ﻣﺠﻠﻪ داﻧﺸﻜﺪه ﭘﺰﺷﻜﻲ اﺻﻔﻬﺎن
ﻣﻘﺎﻟﻪ ﭘﮋوﻫﺸﻲ
ﺳﺎل ﺳﻲام/ﺷﻤﺎره /214ﻫﻔﺘﻪ ﭼﻬﺎرم دي ﻣﺎه 1391
ﺗﺎرﻳﺦ درﻳﺎﻓﺖ91/6/17 :
ﺗﺎرﻳﺦ ﭘﺬﻳﺮش91/8/20 :
ﺑﺮرﺳﻲ ﭘﻠﻲﻣﻮرﻓﻴﺴﻢ ژﻧﺘﻴﻜﻲ C677Tدر ژن MTHFRدر ﺑﻴﻤﺎران ﻣﺒﺘﻼ ﺑﻪ ﻣﻴﮕﺮن در ﻣﻘﺎﻳﺴﻪ ﺑﺎ ﮔﺮوه ﺷﺎﻫﺪ ﻛﺎﻣﻴﺎر ﻫﻤﺖ ،1دﻛﺘﺮ ﺷﻘﺎﻳﻖ ﺣﻖﺟﻮي ﺟﻮاﻧﻤﺮد ،2دﻛﺘﺮ ﻣﺤﻤﺪ ﺳﻌﺎدتﻧﻴﺎ ،3ﻻﻟﻪ رﻓﻴﻌﻲ،4 5
ﻋﻠﻴﺮﺿﺎ زﻧﺪيﻓﺮ ،1ﻣﺤﻤﺪﺣﺴﻦ ﺗﺎجاﻟﺪﻳﻨﻲ ﭼﻜﻴﺪه
ﻣﻘﺪﻣﻪ :ﻣﻴﮕﺮن ﺑﻪ ﻋﻨﻮان ﻓﻨﻮﺗﻴﭙﻲ از اﺧﺘﻼﻻت ﭘﻠﻲژﻧﻲ در ﻧﻈﺮ ﮔﺮﻓﺘﻪ ﻣﻲﺷﻮد و ﻣﻨﻌﻜﺲﻛﻨﻨﺪهي اﺛﺮ ﭼﻨﺪﻳﻦ ﺟﺎﻳﮕﺎه ژﻧﻲ ﻣﻲﺑﺎﺷﺪ ﻛﻪ ﻓﺮاﻳﻨﺪﻫﺎي ﭘﺎﺗﻮﻓﻴﺰﻳﻮﻟﻮژﻳﻜﻲ ﻣﺘﻔﺎوﺗﻲ را ﺗﻌﺪﻳﻞ ﻣﻲﻛﻨﻨﺪ .ﻧﺸﺎن داده ﺷﺪه اﺳﺖ ﻛﻪ اﻟﻞ 677Tدر ژن (Methylenetetrahydrofolate reductase) MTHFR ﺑﻪ ﻃﻮر ﻣﺴﺘﻘﻴﻢ ﺑﺎ ﻛﺎﻫﺶ ﻓﻌﺎﻟﻴﺖ آﻧﺰﻳﻢ و ژﻧﻮﺗﻴﭗ ﻫﻤﻮزﻳﮕﻮت TTﺑﻪ ﻃﻮر ﻏﻴﺮ ﻣﺴﺘﻘﻴﻢ ﺑﺎ ﻫﻴﭙﺮﻫﻤﻮﺳﻴﺴﺘﺌﻴﻨﻤﻲ در ارﺗﺒﺎط اﺳﺖ .در اﻳﻦ ﻣﻄﺎﻟﻌﻪ ارﺗﺒﺎط ﭘﻠﻲﻣﻮرﻓﻴﺴﻢ ژﻧﺘﻴﻜﻲ C677Tدر ژن MTFHRو ﻣﻴﮕﺮن در دو ﮔﺮوه ﻣﺒﺘﻼﻳﺎن ﺑﻪ ﻣﻴﮕﺮن و اﻓﺮاد ﺳﺎﻟﻢ در ﺟﻤﻌﻴﺖ اﻳﺮاﻧﻲ ﺑﺮرﺳﻲ ﮔﺮدﻳﺪ. روشﻫﺎ 203 :ﻧﻔﺮ از اﻓﺮاد ﻣﺒﺘﻼ ﺑﻪ ﻣﻴﮕﺮن و ﺳﺎﻟﻢ در اﻳﻦ ﻣﻄﺎﻟﻌﻪ وارد ﺷﺪﻧﺪ .ﭘﻠﻲﻣﻮرﻓﻴﺴﻢ ژﻧﺘﻴﻜﻲ C677Tدر ژن MTFHRدر 102ﻧﻔﺮ از ﻣﺒﺘﻼﻳﺎن ﺑﻪ ﻣﻴﮕﺮن و 101ﻓﺮد ﺳﺎﻟﻢ ﺑﺎ اﺳﺘﻔﺎده از ﺗﻜﻨﻴﻚ (Polymerase chain reaction-High resolution melting-) PCR-HRMﺑﺮرﺳﻲ ﺷﺪ. ﻳﺎﻓﺘﻪﻫﺎ :ﻓﺮاواﻧﻲ ژﻧﻮﺗﻴﭗﻫﺎ در دو ﮔﺮوه ﻣﻮرد و ﺷﺎﻫﺪ در اﻳﻦ ﻣﻄﺎﻟﻌﻪ اﺧﺘﻼف ﻣﻌﻨﻲداري ﻧﺪاﺷﺖ .اﺧﺘﻼف ﻓﺮاواﻧﻲ ژﻧﻮﺗﻴﭗ TTﻧﻴﺰ در دو ﮔﺮوه ﻣﻌﻨﻲدار
ﻧﺒﻮد ).(OR = 0/667 ،CI95%: 0/188-2/362 ،P = 0/530 ﻧﺘﻴﺠﻪﮔﻴﺮي :اﻳﻦ ﻣﻄﺎﻟﻌﻪ ﻧﺸﺎن داد ﭘﻠﻲﻣﻮرﻓﻴﺴﻢ ژﻧﺘﻴﻜﻲ C677Tدر ژن MTFHRدر اﺳﺘﻌﺪاد اﺑﺘﻼ ﺑﻪ ﻣﻴﮕﺮن ﻧﻘﺸﻲ ﻧﺪاﺷﺖ .اﻳﻦ اوﻟﻴﻦ ﻣﻄﺎﻟﻌﻪاي ﺑﻮد ﻛﻪ ﺑﻪ ﺑﺮرﺳﻲ ﻓﺮاواﻧﻲ اﻳﻦ ﭘﻠﻲﻣﻮرﻓﻴﺴﻢ در ﺟﻤﻌﻴﺖ اﻳﺮاﻧﻲ ﭘﺮداﺧﺖ .ﭘﻴﺸﻨﻬﺎد ﻣﻲﺷﻮد اﻳﻦ ﻣﻄﺎﻟﻌﻪ ﺑﺎ ﺗﻌﺪاد ﻧﻤﻮﻧﻪ ﺑﻴﺸﺘﺮ اﻧﺠﺎم ﺷﻮد ،ﻫﻤﭽﻨﻴﻦ ﻣﻮارد ﺑﺎ و ﺑﺪون اورا ) (Euraﺑﻪ ﻃﻮر ﺟﺪاﮔﺎﻧﻪ ﺑﺮرﺳﻲ ﺷﻮد. واژﮔﺎن ﻛﻠﻴﺪي :ﭘﻠﻲﻣﻮرﻓﻴﺴﻢ ژﻧﺘﻴﻜﻲ ،ﻣﻴﮕﺮن ،ژن (Methylenetetrahydrofolate reductase) MTFHR
ﻣﻘﺪﻣﻪ
اﻳﺠﺎدﻛﻨﻨﺪه ي ﻧﺎﺗﻮاﻧﻲ ﺑﻪ ﺧﻮد اﺧﺘﺼﺎص داده اﺳﺖ و در
ﻣﻴﮕﺮن ﻳﻜﻲ از ﺷـﺎﻳﻊﺗـﺮﻳﻦ اﻧـﻮاع ﺳـﺮ درد در ﻫﻤـﻪ ي
ﺑﻴﻦ زﻧﺎن در ﻣﺮﺗﺒﻪي 12ﻗﺮار دارد .ﺷﻴﻮع ﺣﻤـﻼت ﺳـﺮ
ﺟﻮاﻣــﻊ ﺑﺸــﺮي از ﺟﻤﻠــﻪ اﻳــﺮان ﺑــﻪ ﺷــﻤﺎر ﻣــﻲرود و
درد در زﻧـﺎن ﺗــﺎ 17درﺻــﺪ و در ﻣـﺮدان ﺗــﺎ 6درﺻــﺪ
ﻣﻲ ﺗﻮاﻧﺪ اﺑﻌﺎد زﻧﺪﮔﻲ ﻓﺮد ﻣﺒﺘﻼ را ﺗﺤﺖ ﺗﺄﺛﻴﺮ ﻗﺮار دﻫﺪ.
ﮔﺰارش ﺷﺪه اﺳﺖ .ﻣﻴﮕﺮن ﺷﺎﻣﻞ ﺳﺮ دردﻫﺎي ﻣﻜﺮر ﺑـﻪ
ﺑﺮ اﺳﺎس ﮔـﺰارش ﺳـﺎزﻣﺎن ﺟﻬـﺎﻧﻲ ﺑﻬﺪاﺷـﺖ ،ﻣﻴﮕـﺮن
ﻫﻤــﺮاه ﻋﻼﻳـﻢ ﮔﻮارﺷــﻲ ﻣﺎﻧﻨــﺪ ﺗﻬــﻮع ،اﺳــﺘﻔﺮاغ و ﻧﻴــﺰ
رﺗﺒـــﻪي ﻧـــﻮزدﻫﻢ را در ﺑـــﻴﻦ ﻫﻤـــﻪي اﺧـــﺘﻼﻻت
ﻓﺘﻮﻓﻮﺑﻴﺎ و ﻓﻨﻮﻓﻮﺑﻲ ﻣﻲﺑﺎﺷﺪ .اﻳﻦ ﺳﺮ درد اﻏﻠﺐ ﻣﺎﻫﻴـﺖ
* اﻳﻦ ﻣﻘﺎﻟﻪ ﺣﺎﺻﻞ ﭘﺎﻳﺎنﻧﺎﻣﻪي دورهي دﻛﺘﺮاي ﺣﺮﻓﻪاي در داﻧﺸﮕﺎه ﻋﻠﻮم ﭘﺰﺷﻜﻲ اﺻﻔﻬﺎن اﺳﺖ. 1داﻧﺸﺠﻮي ﭘﺰﺷﻜﻲ ،داﻧﺸﻜﺪهي ﭘﺰﺷﻜﻲ و ﻛﻤﻴﺘﻪي ﺗﺤﻘﻴﻘﺎت داﻧﺸﺠﻮﻳﻲ ،داﻧﺸﮕﺎه ﻋﻠﻮم ﭘﺰﺷﻜﻲ اﺻﻔﻬﺎن ،اﺻﻔﻬﺎن ،اﻳﺮان 2داﻧﺸﻴﺎر ،ﻣﺮﻛﺰ ﺗﺤﻘﻴﻘﺎت ﻓﻴﺰﻳﻮﻟﻮژي ﻛﺎرﺑﺮدي ،داﻧﺸﮕﺎه ﻋﻠﻮم ﭘﺰﺷﻜﻲ اﺻﻔﻬﺎن ،اﺻﻔﻬﺎن ،اﻳﺮان 3داﻧﺸﻴﺎر ،ﻣﺮﻛﺰ ﺗﺤﻘﻴﻘﺎت ﻋﻠﻮم اﻋﺼﺎب و ﮔﺮوه اﻋﺼﺎب ،داﻧﺸﻜﺪهي ﭘﺰﺷﻜﻲ ،داﻧﺸﮕﺎه ﻋﻠﻮم ﭘﺰﺷﻜﻲ اﺻﻔﻬﺎن ،اﺻﻔﻬﺎن ،اﻳﺮان 4ﻣﺮﻛﺰ ﺗﺤﻘﻴﻘﺎت ﻓﻴﺰﻳﻮﻟﻮژي ﻛﺎرﺑﺮدي ،داﻧﺸﮕﺎه ﻋﻠﻮم ﭘﺰﺷﻜﻲ اﺻﻔﻬﺎن ،اﺻﻔﻬﺎن ،اﻳﺮان 5داﻧﺸﺠﻮي ﻛﺎرﺷﻨﺎﺳﻲ ارﺷﺪ ،ﻣﺮﻛﺰ ﺗﺤﻘﻴﻘﺎت ﻓﻴﺰﻳﻮﻟﻮژي ﻛﺎرﺑﺮدي و ﮔﺮوه ﺑﻴﻮﺷﻴﻤﻲ ﺑﺎﻟﻴﻨﻲ ،داﻧﺸﻜﺪي داروﺳﺎزي و ﻣﺮﻛﺰ ﺗﺤﻘﻴﻘﺎت ﻋﻠﻮم داروﻳﻲ ،داﻧﺸﮕﺎه ﻋﻠﻮم ﭘﺰﺷﻜﻲ اﺻﻔﻬﺎن، اﺻﻔﻬﺎن ،اﻳﺮان Email:
[email protected]
ﻧﻮﻳﺴﻨﺪهي ﻣﺴﺆول :ﻣﺤﻤﺪﺣﺴﻦ ﺗﺎجاﻟﺪﻳﻨﻲ
ﻣﺠﻠﻪ داﻧﺸﻜﺪه ﭘﺰﺷﻜﻲ اﺻﻔﻬﺎن – ﺳﺎل / 30ﺷﻤﺎره /214ﻫﻔﺘﻪ ﭼﻬﺎرم دي 1391 www.mui.ac.ir
1935
ﭘﻠﻲﻣﻮرﻓﻴﺴﻢ ژﻧﺘﻴﻜﻲ C677Tدر ژن MTHFRدر ﺑﻴﻤﺎران ﻣﺒﺘﻼ ﺑﻪ ﻣﻴﮕﺮن
ﻛﺎﻣﻴﺎر ﻫﻤﺖ و ﻫﻤﻜﺎران
ﺿﺮﺑﺎندار و ﻳﻚ ﻃﺮﻓﻪ دارد و ﺑﺎ ﻓﻌﺎﻟﻴﺖﻫﺎي ﻓﻴﺰﻳﻜـﻲ و
ﻫﻤﻮﺳﻴﺴــﺘﺌﻴﻦ ﺑــﻪ ﻣﺘﻴــﻮﻧﻴﻦ اﺳــﺖ ) .(8-11ﻣﻮﺗﺎﺳــﻴﻮن
ﺣﺮﻛﺘﻲ ﺗﺸﺪﻳﺪ ﻣـﻲ ﺷـﻮد .در ﻃﺒﻘـﻪﺑﻨـﺪي ﺟﺪﻳـﺪ IHS
C677Tدر ﻣﺘــﻴﻠﻦ ﺗﺘﺮاﻫﻴــﺪروﻓﻮﻻت ردوﻛﺘــﺎز ﺑﺎﻋــﺚ
) ،(International headache societyﻣﻴﮕــﺮن ﺑــﻪ دو
ﺟﺎﻳﮕﺰﻳﻨﻲ واﻟﻴﻦ ﺑﺎ آﻻﻧﻴﻦ ﻣﻲ ﺷﻮد .ژﻧﻮﺗﻴﭗ ﻫﻤﻮزﻳﮕﻮت
دﺳﺘﻪي ﻣﻴﮕﺮن ﻫﻤـﺮاه ﺑـﺎ Euraو ﻣﻴﮕـﺮن ﺑـﺪون Eura
TTﻫﻤــﺮاه ﺑــﺎ اﻓــﺰاﻳﺶ ﺳــﻄﺢ ﺧــﻮﻧﻲ ﻫﻮﻣﻮﺳﻴﺴــﺘﺌﻴﻦ
ﺗﻘﺴﻴﻢ ﺷﺪه اﺳﺖ .ﻧﺰدﻳﻚ ﺑـﻪ 20درﺻـﺪ ﻣﺒﺘﻼﻳـﺎن ﺑـﻪ
ﻣﻲ ﺑﺎﺷﺪ ﻛﻪ ﺳـﺒﺐ اﻓـﺰاﻳﺶ ﺧﻄـﺮ ﺗﺮوﻣﺒـﻮز ورﻳـﺪي و
ﻣﻴﮕﺮن Eura ،را ﺗﺠﺮﺑﻪ ﻛﺮدهاﻧﺪ ).(1-2
آﺗﺮواﺳــﻜﻠﺮوز ﻣــﻲﺷــﻮد .ﻣﻘــﺎدﻳﺮ اﻓــﺰاﻳﺶﻳﺎﻓﺘــﻪي
در ﻣﻄﺎﻟﻌﺎت ﻣﺨﺘﻠﻔﻲ ﺑﺮ اﻳﻦ ﻧﻜﺘﻪ ﺗﺄﻛﻴﺪ ﺷﺪه اﺳﺖ
ﻫﻮﻣﻮﺳﻴﺴﺘﺌﻴﻦ ﻣﻲﺗﻮاﻧﺪ ﺑـﻪ ﻋﻨـﻮان ﻳـﻚ اﺳـﻴﺪ آﻣﻴﻨـﻪ ي
ﻛﻪ ﺑﻴﻤﺎران ﻣﺒﺘﻼ ﺑﻪ ﻣﻴﮕﺮن از ﻧﻮﻋﻲ اﺧـﺘﻼل ﻋﻤﻠﻜـﺮد
ﻣﺤﺮك ﻋﻤﻞ ﻧﻤﺎﻳﺪ و آﺳﺘﺎﻧﻪي ﺳﺮ درد ﻣﻴﮕﺮﻧﻲ را ﻣﺘـﺄﺛﺮ
ﻋﺮوﻗﻲ رﻧﺞ ﻣﻲﺑﺮﻧـﺪ ) .(3اﻟﺘﻬـﺎب ﻣﻮﺿـﻌﻲ ﻧﺎﺷـﻲ از
ﺳﺎزد ) .(11ﻧﺘﻴﺠـﻪي ﺑـﺎﻟﻴﻨﻲ اﻓـﺰاﻳﺶ ﻫﻮﻣـﻮ ﺳﻴﺴـﺘﺌﻴﻦ
آزادﺳــﺎزي ﻣــﺪﻳﺎﺗﻮرﻫﺎ از ﺳــﻠﻮلﻫــﺎي اﻟﺘﻬــﺎﺑﻲ در
ﭘﻼﺳﻤﺎ ﺷـﺎﻣﻞ آﺳـﻴﺐ ﺳـﻠﻮل ﻫـﺎي اﻧـﺪوﺗﻠﻴﺎل و ﺗﻐﻴﻴـﺮ
ﭘﺎﺳﺦ ﻫﺎي ﻧﻮروﻧﻲ و در ﻧﺘﻴﺠﻪ ،وﻗﻮع ﺳـﺮ درد ﻣﻴﮕـﺮن
وﻳﮋﮔﻲ ﻫﺎي اﻧﻌﻘﺎدي ﺧﻮن و ﻛﺎﻫﺶ داﻳﻤﻲ ﺳـﻠﻮل ﻫـﺎي
ﻧﻘﺶ اﺳﺎﺳﻲ دارد .ﻣﺎﺳﺖ ﺳﻞ ﻫﺎي ﻣﻨﻨﮋﻳﺎل در ﻋـﺮوق
Trigeminalﻣﻲ ﺷﻮد ) .(12ﻛﺎﻫﺶ داﻳﻤﻲ ﺳـﻠﻮل ﻫـﺎي
ﻣﻨﻨﮋﻳﺎل و آﻛﺴﻮن ﻫﺎي ﮔﻴﺮﻧﺪه ي درد ﭼﻨـﻴﻦ ﻧﻘﺸـﻲ را
Trigeminalﻣﻨﺠﺮ ﺑـﻪ اﻟﺘﻬـﺎب ﻣﻨﻨـﮋ و ﮔﺸـﺎدي ورﻳـﺪ
ﺑﺎزي ﻣﻲ ﻛﻨﻨـﺪ ) .(4ﺗﻐﻴﻴـﺮات ﻋﺮوﻗـﻲ در وﻗـﻮع CSD
ﻣﻐﺬي و در ﻧﻬﺎﻳﺖ درد ﻫﻤﺮاه ﺑﺎ ﻣﻴﮕﺮن ﻣﻲ ﺷﻮد .از اﻳﻦ
) (Cortical spreading depressionﻣـﺆﺛﺮ ﻫﺴـﺘﻨﺪ ﻛـﻪ
رو ﻋﺪم ﻋﻤﻠﻜـﺮد ﺻـﺤﻴﺢ ﻫﻮﻣﻮﺳﻴﺴـﺘﺌﻴﻦ ﺑـﻪ وﺿـﻮح
ﺧﻮد ﻣﻨﺠﺮ ﺑـﻪ وﻗـﻮع ﻣﻴﮕـﺮن ﻣـﻲ ﺷـﻮﻧﺪ ) .(5در ﻳـﻚ
ﺑﺎﻋﺖ ﭘﻴﺸﺮﻓﺖ ﻣﻴﮕﺮن در ﺑﻴﻤﺎر ﻣﻲﮔـﺮدد ) .(13آﺳـﻴﺐ
ﻣﻄﺎﻟﻌﻪ ﻧﺸﺎن داده ﺷﺪه اﺳﺖ ﻛﻪ در اﻓﺮاد ﻣﺒﺘﻼ ﺑﻪ ﻣﻴﮕﺮن
اﻛﺴــﻴﺪاﺗﻴﻮ ﺑــﻪ اﻧــﺪوﺗﻠﻴﻮم ورﻳــﺪي از ﻃﺮﻳــﻖ اﻳﺠــﺎد
اﺧﺘﻼل ﻋﻤﻠﻜﺮد ﻋﻀﻠﻪ ي ﺻـﺎف ﺑـﻪ ﻋﻠـﺖ اﺧـﺘﻼل در
آﻧﻴﻮن ﻫﺎي ﺳﻮﭘﺮاﻛﺴﻴﺪي ﺑﺎﻋﺚ اﻓﺰاﻳﺶ ﺷـﺎﻧﺲ اﺑـﺘﻼ ﺑـﻪ
(Guanosine mono phosphate) GMPو ﭘﺎﺳﺦﻫـﺎي
ﺑﻴﻤﺎري ﻣﻴﮕﺮن و دﻳﮕﺮ ﺑﻴﻤﺎريﻫﺎي اﺧﺘﻼل ﻋﺮوﻗﻲ ﻣﺎﻧﻨـﺪ
ﻫﻤﻮدﻳﻨﺎﻣﻴﻚ ﺑﻪ ،(Nitric oxide) NOوﺟﻮد دارد ).(6
Strokeﻣﻲﺷﻮد ) .(14ﺗﺤﻘﻴﻘﺎت ﻧﺸﺎن ﻣـﻲدﻫـﺪ C677T
در ﺧﺎﻧﻢﻫﺎي ﻣﺒﺘﻼ ﺑﻪ ﻣﻴﮕﺮن ﺑﺎ Euraدر ﺳـﻨﻴﻦ ﻗﺒـﻞ از
از ﻃﺮﻳــﻖ ﺗﻐﻴﻴــﺮ در ﻓﻌﺎﻟﻴــﺖ آﻧﺰﻳﻤــﻲ ،ﺑﺎﻋــﺚ اﻓــﺰاﻳﺶ
ﻣﻨﻮﭘﻮز ،ﺷﻮاﻫﺪي از اﻓﺰاﻳﺶ ﻓﻌﺎﻟﻴﺖ اﻧﺪوﺗﻠﻴﺎل و اﺧﺘﻼل
ﺳﻮﺑﺴﺘﺮا )ﻫﻮﻣﻮﺳﻴﺴـﺘﺌﻴﻦ( ﻣـﻲ ﮔـﺮدد و ﺧﻄـﺮ ﮔﺴـﺘﺮش
ﻋﻤﻠﻜﺮد ﻋﺮوﻗﻲ وﺟﻮد دارد ).(7
ﻣﻴﮕﺮن و دﻳﮕﺮ ﺑﻴﻤﺎريﻫﺎي ﻋﺮوﻗﻲ را اﻓﺰاﻳﺶ ﻣﻲدﻫﺪ.
ژن ﻣﺘﻴﻠﻦ ﺗﺘﺮاﻓﻮﻻت ردوﻛﺘﺎز ﻳﺎ MTHFR: EC:1.5.1.2
ﻣﺎ در اﻳﻦ ﻣﻄﺎﻟﻌﻪ ﺑﻪ ﺑﺮرﺳـﻲ ارﺗﺒـﺎط ﭘﻠـﻲﻣﻮرﻓﻴﺴـﻢ
،(Methylenetetrahydrofolateدر
ژﻧﺘﻴﻜـــﻲ C677Tدر ژن MTFHRو ﻣﻴﮕـــﺮن در دو
ﻧﺎﺣﻴﻪ ي ژﻧـﻲ 1p36.3ﻗـﺮار ﮔﺮﻓﺘـﻪ اﺳـﺖ و ﻣﺤﺼـﻮل
ﮔﺮوه اﻓﺮاد ﻣﺒﺘﻼ ﺑﻪ ﻣﻴﮕـﺮن و اﻓـﺮاد ﺳـﺎﻟﻢ در ﺟﻤﻌﻴـﺖ
ﭘﺮوﺗﺌﻴﻨــﻲ آن آﻧــﺰﻳﻢ دﺧﻴــﻞ در ﻣﺘﺎﺑﻮﻟﻴﺴــﻢ ﻓــﻮﻻت و
اﻳﺮاﻧﻲ ﭘﺮداﺧﺘﻴﻢ.
)reductase
ﻣﺴﺆول ﺗﻮﻟﻴـﺪ -5ﻣﺘـﻴﻠﻦ ﺗﺘﺮاﻫﻴـﺪروﻓﻮﻻت از 5و 10 ﻣﺘﻴﻠﻦ ﺗﺘﺮاﻫﻴﺪروﻓﻮﻻت ﻣﻲ ﺑﺎﺷـﺪ ﻛـﻪ ﻓـﺮم ﻏﺎﻟـﺐ و در
روشﻫﺎ
ﮔــﺮدش ﻓــﻮﻻت و دﻫﻨــﺪهي ﻛــﺮﺑﻦ در رﻳﻤﺘﻴﻼﺳــﻴﻮن
اﻳﻦ ﺗﺤﻘﻴﻖ ﻳﻚ ﻣﻄﺎﻟﻌﻪ ي ﻣـﻮرد -ﺷـﺎﻫﺪي ﺑـﻮد ﻛـﻪ ﺑـﺎ
1936
ﻣﺠﻠﻪ داﻧﺸﻜﺪه ﭘﺰﺷﻜﻲ اﺻﻔﻬﺎن – ﺳﺎل / 30ﺷﻤﺎره /214ﻫﻔﺘﻪ ﭼﻬﺎرم دي 1391 www.mui.ac.ir
ﭘﻠﻲﻣﻮرﻓﻴﺴﻢ ژﻧﺘﻴﻜﻲ C677Tدر ژن MTHFRدر ﺑﻴﻤﺎران ﻣﺒﺘﻼ ﺑﻪ ﻣﻴﮕﺮن
ﻛﺎﻣﻴﺎر ﻫﻤﺖ و ﻫﻤﻜﺎران
ﻫﺪف ﺗﻌﻴﻴﻦ ارﺗﺒﺎط ﭘﻠﻲ ﻣﻮرﻓﻴﺴﻢ ژﻧﺘﻴﻜـﻲ C677Tدر
ﭘﻠﻲﻣﻮرﻓﻴﺴﻢ C677Tﻣﻲﺑﺎﺷـﺪ ،ﺑـﺎ اﺳـﺘﻔﺎده از ﺗﻜﻨﻴـﻚ
ژن MTHFRدر ﺑﻴﻤﺎران ﻣﺒﺘﻼ ﺑﻪ ﻣﻴﮕﺮن اﻧﺠـﺎم ﺷـﺪ.
PCRﺗﻜﺜﻴﺮ ﻛﺮدﻳﻢ .ﺑﺮاي اﻳﻦ ﻛﺎر از ﭘﺮاﻳﻤﺮﻫـﺎي رﻓـﺖ
ﻧﻤﻮﻧﻪ ﻫﺎ از ﺑﻴﻦ ﺑﻴﻤﺎراﻧﻲ ﻛـﻪ ﺑـﺎ ﻋﻼﻳـﻢ ﺳـﺮ درد ﻳـﻚ
' 5’-TGAAGGAGAAGGTGTCTGCGGGA-3و
ﻃﺮﻓﻪ و ﺿﺮﺑﺎن دار ﻫﻤﺮاه ﺑﺎ ﺗﻬـﻮع ،اﺳـﺘﻔﺮاغ ،ﺗـﺮس از
ﺑﺮﮔﺸﺖ '5’-AGGACGGTGCGGTGAGAGTG-3
ﻧﻮر و اﺣﺴﺎس ﺧﺴﺘﮕﻲ ﺑﻪ درﻣﺎﻧﮕﺎه اﻋﺼﺎب ﺑﻴﻤﺎرﺳﺘﺎن
اﺳﺘﻔﺎده ﺷﺪ.
اﻟﺰﻫﺮا )س( ﻣﺮاﺟﻌﻪ ﻛﺮده ﺑﻮدﻧﺪ و ﺗﻮﺳـﻂ ﻣﺘﺨﺼﺼـﻴﻦ
ﻣﺨﻠﻮط اﺳﺘﻔﺎده ﺷﺪه ﺑﺮاي PCRﺷـﺎﻣﻞ 20ﻧـﺎﻧﻮﮔﺮم
داﺧﻠـــﻲ اﻋﺼـــﺎب ﺑـــﺮ اﺳـــﺎس ﻛﺮاﻳﺘﺮﻳـــﺎ ICHD-2
از DNAﻧﻤﻮﻧﻪ 0/5 ،ﻣﻴﻠﻲﻟﻴﺘﺮ از ﭘﺮاﻳﻤﺮﻫﺎ ﺑـﺎ ﻏﻠﻈـﺖ 10
) (International headache classificationﺑﺮاي آنﻫﺎ
ﻣﻴﻜﺮوﻣﻮل 10 ،ﻣﻴﻜﺮوﻟﻴﺘﺮ Type-it HRM Master Mix
ﻣﻴﮕﺮن ﻛﻼﺳـﻴﻚ )ﺑـﺎ (Euraﻳـﺎ ﻣﻴﮕـﺮن ﺷـﺎﻳﻊ )ﺑـﺪون
و 10ﻣﻴﻜﺮوﻟﻴﺘﺮ آب ﺑﻮد .واﻛﻨﺶ PCRدر ﺳـﻪ ﻣﺮﺣﻠـﻪ
(Euraﺗﺸﺨﻴﺺ داده ﺷﺪ ،اﻧﺘﺨﺎب ﺷﺪﻧﺪ 102 .ﻧﻔـﺮ ﺑـﻪ
اﻧﺠﺎم ﺷﺪ .اﺑﺘﺪا ﻳﻚ دﻗﻴﻘﻪ در 94درﺟـﻪ ي ﺳـﺎﻧﺘﻲ ﮔـﺮاد
ﻋﻨﻮان ﮔﺮوه ﻣﻮرد و 103ﻧﻔـﺮ از اﻓـﺮادي ﻛـﻪ ﻣﺒـﺘﻼ ﺑـﻪ
ﺳﭙﺲ 60ﺛﺎﻧﻴﻪ در 84درﺟﻪ ي ﺳﺎﻧﺘﻲ ﮔﺮاد 60 ،ﺛﺎﻧﻴـﻪ در
ﻣﻴﮕﺮن ﻧﺒﻮدﻧﺪ ،ﺑﻪ ﻋﻨﻮان ﮔـﺮوه ﺷـﺎﻫﺪ اﻧﺘﺨـﺎب ﺷـﺪﻧﺪ.
72درﺟــﻪي ﺳــﺎﻧﺘﻲﮔــﺮاد و در ﻧﻬﺎﻳــﺖ ﭘــﻨﺞ دﻗﻴﻘــﻪ در
ﺳﻦ ،ﺟﻨﺲ ،وﺿﻌﻴﺖ اﻗﺘﺼﺎدي -اﺟﺘﻤﺎﻋﻲ در دو ﮔـﺮوه
72درﺟﻪي ﺳﺎﻧﺘﻲﮔـﺮاد داﺧـﻞ Thermo cyclerاﻧﺠـﺎم
ﻫﻤﺴﺎن ﺑﻮد .ﺑﺮاي اﻓﺮاد ﻣﻮرد ﻣﻄﺎﻟﻌﻪ ﻳﻚ ﭼـﻚ ﻟﻴﺴـﺖ
ﺷﺪ .اﻳﻦ ﭼﺮﺧﻪ 40ﻣﺮﺗﺒـﻪ ﺗﻜـﺮار ﮔﺮدﻳـﺪ .ﺑﻌـﺪ از ﭘﺎﻳـﺎن
ﺷﺎﻣﻞ اﻃﻼﻋﺎت ﻣﺮﺑﻮط ﺑﻪ ﺳـﻦ ،ﺟـﻨﺲ ،ﺷـﻐﻞ ،ﻣـﺪت
PCRﺑــﺮاي ﺗﻌﻴــﻴﻦ ﻧــﻮع اﻟــﻞ Aو Gاز روش HRM
زﻣﺎن اﺑﺘﻼ ،ﻋﻼﻳﻢ ﻣﻴﮕﺮن ،ﻧﻮع ﻣﻴﮕﺮن ،دو ﻃﺮﻓﻪ ﻳﺎ ﻳـﻚ
اﺳﺘﻔﺎده ﺷﺪ.
ﻃﺮﻓﻪ ﺑﻮدن ﺳﺮ درد ﺗﻜﻤﻴﻞ ﺷﺪ .از ﻫﺮ دو ﮔﺮوه ﭘـﺲ از
دادهﻫـﺎ وارد ﻧــﺮماﻓـﺰار آﻣــﺎري SPSSﻧﺴــﺨﻪي 18
ﮔﺮﻓﺘﻦ رﺿﺎﻳﺖ ﻧﺎﻣﻪ ﺟﻬﺖ ﺷﺮﻛﺖ در ﻃﺮح ﺗﺤﻘﻴﻘﺎﺗﻲ ﺑﻪ
) (version 18, SPSS Inc., Chicago, ILﺷﺪ و ﺗﻮﺳﻂ
ﻣﻴــﺰان 2ﺳــﻲﺳــﻲ ﺧــﻮن ﺟﻬــﺖ اﺳــﺘﺨﺮاج DNAاز
آزﻣﻮنﻫﺎي χ2و Logistic regressionﺗﺠﺰﻳﻪ و ﺗﺤﻠﻴـﻞ
ﻟﻜﻮﺳﻴﺖ ﻫﺎ ﮔﺮﻓﺘﻪ ﺷﺪ .ﻧﻤﻮﻧﻪ ي ﺧـﻮن ﮔﺮﻓﺘـﻪ ﺷـﺪه در
ﮔﺮدﻳﺪ .ﺑﺮاي ﺑﺮرﺳﻲ اﻳﻦ ﻛﻪ آﻳـﺎ ژﻧﻮﺗﻴـﭗ ﻣـﻮرد ﻧﻈـﺮ از
ﻟﻮﻟﻪ ﻫﺎي ﺣﺎوي EDTAذﺧﻴﺮه و ﺗـﺎ زﻣـﺎن اﺳـﺘﻔﺎده در
ﺗﻌﺎدل Hardy-Weinbergﭘﻴﺮوي ﻣﻲ ﻛﻨﺪ ،ﺗﺴـﺖ آﻣـﺎري
-20درﺟﻪي ﺳﺎﻧﺘﻲﮔﺮاد ﻧﮕﻬﺪاري ﺷﺪ.
χ2اﺳــﺘﻔﺎده ﺷــﺪ و وﺟــﻮد راﺑﻄــﻪي ﺑــﻴﻦ ﭘﻠــﻲﻣﻮرﻓﻴﺴــﻢ
ﺑـــﺮاي اﺳـــﺘﺨﺮاج DNAاز ﻛﻴـــﺖ اﺳـــﺘﺨﺮاج
C677Tو ﻣﻴﮕﺮن ﺑﺎ اﺳـﺘﻔﺎده از Logistic regressionو
Bio Genetﺳﺎﺧﺖ ﻛﺸـﻮر ﻛـﺮه اﺳـﺘﻔﺎده ﺷـﺪ .ﺗﻌﻴـﻴﻦ
ﺑﺎ ﻣﺤﺎﺳﺒﻪي ﻧﺴﺒﺖ ﺷـﺎﻧﺲ ) (ORﺑـﺎ ﻓﺎﺻـﻠﻪي اﻃﻤﻴﻨـﺎن
ﭘﻠــﻲﻣﻮرﻓﻴﺴــﻢ ژﻧﺘﻴﻜــﻲ C677Tدر ژن MTHFRﺑــﺎ
95درﺻﺪ ) (CI 95%ﻣﻮرد ﺑﺮرﺳﻲ ﻗﺮار ﮔﺮﻓﺖ .در ﺗﻤﺎم
اﺳـــﺘﻔﺎده از ﺗﻜﻨﻴـــﻚ time PCR HRM
Real
آﻧﺎﻟﻴﺰﻫﺎ ﻣﻴﺰان P < 0/05ﻣﻌﻨﻲدار در ﻧﻈﺮ ﮔﺮﻓﺘﻪ ﺷﺪ.
) Polymerase chain reaction-High resolution
(meltingﺑﺮرﺳﻲ ﺷﺪ.
ﻳﺎﻓﺘﻪﻫﺎ
ﺑﺮاي ﺗﻌﻴﻴﻦ ﭘﻠﻲﻣﻮرﻓﻴﺴﻢ ژﻧﺘﻴﻜـﻲ ،C677Tﻗﺴـﻤﺖ
در اﻳﻦ ﻣﻄﺎﻟﻌﻪ ﻓﺮاواﻧـﻲ ژﻧـﻮﺗﻴﭙﻲ C677Tدر دو ﮔـﺮوه
داراي 198ﺟﻔــﺖ ﺑــﺎز از ژن MTHFRرا ﻛــﻪ داراي
ﻣﺒــﺘﻼ ﺑــﻪ ﻣﻴﮕــﺮن و ﺳــﺎﻟﻢ ﺑــﺎ اﺳــﺘﻔﺎده از PCR-HRM
ﻣﺠﻠﻪ داﻧﺸﻜﺪه ﭘﺰﺷﻜﻲ اﺻﻔﻬﺎن – ﺳﺎل / 30ﺷﻤﺎره /214ﻫﻔﺘﻪ ﭼﻬﺎرم دي 1391 www.mui.ac.ir
1937
ﭘﻠﻲﻣﻮرﻓﻴﺴﻢ ژﻧﺘﻴﻜﻲ C677Tدر ژن MTHFRدر ﺑﻴﻤﺎران ﻣﺒﺘﻼ ﺑﻪ ﻣﻴﮕﺮن
ﻛﺎﻣﻴﺎر ﻫﻤﺖ و ﻫﻤﻜﺎران
ﻣﺸﺨﺺ ﮔﺮدﻳﺪ .ﻛﻞ اﻓﺮاد ﻣﻮرد ﻣﻄﺎﻟﻌﻪ 203ﻧﻔﺮ ﺑﻮدﻧـﺪ
ﺧﺎص ﻣﻤﻜﻦ اﺳﺖ روي ﺑﻴﻤـﺎري ﻫـﺎ و راﺑﻄـﻪ ي آن ﻫـﺎ
ﻛﻪ 102ﻧﻔﺮ آن ﻫﺎ ﻣﺒـﺘﻼ ﺑـﻪ ﻣﻴﮕـﺮن و 101ﻧﻔـﺮ ﺳـﺎﻟﻢ
ﻣﺆﺛﺮ ﺑﺎﺷﻨﺪ ﻣﻨﻄﻘﻲ ﺑﻪ ﻧﻈﺮ ﻣـﻲ رﺳـﺪ .ﺗـﺎﻛﻨﻮن ﻣﻄﺎﻟﻌـﺎت
ﺑﻮدﻧﺪ .دو ﮔﺮوه ﺑﻴﻤﺎر و ﺳـﺎﻟﻢ از ﻟﺤـﺎظ ﺳـﻦ و ﺟـﻨﺲ
زﻳﺎدي راﺑﻄﻪي ﻣﺜﺒﺘﻲ ﺑﻴﻦ ژنﻫـﺎي ﻛﺎﻧﺪﻳـﺪ و ﻣﻴﮕـﺮن را
اﺧﺘﻼف ﻣﻌﻨﻲداري ﻧﺪاﺷﺘﻨﺪ )ﺟﺪول .(1
ﻧﺸﺎن دادهاﻧﺪ.
ﻓﺮاواﻧﻲ ژﻧﻮﺗﻴﭗ TTدر ﮔﺮوه ﺳـﺎﻟﻢ 5/9درﺻـﺪ و
ﺑــﻪ ﻃــﻮر ﺑﺮﺟﺴــﺘﻪ ﻧﺸــﺎن داده ﺷــﺪه اﺳــﺖ ﻛــﻪ
در ﮔــﺮوه ﺑﻴﻤــﺎر 3/9درﺻــﺪ ﺑــﻮد ،اﻣــﺎ اﻳــﻦ اﺧــﺘﻼف
ﭘﻠﻲﻣﻮرﻓﻴﺴـﻢﻫـﺎي ،(Dopamine 2 receptor) DRD2
ﻣﻌﻨ ـﻲدار ﻧﺒــﻮد )،CI95%: 0/188-2/362 ،P = 0/530
beta-hydroxylase) DBH
(Dopaminو INSR
.(OR = 0/667ﻓﺮاواﻧﻲ زﻧﻮﺗﻴﭗ ﻫﺎ در دو ﮔﺮوه ﻣﻮرد و
) ،(Insulin receptorدر اﺳﺘﻌﺪاد اﺑﺘﻼ ﺑﻪ ﻣﻴﮕـﺮن ﻧﻘـﺶ
ﺷﺎﻫﺪ در اﻳﻦ ﻣﻄﺎﻟﻌﻪ اﺧـﺘﻼف ﻣﻌﻨـﻲداري ﻧﺸـﺎن ﻧـﺪاد
دارﻧﺪ ).(15-16
)ﺟـــﺪول .(2ﻫﻤﭽﻨـــﻴﻦ ژﻧﻮﺗﻴـــﭗ C677Tاز ﺗﻌـــﺎدل
ﻋــﻼوه ﺑــﺮ اﺧــﺘﻼﻻت ﻧﻮروﻟــﻮژﻳﻜﻲ ،ﺑــﻪ ﻟﺤــﺎظ
Hardy-Weinbergﭘﻴﺮوي ﻣﻲﻛﺮد )،d = 2 ،χ2 = 0/476
ﭘﺎﺗﻮﻓﻴﺰﻳﻠﻮژﻳﻜﻲ ﻣﻲﺗﻮان ﮔﻔﺖ ﻣﻴﮕﺮن در اﺛـﺮ ﺗﻐﻴﻴـﺮ در
.(P = 0/790
ﻛﺸﺶ رگﻫﺎ و ﺗﻐﻴﻴﺮ در ﺟﺮﻳﺎن ﺧﻮن ﻣﻐﺰي ﺑـﻪ وﺟـﻮد ﻣﻲآﻳﺪ ) .(17از اﻳـﻦ رو ،ﻣﻜﺎﻧﻴﺴـﻢﻫـﺎي ﻣﻮﻟﻜـﻮﻟﻲ ﻛـﻪ
ﺑﺤﺚ
ﻧﻘﺶ ﻛﺎرﺑﺮدي در اﻧﺪوﺗﻠﻴﺎل رگ ﻫﺎ دارﻧﺪ ﺑﺎﻳﺪ ﺑﻪ ﻋﻨـﻮان
ﻣﻴﮕﺮن ﺑﻪ ﻋﻨﻮان ﻓﻨﻮﺗﻴﭙﻲ از اﺧﺘﻼﻻت ﭘﻠﻲ ژﻧـﻲ در ﻧﻈـﺮ
ﻳﻜﻲ از ﻣﻮارد ﻛﻠﻴﺪي در اﺳﺘﻌﺪاد اﺑﺘﻼ ﺑﻪ ﻣﻴﮕﺮن در ﻧﻈﺮ
ﮔﺮﻓﺘﻪ ﻣﻲ ﺷﻮد ﻛﻪ ﻣﻨﻌﻜﺲ ﻛﻨﻨﺪهي اﺛـﺮ ﭼﻨـﺪﻳﻦ ﺟﺎﻳﮕـﺎه
ﮔﺮﻓﺘﻪ ﺷﻮﻧﺪ .ﻧﺸﺎن داده ﺷﺪه اﺳﺖ ﻛـﻪ اﻓـﺰاﻳﺶ ﻣﻴـﺰان
ژﻧﻲ ﻛﻪ ﻓﺮاﻳﻨﺪ ﻫﺎي ﭘﺎﺗﻮﻓﻴﺰﻳﻮﻟﻮژﻳﻜﻲ ﻣﺘﻔﺎوﺗﻲ را ﺗﻌـﺪﻳﻞ
ﻫﻤﻮﺳﻴﺘﺌﻴﻦ ﻣﻮﺟﻮد در ﮔﺮدش ﺧﻮن ﺑﺎﻋـﺚ آﺳـﻴﺐ ﺑـﻪ
ﻣﻲﻛﻨﺪ ،ﻣﻲ ﺑﺎﺷﺪ .ﺑﻨﺎﺑﺮاﻳﻦ اﻳﻦ ﻓﺮﺿﻴﻪ ﻛﻪ ﺑﻌﻀﻲ ژن ﻫﺎي
ﺳﻠﻮلﻫﺎ ﻣﻲﺷﻮد ).(18
ﺟﺪول .1اﻃﻼﻋﺎت دﻣﻮﮔﺮاﻓﻴﻚ ﺑﻴﻤﺎران و اﻓﺮاد ﺳﺎﻟﻢ ﻣﻮرد ﻣﻄﺎﻟﻌﻪ
ﺳﻦ )ﺳﺎل( ﺟﻨﺲ
*
ﻣﺒﺘﻼﻳﺎن ﺑﻪ ﻣﻴﮕﺮن
اﻓﺮاد ﺳﺎﻟﻢ
ﻣﻘﺪار P
34/080 ± 9/737
34/77 ± 10/30
0/64
**
زن
)76 (82/6
)71 (78/0
ﻣﺮد
)16 (17/4
)20 (22/0
0/27
* :اﻧﺤﺮاف ﻣﻌﻴﺎر ±ﻣﻴﺎﻧﮕﻴﻦ **) :درﺻﺪ( ﺗﻌﺪاد
ﺟﺪول .2ارﺗﺒﺎط ﺑﻴﻦ ﭘﻠﻲﻣﻮرﻓﻴﺴﻢ ژﻧﺘﻴﻜﻲ C677Tو ﺑﻴﻤﺎري ﻣﻴﮕﺮن ﻣﺒﺘﻼﻳﺎن ﺑﻪ ﻣﻴﮕﺮن
اﻓﺮاد ﺳﺎﻟﻢ
OR
CC
)57 (55/9
)54 (53/5
1/000
ژﻧﻮﺗﻴﭗ
CI 95%
ﻣﻘﺪار P
CT
)41 (40/2
)41 (40/6
1/056
0/728-1/532
0/776
TT
)4 (3/9
)6 (5/9
0/667
0/188-2/362
0/530
1938
ﻣﺠﻠﻪ داﻧﺸﻜﺪه ﭘﺰﺷﻜﻲ اﺻﻔﻬﺎن – ﺳﺎل / 30ﺷﻤﺎره /214ﻫﻔﺘﻪ ﭼﻬﺎرم دي 1391 www.mui.ac.ir
ﭘﻠﻲﻣﻮرﻓﻴﺴﻢ ژﻧﺘﻴﻜﻲ C677Tدر ژن MTHFRدر ﺑﻴﻤﺎران ﻣﺒﺘﻼ ﺑﻪ ﻣﻴﮕﺮن
ﻛﺎﻣﻴﺎر ﻫﻤﺖ و ﻫﻤﻜﺎران
ﻳﻚ ﻣﻄﺎﻟﻌﻪ ي ﻣﺘﺎآﻧﺎﻟﻴﺰي ﻛﻪ ﺑﻪ ﺗـﺎزﮔﻲ اﻧﺠـﺎم ﺷـﺪه
TTو ﻣﻴﮕﺮن ﺑـﻪ ﺧﺼـﻮص ﻣﻴﮕـﺮن ﺑـﺎ Euraرا ﻧﺸـﺎن
اﺳﺖ ،ﻧﺸﺎن ﻣﻲ دﻫﺪ ﻛﻪ ﻣﻴـﺰان ﺑـﺎﻻﻳﻲ از ﻫﻤﻮﺳﻴﺴـﺘﺌﻴﻦ
دادﻧﺪ ) .(23-25ﻫﻤﭽﻨﻴﻦ در ﻣﻄﺎﻟﻌﻪ ي دﻳﮕﺮي ﻛﻪ اﻧﺠﺎم
ﻣﻲ ﺗﻮاﻧﺪ ﺑﻪ ﻋﻨﻮان ﻳﻚ ﻋﺎﻣﻞ ﺧﻄﺮ ﻫﻢ ﺑﺮاي ﺑﻴﻤﺎري ﻫﺎي
ﺷــﺪ ،ارﺗﺒــﺎط ﻣﻌﻨــﻲداري ﺑــﻴﻦ آﻟــﻞ C677Tدر ژن
ﻗﻠﺒﻲ و ﻫﻢ ﻣﻐﺰي ﺑﺎﺷﺪ و ﭘﻴﺸﻨﻬﺎد ﻣـﻲﻛﻨـﺪ ﻛـﻪ ﻛـﺎﻫﺶ
MTHFRو ﻣﻴﮕﺮن ﺑﺎ Euraدر ﺑﻴﻤﺎران اﻓﺴـﺮده ﻧﺸـﺎن
ﻣﻘﺪار ﻫﻤﻮﺳﻴﺴـﺘﺌﻴﻦ ﺑـﻪ وﺳـﻴﻠﻪ ي ﻳـﻚ رژﻳـﻢ ﻏـﺬاﻳﻲ
داده ﺷﺪ ).(26
ﺳــﺎدهي ﻓــﻮﻻت ﻣــﻲﺗﻮاﻧــﺪ ﺧﻄــﺮ ﺑﻴﻤــﺎريﻫــﺎي
در ﻧﻬﺎﻳﺖ ﺑﺎ ﺗﻮﺟﻪ ﺑﻪ ﻣﻄﺎﻟﻌﻪ ﻫﺎي ﻗﺒﻠﻲ در اﻳﻦ زﻣﻴﻨﻪ
ﻗﻠﺒــﻲ -ﻋﺮوﻗــﻲ را ﻛــﺎﻫﺶ ﺑﺪﻫــﺪ ) .(19ﻫﻤﭽﻨــﻴﻦ
ﻛﻪ راﺑﻄﻪ ﻫﺎي ﻣﻌﻨﻲ داري ﺑـﺎ ﻣﻴﮕـﺮن ﺑـﺎ Euraرا ﻧﺸـﺎن
آزﻣﺎﻳﺸﺎت اﻧﺠﺎم ﺷﺪه روي ﻣﺪل ﺣﻴﻮاﻧﻲ ﭘﻴﺸﻨﻬﺎد ﻣﻲ ﻛﻨﺪ
دادهاﻧﺪ ،در ﻣﻄﺎﻟﻌﻪي ﻣﺎ ﻫـﻴﭻ ارﺗﺒـﺎط ﻣﻌﻨـﻲداري دﻳـﺪه
ﻫﻴﭙﺮﻫﻤﻮﺳﻴﺴﺘﺌﻴﻨﻤﻲ ﻣﻤﻜﻦ اﺳﺖ اﺣﺘﻤﺎل اﺑﺘﻼ ﺑﻪ ﻣﻴﮕﺮن
ﻧﺸﺪ و ﻓﺮاواﻧﻲ ﻫﻤﻮزﻳﮕﻮت TTدر ﮔﺮوه ﺑﻴﻤـﺎر ﺑﻴﺸـﺘﺮ
را ﺑﺎ اﻓـﺰاﻳﺶ ﺣﺴﺎﺳـﻴﺖ ﻋـﺮوق ﻣﻐـﺰي اﻓـﺰاﻳﺶ دﻫـﺪ
از ﺷﺎﻫﺪ ﻧﺒﻮد.
) .(20ﻋﻼوه ﺑﺮ اﻳﻦ ،ﻣﻘﺎدﻳﺮ ﺑﺎﻻي ﻫﻤﻮﺳﻴﺘﺌﻴﻦ در اﻓـﺮاد
در ﻣﻄﺎﻟﻌﻪ ي ﻣﺎ ﺑﻪ دﻟﻴـﻞ ﻣﺤـﺪودﻳﺖ ﺗﻌـﺪاد ﻧﻤﻮﻧـﻪ،
ﻣﺒﺘﻼ ﺑـﻪ ﻣﻴﮕـﺮن ﺑـﺎ Euraﮔـﺰارش ﺷـﺪه اﺳـﺖ ).(21
ﺗﻌﺪاد اﻓﺮاد ﻣﺒﺘﻼ ﺑﻪ ﻣﻴﮕﺮن ﺑﺎ Euraﺑﺴﻴﺎر ﻧﺎدر ﺑﻮد و ﺑﻪ
ﻣﻄﺎﻟﻌﻪي دﻳﮕﺮي ﻧﺸﺎن داده اﺳﺖ ﻛﻪ اﻟـﻞ 677Tدر ژن
ﻫﻤﻴﻦ دﻟﻴﻞ اﻣﻜﺎن اﻳﻦ ﻛﻪ ﺑﺘﻮان اﻳﻦ ﭘﻠﻲ ﻣﻮرﻓﻴﺴﻢ را ﺑـﻪ
MTHFRﺑﻪ ﻃﻮر ﻣﺴﺘﻘﻴﻢ ﺑﺎ ﻛـﺎﻫﺶ ﻓﻌﺎﻟﻴـﺖ آﻧـﺰﻳﻢ و
ﺗﻨﻬﺎﻳﻲ در ﻣﻴﮕﺮن ﻫـﺎي ﺑـﺎ Euraﺑﺮرﺳـﻲ ﻛـﺮد ،وﺟـﻮد
ژﻧﻮﺗﻴــﭗ ﻫﻤﻮزﻳﮕــﻮت TTﺑــﻪ ﻃــﻮر ﻏﻴــﺮ ﻣﺴــﺘﻘﻴﻢ ﺑــﺎ
ﻧﺪاﺷﺖ.
ﻫﻴﭙﺮﻫﻤﻮﺳﻴﺴﺘﺌﻴﻨﻤﻲ در ارﺗﺒﺎط اﺳﺖ و ﻓﺮد را ﺑﻪ ﺳـﻤﺖ اﺑﺘﻼ ﺑﻴﻤﺎريﻫﺎي ﻋﺮوﻗﻲ ﻫﺪاﻳﺖ ﻣﻲﻛﻨﺪ ).(10
اﻳﻦ ﻣﻄﺎﻟﻌﻪ ،اوﻟـﻴﻦ ﻣﻄﺎﻟﻌـﻪاي ﺑـﻮد ﻛـﻪ ﺑـﻪ ﺑﺮرﺳـﻲ ﻓﺮاواﻧﻲ اﻳﻦ ﭘﻠﻲ ﻣﻮرﻓﻴﺴﻢ در ﺟﻤﻌﻴﺖ اﻳﺮاﻧﻲ ﭘﺮداﺧـﺖ.
در اﻳﻦ ﻣﻄﺎﻟﻌﻪ ﻣـﺎ ﻓﺮاواﻧـﻲ اﻟـﻞ 677Tرا دو ﮔـﺮوه
ﭘﻴﺸﻨﻬﺎد ﻣﻲﺷﻮد ﻳﻚ ﻣﻄﺎﻟﻌﻪ ي ﻣﺸﺎﺑﻪ ﺑﺎ ﺗﻌـﺪاد ﻧﻤﻮﻧـﻪ ي
اﻓﺮاد ﻣﺒﺘﻼ ﺑﻪ ﻣﻴﮕﺮن و اﻓﺮاد ﺳﺎﻟﻢ ﺑﺎ ﻫﻢ ﻣﻘﺎﻳﺴﻪ ﻛـﺮدﻳﻢ
ﺑﻴﺸﺘﺮ اﻧﺠﺎم ﺷﻮد ،ﻫﻤﭽﻨﻴﻦ ﻣﻮارد اﺑﺘﻼ ﺑـﻪ ﻣﻴﮕـﺮن ﺑـﺎ و
ﻛﻪ ﻫﻴﭻ اﺧﺘﻼف ﻣﻌﻨﻲ داري در اﻳﻦ دو ﮔﺮوه دﻳﺪه ﻧﺸﺪ.
ﺑﺪون Euraرا ﺟﺪاﮔﺎﻧﻪ ﺑﺮرﺳﻲ ﻛﻨﺪ.
در ﻣﻄﺎﻟﻌﻪ اي ﻛـﻪ ﺗﻮﺳـﻂ Leaو ﻫﻤﻜـﺎران اﻧﺠـﺎم ﺷـﺪ راﺑﻄﻪي ﻣﻌﻨﻲداري ﺑﻴﻦ ﭘﻠﻲﻣﻮرﻓﻴﺴﻢ C677Tو ﻣﻴﮕـﺮن
ﺗﺸﻜﺮ و ﻗﺪرداﻧﻲ
ﺑﺎ Euraدﻳﺪه ﺷﺪ ) .(22در اﻳﻦ ﻣﻄﺎﻟﻌﻪ ﻓﺮاواﻧﻲ ژﻧﻮﺗﻴﭗ
ﺑــﺎ ﺗﺸــﻜﺮ از زﺣﻤــﺎت ﺳــﺮﻛﺎر ﺧــﺎﻧﻢ ﻧﺴــﺮﻳﻦ ﺻــﺎﺑﺮي
TTدر ﮔﺮوه ﺑﻴﻤﺎران ﻣﺒـﺘﻼ ﺑـﻪ ﻣﻴﮕـﺮن ﺑﻴﺸـﺘﺮ از اﻓـﺮاد
ﺷﻬﺮﺑﺎﺑﻜﻲ ﻛﻪ در ﺗﻬﻴﻪ و ﺗﺪوﻳﻦ اﻳﻦ ﻣﻘﺎﻟـﻪ ﻣـﺎ را ﻳـﺎري
ﺳﺎﻟﻢ ﺑﻮد .ﭼﻨﺪﻳﻦ ﻣﻄﺎﻟﻌﻪ ارﺗﺒﺎط ﻣﻌﻨﻲ داري ﺑﻴﻦ ژﻧﻮﺗﻴﭗ
ﻧﻤﻮدﻧﺪ.
Zvan B. Associations between cerebral and systemic endothelial function in migraine ;patients: a post-hoc study. BMC Neurol 2011 11: 146. 4. Levy D, Burstein R, Strassman AM. Mast cell involvement in the pathophysiology of migraine ;headache: A hypothesis. Headache 2006
1. Brandes JL. Migraine in women. Continuum (Minneap Minn ) 2012; 18(4): 835-52. 2. Peterlin BL, Calhoun AH, Balzac F. Men, women, and migraine: the role of sex, hormones, obesity, and PTSD. J Fam Pract 2012; 61(4 Suppl): S7-11. 3. Perko D, Pretnar-Oblak J, Sabovic M, Zaletel M,
References
ﻣﺠﻠﻪ داﻧﺸﻜﺪه ﭘﺰﺷﻜﻲ اﺻﻔﻬﺎن – ﺳﺎل / 30ﺷﻤﺎره /214ﻫﻔﺘﻪ ﭼﻬﺎرم دي 1391 www.mui.ac.ir
1939
ﻛﺎﻣﻴﺎر ﻫﻤﺖ و ﻫﻤﻜﺎران
در ﺑﻴﻤﺎران ﻣﺒﺘﻼ ﺑﻪ ﻣﻴﮕﺮنMTHFR در ژنC677T ﭘﻠﻲﻣﻮرﻓﻴﺴﻢ ژﻧﺘﻴﻜﻲ
46(Suppl 1): S13-S18. 5. Dalkara T, Nozari A, Moskowitz MA. Migraine aura pathophysiology: the role of blood vessels and microembolisation. Lancet Neurol 2010; 9(3): 309-17. 6. Devor WN, Napoli R ,Sacca L. Vascular smooth muscle cell dysfunction in patients with migraine. Neurology 2010; 74(1): 94. 7. Tietjen GE, Herial NA, White L, Utley C, Kosmyna JM, Khuder SA. Migraine and biomarkers of endothelial activation in young women. Stroke 2009; 40(9): 2977-82. 8. Goyette P, Sumner JS, Milos R, Duncan AM, Rosenblatt DS, Matthews RG, et al. Human methylenetetrahydrofolate reductase: isolation of cDNA, mapping and mutation identification. Nat Genet 1994; 7(2): 195-200. 9. Heux S, Morin F, Lea RA ,Ovcaric M, Tajouri L, Griffiths LR. The methylentetrahydrofolate reductase gene variant (C677T) as a risk factor for essential hypertension in Caucasians. Hypertens Res 2004; 27(9): 663-7. 10. Frosst P, Blom HJ, Milos R, Goyette P, Sheppard CA, Matthews RG, et al. A candidate genetic risk factor for vascular disease: a common mutation in methylenetetrahydrofolate reductase. Nat Genet 1995; 10(1): 111-3. 11. Graham IM, O'Callaghan P. Vitamins, homocysteine and cardiovascular risk. Cardiovasc Drugs Ther 2002; 16(5): 383-9. 12. Hering-Hanit R, Friedman Z, Schlesinger I, Ellis M. Evidence for activation of the coagulation system in migraine with aura. Cephalalgia 2001; 21(2): 137-9. 13. Parsons AA, Strijbos PJ. The neuronal versus vascular hypothesis of migraine and cortical spreading depression. Curr Opin Pharmacol 2003; 3(1): 73-7. 14. Das UN. Folic acid says NO to vascular diseases. Nutrition 2003; 19(7-8): 686-92. 15. Peroutka SJ, Wilhoit T, Jones K. Clinical susceptibility to migraine with aura is modified by dopamine D2 receptor (DRD2) NcoI alleles. Neurology 1997; 49(1): 201-6. 16. Lea RA, Dohy A, Jordan K, Quinlan S, Brimage PJ, Griffiths LR. Evidence for allelic association of the dopamine beta-hydroxylase gene (DBH) with susceptibility to typical migraine.
Neurogenetics 2000; 3(1): 35-40. 17. Goadsby PJ. Current concepts of the pathophysiology of migraine. Neurol Clin 1997; 15(1): 27-42. 18. Harker LA, Ross R, Slichter SJ, Scott CR. Homocystine-induced arteriosclerosis .The role of endothelial cell injury and platelet response in its genesis. J Clin Invest 1976; 58(3): 731-41. 19. Mei W, Rong Y, Jinming L, Yongjun L, Hui Z. Effect of homocysteine interventions on the risk of cardiocerebrovascular events: a meta-analysis of randomised controlled trials. Int J Clin Pract 2010; 64(2): 208-15. 20. Storer RJ, Goadsby PJ. Microiontophoretic application of serotonin (5HT)1B/1D agonists inhibits trigeminal cell firing in the cat. Brain 1997; 120 (Pt 12): 2171-7. 21. Evers S, Koch HG, Grotemeyer KH, Lange B, Deufel T, Ringelstein EB. Features, symptoms, and neurophysiological findings in stroke associated with hyperhomocysteinemia. Arch Neurol 1997; 54(10): 1276-82. 22. Lea RA, Ovcaric M, Sundholm J, MacMillan J, Griffiths LR. The methylenetetrahydrofolate reductase gene variant C677T influences susceptibility to migraine with aura. BMC Med 2004; 2: 3. 23. . Oterino A, Valle N, Bravo Y, Munoz P, Sanchez-Velasco P, Ruiz-Alegria C, et al. MTHFR T677 homozygosis influences the presence of aura in migraineurs. Cephalalgia 2004; 24(6): 491-4. 24. Goyette P, Sumner JS, Milos R, Duncan AM, Rosenblatt DS, Matthews RG, et al. Human methylenetetrahydrofolate reductase: isolation of cDNA mapping and mutation identification. Nat Genet 1994; 7(4): 551. 25. Gilbody S, Lewis S, Lightfoot T. Methylenetetrahydrofolate reductase (MTHFR) genetic polymorphisms and psychiatric disorders: a HuGE review. Am J Epidemiol 2007; 165(1): 1-13. 26. Samaan Z, Gaysina D, Cohen-Woods S, Craddock N, Jones L, Korszun A, et al. Methylenetetrahydrofolate reductase gene variant (MTHFR C677T) and migraine: a case control study and meta-analysis. BMC Neurol 2011; 11: 66.
1391 ﻫﻔﺘﻪ ﭼﻬﺎرم دي/214 ﺷﻤﺎره/ 30 ﻣﺠﻠﻪ داﻧﺸﻜﺪه ﭘﺰﺷﻜﻲ اﺻﻔﻬﺎن – ﺳﺎل www.mui.ac.ir
1940
Journal of Isfahan Medical School
Original Article
Vol. 30, No. 214, 4th week, January 2013
Received: 7.9.2012
Accepted: 10.11.2012
Genetic Polymorphisms of C677T MTHFR Gene in Migraine Patients Compared with Controls Kamyar Hemat1, Shaghayegh Haghjooy Javanmard MD, PhD2, Mohammad Saadatnia MD3, Laleh Rafiee4, Alireza Zandifar1, Mohamadhasan Tajaddini5
Abstract Background: Migraine is considered the end phenotype of a number of polygenic disorders reflecting the influence of several genetic loci modulating different pathophysiological processes. It has been shown that the 677T allele in methylenetetrahydrofolate reductase (MTHFR) gene is directly correlated with decreased enzymatic activity, and the T/T genotype is indirectly associated with mild hyperhomocysteinaemia which possibly leads to vascular disease. In this case-control study we investigated the association between C677T MTHFR polymorphisms and migraine in an Iranian population. Methods: A total of 205 cases and controls were enrolled to the study. The MTHFR C677T variant was genotyped in 102 unrelated migraine cases and 103 controls by HRM-PCR technique. Findings: There was no significant association between C677T MTHFR polymorphism and migraine in our study. The frequency of TT genotype was not higher in case group compared with the controls (OR = 0.667, 95% CI: 0.188-2.362, P = 0.530). Conclusion: The C677T variant in the MTHFR gene did not influence susceptibility to migraine in our study population. A more reliable conclusion may be drawn from investigations with larger sample size and separated migraine groups, with and without aura. Keywords: Genetic polymorphism, Migraine disorders, Methylenetetrahydrofolate reductase
* This paper is derived from a medical doctorate thesis in Isfahan University of Medical Sciences. 1
Student of Medicine, School of Medicine AND Student Research Committee, Isfahan University of Medical Sciences, Isfahan, Iran Associate Professor, Physiology Research Center, Isfahan University of Medical Sciences, Isfahan, Iran Associate Professor, Neuroscience Research Center AND Department of Neurology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran 4 Physiology Research Center, Isfahan University of Medical Sciences, Isfahan, Iran 5 MSc Student, Physiology Research Center AND Department of Biochemistry, School of Pharmacy AND Isfahan Pharmaceutical Research Center, Isfahan University of Medical Sciences, Isfahan, Iran Corresponding Author: Mohamadhasan Tajaddini, Email:
[email protected] 2 3
1941
1391 ﻫﻔﺘﻪ ﭼﻬﺎرم دي/214 ﺷﻤﺎره/ 30 ﻣﺠﻠﻪ داﻧﺸﻜﺪه ﭘﺰﺷﻜﻲ اﺻﻔﻬﺎن – ﺳﺎل www.mui.ac.ir
