Risk HLA-DQA1 and PLA2R1 alleles in idiopathic membranous nephropathy

Centre for Nephrology, Royal Free Hospital, University College London, London, United Kingdom.
New England Journal of Medicine (Impact Factor: 55.87). 02/2011; 364(7):616-26. DOI: 10.1056/NEJMoa1009742
Source: PubMed

ABSTRACT Idiopathic membranous nephropathy is a major cause of the nephrotic syndrome in adults, but its etiologic basis is not fully understood. We investigated the genetic basis of biopsy-proven cases of idiopathic membranous nephropathy in a white population.
We performed independent genomewide association studies of single-nucleotide polymorphisms (SNPs) in patients with idiopathic membranous nephropathy from three populations of white ancestry (75 French, 146 Dutch, and 335 British patients). The patients were compared with racially matched control subjects; population stratification and quality controls were carried out according to standard criteria. Associations were calculated by means of a chi-square basic allele test; the threshold for significance was adjusted for multiple comparisons (with the Bonferroni method).
In a joint analysis of data from the 556 patients studied (398 men), we identified significant alleles at two genomic loci associated with idiopathic membranous nephropathy. Chromosome 2q24 contains the gene encoding M-type phospholipase A(2) receptor (PLA(2)R1) (SNP rs4664308, P=8.6×10(-29)), previously shown to be the target of an autoimmune response. Chromosome 6p21 contains the gene encoding HLA complex class II HLA-DQ alpha chain 1 (HLA-DQA1) (SNP rs2187668, P=8.0×10(-93)). The association with HLA-DQA1 was significant in all three populations (P=1.8×10(-9), P=5.6×10(-27), and P=5.2×10(-36) in the French, Dutch, and British groups, respectively). The odds ratio for idiopathic membranous nephropathy with homozygosity for both risk alleles was 78.5 (95% confidence interval, 34.6 to 178.2).
An HLA-DQA1 allele on chromosome 6p21 is most closely associated with idiopathic membranous nephropathy in persons of white ancestry. This allele may facilitate an autoimmune response against targets such as variants of PLA2R1. Our findings suggest a basis for understanding this disease and illuminate how adaptive immunity is regulated by HLA.

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Available from: Andrew J Rees, Sep 27, 2015
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    • "CTLA4 rs231775, FAS rs1800682, and TNF rs1800629 genotyped using the predesigned TaqMan SNP genotyping assays C_2415786_20, C_9578811_10, and C_7514879_10, respectively. HLA-A1-B8, HLA-DR1*03:01, and HLA-DR1*04:01 were genotyped indirectly using the tagging SNPs rs3749971 (C_25983472_20) (Santos et al. 2008), rs2187668 (C_58662585_10) (Stanescu et al. 2011), rs660895 (C_26546458_30) (Ahmed et al. 2012). The web-based analysis programme SHEsis ( "
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    ABSTRACT: The precise etiology of autoimmune hepatitis (AIH) remains unknown, although a number of genetic loci have been implicated in the susceptibility of type 1 AIH. The purpose of this study was to test for association of these loci with type 1 AIH in New Zealand Caucasians. 77 AIH patients and 485 healthy controls were genotyped for the SNPs rs2187668 (HLA-DRB*03:01), rs660895 (HLA-DRB*04:01), rs3749971 (HLA-A1-B8-DR3), rs231775 (CLTLA4), rs1800629 (TNF), and rs1800682 (FAS) using predesigned TaqMan SNP genotyping assays. Chi square analysis was used to test for association of allele and genotype with overall AIH, and with severe fibrosis and ALT levels at 6 months. Significant risk of AIH was conferred by the minor alleles of rs2187668 (OR = 2.45, 95% CI 1.65-3.61, p < 0.0001), rs3749971 (OR = 1.89, 95% CI 1.21-2.94, p = 0.004) and rs1800629 (OR = 2.06, 95% CI 1.41-3.01, p = 0.0001). Multivariate analysis showed that rs2187668 was independently associated with type 1 AIH susceptibility (OR = 2.40, 95% CI 1.46-3.93, p = 0.001). The C allele of FAS SNP rs1800682 was associated with increased risk of severe fibrosis at diagnosis (OR = 2.03, 95% CI 1.05-3.93, p = 0.035) and with incomplete normalization of ALT levels at 6 months post-diagnosis (OR = 3.94, 95% CI 1.62-9.54, p = 0.0015). This is the first population-based study to investigate genetic risk loci for type 1 AIH in New Zealand Caucasians. We report significant independent association of HLA-DRB1*03:01 with overall susceptibility to type 1 AIH, as well as FAS with a more aggressive disease phenotype.
    SpringerPlus 07/2013; 2(1):355. DOI:10.1186/2193-1801-2-355
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    • "The association of HLA antigens with the renal diseases has been poorly established. However, it is possible that specific HLA antigens may predispose an individual to other autoimmune or infectious diseases which affect the renal function.[20–22] "
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    Indian Journal of Human Genetics 04/2013; 19(2):219-32. DOI:10.4103/0971-6866.116122
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    • "The critiques of these genetic studies focused on single nucleotide polymorphism have been softened by recent Genome wide Association Studies. These studies confirmed the association of HLA alleles with renal diseases as HLA-DQ alpha 1 chain in idiopathic membranous nephropathy [43], HLA-DRB1 and HLA-DQB1 in hepatitis B virus induced nephropathy [44], HLA-DQ and HLA-B in IgA nephropathy [45]. Altogether, these data suggest interactions between MHC class II proteins and glomerular components even when the underlying mechanism remains unknown. "
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    PLoS ONE 06/2012; 7(6):e35838. DOI:10.1371/journal.pone.0035838 · 3.23 Impact Factor
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