Polymorphisms in genes related to inflammation and endothelial function are associated with ischemic stroke and other vascular events in populations at high risk of stroke Short title: A community-based survey and cohort study in southwestern China

Abstract Background To investigate the incidence of ischemic stroke and other vascular events in a population at high risk of stroke and to identify associations of the 19 single nucleotide polymorphisms (SNPs) in genes related to inflammation and endothelial function and interaction among these SNPs with outcomes. Methods According to the China National Stroke Screening Survey program, we performed this multi-center community-based sectional survey and prospective cohort study in the Sichuan of southwestern China from May 2015 to January 2020. The residents from 8 randomly selected communities volunteered to participate in a face-to-face survey. The 19 SNPs in endothelial function and inflammation genes were measured in the high-risk stroke population. A longitudinal study was conducted to assess the outcomes of recruited people who were at high risk for stroke. These patients were followed up for 4.7 years following a face-to-face survey. The primary outcome was a new ischemic stroke, and the secondary outcome was a composite of new vascular events. Results In the cohort of 2698 individuals who were followed up for 4.7 years, 192 subjects (7.1%) experienced various outcomes. Among them, 118 subjects (4.4%) suffered from new ischemic stroke, 24 subjects (0.9%) experienced hemorrhagic stroke, 53 subjects (2.0%) developed myocardial infarction, and 33 subjects (1.2%) passed away. There were significant differences in genotype distribution of TNF rs3093662, IL6Rrs4845625, and TLR4 rs752998 between subjects with and without outcomes by univariate analyses. Generalized multifactor dimensionality reduction (GMDR) analysis showed a significant SNP-SNP interaction among the 19 SNPs. The best outcome model was interaction among IL6R rs4845625, TLR4 rs1927911, and HABP2 rs932650 (P = 0.004). The high-risk interactive genotypes among the 3 SNPs were independently associated with a higher risk for new ischemic stroke (OR = 2.187, 95%CI: 1.256–5.374, P<0.001) and total vascular events (OR = 2.382, 95%CI: 1.423–5.894, P<0.001) after adjustment with covariates. Conclusion Subjects within the high-risk stroke group exhibited a substantially higher occurrence of ischemic stroke and other vascular events. There were associations of specific SNPs in genes related to inflammation and endothelial function with outcomes. The high-risk interactive genotypes among IL6R rs4845625, TLR4 rs1927911, and HABP2 rs932650 were independently associated with a higher risk for new ischemic stroke and other vascular events.