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

ABSTRACT: OBJECTIVE:African 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. METHODS:In 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. RESULTS:We 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). CONCLUSION:Distinct 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.

SUBMITTER: Lanata CM

PROVIDER: S-EPMC6023154 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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

Lanata Cristina M CM Nititham Joanne J Taylor Kimberly E KE Chung Sharon A SA Torgerson Dara G DG Seldin Michael F MF Pons-Estel Bernardo A BA Tusié-Luna Teresa T Tsao Betty P BP Morand Eric F EF Alarcón-Riquelme Marta E ME Criswell Lindsey A LA

PloS one 20180628 6

<h4>Objective</h4>African 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.<h4>Methods</h4>In this cross-sectional study, 1244 SLE patients from multiethnic case collections were genotyped for 817,810 single-nucleotide polymorphisms (SNPs) acr ...[more]

PMID: 29953444

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Project description:BackgroundPilot studies have estimated cancer incidence in patients with systemic lupus erythematous (SLE). However, the results have been inconclusive. To ascertain the correlation between SLE and malignancy more comprehensively and precisely, we conducted a meta-analysis.MethodsPubMed, the Cochrane Library and Embase databases through June 2014, were searched to identify observational studies evaluating the association between SLE and malignancy. The outcomes from these studies were measured as relative risks (RRs). A random or fixed effects model was chosen to calculate the pooled RR according to heterogeneity test. Between-study heterogeneity was assessed by estimating I2 index. Publication bias was assessed by Egger's test.ResultsA total of 16 papers, including 59,662 SLE patients, were suitable for the meta-analysis. Of these papers, 15 reported RRs for overall malignancy, 12 for non-Hodgkin lymphoma (NHL) and lung cancer, 7 for bladder cancer, 6 for Hodgkin lymphoma (HL) and leukemia, 5 for skin melanoma, and liver and thyroid cancers, 4 for multiple myeloma (MM), and esophageal and vaginal/vulvar cancers and 3 for laryngeal and non-melanoma skin cancers. The pooled RRs were 1.28 (95% CI, 1.17-1.41) for overall cancer, 5.40 (95% CI, 3.75-7.77) for NHL, 3.26(95% CI, 2.17-4.88) for HL, 2.01(95% CI, 1.61-2.52) for leukemia, 1.45(95% CI, 1.04-2.03) for MM, 4.19(95% CI, 1.98-8.87) for laryngeal cancer, 1.59 (95% CI, 1.44-1.76) for lung cancer, 1.86(95% CI, 1.21-2.88) for esophageal cancer, 3.21(95% CI, 1.70-6.05) for liver cancer, 3.67(95% CI, 2.80-4.81) for vaginal/vulvar cancer, 2.11(95% CI, 1.12-3.99) for bladder cancer, 1.51(95% CI, 1.12-2.03) for non-melanoma skin cancer, 1.78(95% CI, 1.35-2.33) for thyroid cancer, and 0.65(95% CI, 0.50-0.85) for skin melanoma. Only the meta-analyses of overall malignancy, NHL, and liver and bladder cancers produced substantial heterogeneity (I2, 57.6% vs 74.3% vs 67.7% vs 82.3%). No apparent publication bias was detected except for NHL studies.ConclusionsOur data support an association between SLE and malignancy, not only demonstrating an increased risk for NHL, HL, leukemia, and some non-hematologic malignancies, including laryngeal, lung, liver, vaginal/vulvar, and thyroid malignancies, but also a reduced risk for skin melanoma. Although an increased risk of MM, and esophageal, bladder and non-melanoma skin cancers was identified from the accumulated data in these studies, this observation requires confirmation.

Project description:BackgroundPatients with systemic lupus erythematosus (SLE) are at risk of developing COVID-19 due to underlying immune abnormalities and regular use of immunosuppressant medications. We aimed to evaluate the presence of SARS-CoV-2 IgG antibodies in patients with SLE with or without previous COVID-19-related symptoms or RT-PCR-confirmed SARS-CoV-2 infection.MethodsFor this analysis, we included patients with SLE from two cohorts based in New York City: the Web-based Assessment of Autoimmune, Immune-Mediated and Rheumatic Patients during the COVID-19 pandemic (WARCOV) study; and the NYU Lupus Cohort (a prospective registry of patients at NYU Langone Health and NYC Health + Hospitals/Bellevue). Patients in both cohorts were tested for SARS-CoV-2 IgG antibodies via commercially available immunoassays, processed through hospital or outpatient laboratories. Patients recruited from the NYU Lupus Cohort, referred from affiliated providers, or admitted to hospital with COVID-19 were tested for SARS-CoV-2 IgG antibodies as part of routine surveillance during follow-up clinical visits.Findings329 patients with SLE were included in this analysis, 146 from the WARCOV study and 183 from the NYU Lupus Cohort, and were tested for SARS-CoV-2 antibodies between April 29, 2020, and Feb 9, 2021. 309 (94%) were women and 91 (28%) were of Hispanic ethnicity. 51 (16%) of 329 patients had a positive SARS-CoV-2 IgG antibody test. Seropositive patients were more likely than seronegative patients to be Hispanic (24 [47%] of 51 vsz 67 [24%] of 278). Other demographic variables, SLE-specific factors, and immunosuppressant use were not associated with SARS-CoV-2 positivity. Of the 29 patients with COVID-19 previously confirmed by RT-PCR, 18 (62%) were on immunosuppressants; 24 (83%) of 29 patients tested positive for SARS-CoV-2 IgG antibodies. Of 17 patients who had symptoms of COVID-19 but negative concurrent RT-PCR testing, one (6%) developed an antibody response. Of 26 patients who had COVID-19-related symptoms but did not undergo RT-PCR testing, six (23%) developed an antibody response. Of 83 patients who had no symptoms of COVID-19 and no RT-PCR testing, four (5%) developed an antibody response. Among 36 patients who were initially SARS-CoV-2 IgG positive, the majority maintained reactivity serially (88% up to 10 weeks, 83% up to 20 weeks, and 80% up to 30 weeks). Seven (70%) of ten patients with confirmed COVID-19 had antibody positivity beyond 30 weeks from disease onset.InterpretationMost patients with SLE and confirmed COVID-19 were able to produce and maintain a serological response despite the use of a variety of immunosuppressants, providing reassurance about the efficacy and durability of humoral immunity and possible protection against re-infection with SARS-CoV-2.FundingNational Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, and Bloomberg Philanthropies COVID-19 Response Initiative Grant.

Dataset Information

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

Publications

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

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