Genetic variation associated with cardiovascular risk in autoimmune diseases

Abstract

Autoimmune diseases have a higher prevalence of cardiovascular events compared to the general population. The objective of this study was to investigate the genetic basis of cardiovascular disease (CVD) risk in autoimmunity. We analyzed genome-wide genotyping data from 6,485 patients from six autoimmune diseases that are associated with a high socio-economic impact. First, for each disease, we tested the association of established CVD risk loci. Second, we analyzed the association of autoimmune disease susceptibility loci with CVD. Finally, to identify genetic patterns associated with CVD risk, we applied the cross-phenotype meta-analysis approach (CPMA) on the genome-wide data. A total of 17 established CVD risk loci were significantly associated with CVD in the autoimmune patient cohorts. From these, four loci were found to have significantly different genetic effects across autoimmune diseases. Six autoimmune susceptibility loci were also found to be associated with CVD risk. Genome-wide CPMA analysis identified 10 genetic clusters strongly associated with CVD risk across all autoimmune diseases. Two of these clusters are highly enriched in pathways previously associated with autoimmune disease etiology (TNFα and IFNγ cytokine pathways). The results of this study support the presence of specific genetic variation associated with the increase of CVD risk observed in autoimmunity.

Fig 1. Genetic variants showing heterogeneous genetic effects on CVD risk across autoimmune diseases.

For each associated SNP (A: rs17465637. B: rs11924705. C: rs2895811. D: rs6789378) the Odds Ratio (OR, black dots) and 95% confidence intervals (horizontal lines) are shown for each of the 6 autoimmune diseases and the combined autoimmune cohort (AID). The SNPs showing a significant association with CVD risk in an autoimmune disease are highlighted in red. For each of the three genotypes of each SNP (risk allele homozygous, heterozygous, non-risk allele homozygous), the incidence of CVD is described in the accompanying table.

Fig 2. Identification of the genetic clusters associated with CVD risk across autoimmune diseases.

A: Hierarchical clustering dendrogram showing the similarity between SNPs with significant evidence of pleiotropy with CVD risk. B: Statistical significance of the association between each genetic cluster and CVD risk for the six autoimmune diseases. Significant associations after multiple test correction are highlighted in white boxes. Abbreviations: GC: genetic cluster.