Heterozygote Genotypes at rs2222823 and rs2811712 SNP Loci are Associated with Cerebral Small Vessel Disease in Han Chinese Population

• Published in: CNS neuroscience & therapeutics Vol. 18; no. 7; pp. 558 - 565
• Main Authors: Li, Wei, Hu, Bo, Li, Gui-Lin, Zhao, Xing-Quan, Xin, Bao-Zhong, Lin, Jin-Xi, Shen, Yuan, Liang, Xian-Hong, Liu, Gai-Fen, Gao, Han-Qing, Liao, Xiao-Ling, Liang, Zhi-Gang, Wang, Yong-Jun
• Format: Journal Article
• Language: English
• Published: Oxford, UK Blackwell Publishing Ltd 01.07.2012; Wiley-Blackwell; John Wiley & Sons, Inc
• Subjects: Adult; Aged; Aging; Aquaporin 4; ARF protein; Arteries; Arteriosclerosis; Asian Continental Ancestry Group - genetics; Biological and medical sciences; Blood-brain barrier; Central nervous system; Cerebral small vessel disease; Cerebral Small Vessel Diseases - diagnosis; Cerebral Small Vessel Diseases - genetics; Cyclin-dependent kinase inhibitors; Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases; Diabetes mellitus; Drinking; Etiology; Female; Genes; Genetic Carrier Screening; Genome-wide association studies; Genome-Wide Association Study - methods; Genomes; Genotype; Genotypes; Headache. Facial pains. Syncopes. Epilepsia. Intracranial hypertension. Brain oedema. Cerebral palsy; Hemorrhage; Heterozygote genotype; Heterozygotes; Homozygotes; Hospitals; Humans; Hyperlipidemia; INK4 protein; Male; Medical sciences; Middle Aged; MYLK gene; Nervous system (semeiology, syndromes); Neurology; Original; Polymorphism, Single Nucleotide - genetics; rs2222823 and rs2811712; Single-nucleotide polymorphism; SNaPshot array; Stroke; Vascular diseases; Vascular diseases and vascular malformations of the nervous system; Heterozygote genotype; Central nervous system; Chinese; Genotype; Cerebral small vessel disease; SNaPshot array; Encephalon; rs2222823 and rs2811712
• ISSN: 1755-5930; 1755-5949; 1755-5949
• DOI: 10.1111/j.1755-5949.2012.00322.x

SUMMARY  Aims 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). Conclusion 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.