title: Risk HLA-DQA1 and PLA(2)R1 alleles in idiopathic membranous nephropathy.
abstract: 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 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).
  
  
  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.
authors.affiliation: Centre for Nephrology, Royal Free Hospital, University College London, London, United Kingdom.
authors.forename: Horia C
authors.initials: HC
authors.lastname: Stanescu
authors.forename: Mauricio
authors.initials: M
authors.lastname: Arcos-Burgos
authors.forename: Alan
authors.initials: A
authors.lastname: Medlar
authors.forename: Detlef
authors.initials: D
authors.lastname: Bockenhauer
authors.forename: Anna
authors.initials: A
authors.lastname: Kottgen
authors.forename: Liviu
authors.initials: L
authors.lastname: Dragomirescu
authors.forename: Catalin
authors.initials: C
authors.lastname: Voinescu
authors.forename: Naina
authors.initials: N
authors.lastname: Patel
authors.forename: Kerra
authors.initials: K
authors.lastname: Pearce
authors.forename: Mike
authors.initials: M
authors.lastname: Hubank
authors.forename: Henry A F
authors.initials: HA
authors.lastname: Stephens
authors.forename: Valerie
authors.initials: V
authors.lastname: Laundy
authors.forename: Sandosh
authors.initials: S
authors.lastname: Padmanabhan
authors.forename: Anna
authors.initials: A
authors.lastname: Zawadzka
authors.forename: Julia M
authors.initials: JM
authors.lastname: Hofstra
authors.forename: Marieke J H
authors.initials: MJ
authors.lastname: Coenen
authors.forename: Martin
authors.initials: M
authors.lastname: den Heijer
authors.forename: Lambertus A L M
authors.initials: LA
authors.lastname: Kiemeney
authors.forename: Delphine
authors.initials: D
authors.lastname: Bacq-Daian
authors.forename: Benedicte
authors.initials: B
authors.lastname: Stengel
authors.forename: Stephen H
authors.initials: SH
authors.lastname: Powis
authors.forename: Paul
authors.initials: P
authors.lastname: Brenchley
authors.forename: John
authors.initials: J
authors.lastname: Feehally
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Rees
authors.forename: Hanna
authors.initials: H
authors.lastname: Debiec
authors.forename: Jack F M
authors.initials: JF
authors.lastname: Wetzels
authors.forename: Pierre
authors.initials: P
authors.lastname: Ronco
authors.forename: Peter W
authors.initials: PW
authors.lastname: Mathieson
authors.forename: Robert
authors.initials: R
authors.lastname: Kleta
mesh_terms: D000483:Alleles; D002889:Chromosomes, Human, Pair 2; D002896:Chromosomes, Human, Pair 6; D005060:Europe; D005260:Female; D055106:Genome-Wide Association Study; D005838:Genotype; D015433:Glomerulonephritis, Membranous / Q000235:genetics*; D006683:HLA-DQ Antigens / Q000235:genetics*; D059848:HLA-DQ alpha-Chains; D006801:Humans; D008297:Male; D016017:Odds Ratio; D020641:Polymorphism, Single Nucleotide; D054507:Receptors, Phospholipase A2 / Q000235:genetics*; D044465:White People / Q000235:genetics
chemical_list: D006683:HLA-DQ Antigens; D059848:HLA-DQ alpha-Chains; C069050:HLA-DQA1 antigen; C516360:PLA2R1 protein, human; D054507:Receptors, Phospholipase A2