Genome-wide association study of homocysteine levels in Filipinos provides evidence for CPS1 in women and a stronger MTHFR effect in young adults.

Abstract

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.

• Authors: Leslie A Lange, Damien C Croteau-Chonka, Amanda F Marvelle, Li Qin, Kyle J Gaulton, Christopher W Kuzawa, Thomas W McDade, Yunfei Wang, Yun Li, Shawn Levy, Judith B Borja, Ethan M Lange, Linda S Adair, Karen L Mohlke
• Journal: Human molecular genetics (Hum Mol Genet) Vol. 19 Issue 10 Pg. 2050-8 (May 15 2010) ISSN: 1460-2083 [Electronic] England
• PMID: 20154341 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Homocysteine
• Methylenetetrahydrofolate Reductase (NADPH2)
• Carbamoyl-Phosphate Synthase (Ammonia)

Topics

• Carbamoyl-Phosphate Synthase (Ammonia) (genetics)
• Cardiovascular Diseases (genetics)
• Female
• Follow-Up Studies
• Genetic Predisposition to Disease
• Genome-Wide Association Study
• Health Surveys
• Homocysteine (blood)
• Humans
• Methylenetetrahydrofolate Reductase (NADPH2) (genetics)
• Mothers
• Nutrition Surveys
• Philippines
• Polymorphism, Single Nucleotide (genetics)
• Quantitative Trait Loci (genetics)
• Reproducibility of Results
• Young Adult