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Genetic Study of Cerebral Small Vessel Disease in Chinese Han Population.

ABSTRACT: Cerebral small vessel disease (CSVD) is a syndrome of clinical, neuroimaging, and neuropathological manifestations caused by disorders that affect small cerebral vessels. Although the pathogenesis of the disease remains unclear, some studies have demonstrated that genetic variants contribute to the development of CSVD. Our study aimed to explore the genetic characteristics of CSVD in the Chinese Han population. We enrolled 182 sporadic CSVD Chinese Han patients whose magnetic resonance imaging results showed grade 2-3 white matter lesions. Target region sequencing of seven monogenic CSVD-related genes, including NOTCH3, HTRA1, COL4A1, COL4A2, GLA, TREX1, and CTSA, was performed, and we identified pathogenic variants by screening the sequencing results and functional predictive analysis. All variants were predicted to be pathogenic by the SIFT Score, Polymorphism Phenotyping-2 score, Mutation Taster, Splice site score calculation, and MaxEntScan. All variants were validated in 300 healthy controls. In total, eight variants were identified in patients with CSVD, including five novel variants, c.1774C>T (NOTCH3), c.3784C>T (NOTCH3), c. 1207C>T (HTRA1), and c. 1274+1G> A (HTRA1), c.1937G>C (COL4A1) and three reported mutations. None of these variants were present in 300 healthy controls. No pathogenic variants in COL4A2, GLA, TREX1, and CTSA were detected. This study identified five novel variants in CSVD-related genes in Chinese Han patients with sporadic CSVD. Our results expand the genetic profile of CSVD.

SUBMITTER: Wang Y

PROVIDER: S-EPMC8990910 | biostudies-literature | 2022

REPOSITORIES: biostudies-literature

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Genetic Study of Cerebral Small Vessel Disease in Chinese Han Population.

Wang Yunchao Y Shi Changhe C Li Yusheng Y Yu Wenkai W Wei Sen S Fan Yu Y Mao Chengyuan C Yang Zhihua Z Yu Lulu L Zhao Zichen Z Li Shanshan S Gao Yuan Y Xu Yuming Y

Frontiers in neurology 20220325

Cerebral small vessel disease (CSVD) is a syndrome of clinical, neuroimaging, and neuropathological manifestations caused by disorders that affect small cerebral vessels. Although the pathogenesis of the disease remains unclear, some studies have demonstrated that genetic variants contribute to the development of CSVD. Our study aimed to explore the genetic characteristics of CSVD in the Chinese Han population. We enrolled 182 sporadic CSVD Chinese Han patients whose magnetic resonance imaging r ...[more]

PMID: 35401403

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Project description:AimsWith 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.MethodsAll 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.ResultsAmong 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).ConclusionThe 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.

Project description:ObjectiveCerebral small vessel diseases (SVDs) are associated with cerebrovascular dysfunction, such as increased blood-brain barrier leakage (permeability surface area product), vascular pulsatility, and decreased cerebrovascular reactivity (CVR). No studies assessed all 3 functions concurrently. We assessed 3 key vascular functions in sporadic and genetic SVD to determine associations with SVD severity, subtype, and interrelations.MethodsIn this prospective, cross-sectional, multicenter INVESTIGATE-SVDs study, we acquired brain magnetic resonance imaging in patients with sporadic SVD/cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), including structural, quantitative microstructural, permeability surface area product, blood plasma volume fraction, vascular pulsatility, and CVR (in response to CO2) scans. We determined vascular function and white matter hyperintensity (WMH) associations, using covariate-adjusted linear regression; normal-appearing white matter and WMH differences, interrelationships between vascular functions, using linear mixed models; and major sources of variance using principal component analyses.ResultsWe recruited 77 patients (45 sporadic/32 CADASIL) at 3 sites. In adjusted analyses, patients with worse WMH had lower CVR (B = -1.78, 95% CI -3.30, -0.27) and blood plasma volume fraction (B = -0.594, 95% CI -0.987, -0.202). CVR was worse in WMH than normal-appearing white matter (eg, CVR: B = -0.048, 95% CI -0.079, -0.017). Adjusting for WMH severity, SVD subtype had minimal influence on vascular function (eg, CVR in CADASIL vs sporadic: B = 0.0169, 95% CI -0.0247, 0.0584). Different vascular function mechanisms were not generally interrelated (eg, permeability surface area product~CVR: B = -0.85, 95% CI -4.72, 3.02). Principal component analyses identified WMH volume/quantitative microstructural metrics explained most variance in CADASIL and arterial pulsatility in sporadic SVD, but similar main variance sources.InterpretationVascular function was worse with higher WMH, and in WMH than normal-appearing white matter. Sporadic SVD-CADASIL differences largely reflect disease severity. Limited vascular function interrelations may suggest disease stage-specific differences. ANN NEUROL 2025;97:483-498.

Dataset Information

Genetic Study of Cerebral Small Vessel Disease in Chinese Han Population.

Publications

Genetic Study of Cerebral Small Vessel Disease in Chinese Han Population.

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