Identification of susceptibility loci and relevant cell type for IgA nephropathy in Han Chinese by integrative genome-wide analysis

Abstract

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.

Keywords

IgA nephropathy (IgAN) / genome-wide association study (GWAS) / relevant cell types / integrative analysis / pleiotropy

参考文献

[1] Zhang H, Barratt J. Is IgA nephropathy the same disease in different parts of the world. Semin Immunopathol 2021; 43(5): 707–715

[2] Coppo R, Amore A, Hogg R, Emancipator S. Idiopathic nephropathy with IgA deposits. Pediatr Nephrol 2000; 15(1–2): 139–150

[3] Magistroni R, D’Agati VD, Appel GB, Kiryluk K. New developments in the genetics, pathogenesis, and therapy of IgA nephropathy. Kidney Int 2015; 88(5): 974–989

[4] Schena FP, Nistor I. Epidemiology of IgA nephropathy: a global perspective. Semin Nephrol 2018; 38(5): 435–442

[5] Li M, Wang L, Shi DC, Foo JN, Zhong Z, Khor CC, Lanzani C, Citterio L, Salvi E, Yin PR, Bei JX, Wang L, Liao YH, Chen J, Chen QK, Xu G, Jiang GR, Wan JX, Chen MH, Chen N, Zhang H, Zeng YX, Liu ZH, Liu JJ, Yu XQ. Genome-wide meta-analysis identifies three novel susceptibility loci and reveals ethnic heterogeneity of genetic susceptibility for IgA nephropathy. J Am Soc Nephrol 2020; 31(12): 2949–2963

[6] Feehally J, Farrall M, Boland A, Gale DP, Gut I, Heath S, Kumar A, Peden JF, Maxwell PH, Morris DL, Padmanabhan S, Vyse TJ, Zawadzka A, Rees AJ, Lathrop M, Ratcliffe PJ. HLA has strongest association with IgA nephropathy in genome-wide analysis. J Am Soc Nephrol 2010; 21(10): 1791–1797

[7] Yu XQ, Li M, Zhang H, Low HQ, Wei X, Wang JQ, Sun LD, Sim KS, Li Y, Foo JN, Wang W, Li ZJ, Yin XY, Tang XQ, Fan L, Chen J, Li RS, Wan JX, Liu ZS, Lou TQ, Zhu L, Huang XJ, Zhang XJ, Liu ZH, Liu JJ. A genome-wide association study in Han Chinese identifies multiple susceptibility loci for IgA nephropathy. Nat Genet 2012; 44(2): 178–182

[8] Kiryluk K, Li Y, Scolari F, Sanna-Cherchi S, Choi M, Verbitsky M, Fasel D, Lata S, Prakash S, Shapiro S, Fischman C, Snyder HJ, Appel G, Izzi C, Viola BF, Dallera N, Del Vecchio L, Barlassina C, Salvi E, Bertinetto FE, Amoroso A, Savoldi S, Rocchietti M, Amore A, Peruzzi L, Coppo R, Salvadori M, Ravani P, Magistroni R, Ghiggeri GM, Caridi G, Bodria M, Lugani F, Allegri L, Delsante M, Maiorana M, Magnano A, Frasca G, Boer E, Boscutti G, Ponticelli C, Mignani R, Marcantoni C, Di Landro D, Santoro D, Pani A, Polci R, Feriozzi S, Chicca S, Galliani M, Gigante M, Gesualdo L, Zamboli P, Battaglia GG, Garozzo M, Maixnerová D, Tesar V, Eitner F, Rauen T, Floege J, Kovacs T, Nagy J, Mucha K, Pączek L, Zaniew M, Mizerska-Wasiak M, Roszkowska-Blaim M, Pawlaczyk K, Gale D, Barratt J, Thibaudin L, Berthoux F, Canaud G, Boland A, Metzger M, Panzer U, Suzuki H, Goto S, Narita I, Caliskan Y, Xie J, Hou P, Chen N, Zhang H, Wyatt RJ, Novak J, Julian BA, Feehally J, Stengel B, Cusi D, Lifton RP, Gharavi AG. Discovery of new risk loci for IgA nephropathy implicates genes involved in immunity against intestinal pathogens. Nat Genet 2014; 46(11): 1187–1196

[9] Li M, Foo JN, Wang JQ, Low HQ, Tang XQ, Toh KY, Yin PR, Khor CC, Goh YF, Irwan ID, Xu RC, Andiappan AK, Bei JX, Rotzschke O, Chen MH, Cheng CY, Sun LD, Jiang GR, Wong TY, Lin HL, Aung T, Liao YH, Saw SM, Ye K, Ebstein RP, Chen QK, Shi W, Chew SH, Chen J, Zhang FR, Li SP, Xu G, Shyong Tai E, Wang L, Chen N, Zhang XJ, Zeng YX, Zhang H, Liu ZH, Yu XQ, Liu JJ. Identification of new susceptibility loci for IgA nephropathy in Han Chinese. Nat Commun 2015; 6(1): 7270

[10] Gharavi AG, Kiryluk K, Choi M, Li Y, Hou P, Xie J, Sanna-Cherchi S, Men CJ, Julian BA, Wyatt RJ, Novak J, He JC, Wang H, Lv J, Zhu L, Wang W, Wang Z, Yasuno K, Gunel M, Mane S, Umlauf S, Tikhonova I, Beerman I, Savoldi S, Magistroni R, Ghiggeri GM, Bodria M, Lugani F, Ravani P, Ponticelli C, Allegri L, Boscutti G, Frasca G, Amore A, Peruzzi L, Coppo R, Izzi C, Viola BF, Prati E, Salvadori M, Mignani R, Gesualdo L, Bertinetto F, Mesiano P, Amoroso A, Scolari F, Chen N, Zhang H, Lifton RP. Genome-wide association study identifies susceptibility loci for IgA nephropathy. Nat Genet 2011; 43(4): 321–327

[11] Kiryluk K, Sanchez-Rodriguez E, Zhou XJ, Zanoni F, Liu L, Mladkova N, Khan A, Marasa M, Zhang JY, Balderes O, Sanna-Cherchi S, Bomback AS, Canetta PA, Appel GB, Radhakrishnan J, Trimarchi H, Sprangers B, Cattran DC, Reich H, Pei Y, Ravani P, Galesic K, Maixnerova D, Tesar V, Stengel B, Metzger M, Canaud G, Maillard N, Berthoux F, Berthelot L, Pillebout E, Monteiro R, Nelson R, Wyatt RJ, Smoyer W, Mahan J, Samhar AA, Hidalgo G, Quiroga A, Weng P, Sreedharan R, Selewski D, Davis K, Kallash M, Vasylyeva TL, Rheault M, Chishti A, Ranch D, Wenderfer SE, Samsonov D, Claes DJ, Akchurin O, Goumenos D, Stangou M, Nagy J, Kovacs T, Fiaccadori E, Amoroso A, Barlassina C, Cusi D, Del Vecchio L, Battaglia GG, Bodria M, Boer E, Bono L, Boscutti G, Caridi G, Lugani F, Ghiggeri G, Coppo R, Peruzzi L, Esposito V, Esposito C, Feriozzi S, Polci R, Frasca G, Galliani M, Garozzo M, Mitrotti A, Gesualdo L, Granata S, Zaza G, Londrino F, Magistroni R, Pisani I, Magnano A, Marcantoni C, Messa P, Mignani R, Pani A, Ponticelli C, Roccatello D, Salvadori M, Salvi E, Santoro D, Gembillo G, Savoldi S, Spotti D, Zamboli P, Izzi C, Alberici F, Delbarba E, Florczak M, Krata N, Mucha K, Pączek L, Niemczyk S, Moszczuk B, Pańczyk-Tomaszewska M, Mizerska-Wasiak M, Perkowska-Ptasińska A, Bączkowska T, Durlik M, Pawlaczyk K, Sikora P, Zaniew M, Kaminska D, Krajewska M, Kuzmiuk-Glembin I, Heleniak Z, Bullo-Piontecka B, Liberek T, Dębska-Slizien A, Hryszko T, Materna-Kiryluk A, Miklaszewska M, Szczepańska M, Dyga K, Machura E, Siniewicz-Luzeńczyk K, Pawlak-Bratkowska M, Tkaczyk M, Runowski D, Kwella N, Drożdż D, Habura I, Kronenberg F, Prikhodina L, van Heel D, Fontaine B, Cotsapas C, Wijmenga C, Franke A, Annese V, Gregersen PK, Parameswaran S, Weirauch M, Kottyan L, Harley JB, Suzuki H, Narita I, Goto S, Lee H, Kim DK, Kim YS, Park JH, Cho B, Choi M, Van Wijk A, Huerta A, Ars E, Ballarin J, Lundberg S, Vogt B, Mani LY, Caliskan Y, Barratt J, Abeygunaratne T, Kalra PA, Gale DP, Panzer U, Rauen T, Floege J, Schlosser P, Ekici AB, Eckardt KU, Chen N, Xie J, Lifton RP, Loos RJF, Kenny EE, Ionita-Laza I, Köttgen A, Julian BA, Novak J, Scolari F, Zhang H, Gharavi AG. Genome-wide association analyses define pathogenic signaling pathways and prioritize drug targets for IgA nephropathy. Nat Genet 2023; 55(7): 1091–1105

[12] Shi D, Zhong Z, Wang M, Cai L, Fu D, Peng Y, Guo L, Mao H, Yu X, Li M. Identification of susceptibility locus shared by IgA nephropathy and inflammatory bowel disease in a Chinese Han population. J Hum Genet 2020; 65(3): 241–249

[13] Floege J, Feehally J. The mucosa-kidney axis in IgA nephropathy. Nat Rev Nephrol 2016; 12(3): 147–156

[14] Gesualdo L, Di Leo V, Coppo R. The mucosal immune system and IgA nephropathy. Semin Immunopathol 2021; 43(5): 657–668

[15] Cheung CK, Barratt J. Further evidence for the mucosal origin of pathogenic IgA in IgA nephropathy. J Am Soc Nephrol 2022; 33(5): 873–875

[16] Fellström BC, Barratt J, Cook H, Coppo R, Feehally J, de Fijter JW, Floege J, Hetzel G, Jardine AG, Locatelli F, Maes BD, Mercer A, Ortiz F, Praga M, Sørensen SS, Tesar V, Del Vecchio L; NEFIGAN Trial Investigators. Targeted-release budesonide versus placebo in patients with IgA nephropathy (NEFIGAN): a double-blind, randomised, placebo-controlled phase 2b trial. Lancet 2017; 389(10084): 2117–2127

[17] Chung D, Yang C, Li C, Gelernter J, Zhao H. GPA: a statistical approach to prioritizing GWAS results by integrating pleiotropy and annotation. PLoS Genet 2014; 10(11): e1004787

[18] Liu JZ, van Sommeren S, Huang H, Ng SC, Alberts R, Takahashi A, Ripke S, Lee JC, Jostins L, Shah T, Abedian S, Cheon JH, Cho J, Dayani NE, Franke L, Fuyuno Y, Hart A, Juyal RC, Juyal G, Kim WH, Morris AP, Poustchi H, Newman WG, Midha V, Orchard TR, Vahedi H, Sood A, Sung JY, Malekzadeh R, Westra HJ, Yamazaki K, Yang SK; International Multiple Sclerosis Genetics Consortium; International IBD Genetics Consortium; Barrett JC, Alizadeh BZ, Parkes M, Bk T, Daly MJ, Kubo M, Anderson CA, Weersma RK. Association analyses identify 38 susceptibility loci for inflammatory bowel disease and highlight shared genetic risk across populations. Nat Genet 2015; 47(9): 979–986

[19] Zhu Z, Lee PH, Chaffin MD, Chung W, Loh PR, Lu Q, Christiani DC, Liang L. A genome-wide cross-trait analysis from UK Biobank highlights the shared genetic architecture of asthma and allergic diseases. Nat Genet 2018; 50(6): 857–864

[20] Wu D, Dou J, Chai X, Bellis C, Wilm A, Shih CC, Soon WWJ, Bertin N, Lin CB, Khor CC, DeGiorgio M, Cheng S, Bao L, Karnani N, Hwang WYK, Davila S, Tan P, Shabbir A, Moh A, Tan EK, Foo JN, Goh LL, Leong KP, Foo RSY, Lam CSP, Richards AM, Cheng CY, Aung T, Wong TY, Ng HH; SG10K Consortium; Liu J, Wang C. Large-scale whole-genome sequencing of three diverse Asian populations in Singapore. Cell 2019; 179(3): 736–749.e15

[21] Chang CC, Chow CC, Tellier LC, Vattikuti S, Purcell SM, Lee JJ. Second-generation PLINK: rising to the challenge of larger and richer datasets. Gigascience 2015; 4(1): 7

[22] 1000 Genomes Project Consortium; Auton A, Brooks LD, Durbin RM, Garrison EP, Kang HM, Korbel JO, Marchini JL, McCarthy S, McVean GA, Abecasis GR. A global reference for human genetic variation. Nature 2015; 526(7571): 68–74

[23] Loh PR, Danecek P, Palamara PF, Fuchsberger C, Reshef YA, Finucane HK, Schoenherr S, Forer L, McCarthy S, Abecasis GR, Durbin R, Price AL. Reference-based phasing using the Haplotype Reference Consortium panel. Nat Genet 2016; 48(11): 1443–1448

[24] Das S, Forer L, Schönherr S, Sidore C, Locke AE, Kwong A, Vrieze SI, Chew EY, Levy S, McGue M, Schlessinger D, Stambolian D, Loh PR, Iacono WG, Swaroop A, Scott LJ, Cucca F, Kronenberg F, Boehnke M, Abecasis GR, Fuchsberger C. Next-generation genotype imputation service and methods. Nat Genet 2016; 48(10): 1284–1287

[25] Danecek P, Bonfield JK, Liddle J, Marshall J, Ohan V, Pollard MO, Whitwham A, Keane T, McCarthy SA, Davies RM, Li H. Twelve years of SAMtools and BCFtools. Gigascience 2021; 10(2): giab008

[26] Willer CJ, Li Y, Abecasis GR. METAL: fast and efficient meta-analysis of genomewide association scans. Bioinformatics 2010; 26(17): 2190–2191

[27] Bulik-Sullivan BK, Loh PR, Finucane HK, Ripke S, Yang J; Schizophrenia Working Group of the Psychiatric Genomics Consortium; Patterson N, Daly MJ, Price AL, Neale BM. LD score regression distinguishes confounding from polygenicity in genome-wide association studies. Nat Genet 2015; 47(3): 291–295

[28] Watanabe K, Taskesen E, van Bochoven A, Posthuma D. Functional mapping and annotation of genetic associations with FUMA. Nat Commun 2017; 8(1): 1826

[29] GTEx Consortium. The Genotype-Tissue Expression (GTEx) pilot analysis: multitissue gene regulation in humans. Science 2015; 348(6235): 648–660

[30] Lu Q, Powles RL, Abdallah S, Ou D, Wang Q, Hu Y, Lu Y, Liu W, Li B, Mukherjee S, Crane PK, Zhao H. Systematic tissue-specific functional annotation of the human genome highlights immune-related DNA elements for late-onset Alzheimer’s disease. PLoS Genet 2017; 13(7): e1006933

[31] Finucane HK, Bulik-Sullivan B, Gusev A, Trynka G, Reshef Y, Loh PR, Anttila V, Xu H, Zang C, Farh K, Ripke S, Day FR; ReproGen Consortium; Schizophrenia Working Group of the Psychiatric Genomics Consortium; RACI Consortium; Purcell S, Stahl E, Lindstrom S, Perry JR, Okada Y, Raychaudhuri S, Daly MJ, Patterson N, Neale BM, Price AL. Partitioning heritability by functional annotation using genome-wide association summary statistics. Nat Genet 2015; 47(11): 1228–1235

[32] Roadmap Epigenomics Consortium; Kundaje A, Meuleman W, Ernst J, Bilenky M, Yen A, Heravi-Moussavi A, Kheradpour P, Zhang Z, Wang J, Ziller MJ, Amin V, Whitaker JW, Schultz MD, Ward LD, Sarkar A, Quon G, Sandstrom RS, Eaton ML, Wu YC, Pfenning AR, Wang X, Claussnitzer M, Liu Y, Coarfa C, Harris RA, Shoresh N, Epstein CB, Gjoneska E, Leung D, Xie W, Hawkins RD, Lister R, Hong C, Gascard P, Mungall AJ, Moore R, Chuah E, Tam A, Canfield TK, Hansen RS, Kaul R, Sabo PJ, Bansal MS, Carles A, Dixon JR, Farh KH, Feizi S, Karlic R, Kim AR, Kulkarni A, Li D, Lowdon R, Elliott G, Mercer TR, Neph SJ, Onuchic V, Polak P, Rajagopal N, Ray P, Sallari RC, Siebenthall KT, Sinnott-Armstrong NA, Stevens M, Thurman RE, Wu J, Zhang B, Zhou X, Beaudet AE, Boyer LA, De Jager PL, Farnham PJ, Fisher SJ, Haussler D, Jones SJ, Li W, Marra MA, McManus MT, Sunyaev S, Thomson JA, Tlsty TD, Tsai LH, Wang W, Waterland RA, Zhang MQ, Chadwick LH, Bernstein BE, Costello JF, Ecker JR, Hirst M, Meissner A, Milosavljevic A, Ren B, Stamatoyannopoulos JA, Wang T, Kellis M. Integrative analysis of 111 reference human epigenomes. Nature 2015; 518(7539): 317–330

[33] Giambartolomei C, Vukcevic D, Schadt EE, Franke L, Hingorani AD, Wallace C, Plagnol V. Bayesian test for colocalisation between pairs of genetic association studies using summary statistics. PLoS Genet 2014; 10(5): e1004383

[34] Liu B, Gloudemans MJ, Rao AS, Ingelsson E, Montgomery SB. Abundant associations with gene expression complicate GWAS follow-up. Nat Genet 2019; 51(5): 768–769

[35] Adzhubei IA, Schmidt S, Peshkin L, Ramensky VE, Gerasimova A, Bork P, Kondrashov AS, Sunyaev SR. A method and server for predicting damaging missense mutations. Nat Methods 2010; 7(4): 248–249

[36] Sim NL, Kumar P, Hu J, Henikoff S, Schneider G, Ng PC. SIFT web server: predicting effects of amino acid substitutions on proteins. Nucleic Acids Res 2012; 40(Web Server issue): W452–457

[37] GTEx Consortium. The genotype-tissue expression (GTEx) project. Nat Genet 2013; 45(6): 580–585

[38] Fanucchi S, Fok ET, Dalla E, Shibayama Y, Börner K, Chang EY, Stoychev S, Imakaev M, Grimm D, Wang KC, Li G, Sung WK, Mhlanga MM. Immune genes are primed for robust transcription by proximal long noncoding RNAs located in nuclear compartments. Nat Genet 2019; 51(1): 138–150

[39] He B, Chen C, Teng L, Tan K. Global view of enhancer-promoter interactome in human cells. Proc Natl Acad Sci USA 2014; 111(21): E2191–E2199

[40] Ahmad Mokhtar AM, Hashim IF, Mohd Zaini Makhtar M, Salikin NH, Amin-Nordin S. The role of RhoH in TCR signalling and its involvement in diseases. Cells 2021; 10(4): 950

[41] Tamehiro N, Nishida K, Sugita Y, Hayakawa K, Oda H, Nitta T, Nakano M, Nishioka A, Yanobu-Takanashi R, Goto M, Okamura T, Adachi R, Kondo K, Morita A, Suzuki H. Ras homolog gene family H (RhoH) deficiency induces psoriasis-like chronic dermatitis by promoting T_H17 cell polarization. J Allergy Clin Immunol 2019; 143(5): 1878–1891

[42] Tang Y, He H, Hu P, Xu X. T lymphocytes in IgA nephropathy. Exp Ther Med 2020; 20(1): 186–194

[43] Schmidt T, Luebbe J, Kilian C, Riedel JH, Hiekmann S, Asada N, Ginsberg P, Robben L, Song N, Kaffke A, Peters A, Borchers A, Flavell RA, Gagliani N, Pelzcar P, Huber S, Huber TB, Turner JE, Paust HJ, Krebs CF, Panzer U. IL-17 receptor C signaling controls CD4⁺ T_H17 immune responses and tissue injury in immune-mediated kidney diseases. J Am Soc Nephrol 2021; 32(12): 3081–3098

[44] Ruszkowski J, Lisowska KA, Pindel M, Heleniak Z, Dębska-Ślizień A, Witkowski JM. T cells in IgA nephropathy: role in pathogenesis, clinical significance and potential therapeutic target. Clin Exp Nephrol 2019; 23(3): 291–303

[45] Yang L, Zhang X, Peng W, Wei M, Qin W. MicroRNA-155-induced T lymphocyte subgroup drifting in IgA nephropathy. Int Urol Nephrol 2017; 49(2): 353–361

[46] Du W, Gao CY, You X, Li L, Zhao ZB, Fang M, Ye Z, Si M, Lian ZX, Yu X. Increased proportion of follicular helper T cells is associated with B cell activation and disease severity in IgA nephropathy. Front Immunol 2022; 13: 901465

[47] Lin FJ, Jiang GR, Shan JP, Zhu C, Zou J, Wu XR. Imbalance of regulatory T cells to Th17 cells in IgA nephropathy. Scand J Clin Lab Invest 2012; 72(3): 221–229

[48] Lin JR, Wen J, Zhang H, Wang L, Gou FF, Yang M, Fan JM. Interleukin-17 promotes the production of underglycosylated IgA1 in DAKIKI cells. Ren Fail 2018; 40(1): 60–67

[49] Jiang P, Zheng C, Xiang Y, Malik S, Su D, Xu G, Zhang M. The involvement of TH17 cells in the pathogenesis of IBD. Cytokine Growth Factor Rev 2023; 69: 28–42

[50] Jeong J, Lee HK. The role of CD4⁺ T cells and microbiota in the pathogenesis of asthma. Int J Mol Sci 2021; 22(21): 11822

[51] Qing J, Li C, Hu X, Song W, Tirichen H, Yaigoub H, Li Y. Differentiation of T helper 17 cells may mediate the abnormal humoral immunity in IgA nephropathy and inflammatory bowel disease based on shared genetic effects. Front Immunol 2022; 13: 916934

[52] Han Y, Jia Q, Jahani PS, Hurrell BP, Pan C, Huang P, Gukasyan J, Woodward NC, Eskin E, Gilliland FD, Akbari O, Hartiala JA, Allayee H. Genome-wide analysis highlights contribution of immune system pathways to the genetic architecture of asthma. Nat Commun 2020; 11(1): 1776

[53] Zhang X, Huo C, Liu Y, Su R, Zhao Y, Li Y. Mechanism and disease association with a ubiquitin conjugating E2 enzyme: UBE2L3. Front Immunol 2022; 13: 793610

[54] Lechner SM, Abbad L, Boedec E, Papista C, Le Stang MB, Moal C, Maillard J, Jamin A, Bex-Coudrat J, Wang Y, Li A, Martini PG, Monteiro RC, Berthelot L. IgA1 protease treatment reverses mesangial deposits and hematuria in a model of IgA nephropathy. J Am Soc Nephrol 2016; 27(9): 2622–2629

[55] Neubert K, Meister S, Moser K, Weisel F, Maseda D, Amann K, Wiethe C, Winkler TH, Kalden JR, Manz RA, Voll RE. The proteasome inhibitor bortezomib depletes plasma cells and protects mice with lupus-like disease from nephritis. Nat Med 2008; 14(7): 748–755

[56] Bontscho J, Schreiber A, Manz RA, Schneider W, Luft FC, Kettritz R. Myeloperoxidase-specific plasma cell depletion by bortezomib protects from anti-neutrophil cytoplasmic autoantibodies-induced glomerulonephritis. J Am Soc Nephrol 2011; 22(2): 336–348

[57] Wan YY, Flavell RA. TGF-beta and regulatory T cell in immunity and autoimmunity. J Clin Immunol 2008; 28(6): 647–659

[58] International Genetics of Ankylosing Spondylitis Consortium (IGAS); Cortes A, Hadler J, Pointon JP, Robinson PC, Karaderi T, Leo P, Cremin K, Pryce K, Harris J, Lee S, Joo KB, Shim SC, Weisman M, Ward M, Zhou X, Garchon HJ, Chiocchia G, Nossent J, Lie BA, FørreØ, Tuomilehto J, Laiho K, Jiang L, Liu Y, Wu X, Bradbury LA, Elewaut D, Burgos-Vargas R, Stebbings S, Appleton L, Farrah C, Lau J, Kenna TJ, Haroon N, Ferreira MA, Yang J, Mulero J, Fernandez-Sueiro JL, Gonzalez-Gay MA, Lopez-Larrea C, Deloukas P, Donnelly P; Australo-Anglo-American Spondyloarthritis Consortium (TASC); Groupe Française d'Etude Génétique des Spondylarthrites (GFEGS); Nord-Trøndelag Health Study (HUNT); Spondyloarthritis Research Consortium of Canada (SPARCC); Wellcome Trust Case Control Consortium 2 (WTCCC2); Bowness P, Gafney K, Gaston H, Gladman DD, Rahman P, Maksymowych WP, Xu H, Crusius JB, van der Horst-Bruinsma IE, Chou CT, Valle-Oñate R, Romero-Sánchez C, Hansen IM, Pimentel-Santos FM, Inman RD, Videm V, Martin J, Breban M, Reveille JD, Evans DM, Kim TH, Wordsworth BP, Brown MA. Identification of multiple risk variants for ankylosing spondylitis through high-density genotyping of immune-related loci. Nat Genet 2013; 45(7): 730–738

[59] Langefeld CD, Ainsworth HC, Cunninghame Graham DS, Kelly JA, Comeau ME, Marion MC, Howard TD, Ramos PS, Croker JA, Morris DL, Sandling JK, Almlöf JC, Acevedo-Vásquez EM, Alarcón GS, Babini AM, Baca V, Bengtsson AA, Berbotto GA, Bijl M, Brown EE, Brunner HI, Cardiel MH, Catoggio L, Cervera R, Cucho-Venegas JM, Dahlqvist SR, D’Alfonso S, Da Silva BM, de la Rúa Figueroa I, Doria A, Edberg JC, Endreffy E, Esquivel-Valerio JA, Fortin PR, Freedman BI, Frostegård J, García MA, de la Torre IG, Gilkeson GS, Gladman DD, Gunnarsson I, Guthridge JM, Huggins JL, James JA, Kallenberg CGM, Kamen DL, Karp DR, Kaufman KM, Kottyan LC, Kovács L, Laustrup H, Lauwerys BR, Li QZ, Maradiaga-Ceceña MA, Martín J, McCune JM, McWilliams DR, Merrill JT, Miranda P, Moctezuma JF, Nath SK, Niewold TB, Orozco L, Ortego-Centeno N, Petri M, Pineau CA, Pons-Estel BA, Pope J, Raj P, Ramsey-Goldman R, Reveille JD, Russell LP, Sabio JM, Aguilar-Salinas CA, Scherbarth HR, Scorza R, Seldin MF, Sjöwall C, Svenungsson E, Thompson SD, Toloza SMA, Truedsson L, Tusié-Luna T, Vasconcelos C, Vilá LM, Wallace DJ, Weisman MH, Wither JE, Bhangale T, Oksenberg JR, Rioux JD, Gregersen PK, Syvänen AC, Rönnblom L, Criswell LA, Jacob CO, Sivils KL, Tsao BP, Schanberg LE, Behrens TW, Silverman ED, Alarcón-Riquelme ME, Kimberly RP, Harley JB, Wakeland EK, Graham RR, Gaffney PM, Vyse TJ. Transancestral mapping and genetic load in systemic lupus erythematosus. Nat Commun 2017; 8(1): 16021

[60] Kim K, Bang SY, Lee HS, Cho SK, Choi CB, Sung YK, Kim TH, Jun JB, Yoo DH, Kang YM, Kim SK, Suh CH, Shim SC, Lee SS, Lee J, Chung WT, Choe JY, Shin HD, Lee JY, Han BG, Nath SK, Eyre S, Bowes J, Pappas DA, Kremer JM, Gonzalez-Gay MA, Rodriguez-Rodriguez L, Ärlestig L, Okada Y, Diogo D, Liao KP, Karlson EW, Raychaudhuri S, Rantapää-Dahlqvist S, Martin J, Klareskog L, Padyukov L, Gregersen PK, Worthington J, Greenberg JD, Plenge RM, Bae SC. High-density genotyping of immune loci in Koreans and Europeans identifies eight new rheumatoid arthritis risk loci. Ann Rheum Dis 2015; 74(3): e13

[61] Li H, Hostager BS, Arkee T, Bishop GA. Multiple mechanisms for TRAF3-mediated regulation of the T cell costimulatory receptor GITR. J Biol Chem 2021; 297(3): 101097

[62] Astle WJ, Elding H, Jiang T, Allen D, Ruklisa D, Mann AL, Mead D, Bouman H, Riveros-Mckay F, Kostadima MA, Lambourne JJ, Sivapalaratnam S, Downes K, Kundu K, Bomba L, Berentsen K, Bradley JR, Daugherty LC, Delaneau O, Freson K, Garner SF, Grassi L, Guerrero J, Haimel M, Janssen-Megens EM, Kaan A, Kamat M, Kim B, Mandoli A, Marchini J, Martens JHA, Meacham S, Megy K, O’Connell J, Petersen R, Sharifi N, Sheard SM, Staley JR, Tuna S, van der Ent M, Walter K, Wang SY, Wheeler E, Wilder SP, Iotchkova V, Moore C, Sambrook J, Stunnenberg HG, Di Angelantonio E, Kaptoge S, Kuijpers TW, Carrillo-de-Santa-Pau E, Juan D, Rico D, Valencia A, Chen L, Ge B, Vasquez L, Kwan T, Garrido-Martín D, Watt S, Yang Y, Guigo R, Beck S, Paul DS, Pastinen T, Bujold D, Bourque G, Frontini M, Danesh J, Roberts DJ, Ouwehand WH, Butterworth AS, Soranzo N. The allelic landscape of human blood cell trait variation and links to common complex disease. Cell 2016; 167(5): 1415–1429.e19

[63] Jonsson S, Sveinbjornsson G, de Lapuente Portilla AL, Swaminathan B, Plomp R, Dekkers G, Ajore R, Ali M, Bentlage AEH, Elmér E, Eyjolfsson GI, Gudjonsson SA, Gullberg U, Gylfason A, Halldorsson BV, Hansson M, Holm H, JohanssonÅ, Johnsson E, Jonasdottir A, Ludviksson BR, Oddsson A, Olafsson I, Olafsson S, Sigurdardottir O, Sigurdsson A, Stefansdottir L, Masson G, Sulem P, Wuhrer M, Wihlborg AK, Thorleifsson G, Gudbjartsson DF, Thorsteinsdottir U, Vidarsson G, Jonsdottir I, Nilsson B, Stefansson K. Identification of sequence variants influencing immunoglobulin levels. Nat Genet 2017; 49(8): 1182–1191

[64] Johansson Å, Rask-Andersen M, Karlsson T, Ek WE. Genome-wide association analysis of 350 000 Caucasians from the UK Biobank identifies novel loci for asthma, hay fever and eczema. Hum Mol Genet 2019; 28(23): 4022–4041

[65] van der Harst P, Verweij N. Identification of 64 novel genetic loci provides an expanded view on the genetic architecture of coronary artery disease. Circ Res 2018; 122(3): 433–443

[66] Vujkovic M, Keaton JM, Lynch JA, Miller DR, Zhou J, Tcheandjieu C, Huffman JE, Assimes TL, Lorenz K, Zhu X, Hilliard AT, Judy RL, Huang J, Lee KM, Klarin D, Pyarajan S, Danesh J, Melander O, Rasheed A, Mallick NH, Hameed S, Qureshi IH, Afzal MN, Malik U, Jalal A, Abbas S, Sheng X, Gao L, Kaestner KH, Susztak K, Sun YV, DuVall SL, Cho K, Lee JS, Gaziano JM, Phillips LS, Meigs JB, Reaven PD, Wilson PW, Edwards TL, Rader DJ, Damrauer SM, O'Donnell CJ, Tsao PS; HPAP Consortium; Regeneron Genetics Center; VA Million Veteran Program; Chang KM, Voight BF, Saleheen D. Discovery of 318 new risk loci for type 2 diabetes and related vascular outcomes among 1.4 million participants in a multi-ancestry meta-analysis. Nat Genet 2020; 52(7): 680–691

[67] Murea M, Lu L, Ma L, Hicks PJ, Divers J, McDonough CW, Langefeld CD, Bowden DW, Freedman BI. Genome-wide association scan for survival on dialysis in African-Americans with type 2 diabetes. Am J Nephrol 2011; 33(6): 502–509

[68] Marigorta UM, Navarro A. High trans-ethnic replicability of GWAS results implies common causal variants. PLoS Genet 2013; 9(6): e1003566

[69] Orlando G, Law PJ, Palin K, Tuupanen S, Gylfe A, Hänninen UA, Cajuso T, Tanskanen T, Kondelin J, Kaasinen E, Sarin AP, Kaprio J, Eriksson JG, Rissanen H, Knekt P, Pukkala E, Jousilahti P, Salomaa V, Ripatti S, Palotie A, Järvinen H, Renkonen-Sinisalo L, Lepistö A, Böhm J, Mecklin JP, Al-Tassan NA, Palles C, Martin L, Barclay E, Tenesa A, Farrington S, Timofeeva MN, Meyer BF, Wakil SM, Campbell H, Smith CG, Idziaszczyk S, Maughan TS, Kaplan R, Kerr R, Kerr D, Buchanan DD, Win AK, Hopper J, Jenkins M, Lindor NM, Newcomb PA, Gallinger S, Conti D, Schumacher F, Casey G, Taipale J, Cheadle JP, Dunlop MG, Tomlinson IP, Aaltonen LA, Houlston RS. Variation at 2q35 (PNKD and TMBIM1) influences colorectal cancer risk and identifies a pleiotropic effect with inflammatory bowel disease. Hum Mol Genet 2016; 25(11): 2349–2359

[70] Gregersen LH, Mitter R, Ugalde AP, Nojima T, Proudfoot NJ, Agami R, Stewart A, Svejstrup JQ. SCAF4 and SCAF8, mRNA anti-terminator proteins. Cell 2019; 177(7): 1797–1813

[71] Bishop GA. TRAF3 as a powerful and multitalented regulator of lymphocyte functions. J Leukoc Biol 2016; 100(5): 919–926

[72] Sun X, Zhang H, Wang D, Ma D, Shen Y, Shang Y. DLP, a novel Dim1 family protein implicated in pre-mRNA splicing and cell cycle progression. J Biol Chem 2004; 279(31): 32839–32847

[73] Yao X, Yan C, Zhang L, Li Y, Wan Q. LncRNA ENST00113 promotes proliferation, survival, and migration by activating PI3K/Akt/mTOR signaling pathway in atherosclerosis. Medicine (Baltimore) 2018; 97(16): e0473

[74] Tian ZH, Yuan C, Yang K, Gao XL. Systematic identification of key genes and pathways in clear cell renal cell carcinoma on bioinformatics analysis. Ann Transl Med 2019; 7(5): 89

Acknowledgements

We are grateful to all the subjects and healthy volunteers who participated in this work. We thank Professor Jianjun Liu for reviewing the article and providing constructive suggestions. This work was supported by Guangdong–Hong Kong Joint Laboratory on Immunological and Genetic Kidney Diseases (No. 2019B121205005), National Natural Science Foundation of China (Nos. 81920108008, 81770661, 82170714, and 82003561), Guangzhou Municipal Science and Technology Project of China (No. 202201011246), Basic and Applied Basic Research Foundation of Guangdong Province (No. 2021A1515111054) and Fundamental Research Funds for the Central Universities (No. 2019kfyXJJS036).

Compliance with ethics guidelines

Conflicts of interest Ming Li , Xingjie Hao, Dianchun Shi, Shanshan Cheng, Zhong Zhong, Lu Cai, Minghui Jiang, Lin Ding, Lanbo Ding, Chaolong Wang, and Xueqing Yu declare that they have no conflict of interest.

The study was approved by the Institutional Review Board at the Guangdong Provincial People’s Hospital (No. GDREC2019272H) and the First Affiliated Hospital of Sun Yat-sen University (No. 2016215) according to the Declaration of Helsinki and the study was performed in accordance with the ethical standards as laid down in the 1964 Declaration of Helsinki and its later amendments or comparable ethical standards. Informed consent was obtained from all patients for being included in the study.

Electronic Supplementary Material

Supplementary material is available in the online version of this article at https://doi.org/10.1007/s11684-024-1086-2 and is accessible for authorized users.

版权

2024 Higher Education Press