TY - JOUR
T1 - Risk HLA-DQA1 and PLA2R1 alleles in idiopathic membranous nephropathy
AU - Stanescu, Horia C.
AU - Arcos-Burgos, Mauricio
AU - Medlar, Alan
AU - Bockenhauer, Detlef
AU - Kottgen, Anna
AU - Dragomirescu, Liviu
AU - Voinescu, Catalin
AU - Patel, Naina
AU - Pearce, Kerra
AU - Hubank, Mike
AU - Stephens, Henry A F
AU - Laundy, Valerie
AU - Padmanabhan, Sandosh
AU - Zawadzka, Anna
AU - Hofstra, Julia M.
AU - Coenen, Marieke J H
AU - Den Heijer, Martin
AU - Kiemeney, Lambertus A L M
AU - Bacq-Daian, Delphine
AU - Stengel, Benedicte
AU - Powis, Stephen H.
AU - Brenchley, Paul
AU - Feehally, John
AU - Rees, Andrew J.
AU - Debiec, Hanna
AU - Wetzels, Jack F M
AU - Ronco, Pierre
AU - Mathieson, Peter W.
AU - Kleta, Robert
PY - 2011/2/17
Y1 - 2011/2/17
N2 - BACKGROUND: 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. METHODS: 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). RESULTS: 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 A2 receptor (PLA2R1) (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×, 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). CONCLUSIONS: 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. Copyright © 2011 Massachusetts Medical Society.
AB - BACKGROUND: 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. METHODS: 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). RESULTS: 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 A2 receptor (PLA2R1) (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×, 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). CONCLUSIONS: 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. Copyright © 2011 Massachusetts Medical Society.
U2 - 10.1056/NEJMoa1009742
DO - 10.1056/NEJMoa1009742
M3 - Article
SN - 1533-4406
VL - 364
SP - 616
EP - 626
JO - New England Journal Of Medicine
JF - New England Journal Of Medicine
IS - 7
ER -