Meta-analysis followed by replication identifies loci in or near CDKN1B, TET3, CD80, DRAM1, and ARID5B as associated with systemic lupus erythematosus in Asians

Abstract

Systemic lupus erythematosus (SLE) is a prototype autoimmune disease with a strong genetic involvement and ethnic differences. Susceptibility genes identified so far only explain a small portion of the genetic heritability of SLE, suggesting that many more loci are yet to be uncovered for this disease. In this study, we performed a meta-analysis of genome-wide association studies on SLE in Chinese Han populations and followed up the findings by replication in four additional Asian cohorts with a total of 5,365 cases and 10,054 corresponding controls. We identified genetic variants in or near CDKN1B, TET3, CD80, DRAM1, and ARID5B as associated with the disease. These findings point to potential roles of cell-cycle regulation, autophagy, and DNA demethylation in SLE pathogenesis. For the region involving TET3 and that involving CDKN1B, multiple independent SNPs were identified, highlighting a phenomenon that might partially explain the missing heritability of complex diseases.

Figure 1

Flow Chart of the Experimental Process and SNP Selection Criteria

Figure 2

Manhattan Plot on the Meta-analysis Results of the Two SLE GWASs on Two Chinese Populations in Hong Kong and Anhui, China Known susceptibility genes are labeled in black, and genes identified in this study are labeled in red. The y axis is the −log₁₀(p_meta) for the autosomal SNPs from the two GWASs.

Figure 3

Association with SLE across the Five Regions (A–E) Regional association plots show association from meta-analysis (−log₁₀(p_meta)) versus chromosomal position (kb) for all the SNPs in a 500 kb region centered on the newly validated SNP. p_meta values are plotted for all SNPs, shaded white to red by the degree of LD (r²; see insets) with the validated SNP in the respective region (A, rs10845606; B, rs4852234; C, 4948496; D, rs6804441; and E, rs4622329). Local recombination rates (cM/Mb, blue lines) estimated from HapMap CHB and JPT samples are plotted against the secondary y axis, showing recombination hotspots across the region and haplotype blocks in between. Genes in the respective regions are labeled below the plots. Chromosomal regions are as follows: (A) 12p13, (B) 2p13, (C) 10q21, (D) 3q13, and (E) 12q23.

Figure 4

Forest Plot of Odds Ratios for the SNPs Surpassing Genome-wide Significance of 5 × 10⁻⁸ by Joint Analysis The bars are 95% confidence intervals of odds ratios (ORs).

Figure 5

Potential Roles of the Identified Susceptibility Genes in SLE Etiology Genes labeled in red are the ones identified in this study. Environmental triggers such as UV irradiation cause damage to cells. In affected individuals, genetic variants in DRAM1, ATG5, and CDKN1B (encoding p27^kip1) might lead to defects in apoptosis or autophagy and thus increase exposure of nuclear autoantigens to the immune system. Interaction between CD28 and CD80 or CD86 plays a vital role in T cell activation. Upon T cell activation, p27^kip1 is phosphorylated and the CDK-cyclin complex is released, allowing cell-cycle progression. Upregulation of p27^kip1 is essential for induction of tolerance. p27^kip1 also plays a role in dendritic cell apoptosis. Activated autoreactive Th2 cells interact with B cells and induce B cell differentiation and production of autoantibodies. Autoreactive Th1 and Th17 cells can exacerbate this process by secreting proinflammatory cytokines and chemokines, enhancing immune-complex deposition and end-organ damage. Susceptibility genes such as CREBL2, ARID5B, and TET3 are involved in DNA and histone modification and might regulate expression of genes in T and B lymphocytes involved in autoimmunity.