BACKGROUND AND OBJECTIVES: 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. DESIGN, SETTINGS, PARTICIPANTS, & MEASUREMENTS: 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. CONCLUSION: 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.
BACKGROUND AND OBJECTIVES: 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. DESIGN, SETTINGS, PARTICIPANTS, & MEASUREMENTS: 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. CONCLUSION: 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: Horia C Stanescu; Mauricio Arcos-Burgos; Alan Medlar; Detlef Bockenhauer; Anna Kottgen; Liviu Dragomirescu; Catalin Voinescu; Naina Patel; Kerra Pearce; Mike Hubank; Henry A F Stephens; Valerie Laundy; Sandosh Padmanabhan; Anna Zawadzka; Julia M Hofstra; Marieke J H Coenen; Martin den Heijer; Lambertus A L M Kiemeney; Delphine Bacq-Daian; Benedicte Stengel; Stephen H Powis; Paul Brenchley; John Feehally; Andrew J Rees; Hanna Debiec; Jack F M Wetzels; Pierre Ronco; Peter W Mathieson; Robert Kleta Journal: N Engl J Med Date: 2011-02-17 Impact factor: 91.245
Authors: Laurence H Beck; Fernando C Fervenza; David M Beck; Ramon G B Bonegio; Fahim A Malik; Stephen B Erickson; Fernando G Cosio; Daniel C Cattran; David J Salant Journal: J Am Soc Nephrol Date: 2011-07-22 Impact factor: 10.121
Authors: Sejoong Kim; Ho Jun Chin; Ki Young Na; Suhnggwon Kim; Jieun Oh; Wookyung Chung; Jung Woo Noh; Young Ki Lee; Jong Tae Cho; Eun Kyoung Lee; Dong-Wan Chae Journal: Nephron Clin Pract Date: 2010-08-31
Authors: Julia M Hofstra; Hanna Debiec; Colin D Short; Timotheé Pellé; Robert Kleta; Peter W Mathieson; Pierre Ronco; Paul E Brenchley; Jack F Wetzels Journal: J Am Soc Nephrol Date: 2012-09-06 Impact factor: 10.121
Authors: Peggy Sekula; Yong Li; Horia C Stanescu; Matthias Wuttke; Arif B Ekici; Detlef Bockenhauer; Gerd Walz; Stephen H Powis; Jan T Kielstein; Paul Brenchley; Kai-Uwe Eckardt; Florian Kronenberg; Robert Kleta; Anna Köttgen Journal: Nephrol Dial Transplant Date: 2016-02-04 Impact factor: 5.992