Phosphorylation-related SNPs influence lipid levels and rheumatoid arthritis risk by altering gene expression and plasma protein levels

Objectives. Phosphorylation-related single-nucleotide polymorphisms (phosSNPs) are missense SNPs that may influence protein phosphorylation. The aim of this study was to evaluate the effect of phosSNPs on lipid levels and RA. Methods. We examined the association of phosSNPs with lipid levels and RA in large-scale genome-wide association studies (GWAS) and performed random sampling and fgwas analyses to determine whether the phosSNPs associated with lipid levels and RA were significantly enriched. Furthermore, we performed QTL analysis and Mendelian randomization analysis to obtain additional evidence to be associated with the identified phosSNPs and genes. Results. We found 483 phosSNPs for lipid levels and 243 phosSNPs for RA in the GWAS loci (P < 1.0 x 10(-5)). SNPs associated with high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, Total cholesterol (TC) and RA were significantly enriched with phosSNPs. Almost all of the identified phosSNPs showed expression quantitative trait loci (eQTL) effects. A total of 48 protein QTLs and 9 metabolite QTLs were found. The phosSNP rs3184504 (p.Trp262Arg) at SH2B3 was significantly associated with RA, SH2B3 expression level, and plasma levels of high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, TC, hypoxanthine and 80 proteins, including beta-2-microglobulin. SH2B3 was differentially expressed between RA cases and controls in peripheral blood mononuclear cells and synovial tissues. Mendelian randomization analysis showed that SH2B3 expression level was significantly associated with TC level and RA. Plasma beta-2-microglobulin level was causally associated with high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, TC levels and RA. Conclusion. The findings suggested that phosSNPs may play important roles in lipid metabolism and the pathological mechanisms of RA. PhosSNPs may influence lipid levels and RA risk by altering gene expression and plasma protein levels.