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ABIN1 dysfunction as a genetic basis for lupus nephritis.

ABSTRACT: The genetic factors underlying the pathogenesis of lupus nephritis associated with systemic lupus erythematosus are largely unknown, although animal studies indicate that nuclear factor (NF)-?B is involved. We reported previously that a knockin mouse expressing an inactive form of ABIN1 (ABIN1[D485N]) develops lupus-like autoimmune disease and demonstrates enhanced activation of NF-?B and mitogen-activated protein kinases in immune cells after toll-like receptor stimulation. In the current study, we show that ABIN1[D485N] mice develop progressive GN similar to class III and IV lupus nephritis in humans. To investigate the clinical relevance of ABIN1 dysfunction, we genotyped five single-nucleotide polymorphisms in the gene encoding ABIN1, TNIP1, in samples from European-American, African American, Asian, Gullah, and Hispanic participants in the Large Lupus Association Study 2. Comparing cases of systemic lupus erythematosus with nephritis and cases of systemic lupus erythematosus without nephritis revealed strong associations with lupus nephritis at rs7708392 in European Americans and rs4958881 in African Americans. Comparing cases of systemic lupus erythematosus with nephritis and healthy controls revealed a stronger association at rs7708392 in European Americans but not at rs4958881 in African Americans. Our data suggest that variants in the TNIP1 gene are associated with the risk for lupus nephritis and could be mechanistically involved in disease development via aberrant regulation of NF-?B and mitogen-activated protein kinase activity.

SUBMITTER: Caster DJ

PROVIDER: S-EPMC3810087 | biostudies-literature | 2013 Nov

REPOSITORIES: biostudies-literature

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ABIN1 dysfunction as a genetic basis for lupus nephritis.

Caster Dawn J DJ Korte Erik A EA Nanda Sambit K SK McLeish Kenneth R KR Oliver Rebecca K RK G'sell Rachel T RT Sheehan Ryan M RM Freeman Darrell W DW Coventry Susan C SC Kelly Jennifer A JA Guthridge Joel M JM James Judith A JA Sivils Kathy L KL Alarcon-Riquelme Marta E ME Scofield R Hal RH Adrianto Indra I Gaffney Patrick M PM Stevens Anne M AM Freedman Barry I BI Langefeld Carl D CD Tsao Betty P BP Pons-Estel Bernardo A BA Jacob Chaim O CO Kamen Diane L DL Gilkeson Gary S GS Brown Elizabeth E EE Alarcon Graciela S GS Edberg Jeffrey C JC Kimberly Robert P RP Martin Javier J Merrill Joan T JT Harley John B JB Kaufman Kenneth M KM Reveille John D JD Anaya Juan-Manuel JM Criswell Lindsey A LA Vila Luis M LM Petri Michelle M Ramsey-Goldman Rosalind R Bae Sang-Cheol SC Boackle Susan A SA Vyse Timothy J TJ Niewold Timothy B TB Cohen Philip P Powell David W DW

Journal of the American Society of Nephrology : JASN 20130822 11

The genetic factors underlying the pathogenesis of lupus nephritis associated with systemic lupus erythematosus are largely unknown, although animal studies indicate that nuclear factor (NF)-κB is involved. We reported previously that a knockin mouse expressing an inactive form of ABIN1 (ABIN1[D485N]) develops lupus-like autoimmune disease and demonstrates enhanced activation of NF-κB and mitogen-activated protein kinases in immune cells after toll-like receptor stimulation. In the current study ...[more]

PMID: 23970121

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Project description:ObjectiveAfrican Americans, East Asians, and Hispanics with systemic lupus erythematous (SLE) are more likely to develop lupus nephritis (LN) than are SLE patients of European descent. The etiology of this difference is not clear, and this study was undertaken to investigate how genetic variants might explain this effect.MethodsIn this cross-sectional study, 1244 SLE patients from multiethnic case collections were genotyped for 817,810 single-nucleotide polymorphisms (SNPs) across the genome. Continental genetic ancestry was estimated utilizing the program ADMIXTURE. Gene-based testing and pathway analysis was performed within each ethnic group and meta-analyzed across ethnicities. We also performed candidate SNP association tests with SNPs previously established as risk alleles for SLE, LN, and chronic kidney disease (CKD). Association testing and logistic regression models were performed with LN as the outcome, adjusted for continental ancestries, sex, disease duration, and age.ResultsWe studied 255 North European, 263 South European, 238 Hispanic, 224 African American and 264 East Asian SLE patients, of whom 606 had LN (48.7%). In genome-wide gene-based and candidate SNP analyses, we found distinct genes, pathways and established risk SNPs associated with LN for each ethnic group. Gene-based analyses showed significant associations between variation in ZNF546 (p = 1.0E-06), TRIM15 (p = 1.0E-06), and TRIMI0 (p = 1.0E-06) and LN among South Europeans, and TTC34 (p = 8.0E-06) was significantly associated with LN among Hispanics. The SNP rs8091180 in NFATC1 was associated with LN (OR 1.43, p = 3.3E-04) in the candidate SNP meta-analysis with the highest OR among African-Americans (OR 2.17, p = 0.0035).ConclusionDistinct genetic factors are associated with the risk of LN in SLE patients of different ethnicities. CKD risk alleles may play a role in the development of LN in addition to SLE-associated risk variants. These findings may further explain the clinical heterogeneity of LN risk and response to therapy observed between different ethnic groups.

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ABIN1 dysfunction as a genetic basis for lupus nephritis.

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ABIN1 dysfunction as a genetic basis for lupus nephritis.

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