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PLA2R-associated membranous glomerulopathy is modulated by common variants in PLA2R1 and HLA-DQA1 genes

Genes & Immunity volume 15, pages 556–561 (2014)Cite this article

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Abstract

Membranous glomerulopathy (MG) is most commonly caused by autoantibodies directed against the podocyte phospholipase A2 receptor (PLA2R1) and common variants in this gene are associated with MG. Here for the first time, we carried out a large case–control association study (n=1512) of PLA2R-positive and -negative MG to determine the extent of association in these pathologic subtypes. We performed four separate sets of analyses to determine significance of the single-nucleotide polymorphisms (SNPs) and their haplotypes followed by joint analysis and trans-ethnic mapping to increase power. The PLA2R1 SNP rs35771982 was most strongly associated with PLA2R-positive MG (P=1.4 × 10−14, odds ratio (ORGG)=1.98). The associations of other SNPs in PLA2R1 could be explained because of linkage disequilibrium with the G-allele. Haplotypes in PLA2R1 did not exceed the significance of rs35771982 even after 10 000 permutations. PLA2R1 variants were only associated with PLA2R-positive MG and predominantly in Caucasians. PLA2R1 variants did not associate with MG in African Americans (AA). There was strong epistasis between HLA-DQA1 SNP rs2187668 and the PLA2R1 variant rs35771982. Thus, common variants in the PLA2R1, particularly rs35771982, modulate PLA2R-positive MG with HLA-DQA1 in Caucasians. PLA2R-negative MG especially in AA, may provide a novel opportunity to discover new genes underlying MG.

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References

  1. Beck LH, Bonegio RG, Lambeau G, Beck DM, Powell DW, Cummins TD et al. M-type phospholipase A2 receptor as target antigen in idiopathic membranous nephropathy. N Engl J Med 2009; 361: 11–21.

    Article  CAS  Google Scholar 

  2. Qin W, Beck LH Jr, Zeng C, Chen Z, Li S, Zuo K et al. Anti-phospholipase A2 receptor antibody in membranous nephropathy. J Am Soc Nephrol 2011; 22: 1137–1143.

    Article  CAS  Google Scholar 

  3. Larsen CP, Messias NC, Silva FG, Messias E, Walker PD . Determination of primary versus secondary membranous glomerulopathy utilizing phospholipase A2 receptor (PLA2R1) staining in renal biopsies. Mod Pathol 2013; 26: 709–715.

    Article  CAS  Google Scholar 

  4. Hoxha E, Kneissler U, Stege G, Zahner G, Thiele I, Panzer U et al. Enhanced expression of the M-type phospholipase A2 receptor in glomeruli correlates with serum receptor antibodies in primary membranous nephropathy. Kidney Int 2012; 82: 797–804.

    Article  CAS  Google Scholar 

  5. Stanescu HC, Arcos-Burgos M, Medlar A, Bockenhauer D, Kottgen A, Dragomirescu L et al. Risk HLA-DQA1 and PLA2R1 alleles in idiopathic membranous nephropathy. N Engl J Med 2011; 364: 616–626.

    Article  CAS  Google Scholar 

  6. Liu YH, Chen CH, Chen SY, Lin YJ, Liao WL, Tsai CH et al. Association of phospholipase A2 receptor 1 polymorphisms with idiopathic membranous nephropathy in Chinese patients in Taiwan. J Biomed Sci. 2010; 17: 81.

    Article  Google Scholar 

  7. Kim S, Chin HJ, Na KY, Oh J, Chung W, Noh JW et al. Single nucleotide polymorphisms in the phospholipase A2 receptor gene are associated with genetic susceptibility to idiopathic membranous nephropathy. Nephron Clin Pract 2011; 117: c253–c258.

    Article  Google Scholar 

  8. Coenen MJ, Hofstra JM, Debiec H, Stanescu HC, Medlar AJ, Stengel B et al. Phospholipase A2 Receptor (PLA2R1) Sequence Variants in Idiopathic Membranous Nephropathy. J Am Soc Nephrol 2013; 24: 677–683.

    Article  CAS  Google Scholar 

  9. Lv J, Hou W, Zhou X, Liu G, Zhou F, Zhao N et al. Interaction between PLA2R1 and HLA-DQA1 variants associates with Anti-PLA2R antibodies and membranous nephropathy. J Am Soc Nephrol 2013; 24: 1323–1329.

    Article  CAS  Google Scholar 

  10. Morris AP . Transethnic meta-analysis of genomewide association studies. Genet Epidemiol 2011; 35: 809–822.

    Article  Google Scholar 

  11. Ritchie MD, Hahn LW, Moore JH . Power of multifactor dimensionality reduction for detecting gene-gene interactions in the presence of genotyping error, missing data, phenocopy, and genetic heterogeneity. Genet Epidemiol 2003; 24: 150–157.

    Article  Google Scholar 

  12. Skol AD, Scott LJ, Abecasis GR, Boehnke M . Joint analysis is more efficient than replication-based analysis for two-stage genome-wide association studies. Nat Gent 2006; 38: 209–213.

    Article  CAS  Google Scholar 

  13. Pulit SL, Voight BF, de Bakker PIW . Multiethnic genetic association studies improve power for locus discovery. PLoS ONE 2010; 5: e12600.

    Article  Google Scholar 

  14. Edwards AO, Ritter R III, Abel KJ, Manning A, Panhuysen C, Farrer LA . Complement factor H polymorphism and age-related macular degeneration. Science 2005; 308: 421–424.

    Article  CAS  Google Scholar 

  15. Larsen CP, Beggs ML, Saeed M, Walker PD . Apolipoprotein L1 risk variants associate with systemic lupus erythematosus-associated collapsing glomerulopathy. J Am Soc Nephrol 2013; 24: 722–725.

    Article  CAS  Google Scholar 

  16. Purcell S, Neale B, Todd-Brown K, Thomas L, Ferreira MA, Bender D et al. PLINK: a tool set for whole-genome association and population-based linkage analyses. Am J Hum Genet 2007; 81: 559–575.

    Article  CAS  Google Scholar 

  17. Barrett JC, Fry B, Maller J, Daly MJ . Haploview: analysis and visualization of LD and haplotype maps. Bioinformatics 2005; 21: 263–265.

    Article  CAS  Google Scholar 

  18. Hahn LW, Ritchie MD, Moore JH . Multifactor dimensionality reduction software for detecting gene-gene and gene-environment interactions. Bioinformatics 2003; 19: 376–382.

    Article  CAS  Google Scholar 

  19. Storey JD, Tibshirani R . Statistical significance for genomewide studies. Proc Natl Acad Sci USA 2003; 100: 9440–9445.

    Article  CAS  Google Scholar 

  20. Jameson BA, Wolf H . The antigenic index: a novel algorithm for predicting antigenic determinants. Comput Appl Biosci 1988; 4: 181–186.

    CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Department of Genomics, Nephropath, Little Rock, AR, USA

    M Saeed, M L Beggs, P D Walker & C P Larsen

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  1. M Saeed
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  2. M L Beggs
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Correspondence to C P Larsen.

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Saeed, M., Beggs, M., Walker, P. et al. PLA2R-associated membranous glomerulopathy is modulated by common variants in PLA2R1 and HLA-DQA1 genes. Genes Immun 15, 556–561 (2014). https://doi.org/10.1038/gene.2014.50

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