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Mechanistic insights into environmental and genetic risk factors for systemic lupus erythematosus.

ABSTRACT: Systemic lupus erythematosus (SLE) is an autoimmune disease involving multiple organ systems with diverse presentation, primarily affecting women of reproductive age. Various genetic and environmental risk factors are involved in the pathogenesis of SLE, and many SLE susceptibility genes have been identified recently; however, gene therapy is not a viable clinical option at this time. Thus, environmental risks factors, particularly regional characteristics that can be controlled, need to be further investigated. Here, we systematically explored these risk factors, including ultraviolet radiation, seasonal distribution, geographical distribution, and climate factors, and also summarized the mechanisms related to these risk factors. Probable mechanisms were explicated in at least four aspects including inflammatory mediators, apoptosis and autophagy in keratinocytes, epigenetic factors, and gene-environment interactions. This information is expected to provide practical insights into these risk factors in order to benefit patients with SLE and facilitate the development of potential therapeutic strategies.

SUBMITTER: Pan Q

PROVIDER: S-EPMC6456562 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Mechanistic insights into environmental and genetic risk factors for systemic lupus erythematosus.

Pan Qingjun Q Chen Jinxia J Guo Linjie L Lu Xing X Liao Shuzhen S Zhao Chunfei C Wang Sijie S Liu Huafeng H

American journal of translational research 20190315 3

Systemic lupus erythematosus (SLE) is an autoimmune disease involving multiple organ systems with diverse presentation, primarily affecting women of reproductive age. Various genetic and environmental risk factors are involved in the pathogenesis of SLE, and many SLE susceptibility genes have been identified recently; however, gene therapy is not a viable clinical option at this time. Thus, environmental risks factors, particularly regional characteristics that can be controlled, need to be furt ...[more]

PMID: 30972159

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Project description:ObjectiveThrombosis is a serious complication of systemic lupus erythematosus (SLE). We investigated whether genetic variants implicated in thrombosis pathways are associated with thrombosis among 2 ethnically diverse SLE cohorts.MethodsOur discovery cohort consisted of 1698 patients with SLE enrolled in the University of California, San Francisco, Lupus Genetics Project and our replication cohort included 1361 patients with SLE enrolled in the PROFILE cohort. Patients fulfilled American College of Rheumatology SLE criteria, and data relevant to thrombosis were available. Thirty-three single nucleotide polymorphisms (SNP) previously shown to be associated with risk of deep venous thrombosis in the general population or implicated in thrombosis pathways were genotyped and tested for association with thrombosis in bivariate allelic analyses. SNP with p < 0.1 in the bivariate analyses were further tested in multivariable logistic regression models adjusted for age, sex, disease duration, antiphospholipid antibody status, smoking, nephritis, and medications.ResultsIn the discovery cohort, 23% of patients with SLE experienced a thrombotic event. SNP in the following genes demonstrated association with thrombosis risk overall in the discovery or replication cohorts and were assessed using metaanalytic methods: factor V Leiden (FVL) rs6025 (OR 1.85, p = 0.02) and methylenetetrahydrofolate reductase (MTHFR) rs1801133 (OR 0.75, p = 0.04) in whites, and fibrinogen gamma (FGG) rs2066865 (OR 1.91, p = 0.01) in Hispanic Americans. SNP in these genes showed association with venous thrombosis risk in whites: MTHFR rs1801131 (OR 1.51, p = 0.01), MTHFR rs1801133 (OR 0.70, p = 0.04), FVL rs6025 (OR 2.69, p = 0.002), and FGG rs2066865 (OR 1.49, p = 0.02) in whites. A SNP in FGG rs2066865 (OR 2.19, p = 0.003) demonstrated association with arterial thrombosis risk in Hispanics.ConclusionOur results implicate specific genetic risk factors for thrombosis in patients with SLE and suggest that genetic risk for thrombosis differs across ethnic groups.

Project description:ObjectiveTo identify interactions between genetic factors and current or recent smoking in relation to risk of developing systemic lupus erythematosus (SLE).MethodsFor the study, 673 patients with SLE (diagnosed according to the American College of Rheumatology 1997 updated classification criteria) were matched by age, sex, and race (first 3 genetic principal components) to 3,272 control subjects without a history of connective tissue disease. Smoking status was classified as current smoking/having recently quit smoking within 4 years before diagnosis (or matched index date for controls) versus distant past/never smoking. In total, 86 single-nucleotide polymorphisms and 10 classic HLA alleles previously associated with SLE were included in a weighted genetic risk score (wGRS), with scores dichotomized as either low or high based on the median value in control subjects (low wGRS being defined as less than or equal to the control median; high wGRS being defined as greater than the control median). Conditional logistic regression models were used to estimate both the risk of SLE and risk of anti-double-stranded DNA autoantibody-positive (dsDNA+) SLE. Additive interactions were assessed using the attributable proportion (AP) due to interaction, and multiplicative interactions were assessed using a chi-square test (with 1 degree of freedom) for the wGRS and for individual risk alleles. Separate repeated analyses were carried out among subjects of European ancestry only.ResultsThe mean ± SD age of the SLE patients at the time of diagnosis was 36.4 ± 15.3 years. Among the 673 SLE patients included, 92.3% were female and 59.3% were dsDNA+. Ethnic distributions were as follows: 75.6% of European ancestry, 4.5% of Asian ancestry, 11.7% of African ancestry, and 8.2% classified as other ancestry. A high wGRS (odds ratio [OR] 2.0, P = 1.0 × 10-51 versus low wGRS) and a status of current/recent smoking (OR 1.5, P = 0.0003 versus distant past/never smoking) were strongly associated with SLE risk, with significant additive interaction (AP 0.33, P = 0.0012), and associations with the risk of anti-dsDNA+ SLE were even stronger. No significant multiplicative interactions with the total wGRS (P = 0.58) or with the HLA-only wGRS (P = 0.06) were found. Findings were similar in analyses restricted to only subjects of European ancestry.ConclusionThe strong additive interaction between an updated SLE genetic risk score and current/recent smoking suggests that smoking may influence specific genes in the pathogenesis of SLE.

Dataset Information

Mechanistic insights into environmental and genetic risk factors for systemic lupus erythematosus.

Publications

Mechanistic insights into environmental and genetic risk factors for systemic lupus erythematosus.

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