title: Heterozygote genotypes at rs2222823 and rs2811712 SNP loci are associated with cerebral small vessel disease in Han Chinese population.
abstract: OBJECTIVE
  With developments of etiology of cerebral small vessel disease (CSVD) and genome-wide association study (GWAS) of stroke, the genetic studies of CSVD are focused on genes related to blood-brain barrier (BBB) and aging. The project aims to investigate the association between CSVD and susceptibility loci and candidate genes.
  
  
  METHODS
  All study subjects admitted Beijing Tiantan Hospital from June 2009 to September 2010 including 197 cerebral small vessel disease patients(S), 198 large artery atherosclerosis control individuals (vascular stenotic rate ≥50% diameter reduction) (L), 200 hypertensive intracerebral hemorrhage control individuals (H) and 197 stroke-free control individuals (C). 15 SNPs in 4 genes (MYLK, AQP4, NINJ2, and INK4/ARF) were genotyped using Multiplex Snapshot assay. Each SNP was first examined between the groups S and C in different genetic models (codominant, dominant, recessive, overdominant, and log-additive). Permutation correction was used to adjust for multiple testing. The significant SNP loci were further analyzed in comparing S with L and H, respectively. Subgroup analysis was also performed for each risk-factor category.
  
  
  RESULTS
  Among the 15 SNPs, rs2222823 and rs2811712 were found to be significantly associated with CSVD after multiple-testing adjustment. The heterozygote (A/T) of rs2222823 of MYLK has an odds ratio of 0.52 (95% CI =[0.35, 0.79], P= 0.002, adjusted P= 0.031) when compared with homozygotes. The heterozygote (C/T) of rs2811712 of INK4/ARF has an odds ratio of 1.75 (95% CI =[1.13-2.71], P= 0.004, adjusted P= 0.050). The SNP rs2222823 was significant (P= 0.035) in comparing S with H. In comparing S versus L, it is significant for the subgroups of patients without diabetes (P= 0.012) and drinking (P= 0.018). rs2811712 was significant in comparing S with L for the subgroups of patients with hyperlipidemia (P= 0.029) and drinking (P= 0.04).
  
  
  CONCLUSIONS
  The heterozygotes (T/A) at the rs2222823 SNP locus of MYLK gene decreases the risk of having cerebral small vessel disease, while the heterozygotes (C/T) at the rs2811712 SNP locus of INK4/ARF gene increases the risk, suggesting that the MYLK and INK4/ARF are the associated genes of cerebral small vessel disease in Han Chinese population.
authors.affiliation: Department of Neurology, Beijing Tiantan Hospital, Capital Medical University, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Li
authors.forename: Bo
authors.initials: B
authors.lastname: Hu
authors.forename: Gui-Lin
authors.initials: GL
authors.lastname: Li
authors.forename: Xing-Quan
authors.initials: XQ
authors.lastname: Zhao
authors.forename: Bao-Zhong
authors.initials: BZ
authors.lastname: Xin
authors.forename: Jin-Xi
authors.initials: JX
authors.lastname: Lin
authors.forename: Yuan
authors.initials: Y
authors.lastname: Shen
authors.forename: Xian-Hong
authors.initials: XH
authors.lastname: Liang
authors.forename: Gai-Fen
authors.initials: GF
authors.lastname: Liu
authors.forename: Han-Qing
authors.initials: HQ
authors.lastname: Gao
authors.forename: Xiao-Ling
authors.initials: XL
authors.lastname: Liao
authors.forename: Zhi-Gang
authors.initials: ZG
authors.lastname: Liang
authors.forename: Yong-Jun
authors.initials: YJ
authors.lastname: Wang
mesh_terms: D000328:Adult; D000368:Aged; D044466:Asian People / Q000235:genetics*; D059345:Cerebral Small Vessel Diseases / Q000175:diagnosis / Q000235:genetics*; D005260:Female; D006580:Genetic Carrier Screening; D055106:Genome-Wide Association Study / Q000379:methods; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*