Identification of the VLDLR locus associated with giant cell arteritis and the possible causal role of low-density lipoprotein cholesterol in its pathogenesis

Objectives To elucidate the association between genetic variants and the risk of GCA via large-scale genome-wide association studies (GWAS). In addition, to assess the causal effect of a specific molecule by employing the obtained GWAS results as genetic epidemiological tools.Methods We applied additional variant quality control to the publicly available GWAS results from the biobanks of the UK (UKBB) and Finland (FinnGen), which comprised 532 cases vs 408 565 controls and 884 cases vs 332 115 controls, respectively. We further meta-analysed these two sets of results. We performed two-sample Mendelian randomization (MR) to test the causal effect of low-density lipoprotein (LDL) cholesterol on the risk of GCA.Results The MHC class II region showed significant associations in UKBB, FinnGen and the meta-analysis. The VLDLR region was associated with GCA risk in the meta-analysis. The T allele of rs7044155 increased the expression of VLDLR, decreased the LDL cholesterol level and decreased the disease risk. The subsequent MR results indicated that a 1 s.d. increase in LDL cholesterol was associated with an increased risk of GCA (odds ratio 1.21, 95% CI 1.01-1.45; P = 0.04).Conclusions Our study identified associations between GCA risk and the MHC class II and VLDLR regions. Moreover, LDL cholesterol was suggested to have a causal effect on the risk of developing GCA. Graphical Abstract