title: A comprehensive association analysis of homocysteine metabolic pathway genes in Singaporean Chinese with ischemic stroke.
abstract: BACKGROUND
  The effect of genetic factors, apart from 5,10-methylenetetrahydrofolate reductase (MTHFR) polymorphisms, on elevated plasma homocysteine levels and increasing ischemic stroke risk have not been fully elucidated. We conducted a comprehensive analysis of 25 genes involved in homocysteine metabolism to investigate association of common variants within these genes with ischemic stroke risk.
  
  
  RESULTS
  The study was done in two stages. In the initial study, SNP and haplotype-based association analyses were performed using 147 tagging Single Nucleotide Polymorphisms (SNPs) in 360 stroke patients and 354 non-stroke controls of Singaporean Chinese ethnicity. Joint association analysis of significant SNPs was then performed to assess the cumulative effect of these variants on ischemic stroke risk. In the replication study, 8 SNPs were selected for validation in an independent set of 420 matched case-control pairs of Singaporean Chinese ethnicity. SNP analysis from the initial study suggested 3 risk variants in the MTRR, SHMT1 and TCN2 genes which were moderately associated with ischemic stroke risk, independent of known stroke risk factors. Although the replication study failed to support single-SNP associations observed in the initial study, joint association analysis of the 3 variants in combined initial and replication samples revealed a trend of elevated risk with an increased number of risk alleles (Joint P(trend) = 1.2×10(-6)).
  
  
  CONCLUSIONS
  Our study did not find direct evidence of associations between any single polymorphisms of homocysteine metabolic pathway genes and ischemic stroke, but suggests that the cumulative effect of several small to moderate risk variants from genes involved in homocysteine metabolism may jointly confer a significant impact on ischemic stroke risk.
authors.affiliation: Human Genetics, Genome Institute of Singapore, Singapore.
authors.forename: Hui-Qi
authors.initials: HQ
authors.lastname: Low
authors.forename: Christopher P L H
authors.initials: CP
authors.lastname: Chen
authors.forename: Katherine
authors.initials: K
authors.lastname: Kasiman
authors.forename: Anbupalam
authors.initials: A
authors.lastname: Thalamuthu
authors.forename: Seok-Shin
authors.initials: SS
authors.lastname: Ng
authors.forename: Jia-Nee
authors.initials: JN
authors.lastname: Foo
authors.forename: Hui-Meng
authors.initials: HM
authors.lastname: Chang
authors.forename: Meng-Cheong
authors.initials: MC
authors.lastname: Wong
authors.forename: E-Shyong
authors.initials: ES
authors.lastname: Tai
authors.forename: Jianjun
authors.initials: J
authors.lastname: Liu
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D044466:Asian People; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics; D006239:Haplotypes / Q000235:genetics; D006710:Homocysteine / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D012846:Singapore / Q000453:epidemiology; D020521:Stroke / Q000453:epidemiology / Q000235:genetics* / Q000378:metabolism*
chemical_list: D006710:Homocysteine