Institute for Medical Informatics, Statistics and Epidemiology, University of Leipzig, Leipzig, Germany.
LIFE Research Center for Civilization Diseases, University of Leipzig, Leipzig, Germany.
PLoS One. 2020 May 29;15(5):e0233728. doi: 10.1371/journal.pone.0233728. eCollection 2020.
Carotid artery plaque is an established marker of subclinical atherosclerosis with pronounced sex-dimorphism. Here, we aimed to identify genetic variants associated with carotid plaque burden (CPB) and to examine potential sex-specific genetic effects on plaque sizes.
We defined six operationalizations of CPB considering plaques in common carotid arteries, carotid bulb, and internal carotid arteries. We performed sex-specific genome-wide association analyses for all traits in the LIFE-Adult cohort (n = 727 men and n = 550 women) and tested significantly associated loci for sex-specific effects. In order to identify causal genes, we analyzed candidate gene expression data for correlation with CPB traits and corresponding sex-specific effects. Further, we tested if previously reported SNP associations with CAD and plaque prevalence are also associated with CBP. We found seven loci with suggestive significance for CPB (p<3.33x10-7), explaining together between 6 and 13% of the CPB variance. Sex-specific analysis showed a genome-wide significant hit for men at 5q31.1 (rs201629990, β = -0.401, p = 5.22x10-9), which was not associated in women (β = -0.127, p = 0.093) with a significant difference in effect size (p = 0.008). Analyses of gene expression data suggested IL5 as the most plausible candidate, as it reflected the same sex-specific association with CPBs (p = 0.037). Known plaque prevalence or CAD loci showed no enrichment in the association with CPB.
We showed that CPB is a complementary trait in analyzing genetics of subclinical atherosclerosis. We detected a novel locus for plaque size in men only suggesting a role of IL5. Several estrogen response elements in this locus point towards a functional explanation of the observed sex-specific effect.
颈动脉斑块是亚临床动脉粥样硬化的既定标志物，具有明显的性别二态性。在这里，我们旨在确定与颈动脉斑块负担（CPB）相关的遗传变异，并研究斑块大小的潜在性别特异性遗传效应。
我们根据颈总动脉、颈动脉窦和颈内动脉的斑块定义了 CPB 的六种操作定义。我们对 LIFE-Adult 队列中的所有特征进行了性别特异性全基因组关联分析（n = 727 名男性和 n = 550 名女性），并测试了显著相关的基因座是否存在性别特异性效应。为了确定候选基因，我们分析了候选基因表达数据与 CPB 特征及其相应的性别特异性效应的相关性。此外，我们还测试了以前报道的与 CAD 和斑块患病率相关的 SNP 关联是否也与 CBP 相关。我们发现了七个与 CPB 具有提示意义的基因座（p<3.33x10-7），共同解释了 CPB 变异的 6%至 13%。性别特异性分析显示，男性在 5q31.1 上存在全基因组显著命中（rs201629990，β = -0.401，p = 5.22x10-9），而女性则不相关（β = -0.127，p = 0.093），且效应大小存在显著差异（p = 0.008）。基因表达数据分析表明，IL5 是最有可能的候选基因，因为它反映了与 CPB 的相同性别特异性关联（p = 0.037）。已知的斑块患病率或 CAD 基因座在与 CPB 的关联中没有富集。
我们表明 CPB 是分析亚临床动脉粥样硬化遗传的补充特征。我们在仅男性中检测到一个新的斑块大小基因座，表明 IL5 发挥作用。该基因座中的多个雌激素反应元件表明观察到的性别特异性效应具有功能解释。
