598 Ïàòåíò Àâñòðàëèè 647609
More informationClassroom Cantatas. can ta ta singers. Mendell Elementary School. The Games We Play
Composed and Performed by Ms. Kelly and Ms. Marroquin s 2nd Grade Classes Classroom Cantatas Mendell Elementary School The Games We Play Cantata Singers, 2016 can ta ta singers Kenn Nesbitt Baseball is
More informationPHIL THE FLUTER S BALL
PHIL THE FLTER S BALL A song by Percy French (1854 1920) Arranged by Donald Williams for Singer (Ten/Bar) with Piano and Descant Recorder (or Flute) PIANO SCORE Arranged and Set by DFW, November 20 Phil
More informationI Can Hear the Bells
rom: Hairspray an Hear the ells by MAR SHAMAN Lyrics by: SOTT WTTMAN and MAR SHAMAN Published Under License rom Alfred Publishing o., nc. 2001 WNN ROOK WAY MUS and WALL WOO ENTERTANMENT This Arrangement
More informationClassroom Cantatas. can ta ta singers. Mendell Elementary School. Musical Mysteries. The Book Theme Songs
Composed and Performed by Ms. Kelley s and Ms. Marroquin s 2nd Grade Classes Classroom Cantatas Mendell Elementary School Musical Mysteries The Book Theme Songs Cantata Singers, 201 can ta ta singers Tell
More informationEXSULTET. Re joice and sing now, all the round earth, bright with a glo ri ous splen dor,
2 for the choirs of St. John s Cathedral, Denver, Colorado Based on Easter Exsultet, Book of Common Prayer For the Easter Vigil EXSULTET John Repulski Handbells used: Freely unmeasured Handbells Soprano
More informationThe Hundred Dresses Musical Overview Product Code: HE9000
The Hundred Dresses Musical Overvie Product Code: HE9000 To help you find the perfect musical for your next performance, e have provided this overvie of the vocal and orchestral demands for this title
More informationClassroom Cantatas. can ta ta singers. Mendell Elementary School. Countries and Oceans. Continent Cantata
Composed and Perormed by Ms. Kelley s and Ms. Murphy s 2nd Grade Classes Classroom Cantatas Mendell Elementary School Countries and Oceans Continent Cantata Cantata Singers, 201 can ta ta singers COUNTRIES
More informationStodola Pumpa. Sto- do- la, Sto- do- la, Sto- do- la pum- pa Sto- do- la pum- pa, sto- do- la pum- pa
Stodola Pumpa Up from the valley we will make our way. Leaving behind the worries of the day. Being at one with all that we survey, Singing aloud this joyous song. Oh, Greeting the sunlight in the morning
More informationSix Songs for a Young Man
Six Songs or a Young Man or Baritone and Piano by Alan Belkin or Réal Alan Belkin, 2007 My Six Songs or a Young Man cover my entire comosing career to date, rom 1974 to the 2008. Although not originally
More information10 11 Route Map. ook. Colnbrook. Datchet. Po oy. Poyle. loughh. Slo ug. Windsor & Eton Riverside. tchet. Datchet. Windsor r& Sunnymeads.
W Welley meter R t i 6 4 River ver er r Thames Thames Thames Eto t Wick, Colenor ort to Cr escent Winsor r& Et Central Bus Stati Slough Winsor & Et Riversie Datc che et, The G r ee en Datchet Datchet Sunnymeas
More informationfrom the musical Chicago RAZZLE DAZZLE for S.A.B. voices and piano with optional SoundPax and SoundTrax CD* Preview Only simile
2 Arranged by LARRY SHACKLEY BARITONE 8 PIANO ALTO Moderate swing (q = ca. 120) mf 4 SOPRANO 5 mf from the musical Chicago RAZZLE DAZZLE for S.A.B. voices and piano with optional SoundPax and SoundTrax
More informationRemote Control Setup
Remote Control Setup Personalizing Your Remote Controls What you ll find in this chapter: IMPROVING RECEIVER CONTROL CONTROLLING OTHER COMPONENTS THE RECOVER BUTTON SENDING DISCRETE POWER ON AND OFF 7
More informationGift of Heaven. œ œ. œ œ œ. j œ. œ œ œ œ œ œ. (Asus4) (Am) Csus4 Cm. va - tion: œ œ
2 Composed for the dedication Mass Bauccio Commons, University Portland, September 25, 2010 Soprano Alto Tenor Bass Keyboard.. ift Heaven OSTINATO REFRAIN Prayerfully, confidently (q = ca. 7) Capo 3: Bread,
More informationPerusal only. So - leil. go sur. les flots. Vo-guons
Commissioned by Arts Buau or Continents or Unisong Festival, Ottawa, Canada UNITED IN SONG TOUS UNIS EN CHANSON SATB with optional tble choir and piano our hands Fnch translation by Gilles Plante Moderately,
More informationA beginner piano method with coloured alphabet and pre-staff reading.
. The Middle Alphabet The Keyboard Express John F Keller, 009 A beginner piano method with coloured alphabet and pre-staff reading. by John Keller Play it all staccato Bottom, Top, Middle centre of keyboard
More informationUNIFORM PRIVATE LAW CONVENTIONS AND THE LAW OF TREATIES
UNIFORM PRIVATE LAW CONVENTIONS AND THE LAW OF TREATIES Jür gen BASEDOW SUMMARY: I. In tro duc tion. II. The Treaty as a Ve hi cle of Uni form Private Law: a Historical Survey. III. In ter na tional Trea
More informationFrom the editor... Ray Sprague. Translation:
2 From the editor... Giovanni Pierluigi da Palestra is the acknoledged master of the sixteenthcentury sacred polyphonic style, and his music represents the epitome of the classic Renaissance ideals of
More informationOp er at ing In struc tions
Op er at ing In struc tions UHF WIRE LESS MICROPHONE SYSTEM User Guide Ta ble of Con tents Sec tion 1 - Quick Set-Up....1 Sec tion 2 - Sys tem De scrip tion...2 Sec tion 3 - De tailed Com po nent De scrip
More informationPerformance Suggestions
Thank you for purhas th CuthbertPrae! donload produt. Your donload entitles you unlimited opies parts sores ontaed here for your speifi mtry or personal use. Please do not pass opies outside your on use
More informationI Am a Daughter of God I Am a Daughter of God (flute obbligato) Follow Me Live the Legacy Woman of Faith...
Table of Contents Am a Daughter of God.............................. 1 Am a Daughter of God (flute obbligato)................ 6 Follow Me........................................ 7 Live Legacy....................................
More informationPerformance Suggestions
Thank you for purhasg this CuthbertPraise! donload produt Your donload entitles you unlimited opies parts sores ontaed here for your speifi mistry or personal use Please do not pass opies outside your
More informationPlease note that not all pages are included. This is purposely done in order to protect our property and the work of our esteemed composers.
Pease note that not a pages are incuded This is purposey done in order to protect our property and the work of our esteemed composers f you woud ike to see this work in its entirety, pease order onine
More informationRUDOLPH, FROSTY, AND SUZY. Rudolph, the Red-Nosed Reindeer Frosty, the Snowman Suzy Snowflake
2 SOPRANO ALTO TENOR BASS 5 PIANO Su Em/G RUDOLPH, FROSTY, AND SUZY Rudolph, the Red-Nosed Reindeer Frosty, the Snowman Suzy Snowlake or S.A.T.B. voices and piano with optional SoundPax and SoundTrax CD*
More information4. My Girl. say. She thought I'd had e - nough of her. Why can't she see? in and watch T. V. on my own, ev - ery now and then.
4. My Girl 7 Q - Sarah: "Maybe I'm not such a good judge of character." Faster Slowly q = 120 Emmo My girl's mad at me 6 I did-n't want to see the film to - night. I found it hard to 9 say. She thought
More informationAGASTAT 2100 Series, Miniature Electropneumatic Timing Relay
12 4 Product Facts n High Repeat Accuracy over voltage and temperature extremes n Hermetically sealed units are designed for high shock and vibration applications n Instant recycling easy linear adjustment
More informationLitera. Circle Roles. Name: Name: ame: Title of Book:
Literature Circle Roles ssion Discu tor Direc Date: Name: me: ntur e: Title of r: Autho ry Adve Nam ing A Book : Name: ina Stellar SummarizerLiterary Lum Date: Date: rtist Title of Book: cle Na Author:
More informationCollege of MUSIC. James Forger, DEAN UNDERGRADUATE PROGRAMS. Ad mis sion as a Ju nior to the Col lege of Mu sic
College of MUSIC James Forger, DEAN The College of Music offers undergraduate programs leading to the de grees of Bach e lor of Mu sic and Bach e lor of Arts, and grad u - ate pro grams lead ing to the
More informationThe essential and the derivative moods of Aristotelian syllogism
PHILOSOPHY & RELIGION RESEARCH ARTICLE The essential and the derivative moods of Aristotelian syllogism Lei Ma 1 * Received: 21 October 2016 Accepted: 08 January 2017 Published: 01 February 2017 *Corresponding
More informationA beginner piano method with pre-staff kids notes and keyboard guides
. The Keyboard Express John F Keller, 009 A beginner piano method with pre-staff kids notes and keyboard guides by John Keller Express Stave by John Keller The Keyboard Express and Express Stave by John
More informationSUMARIO: I. Globalization. II. Globalization and the Legal Field. III. Globa li za tion and Le gal Edu ca tion. I. GLOBALIZATION
GLOBALIZATION AND LEGAL EDUCATION: A VIEW FROM MEXICO* José Ma ría SERNA DE LA GARZA** Para mi querido Boletín, mismo que tuve el honor de dirigir en tre 2000 y 2006 SUMARIO: I. Globalization. II. Globalization
More informationPraise to the Lord, the Almighty q = 135 Driving
Lead Sheet Ps 95:3 ome, let us sing oy Lord; let us shout aloud Rock of our salvation Let us come ee him ith thanksgiving exl him ith music song or Lord is great od, great King aove all gods (NIV) INTRO
More informationIn memory of James Rygelski. Shepherds, Run Along Przybieżeli do Betlejem pasterze. SATB and Piano (opt. Brass Ensemble or Chamber Orchestra) più
2 Traditional olish Carol Allegro moderato ( q = 120 ) più 4 iano? 4 simile 5,? 8? n MSM501735 sim In memory o ames Rygelski Shepherds, Run Along rzybieżeli do Betleem terze SATB and iano (opt Brass Ensemble
More informationFrom: Bruno Mars - Unorthodox Jukebox. When I Was Your Man. PETER HERNANDEZ, PHILIP LAWRENCE, ARI LEVINE and ANDREW WYATT. Arranged by MAC HUFF
From: Bruno Mars - Unorthodox Jukebox When I Was Your Man by PETER HERNANDEZ, PHILIP LAWRENCE, ARI LEVINE and ANDREW WYATT Arranged by MAC HUFF Published Under License From Alfred Publishing Co., Inc.
More informationI Sing the Mighty Power of God. Em7. œ œœœ. of the. God, Lord, power of flow'r. œ œ. seas with. Word, blow. His. or - dis - that are life
Sg Mighty Poer of od Hymn #59 nclusive Language for vs 3 ("man" orgal) ords by saac Watts music: esangbuch der Herzogl sus4 & # c m7 sus2 sus4 1 2 3 There's sg sg not might y good ness a plant or poer
More informationThe Effect of Female Media Body Images on Body Image Dissatisfaction in Female Athletes and Nonathletes
ORİJİNAL ARAŞTIRMA The Effect of Female Media Body Images on Body Image Dissatisfaction in Female Athletes and Nonathletes Serdar TOK, a İnci GÜNEŞ, b Mehmet KOYUNCU, c Birol DOĞAN, a A. Meliha CANPOLAT
More informationGlory to God 3 Mass of the Desert Tom Booth Choral arr. by Ed Bolduc
INTRO (q = ca 112) &? lory to od Mass of the esert horal arr by d Bolduc 2 «Soprano lto % RFRIN F lo ry to od in the F &? highest, and on earth peace to peo ple of good n n ill to Verses VRS 1 & 1 We praise
More information1920's Music Pack 5 0
1920's Music Pack 5 0 SUNNY SIDE O THE STREET C E7 Grab your coat and get your hat, leave your wor -ry on the door step," Am Dm C Just di -rect your feet, to the Sun -ny Side of the Street. C E7 Can't
More information