title: HLA-DQA1 and PLA2R1 polymorphisms and risk of idiopathic membranous nephropathy.
abstract: OBJECTIVE
  Single nucleotide polymorphisms (SNPs) within HLA complex class II HLA-DQ α-chain 1 (HLA-DQA1) and M-type phospholipase A2 receptor (PLA2R1) genes were identified as strong risk factors for idiopathic membranous nephropathy (IMN) development in a recent genome-wide association study. Copy number variants (CNVs) within the Fc gamma receptor III (FCGR3) locus have been associated with several autoimmune diseases, but their role in IMN has not been studied. This study aimed to validate the association of HLA-DQA1 and PLA2R1 risk alleles with IMN in a Spanish cohort, test the putative association of FCGR3A and FCGR3B CNVs with IMN, and assess the use of these genetic factors to predict the clinical outcome of the disease.
  
  
  METHODS
  A Spanish cohort of 89 IMN patients and 286 matched controls without nephropathy was recruited between October of 2009 and July of 2012. Case-control studies for SNPs within HLA-DQA1 (rs2187668) and PLA2R1 (rs4664308) genes and CNVs for FCGR3A and FCGR3B genes were performed. The contribution of these polymorphisms to predict clinical outcome and renal function decline was analyzed.
  
  
  RESULTS
  This study validated the association of these HLA-DQA1 and PLA2R1 SNPs with IMN in a Spanish cohort and its increased risk when combining both risk genotypes. No significant association was found between FCGR3 CNVs and IMN. These results revealed that HLA-DQA1 and PLA2R1 genotype combination adjusted for baseline proteinuria strongly predicted response to immunosuppressive therapy. HLA-DQA1 genotype adjusted for proteinuria was also linked with renal function decline.
  
  
  CONCLUSIONS
  This study confirms that HLA-DQA1 and PLA2R1 genotypes are risk factors for IMN, whereas no association was identified for FCGR3 CNVs. This study provides, for the first time, evidence of the contribution of these HLA-DQA1 and PLA2R1 polymorphisms in predicting IMN response to immunosuppressors and disease progression. Future studies are needed to validate and identify prognostic markers.
authors.affiliation: Molecular Biology Laboratory and, †Nephrology Department, Fundació Puigvert, Instituto de Investigaciones Biomédicas Sant Pau (IIB-Sant Pau), Universitat Autònoma de Barcelona, Red de Investigación Renal, Instituto de Investigación Carlos III, Barcelona, Spain.
authors.forename: Gemma
authors.initials: G
authors.lastname: Bullich
authors.forename: José
authors.initials: J
authors.lastname: Ballarín
authors.forename: Artur
authors.initials: A
authors.lastname: Oliver
authors.forename: Nadia
authors.initials: N
authors.lastname: Ayasreh
authors.forename: Irene
authors.initials: I
authors.lastname: Silva
authors.forename: Sheila
authors.initials: S
authors.lastname: Santín
authors.forename: Montserrat M
authors.initials: MM
authors.lastname: Díaz-Encarnación
authors.forename: Roser
authors.initials: R
authors.lastname: Torra
authors.forename: Elisabet
authors.initials: E
authors.lastname: Ars
mesh_terms: D000328:Adult; D000368:Aged; D001706:Biopsy; D016022:Case-Control Studies; D018450:Disease Progression; D005260:Female; D058851:GPI-Linked Proteins / Q000235:genetics; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D015433:Glomerulonephritis, Membranous / Q000188:drug therapy / Q000235:genetics* / Q000276:immunology; D059848:HLA-DQ alpha-Chains / Q000235:genetics*; D006801:Humans; D007166:Immunosuppressive Agents / Q000627:therapeutic use; D007668:Kidney / Q000187:drug effects / Q000276:immunology / Q000503:physiopathology; D008297:Male; D008875:Middle Aged; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D011507:Proteinuria / Q000235:genetics / Q000276:immunology; D017452:Receptors, IgG / Q000235:genetics; D054507:Receptors, Phospholipase A2 / Q000235:genetics*; D012074:Remission Induction; D012307:Risk Factors; D013030:Spain; D016896:Treatment Outcome
chemical_list: C496124:FCGR3A protein, human; C428200:FCGR3B protein, human; D058851:GPI-Linked Proteins; D059848:HLA-DQ alpha-Chains; C069050:HLA-DQA1 antigen; D007166:Immunosuppressive Agents; C516360:PLA2R1 protein, human; D017452:Receptors, IgG; D054507:Receptors, Phospholipase A2