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.

Epigenetic Function of TET Family, 5-Methylcytosine, and 5-Hydroxymethylcytosine in Hematologic Malignancies

“…Studies indicate that different TET proteins have different areas of high expression, tissue specificity, and related diseases [47-52]. TET1, the first member of TET family located in 10q22, is highly expressed in embryonic stem cells, adult skeletal muscle, heart, kidney, spleen, testis, placenta, salivary gland, adrenal gland, ovary, prostate, fetal brain, and fetal liver.…”

“…TET3, located in 2p13.1, is highly expressed in hematopoietic cells, colon, adult skeletal muscle, adrenal gland, peripheral blood lymphocytes, and fetal brain. It is correlated with systemic lupus erythematosus [52], colon cancer [49], neuropsychiatric disorders [48], rapid behavioral adaptation [51], and kidney fibrosis [50]. …”

The Contribution of Meta-Analysis of Genome-Wide Association Studies in Investigating the Genetic Susceptibility to Lupus

“…Therefore, the genetics community has widely adopted the approach of combining summary statistics from multiple GWAS into a single meta-analysis to increase the statistical power of the analysis by augmenting the effective sample size. For example, we performed meta-analysis of two existing GWASs on Chinese Han populations and followed the findings by further replication in several additional Asian cohorts, and identified genetic variants in or near five genes as associated with SLE: CDKN1B, TET3, CD80, DRAM1, and ARID5B (Yang et al, 2013). In addition, we discovered multiple independent susceptibility variants for the disease in the 11q23.3 region (Zhang et al, 2014).…”

Update on immunoglobulin A nephropathy, Part I: Pathophysiology

“…The same region had been previously associated with several autoimmune diseases [20][21][22][23][24][25][26][27] . Another MHC locus has been found in the region that includes the HLA-DPA1, BPB1 and DPB2 genes.…”