Common genetic variants on chromosome 9p21 confers risk of ischemic stroke: A large-scale genetic association study

The objective of this experiment was to observe the allele frequency and genotype distribution of some 9p21 SNPs in the Anhui Han population, and to study its relationship with the susceptibility to ischemic stroke. For this purpose, a collection of 992 patients with ischemic stroke confirmed and hospitalized in our hospital from October 2017 to October 2020 were used as the IS case group, and 951 normal people who had a healthy physical examination in the physical examination center of our hospital during the same period were selected as the control group. After informed consent, cubital venous blood of all subjects was collected, and epidemiological data of the subjects were collected; the rs2383206, rs2383207, rs10757274, and rs1333049 on chromosome 9p21 as the sites to be tested, using Sequenom Mass Array system for genotyping, using Haploview4.2 software to calculate whether the genotype distribution meets Hardy-Weinberg equilibrium. Results showed that there were no significant differences between the two groups in gender, age, and smoking history. There are significant differences in the levels of hypertension, diabetes and hyperlipidemia, total cholesterol, triglycerides, HDL-C and apolipoprotein A1 between the two groups of study subjects. The genotype frequencies of the participating populations were in a balanced state. The results of the association analysis between SNPs and IS susceptibility showed that rs2383207, rs10757274, rs1333049 and rs2383206 are the susceptibility sites of ischemic stroke. It concluded that in Anhui, China, the inheritance of chromosome 9p21 region is associated with ischemic stroke.

Metabolic dysregulation of the lysophospholipid/autotaxin axis in the chromosome 9p21 gene SNP rs10757274

AimsCommon chromosome 9p21 SNPs increase coronary heart disease (CHD) risk, independent of “traditional lipid risk factors”. However, lipids comprise large numbers of structurally-related molecules not measured in traditional risk measurements, and many have inflammatory bioactivities. Here we applied lipidomic and genomic approaches to three model systems, to characterize lipid metabolic changes in common Chr9p21 SNPs which confer ∼30% elevated CHD risk associated with altered expression of ANRIL, a long ncRNA.Methods and ResultsUntargeted and targeted lipidomics was applied to plasma samples from Northwick Park Heart Study II (NPHSII) homozygotes for AA or GG in rs10757274. Elevated risk GG correlated with reduced lysophosphospholipids (lysoPLs), lysophosphatidic acids (lysoPA) and autotaxin (ATX). Five other risk SNPs did not show this phenotype. Correlation and network analysis showed that lysoPL-lysoPA interconversion was uncoupled from ATX in GG, indicating metabolic dysregulation. To identify candidate genes, transcriptomic data from shRNA downregulation of ANRIL in HEK293 cells was mined. Significantly-altered expression of several lysoPL/lysoPA metabolising enzymes was found (MBOAT2, PLA2G4C, LPCAT2, ACSL6, PNPLA2, PLBD1, PLPP1, PLPP2 and PLPPR2). Next, vascular smooth muscle cells differentiated from iPSCs of individuals homozygous for Chr9p21 risk SNPs were examined. Here, the presence of risk alleles was associated with altered expression of several lysoPL/lysoPA enzymes. Importantly, for several, deletion of the risk locus fully or partially reversed their expression to non-risk haplotype levels: ACSL3, DGKA, PLA2G2A, LPCAT2, LPL, PLA2G3, PNPLA3, PLA2G12A LIPC, LCAT, PLA2G6, ACSL1, MBOAT2.ConclusionA Chr9p21 risk SNP associates with complex alterations in immune-bioactive phospholipids and their enzymatic metabolism. Lipid metabolites and genomic pathways associated with CHD pathogenesis in Chr9p21 and ANRIL-associated disease are demonstrated.One sentence summaryInflammatory phospholipid metabolism defines a cardiovascular disease SNP

Genetic variants on chromosome 9p21 confer risks of cerebral infarction in the Chinese population: a meta-analysis

Ischemic stroke (IS) is the leading cause of disability. Researchers have demonstrated that IS is more a multifactorial disorder than a single-factor disease. At present, no consistent conclusions have been reached on susceptibility loci for IS on chromosome 9p21. We conducted this meta-analysis to verify whether genetic loci on chromosome 9p21 reported domestically and abroad could be responsible for IS in Chinese populations. We analyzed data from eight studies that covered a total of 9756 individuals with Chinese ancestry comprising 4254 cases and 5502 controls. Each of the four reported susceptibility loci (rs2383206, rs2383207, rs10757274, and rs10757278) was analyzed separately. The odds ratios (ORs) of rs2383206 and rs10757274 were 1.09 (95% confidence interval (CI): 1.02–1.06, P = 0.01) and 1.09 (95% CI: 1.01–1.17, P = 0.03), respectively. For rs2383207, OR value was 0.91 (95% CI: 0.84–0.98, P = 0.01). No statistical association was identified for rs10757278. We have verified previous associations for IS in Chinese populations on chromosome 9p21. Loci rs2383206 and rs10757274 may increase susceptibility to IS. Mutation at locus rs2383207 may be beneficial. However, we are unable to identify any association between rs10757278 and IS.