Dataset Information

Variations in the complement regulatory genes factor H (CFH) and factor H related 5 (CFHR5) are associated with membranoproliferative glomerulonephritis type II (dense deposit disease).

ABSTRACT:

Introduction

Membranoproliferative glomerulonephritis type II or dense deposit disease (MPGN II/DDD) causes chronic renal dysfunction that progresses to end stage renal disease in about half of patients within 10 years of diagnosis. Deficiency of and mutations in the complement factor H (CFH) gene are associated with the development of MPGN II/DDD, suggesting that dysregulation of the alternative pathway of the complement cascade is important in disease pathophysiology.

Subjects

Patients with MPGN II/DDD were studied to determine whether specific allele variants of CFH and CFHR5 segregate preferentially with the MPGN II/DDD disease phenotype. The control group was compromised of 131 people in whom age related macular degeneration had been excluded.

Results

Allele frequencies of four single nucleotide polymorphisms in CFH and three in CFHR5 were significantly different between MPGN II/DDD patients and controls.

Conclusion

We have identified specific allele variants of CFH and CFHR5 associated with the MPGN II/DDD disease phenotype. While our data can be interpreted to further implicate complement in the pathogenesis of MPGN II/DDD, these associations could also be unrelated to disease pathophysiology. Functional studies are required to resolve this question.

SUBMITTER: Abrera-Abeleda MA

PROVIDER: S-EPMC2564553 | biostudies-literature | 2006 Jul

REPOSITORIES: biostudies-literature

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Publications

Variations in the complement regulatory genes factor H (CFH) and factor H related 5 (CFHR5) are associated with membranoproliferative glomerulonephritis type II (dense deposit disease).

Abrera-Abeleda M A MA Nishimura C C Smith J L H JL Sethi S S McRae J L JL Murphy B F BF Silvestri G G Skerka C C Józsi M M Zipfel P F PF Hageman G S GS Smith R J H RJ

Journal of medical genetics 20051118 7

<h4>Introduction</h4>Membranoproliferative glomerulonephritis type II or dense deposit disease (MPGN II/DDD) causes chronic renal dysfunction that progresses to end stage renal disease in about half of patients within 10 years of diagnosis. Deficiency of and mutations in the complement factor H (CFH) gene are associated with the development of MPGN II/DDD, suggesting that dysregulation of the alternative pathway of the complement cascade is important in disease pathophysiology.<h4>Subjects</h4>P ...[more]

PMID: 16299065

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Project description:Rationale & objectiveMembranoproliferative glomerulonephritis (MPGN), encompassing several distinct diseases, is a rare but significant cause of kidney failure in the United States. The potential etiologies of MPGN are unclear, but prior studies have suggested dysregulation of the alternative complement pathway and, recently, autoimmunity as potential mechanisms driving MPGN pathogenesis. In this study, we examined HLA associations with end-stage kidney disease (ESKD) due to MPGN and dense deposit disease (DDD) in a large racially and ethnically diverse US-based cohort.Study designCase-control study.Setting & participantsUsing US Renal Data System (USRDS) and United Network for Organ Sharing (UNOS) data, we identified 3,424 patients with kidney failure due to MPGN and 263 due to DDD. We matched patients to kidney donor controls on designated race and ethnicity in a 1:15 ratio.Exposure58 class I and II HLA serotypes.OutcomeCase-control status.Analytical approachFor each disease cohort, univariable and multivariable logistic regression analyses were used to investigate associations between the disease and 58 HLA serotypes. In subgroup analyses, we investigated HLA associations in White and Black patients. We also studied antiglomerular basement membrane (anti-GBM) nephritis as a positive-control outcome. We applied a Bonferroni correction to account for multiple comparisons.ResultsEighteen serotypes were significantly associated with the odds of having MPGN in univariable analyses, with DR17 having the strongest association (odds ratio [OR], 1.55 [95% CI, 1.44-1.68], P=4.33e-28). No significant associations were found between any HLA serotype and DDD. Designated race-specific analyses showed comparable findings. We recapitulated known HLA associations in anti-GBM nephritis.LimitationsReliance on HLA serotypes (rather than genotype), lack of biopsy-confirmed diagnoses.ConclusionsHLA-DR17 is associated with ESKD due to MPGN in a racially and ethnically diverse cohort. The strength of association was similar in White and Black patients, suggesting a role in the pathogenesis of MPGN. No HLA associations were observed in patients with DDD.Plain-language summaryPrior studies have suggested dysregulation of the alternative complement pathway as a potential etiology of membranoproliferative glomerulonephritis (MPGN), but recent evidence from a British White population has implicated an autoimmune mechanism in MPGN pathogenesis. We investigated HLA associations between MPGN and dense deposit disease (DDD) in a large racially and ethnically diverse cohort of patients. We found that HLA-DR17 is associated with end-stage kidney disease (ESKD) due to MPGN in both White and Black patients. By contrast, no significant HLA associations with ESKD due to DDD were identified. These results suggest a role for autoimmunity in some cases of MPGN and highlight differences in the disease etiology of MPGN compared with DDD.

Dataset Information

Variations in the complement regulatory genes factor H (CFH) and factor H related 5 (CFHR5) are associated with membranoproliferative glomerulonephritis type II (dense deposit disease).

Introduction

Subjects

Results

Conclusion

Publications

Variations in the complement regulatory genes factor H (CFH) and factor H related 5 (CFHR5) are associated with membranoproliferative glomerulonephritis type II (dense deposit disease).

Similar Datasets

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