Multiple variants in 5q31.1 are associated with systemic lupus erythematosus susceptibility and sub-phenotypes in the Han Chinese population

Abstract

Background

A previous study provided evidence for genetic association between PPP2CA on 5q31.1 and systemic lupus erythematosus (SLE) across multi-ancestral cohorts, but failed to find significant evidence for association in the Chinese Han population.

Objective

To explore the association between this locus and SLE using data from our previously published genome-wide association study (GWAS) of SLE in Han Chinese population.

Methods

SNPs rs7726414 and rs244689 (near TCF7 and PPP2CA in 5q31.1) were selected as candidate independent associations from a large-scale study in a Han Chinese population consisting of 1,047 cases and 1,205 controls (a previously published GWAS). Subsequently 3,509 cases and 8,246 controls were genotyped in two further replication studies. We then further investigated the SNPs' associations with SLE sub-phenotypes, and gene expression in peripheral blood mononuclear cells from cases and controls (analyzed by real-time PCR).

Results

Highly significant associations with SLE in the Chinese Han were detected for SNPs rs7726414 and rs244689 by combining the genotype data from our previous GWAS and two independent replication cohorts (rs7726414, P_combined =1.66×10^-13, OR=1.42; rs244689, P_combined = 1.21×10^-20, OR=1.29). Further conditional analyses indicated that these two SNPs contribute to disease susceptibility independently from each other. A significant association was found for rs7726414 with SLE age at diagnosis < 20 years (P = 0.00027). The expression levels of TCF7 and PPP2CA messenger RNA (mRNA) in patients with SLE were significantly decreased compared with those in healthy controls.

Conclusions

This study finds evidence for multiple associations with SLE in 5q31.1 at genome-wide levels of significance for the first time in a Han Chinese population, in a combined genotype dataset of 4,556 cases and 9,451 controls. These findings suggested that variants in the 5q31.1 locus not only provide novel insights into the genetic architecture of SLE but also contribute to the complex sub-phenotypes of SLE.

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