Genome-wide association study of homocysteine levels in Filipinos provides evidence for CPS1 in women and a stronger MTHFR effect in young adults.
Plasma homocysteine (Hcy) 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 Hcy in 1786 unrelated Filipino women from the Cebu Longitudinal Health and Nutrition Survey (CLHNS). The most strongly associated single-nucleotide polymorphism (SNP) (rs7422339, P = 4.7 x 10(-13)) encodes Thr1405Asn in the gene CPS1 and explained 3.0% of variation in the Hcy 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 1679 CLHNS young adult offspring. The MTHFR C677T SNP was strongly associated with Hcy (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 Hcy in the offspring (interaction P = 1.2 x 10(-5)). Furthermore, although 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 Hcy levels in women and suggest that genetic effects on Hcy may differ across developmental stages.
Lange
Leslie A
LA
Department of Genetics, University of North Carolina, Chapel Hill, NC 27599, USA.
Croteau-Chonka
Damien C
DC
Marvelle
Amanda F
AF
Qin
Li
L
Gaulton
Kyle J
KJ
Kuzawa
Christopher W
CW
McDade
Thomas W
TW
Wang
Yunfei
Y
Li
Yun
Y
Levy
Shawn
S
Borja
Judith B
JB
Lange
Ethan M
EM
Adair
Linda S
LS
Mohlke
Karen L
KL
D002222:Carbamoyl-Phosphate Synthase (Ammonia) / Q000235:genetics*; D002318:Cardiovascular Diseases / Q000235:genetics; D005260:Female; D005500:Follow-Up Studies; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006306:Health Surveys; D006710:Homocysteine / Q000097:blood*; D006801:Humans; D042965:Methylenetetrahydrofolate Reductase (NADPH2) / Q000235:genetics*; D009035:Mothers; D009749:Nutrition Surveys; D010679:Philippines; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D040641:Quantitative Trait Loci / Q000235:genetics; D015203:Reproducibility of Results; D055815:Young Adult
D006710:Homocysteine; D042965:Methylenetetrahydrofolate Reductase (NADPH2); D002222:Carbamoyl-Phosphate Synthase (Ammonia)