Identification of susceptibility loci and relevant cell type for IgA nephropathy in Han Chinese by integrative genome-wide analysis
Ming Li1,2,3, Xingjie Hao4, Dianchun Shi1,2,3, Shanshan Cheng4, Zhong Zhong2,5, Lu Cai2,5, Minghui Jiang4, Lin Ding4, Lanbo Ding4, Chaolong Wang4(), Xueqing Yu1,2,3()
. Department of Nephrology, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences, Guangzhou 510080, China . Department of Nephrology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080, China . Guangdong-Hong Kong Joint Laboratory on Immunological and Genetic Kidney Diseases, Guangzhou 510080, China . Department of Epidemiology and Biostatistics, Ministry of Education Key Laboratory of Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China . NHC Key Laboratory of Nephrology (Sun Yat-sen University), and Guangdong Provincial Key Laboratory of Nephrology, Guangzhou 510080, China
Although many susceptibility loci for IgA nephropathy (IgAN) have been identified, they only account for 11.0% of the overall IgAN variance. We performed a large genome-wide meta-analysis of IgAN in Han Chinese with 3616 cases and 10 417 controls to identify additional genetic loci of IgAN. Considering that inflammatory bowel disease (IBD) and asthma might share an etiology of dysregulated mucosal immunity with IgAN, we performed cross-trait integrative analysis by leveraging functional annotations of relevant cell type and the pleiotropic information from IBD and asthma. Among 8 669 456 imputed variants, we identified a novel locus at 4p14 containing the long noncoding RNA LOC101060498. Cell type enrichment analysis based on annotations suggested that PMA-I-stimulated CD4+CD25–IL17+ Th17 cell was the most relevant cell type for IgAN, which highlights the essential role of Th17 pathway in the pathogenesis of IgAN. Furthermore, we identified six more novel loci associated with IgAN, which included three loci showing pleiotropic effects with IBD or asthma (2q35/PNKD, 6q25.2/SCAF8, and 22q11.21/UBE2L3) and three loci specific to IgAN (14q32.32/TRAF3, 16q22.2/TXNL4B, and 21q21.3/LINC00113) in the pleiotropic analysis. Our findings support the involvement of mucosal immunity, especially T cell immune response and IL-17 signal pathway, in the development of IgAN and shed light on further investigation of IgAN.
. [J]. Frontiers of Medicine, 2024, 18(5): 862-877.
Ming Li, Xingjie Hao, Dianchun Shi, Shanshan Cheng, Zhong Zhong, Lu Cai, Minghui Jiang, Lin Ding, Lanbo Ding, Chaolong Wang, Xueqing Yu. Identification of susceptibility loci and relevant cell type for IgA nephropathy in Han Chinese by integrative genome-wide analysis. Front. Med., 2024, 18(5): 862-877.
rs11736377, 4p14, intergenic variant close to LOC101060498
No evidence for effects on gene expression levels
Vitiligo, Graves’ disease, psoriasis, and autoimmune traits
LOC101060498 is chromatin interacted with the adjacent immune-related gene RHOH, which is important for the development, migration, and signaling of T cells [40]. The involvement of RHOH in autoimmune-related diseases might be due to its ability to regulate T helper cell-induced cytokine production, especially in the Th17-cell differentiation [40]
rs1473901, 2q35, intron variant of PNKD
Associated with expression level of PNKD in blood, thyroid, skin, spleen, and liver
PNKD plays a role in regulation of myofibrillogenesis. The dysfunctional PNKD can reduce glutathione levels in cells and result in increasing oxidative stress levels, which has been linked to inflammation [69]
rs10872710, 6q25.2, intron variant of SCAF8
No evidence for effects on gene expression levels
Estimated glomerular filtration rate and diabetic nephropathy
SCAF8 is the anti-terminator protein required to prevent early mRNA termination during transcription. SCAF8 can suppress the use of early, alternative poly(A) sites, which prevents the accumulation of nonfunctional truncated proteins. SCAF8 also acts as a positive regulator of transcript elongation [70]
rs1811069, 22q11.21, intergenic variant close to UBE2L3
Associated with expression level of UBE2L3 in blood, mucosa, and muscularis of esophagus and skin
UBE2L3 encodes a member of the E2 ubiquitin-conjugating enzyme family involved in ubiquitin/proteasome-dependent degradation. The ubiquitin/proteasome pathway is involved in the development of multiple kidney diseases [53]
rs8004192, 14q32.32, intron variant of TRAF3
Associated with expression level of TRAF3 in mucosa of esophagus, brain, and thyroid
Hematological traits, serum IgA level, systemic lupus erythematosus, multiple sclerosis, eczema, and asthma
TRAF3 encoding a member of the TNF receptor associated factor protein family participates in the signal transduction of CD40 and plays a role in T cell dependent immune responses and the regulation of antiviral responses [61]. TRAF3 is required for normal signaling by the T cell antigen receptor, and cytoplasmic TRAF3 restrains nuclear factor κB activation in T and B cells [71]
rs77303550, 16q22.2, intron variant of TXNL4B
Associated with expression level of TXNL4B in cultured fibroblasts
Cardiovascular disease and type II diabetes mellitus
TXNL4B plays an essential role in pre-mRNA splicing and is required in cell cycle progression for S/G(2) transition [72]
rs80271593, 21q21.3, intergenic variant close to LINC00113
No evidence for effects on gene expression levels
Chronic renal failure
LINC00113 promotes proliferation, survival, and migration by activating PI3K/Akt/mTOR signaling pathway in atherosclerosis [73]. It is downregulated in clear cell renal cell carcinoma samples compared with normal samples [74]
Tab.3
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