Genetic contributions to lupus nephritis in a multi-ethnic cohort of systemic lupus erythematous patients

Abstract

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.

A phenotypic and genomics approach in a multi-ethnic cohort to subtype systemic lupus erythematosus

“…Lupus nephritis, a severe outcome of lupus that drives disease mortality, was found to be significantly correlated with genetic variants in ITGAM, TNFSF4, APOL1, PDGFRA, and SLC5A11 , among others. The HLA-DR2 and HLA-DR3 alleles have also been associated with susceptibility and autoantibody production in lupus 12–15 . Overall, hypomethylation of interferon-responsive genes has been associated with higher disease activity and renal disease, as well as production of autoantibodies 16–18 .…”

Racial and Ethnic Differences in the Prevalence and Time to Onset of Manifestations of Systemic Lupus Erythematosus: The California Lupus Surveillance Project

“…This is despite the fact that Asian/Pacific Islanders have the highest average levels of income and education and the best access to health care among racial/ethnic minority groups in San Francisco County , suggesting that there may be additional underlying factors that increase risk in this population. In African Americans, certain genotypes increase the risk of lupus nephritis, and although this is a potential mechanism among Asians, it remains understudied .…”

Cardiac phenotype in mouse models of systemic autoimmunity

“…Current studies in mouse models rely heavily on inbred mouse strains; however, these cannot mimic the genetically diverse human population. Yet, variable susceptibility based on genetic variation has emerged as a critical factor determining the risk of developing autoimmunity as well as determining the main target organ in systemic autoimmunity (Almlöf et al, 2017; Lanata et al, 2018). Importantly, mouse genetic diversity panels have been generated to overcome this limitation.…”