Skip to main content
Log in

Genome-wide association study identifies TNFSF13 as a susceptibility gene for IgA in a South Chinese population in smokers

  • Original Paper
  • Published:
Immunogenetics Aims and scope Submit manuscript

Abstract

IgA is an important factor in our immune system. There are many diseases associated with it, such as IgA nephropathy, IgA deficiency, and so on. In order to describe the relationship between the genes and the IgA level, we performed a genome-wide association study of serum IgA with 1,999 healthy Chinese men in the first stage and replicated on an independent Chinese sample with 1,496 subjects in the second stage. Association between each SNP with IgA was estimated by multivariate linear regression analysis conditioned on age and smoke. Haplotype analysis for the block around the top SNP was performed. In the first stage, one genomic locus was identified to be significantly associated with IgA. The loci is TNFSF13 (17p13.1; rs3803800; P = 6.26 × 10−8). In smoke-specific analysis, rs3803800 was approximately significantly associated with IgA levels in smokers (P = 3.96 × 10−7), while no association was observed in nonsmokers (P = 2.28 × 10−1). In addition, we performed the haplotype analysis on chromosome 17 with the SNPs around rs3803800. Although the total P value for the haplotype did not acquire significant difference, three haplotypes (TGAG, CACG, and CACA) reached significant (P < 0.05). In conclusion, TNFSF13 could be a susceptible gene which was discovered having relationship with serum IgA level, and smoke might be a factor infecting the IgA level.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1
Fig. 2

Similar content being viewed by others

References

  • Al-Ghamdi HS, Anil S (2007) Serum antibody levels in smoker and non-smoker Saudi subjects with chronic periodontitis. J Periodontol 78:1043–1050

    Article  PubMed  Google Scholar 

  • Andersen P, Pedersen OF, Bach B, Bonde GJ (1982) Serum antibodies and immunoglobulins in smokers and nonsmokers. Clin Exp Immunol 47:467–473

    PubMed  CAS  Google Scholar 

  • Blount DG, Pritchard DI, Heaton PR (2005) Age-related alterations to immune parameters in Labrador retriever dogs. Vet Immunol Immunopathol 108:399–407

    Article  PubMed  CAS  Google Scholar 

  • Cai GY, Chen XM (2009) Immunoglobulin A nephropathy in China: progress and challenges. Am J Nephrol 30:268–273

    Article  PubMed  CAS  Google Scholar 

  • Castigli E, Scott S, Dedeoglu F, Bryce P, Jabara H, Bhan AK, Mizoguchi E, Geha RS (2004) Impaired IgA class switching in APRIL-deficient mice. Proc Natl Acad Sci U S A 101:3903–3908

    Article  PubMed  CAS  Google Scholar 

  • Cerutti A (2008) The regulation of IgA class switching. Nat Rev Immunol 8:421–434

    Article  PubMed  CAS  Google Scholar 

  • Cheng YC, Kao WH, Mitchell BD, O’Connell JR, Shen H, McArdle PF, Gibson Q, Ryan KA, Shuldiner AR, Pollin TI (2009) Genome-wide association scan identifies variants near matrix metalloproteinase (MMP) genes on chromosome 11q21-22 strongly associated with serum MMP-1 levels. Circ Cardiovasc Genet 2:329–337

    Article  PubMed  CAS  Google Scholar 

  • Fasching CE, Grossman T, Corthésy B, Plaut AG, Weiser JN, Janoff EN (2007) Impact of the molecular form of immunoglobulin A on functional activity in defense against Streptococcus pneumoniae. Infect Immun 75:1801–1810

    Article  PubMed  CAS  Google Scholar 

  • 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 (2010) HLA has strongest association with IgA nephropathy in genome-wide analysis. J Am Soc Nephrol 21:1791–1797

    Article  PubMed  CAS  Google Scholar 

  • Ferreira RC, Pan-Hammarström Q, Graham RR, Fontán G, Lee AT, Ortmann W, Wang N, Urcelay E, Fernández-Arquero M, Núñez C, Jorgensen G, Ludviksson BR, Koskinen S, Haimila K, Padyukov L, Gregersen PK, Hammarström L, Behrens TW (2012) High-density SNP mapping of the HLA region identifies multiple independent susceptibility loci associated with selective IgA deficiency. PLoS Genet 8:e1002476

    Article  PubMed  CAS  Google Scholar 

  • 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 (2011) Genome-wide association study identifies susceptibility loci for IgA nephropathy. Nat Genet 43:321–327

    Article  PubMed  CAS  Google Scholar 

  • Gonzalez-Quintela A, Alende R, Gude F, Campos J, Rey J, Meijide LM, Fernandez-Merino C, Vidal C (2008) Serum levels of immunoglobulins (IgG, IgA, IgM) in a general adult population and their relationship with alcohol consumption, smoking and common metabolic abnormalities. Clin Exp Immunol 151:42–50

    Article  PubMed  CAS  Google Scholar 

  • Grundbacher FJ (1974) Heritability estimates and genetic and environmental correlations for the human immunoglobulins G, M, and A. Am J Hum Genet 26:1–12

    PubMed  CAS  Google Scholar 

  • Hardenberg G, Planelles L, Schwarte CM, van Bostelen L, Le Huong T, Hahne M, Medema JP (2007) Specific TLR ligands regulate APRIL secretion by dendritic cells in a PKR-dependent manner. Eur J Immunol 37:2900–2911

    Article  PubMed  CAS  Google Scholar 

  • Hardenberg G, van Bostelen L, Hahne M, Medema JP (2008) Thymus-independent class switch recombination is affected by APRIL. Immunol Cell Biol 86:530–534

    Article  PubMed  CAS  Google Scholar 

  • HogenEsch H, Thompson S, Dunham A, Ceddia M, Hayek M (2004) Effect of age on immune parameters and the immune response of dogs to vaccines: a cross-sectional study. Vet Immunol Immunopathol 97:77–85

    Article  PubMed  CAS  Google Scholar 

  • James T et al (1974) Biologic variation of human serum immunoglobulin concentration sex–age specific effects. J Chron Dis 27:507–516

    Article  Google Scholar 

  • Koyama T, Tsukamoto H, Masumoto K, Himeji D, Hayashi K, Harada M, Horiuchi T (2003) A novel polymorphism of the human APRIL gene is associated with systemic lupus erythematosus. Rheumatology 42:980–985

    Article  PubMed  CAS  Google Scholar 

  • Li LS, Liu ZH (2004) Epidemiologic data of renal diseases from a single unit in China: analysis based on 13,519 renal biopsies. Kidney Int 66:920–923

    Article  PubMed  Google Scholar 

  • Liao Ming, Ye Fanghui, Zhang Bing, Huang Lulu, Xiao Qiang, Qin Min, Mo Linjian, Tan Aihua, Gao Yong, Lu Zheng, Wu Chunlei, Zhang Youjie, Zhang Haiying, Qin Xue, Hu Yanling, Yang Xiaobo, Mo Zengnan (2012) Genome-wide association study identifies common variants at TNFRSF13B associated with IgG level in a healthy Chinese male population. Genes Immun 1–5

  • Litinskiy MB, Nardelli B, Hilbert DM, He B, Schaffer A, Casali P, Cerutti A (2002) DCs induce CD40-independent immunoglobulin class switching through BLyS and APRIL. Nat Immunol 3:822–829

    Article  PubMed  CAS  Google Scholar 

  • Liu XQ, Paterson AD, He N, St George-Hyslop P, Rauta V, Gronhagen-Riska C, Laakso M, Thibaudin L, Berthoux F, Cattran D, Pei Y (2008) IL5RA and TNFRSF6B gene variants are associated with sporadic IgA nephropathy. J Am Soc Nephrol 19:1025–1033

    Article  PubMed  CAS  Google Scholar 

  • Otten MA, van Egmond M (2004) The Fc receptor for IgA (FcalphaRI, CD89). Immunol Lett 92:23–31

    Article  PubMed  CAS  Google Scholar 

  • Price AL, Patterson NJ, Plenge RM, Weinblatt ME, Shadick NA, Reich D (2006) Principal components analysis corrects for stratification in genome-wide association studies. Nat Genet 38:904–909

    Article  PubMed  CAS  Google Scholar 

  • Purcell S, Neale B, Todd-Brown K, Thomas L, Ferreira MA, Bender D, Maller J, Sklar P, de Bakker PI, Daly MJ, Sham PC (2007) PINK: a tool set for whole-genome association and population-based linkage analyses. Am J Hum Genet 81:559–575

    Article  PubMed  CAS  Google Scholar 

  • Rodriguez-Segade S, Camiña MF, Carnero A, Lorenzo MJ, Alban A, Quinteiro C, Lojo S (1996) High serum IgA concentrations in patients with diabetes mellitus: age wise distribution and relation to chronic complications. Clin Chem 42:1064–1067

    PubMed  CAS  Google Scholar 

  • Schaid DJ, Rowland CM, Tines DE, Jacobson RM, Poland GA (2002) Score tests for association between traits and haplotypes when linkage phase is ambiguous. Am J Hum Genet 70:425–434

    Article  PubMed  Google Scholar 

  • Smith NL, Huffman JE, Strachan DP, Huang J, Dehghan A, Trompet S, Lopez LM, Shin SY, Baumert J, Vitart V, Bis JC, Wild SH, Rumley A, Yang Q, Uitterlinden AG, Stott DJ, Davies G, Carter AM, Thorand B, Polašek O, McKnight B, Campbell H, Rudnicka AR, Chen MH, Buckley BM, Harris SE, Peters A, Pulanic D, Lumley T, de Craen AJ, Liewald DC, Gieger C, Campbell S, Ford I, Gow AJ, Luciano M, Porteous DJ, Guo X, Sattar N, Tenesa A, Cushman M, Slagboom PE, Visscher PM, Spector TD, Illig T, Rudan I, Bovill EG, Wright AF, McArdle WL, Tofler G, Hofman A, Westendorp RG, Starr JM, Grant PJ, Karakas M, Hastie ND, Psaty BM, Wilson JF, Lowe GD, O’Donnell CJ, Witteman JC, Jukema JW, Deary IJ, Soranzo N, Koenig W, Hayward C (2011) Genetic predictors of fibrin D-dimer levels in healthy adults. Circulation 123:1864–1872

    Article  PubMed  CAS  Google Scholar 

  • Stoica G, Macarie E, Michiu V, Stoica RC (1980) Biologic variation of human immunoglobulin concentration. I. Sex-age specific effects on serum levels of IgG, IgA, IgM and IgD. Med Interne 18:323–332

    PubMed  CAS  Google Scholar 

  • Tan A, Gao Y, Yang X, Zhang H, Qin X, Mo L, Peng T, Xia N, Mo Z (2011) Low serum osteocalcin level is a potential marker for metabolic syndrome: results from a Chinese male population survey. Metabolism 60:1186–1192

    Article  PubMed  CAS  Google Scholar 

  • Vuong MT, Lundberg S, Gunnarsson I, Wramner L, Seddighzadeh M, Hahn-Zoric M, Fernström A, Hanson LA, Do LT, Jacobson SH, Padyukov L (2009) Genetic variation in the transforming growth factor-beta1 gene is associated with susceptibility to IgA nephropathy. Nephrol Dial Transplant 24:3061–3067

    Article  PubMed  CAS  Google Scholar 

  • Woof JM, Kerr MA (2004) IgA function—variations on a theme. Immunology 113:175–177

    Article  PubMed  CAS  Google Scholar 

  • You F, Zhou L, Liu X, Fan J, Ke Z, Ren W (2012) Molecular structure, expression analysis and functional characterization of APRIL (TNFSF13) gene in bat (Vespertilio superans Thomas). Gene 498:196–202

    Article  PubMed  CAS  Google Scholar 

  • 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 (2011) A genome-wide association study in Han Chinese identifies multiple susceptibility loci for IgA nephropathy. Nat Genet 44:178–182

    Article  PubMed  Google Scholar 

  • Zhao Z, Timofeev N, Hartley SW, Chui DH, Fucharoen S, Perls TT, Steinberg MH, Baldwin CT, Sebastiani P (2008) Imputation of missing genotypes: an empirical evaluation of IMPUTE. BMC Genet 12:85

    Article  Google Scholar 

Download references

Conflict of interest

The authors have declared no conflict of interest.

Acknowledgment

This study was partially supported by grants from the National Natural Science Foundation of China (81060213, 81060234, 30945204, 30360124, 30260110), Key Program and University Talents Highland Innovation Team of Guangxi (2012012D003, GJR201147-09), Chairman Science and Technology Fund and Tackle Program of Guangxi (1116-03, GKG1298003-07-01), Guangxi Science Fund for Distinguished Young Scholars (2012GXNSFFA060009), Guangxi Provincial Department of Finance and Education (2009GJCJ150), intramural funding from Fudan-VARI Center for genetic Epidemiology and intramural funding from Fudan University Institute of Urology, Guangxi Natural Science Foundation (2011GXNSFB018100).The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Author information

Authors and Affiliations

Authors

Corresponding authors

Correspondence to Hu Yanling or Mo Zengnan.

Additional information

Chen Yang, Wang Jie, and Yang Yanlong contributed equally to this work.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary Material Fig. 1

The Q-Q plot of genome-wide association analyses for serum IgA level (DOC 541 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Yang, C., Jie, W., Yanlong, Y. et al. Genome-wide association study identifies TNFSF13 as a susceptibility gene for IgA in a South Chinese population in smokers. Immunogenetics 64, 747–753 (2012). https://doi.org/10.1007/s00251-012-0636-y

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00251-012-0636-y

Keywords

Navigation