AUTHOR=Li Jie , Zhang Ping , Yi Xingyang , Luo Hua , Yu Ming , Chen Hong , Wang Chun 

TITLE=Sex-specific association between inflammation and endothelial function relevant gene and vulnerable carotid plaque

JOURNAL=Frontiers in Physiology

VOLUME=13

YEAR=2022

URL=https://www.frontiersin.org/journals/physiology/articles/10.3389/fphys.2022.977578

DOI=10.3389/fphys.2022.977578

ISSN=1664-042X

ABSTRACT=<p><bold>Objectives:</bold> We aimed to explore sex-specific association between genes involved in inflammation and endothelial function and vulnerable carotid plaque, a subclinical precursor of ischemic stroke.</p><p><bold>Methods:</bold> Carotid plaque and plaque phenotype were assessed by carotid ultrasound in high-risk participants for stroke drawn from a multicenter, cross-sectional survey in southwestern China. We examined 18 single nucleotide polymorphisms (SNPs) in 10 genes related to inflammation and endothelial function. Sex differences in the genotype of the candidate SNPs and risk of vulnerable carotid plaques were assessed. Interaction tests were performed to identify the SNPs that might modify the association between the sex and vulnerable plaques. For SNPs with suggestive evidence for interaction with sex (<italic>p</italic> for interaction&lt;0.05), stratification analysis by sex was performed to evaluate the sex-specific association between the SNP and vulnerable plaques.</p><p><bold>Results:</bold> 2,644 high-risk individuals were enrolled, comprising 1,202 (45.5%) men and 1,442 (54.5%) women. Vulnerable carotid plaques were detected in 425 (16.1%) participants. Among candidate SNPs, the genotype frequencies of 5 SNPs (<italic>TNFSF4</italic> rs11811788, <italic>TNFSF4</italic> rs1234313, <italic>IL6R</italic> rs4845625, <italic>VCAM1</italic> rs2392221, and <italic>ITGA2</italic> rs1991013) were significantly different between sex (all <italic>p</italic> &lt; 0.05). Univariable and multivariable analyses suggested that male individuals had a significantly higher prevalence of vulnerable carotid plaques (20.0% vs. 12.8%, adjusted OR 1.72, 95% CI 1.12–2.66, <italic>p</italic> = 0.014), while none of the candidate SNPs was significantly associated with vulnerable plaques (all <italic>p</italic> &gt; 0.05). Interaction tests found the association between sex and vulnerable plaques is affected by the genotype of <italic>IL6R</italic> rs4845625 (<italic>p</italic> for interaction = 0.031). Stratification analysis revealed a strong association between <italic>IL6R</italic> rs4845625 and vulnerable carotid plaque in man (dominant model TT vs. CT + CC: adjusted OR 1.52, 95% CI 1.12–2.07, <italic>p</italic> = 0.007; codominant model TT vs. CC: adjusted OR 1.50, 95% CI 1.00–2.25, <italic>p</italic> = 0.048) but not in women (<italic>p</italic> &gt; 0.05 in all genetic models).</p><p><bold>Conclusion:</bold> The rs4845625 polymorphism in <italic>IL6R</italic> has sex-specific effects on vulnerable carotid plaque in Chinese Han high-risk individuals for stroke. Our findings provide a plausible genetic basis underlying the sex difference in carotid plaque vulnerability.</p>