A Genome-wide Association Study in Han Chinese Identifies Multiple Susceptibility Loci for IgA Nephropathy

Overview

Journal Nat Genet

Specialty Genetics

Date 2011 Dec 27

PMID 22197929

Citations 151

Authors

Xue-Qing Yu

Ming Li

Hong Zhang

Hui-Qi Low

Xin Wei

Jin-Quan Wang

Liang-Dan Sun

Kar-Seng Sim

Yi Li

Jia-Nee Foo

Wei Wang

Zhi-Jian Li

Xian-Yong Yin

Xue-Qing Tang

Li Fan

Jian Chen

Rong-Shan Li

Jian-Xin Wan

Zhang-Suo Liu

Tan-Qi Lou

Li Zhu

Xiao-Jun Huang

Xue-Jun Zhang

Zhi-Hong Liu

Jian-Jun Liu

Affiliations

Soon will be listed here.

Abstract

We performed a two-stage genome-wide association study of IgA nephropathy (IgAN) in Han Chinese, with 1,434 affected individuals (cases) and 4,270 controls in the discovery phase and follow-up of the top 61 SNPs in an additional 2,703 cases and 3,464 controls. We identified associations at 17p13 (rs3803800, P = 9.40 × 10(-11), OR = 1.21; rs4227, P = 4.31 × 10(-10), OR = 1.23) and 8p23 (rs2738048, P = 3.18 × 10(-14), OR = 0.79) that implicated the genes encoding tumor necrosis factor (TNFSF13) and α-defensin (DEFA) as susceptibility genes. In addition, we found multiple associations in the major histocompatibility complex (MHC) region (rs660895, P = 4.13 × 10(-20), OR = 1.34; rs1794275, P = 3.43 × 10(-13), OR = 1.30; rs2523946, P = 1.74 × 10(-11), OR = 1.21) and confirmed a previously reported association at 22q12 (rs12537, P = 1.17 × 10(-11), OR = 0.78). We also found that rs660895 was associated with clinical subtypes of IgAN (P = 0.003), proteinuria (P = 0.025) and IgA levels (P = 0.047). Our findings show that IgAN is associated with variants near genes involved in innate immunity and inflammation.

Citing Articles

Inflammatory Bowel Diseases and Nephropathies: Exploring the Gut-Kidney Axis.

De Sire R, La Mantia A, Bonacci L, Testa A, Guarino A, Rispo A Life (Basel). 2025; 14(12.

PMID: 39768250 PMC: 11678131. DOI: 10.3390/life14121541.

What is new in the pathogenesis and treatment of IgA glomerulonephritis.

Salvadori M, Rosso G World J Nephrol. 2024; 13(4):98709.

PMID: 39723359 PMC: 11572654. DOI: 10.5527/wjn.v13.i4.98709.

Towards Risk Stratification in Clinical Care for IgA Nephropathy: Genetic Risk Scores: Comments on the Study "Clinical Application of Polygenic Risk Score in IgA Nephropathy".

Berthier C, Ju W Phenomics. 2024; 4(5):527-530.

PMID: 39723228 PMC: 11666848. DOI: 10.1007/s43657-024-00184-8.

Post-transplant glomerular diseases: update on pathophysiology, risk factors and management strategies.

Regalia A, Abinti M, Alfieri C, Campise M, Verdesca S, Zanoni F Clin Kidney J. 2024; 17(12):sfae320.

PMID: 39664990 PMC: 11630810. DOI: 10.1093/ckj/sfae320.

Analysis of a Familial IgAN Accompanied by COL4A3 Mutation.

Lin S, Deng J, Jiang H, Xiang S, Lin W, Qian F J Inflamm Res. 2024; 17:9269-9283.

PMID: 39583860 PMC: 11585981. DOI: 10.2147/JIR.S480279.

References

Maruhashi Y, Nakajima M, Akazawa H, Shimoyama H, Nishiguchi M, Yamoto Y . Analysis of macrophages in urine sediments in children with IgA nephropathy. Clin Nephrol. 2004; 62(5):336-43. DOI: 10.5414/cnp62336. View

Cao H, Li M, Nie J, Wang W, Zhou S, Yu X . Human leukocyte antigen DRB1 alleles predict risk and disease progression of immunoglobulin A nephropathy in Han Chinese. Am J Nephrol. 2008; 28(4):684-91. PMC: 2786014. DOI: 10.1159/000122111. View

Abecasis G, Altshuler D, Auton A, Brooks L, Durbin R, Gibbs R . A map of human genome variation from population-scale sequencing. Nature. 2010; 467(7319):1061-73. PMC: 3042601. DOI: 10.1038/nature09534. View

Gharavi A, Yan Y, Scolari F, Schena F, Frasca G, Ghiggeri G . IgA nephropathy, the most common cause of glomerulonephritis, is linked to 6q22-23. Nat Genet. 2000; 26(3):354-7. DOI: 10.1038/81677. View

Hsu S . Racial and genetic factors in IgA nephropathy. Semin Nephrol. 2008; 28(1):48-57. DOI: 10.1016/j.semnephrol.2007.10.006. View

Levy M, Berger J . Worldwide perspective of IgA nephropathy. Am J Kidney Dis. 1988; 12(5):340-7. DOI: 10.1016/s0272-6386(88)80021-0. View

Barratt J, Feehally J . IgA nephropathy. J Am Soc Nephrol. 2005; 16(7):2088-97. DOI: 10.1681/ASN.2005020134. View

Donadio J, Grande J . IgA nephropathy. N Engl J Med. 2002; 347(10):738-48. DOI: 10.1056/NEJMra020109. View

Purcell S, Neale B, Todd-Brown K, Thomas L, Ferreira M, Bender D . PLINK: a tool set for whole-genome association and population-based linkage analyses. Am J Hum Genet. 2007; 81(3):559-75. PMC: 1950838. DOI: 10.1086/519795. View

10.

Castigli E, Scott S, Dedeoglu F, Bryce P, Jabara H, Bhan A . Impaired IgA class switching in APRIL-deficient mice. Proc Natl Acad Sci U S A. 2004; 101(11):3903-8. PMC: 374342. DOI: 10.1073/pnas.0307348101. View

11.

Yu H, Chu K, Yang Y, Lee J, Wang L, Lin Y . Genetics and immunopathogenesis of IgA nephropathy. Clin Rev Allergy Immunol. 2010; 41(2):198-213. DOI: 10.1007/s12016-010-8232-0. View

12.

Tsuchiya N, Kobayashi S, Hashimoto H, Ozaki S, Tokunaga K . Association of HLA-DRB1*0901-DQB1*0303 haplotype with microscopic polyangiitis in Japanese. Genes Immun. 2005; 7(1):81-4. DOI: 10.1038/sj.gene.6364262. View

13.

Fennessy M, Hitman G, Moore R, Metcalfe K, Medcraft J, Sinico R . HLA-DQ gene polymorphism in primary IgA nephropathy in three European populations. Kidney Int. 1996; 49(2):477-80. DOI: 10.1038/ki.1996.67. View

14.

Stangou M, Alexopoulos E, Papagianni A, Pantzaki A, Bantis C, Dovas S . Urinary levels of epidermal growth factor, interleukin-6 and monocyte chemoattractant protein-1 may act as predictor markers of renal function outcome in immunoglobulin A nephropathy. Nephrology (Carlton). 2009; 14(6):613-20. DOI: 10.1111/j.1440-1797.2008.01051.x. View

15.

Neusser M, Lindenmeyer M, Edenhofer I, Gaiser S, Kretzler M, Regele H . Intrarenal production of B-cell survival factors in human lupus nephritis. Mod Pathol. 2010; 24(1):98-107. DOI: 10.1038/modpathol.2010.184. View

16.

Browning S, Browning B . Rapid and accurate haplotype phasing and missing-data inference for whole-genome association studies by use of localized haplotype clustering. Am J Hum Genet. 2007; 81(5):1084-97. PMC: 2265661. DOI: 10.1086/521987. View

17.

Kiryluk K, Julian B, Wyatt R, Scolari F, Zhang H, Novak J . Genetic studies of IgA nephropathy: past, present, and future. Pediatr Nephrol. 2010; 25(11):2257-68. PMC: 2937145. DOI: 10.1007/s00467-010-1500-7. View

18.

Paterson A, Liu X, Wang K, Magistroni R, Song X, Kappel J . Genome-wide linkage scan of a large family with IgA nephropathy localizes a novel susceptibility locus to chromosome 2q36. J Am Soc Nephrol. 2007; 18(8):2408-15. DOI: 10.1681/ASN.2007020241. View

19.

Saraheimo M, Forsblom C, Pettersson-Fernholm K, Flyvbjerg A, Groop P, Frystyk J . Increased levels of alpha-defensin (-1, -2 and -3) in type 1 diabetic patients with nephropathy. Nephrol Dial Transplant. 2007; 23(3):914-8. DOI: 10.1093/ndt/gfm711. View

20.

Kawabata Y, Ikegami H, Awata T, Imagawa A, Maruyama T, Kawasaki E . Differential association of HLA with three subtypes of type 1 diabetes: fulminant, slowly progressive and acute-onset. Diabetologia. 2009; 52(12):2513-21. DOI: 10.1007/s00125-009-1539-9. View