Meta-analysis followed by replication identifies novel genetic variants in X chromosome associated with systemic lupus erythematosus in Asians and analysis of genetic differences between male and female cases

Abstract

Systemic lupus erythematosus (SLE) is an autoimmune disease with a strong genetic component and dramatic gender difference in disease prevalence. Involvement of genetic variants on the X-chromosome in SLE susceptibility, especially in non-European populations, has not been adequately explored. In this study, we aimed at identifying genetic variants on the X chromosome associated with disease susceptibility in Asian populations. Meta-analysis was performed on two genome-wide association studies (GWAS) on SLE on Chinese Han populations, focusing on X chromosome SNPs and female samples at first. The prominent signals were further replicated in three independent cohorts, with a total of 5021 female cases and 5700 matched controls. Furthermore, 355 male cases and 4388 corresponding male controls were also used for replication to explore possible gender differences. Variants in or near PRPS2, NAA10 and TMEM187 were shown to be associated with SLE in Asian populations, surpassing genome-wide significance. In addition, two previously reported loci in European populations, IRAK1 (rs1059702), and MECP2 (rs2734647) were also replicated in our study. We also identified a variant upstream of L1CAM with suggestive association, which showed clear interaction with SNPs in NAA10. Independent contributions of these variants were tested using various methods and clearly independent effect of IRAK1 and MECP2 was demonstrated. This study delineates multiple independent signals towards SLE susceptibility from the X-chromosome in Asian populations, expanding our understanding of the role of X-chromosome variants in SLE susceptibility. A comparison was conducted genome-wide on effect sizes of susceptibility variants between male and female cases, and their implication on the sex differences on SLE prevalence was discussed.