Genome-wide analysis of carotid plaque burden suggests a role of IL5 in men

PLoS One. 2020 May 29;15(5):e0233728. doi: 10.1371/journal.pone.0233728. eCollection 2020.

Abstract

Background: 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.

Methods and results: 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.

Conclusions: 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Arteriosclerosis / genetics*
  • Carotid Artery Diseases / genetics*
  • Carotid Artery, External / diagnostic imaging
  • Carotid Artery, External / pathology
  • Carotid Artery, Internal / diagnostic imaging
  • Carotid Artery, Internal / pathology
  • Cohort Studies
  • Female
  • Genetic Predisposition to Disease / genetics*
  • Genome-Wide Association Study
  • Humans
  • Interleukin-5* / genetics
  • Interleukin-5* / physiology
  • Male
  • Middle Aged
  • Plaque, Atherosclerotic / genetics*
  • Sex Characteristics*
  • Sex Factors

Substances

  • IL5 protein, human
  • Interleukin-5

Grants and funding

LIFE-Adult is funded by the Leipzig Research Center for Civilization Diseases (LIFE). LIFE is an organizational unit affiliated to the Medical Faculty of the University of Leipzig. LIFE is funded by means of the European Union, by the European Regional Development Fund (ERDF) and by funds of the Free State of Saxony within the framework of the excellence initiative. JP was funded by the Federal Ministry of Education and Research (BMBF), Germany, FKZ: 01EO1501.AD2-7117 and a grant of the Medical Faculty of Leipzig (HIMAG-108, SAHSA). We acknowledge support from Leipzig University for Open Access Publishing. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.