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Genome-Wide Association Study of Homocysteine Levels in Filipinos Provides Evidence for CPS1 in Women and a Stronger MTHFR Effect in Young Adults

Lange, Leslie A.; Croteau-Chonka, Damien C.; Marvelle, Amanda F.; Qin, Li; Gaulton, Kyle J.; Kuzawa, Christopher W.; McDade, Thomas W.; Wang, Yunfei; Li, Yun; Levy, Shawn; Borja, Judith B.; Lange, Ethan M.; Adair, Linda S.; & Mohlke, Karen L. (2010). Genome-Wide Association Study of Homocysteine Levels in Filipinos Provides Evidence for CPS1 in Women and a Stronger MTHFR Effect in Young Adults. Human Molecular Genetics, 19(10), 2050-8. PMCID: PMC2860887

Lange, Leslie A.; Croteau-Chonka, Damien C.; Marvelle, Amanda F.; Qin, Li; Gaulton, Kyle J.; Kuzawa, Christopher W.; McDade, Thomas W.; Wang, Yunfei; Li, Yun; Levy, Shawn; Borja, Judith B.; Lange, Ethan M.; Adair, Linda S.; & Mohlke, Karen L. (2010). Genome-Wide Association Study of Homocysteine Levels in Filipinos Provides Evidence for CPS1 in Women and a Stronger MTHFR Effect in Young Adults. Human Molecular Genetics, 19(10), 2050-8. PMCID: PMC2860887

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Plasma homocysteine level is associated with cardiovascular disease and may play an etiologic role in vascular damage, a precursor for atherosclerosis. We performed a genome-wide association study for homocysteine in 1,786 unrelated Filipino women from the Cebu Longitudinal Health and Nutrition Survey (CLHNS). The most strongly associated SNP (rs7422339, P = 4.7 x 10(-13)) encodes Thr1405Asn in the gene CPS1 and explained 3.0% of variation in homocysteine level. The widely studied MTHFR C677T SNP (rs1801133) was also highly significant (P = 8.7 x 10(-10)) and explained 1.6% of the trait variation. We also genotyped these two SNPs in 1,679 CLHNS young adult offspring. The MTHFR C677T SNP was strongly associated with homocysteine (P = 1.9 x 10(-26)) and explained approximately 5.1% of the variation in the offspring. In contrast, the CPS1 variant was significant only in females (P = 0.11 in all; P = 0.0087 in females). Combined analysis of all samples confirmed that the MTHFR variant was more strongly associated with homocysteine in the offspring (interaction P = 1.2 x 10(-5)). Furthermore, while there was evidence for a positive synergistic effect between the CPS1 and MTHFR SNPs in the offspring (interaction P = 0.0046), there was no significant evidence for an interaction in the mothers (P = 0.55). These data confirm a recent finding that CPS1 is a locus influencing homocysteine levels in women and suggests that genetic effects on homocysteine may differ across developmental stages.




JOUR



Lange, Leslie A.
Croteau-Chonka, Damien C.
Marvelle, Amanda F.
Qin, Li
Gaulton, Kyle J.
Kuzawa, Christopher W.
McDade, Thomas W.
Wang, Yunfei
Li, Yun
Levy, Shawn
Borja, Judith B.
Lange, Ethan M.
Adair, Linda S.
Mohlke, Karen L.



2010


Human Molecular Genetics

19

10

2050-8







10.1093/hmg/ddq062

PMC2860887


28