High genetic risk score is associated with early disease onset, damage accrual and decreased survival in systemic lupus erythematosus

Reid, Sarah; Alexsson, Andrei; Frodlund, Martina; Morris, David L.; Sandling, Johanna K.; Bolin, Karin; Svenungsson, Elisabet; Jönsen, Andreas; Bengtsson, Christine; Gunnarsson, Iva; Rodriguez, Vera Illescas; Bengtsson, Anders; Arve, Sabine; Rantapää‐Dahlqvist, Solbritt; Eloranta, Maija‐Leena; Syvänen, Ann‐Christine; Sjöwall, Christopher; Vyse, Timothy J.; Rönnblom, Lars; Leonard, Dag

doi:10.1136/annrheumdis-2019-216227

Cited by 93 publications

(86 citation statements)

References 46 publications

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“…Recently, a Swedish group found that a higher cumulative genetic risk score spanning 57 SLE-associated loci was implicated in SLE onset, severity, organ damage, and death; however, APOL1 was not identi ed likely due to a lack of patients with African continental ancestry (38). The current study highlights the need to perform additional genetic susceptibility analyses in SLE patients of diverse ancestral backgrounds.…”

Section: Apol1 Genotype Is Associated With Case Fatalitymentioning

confidence: 76%

“…SLE is an extremely heterogeneous disease, with variation in clinical manifestations, race and ethnicity, disease onset, medication requirements, and disease activity all contributing to morbidity and mortality (24,36,37). Genetic susceptibility to early damage accrual, particularly in renal and cardiovascular domains, is implicated in early SLE deaths (38).…”

Section: Apol1 Genotype Is Associated With Case Fatalitymentioning

confidence: 99%

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Apolipoprotein L1 Risk Genotypes in Ghanaian Systemic Lupus Erythematosus Patients: A Prospective Cohort Study

Blazer

Dey

Nwaukoni

et al. 2020

Preprint

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Objective: Two Apolipoprotein L1 (APOL1) risk variants (RV) are enriched in sub-Saharan African populations due to a conferred resistance to Trypanosoma brucei. This comes at the cost of progressive renal disease by multiple causes including systemic lupus erythematosus (SLE). In African Americans, APOL1 high-risk genotypes have emerged as an important risk factor for progressive lupus nephritis. Despite emerging reports that SLE is common in Ghana, where APOL1 variant allelic frequencies are high, the regional contribution to SLE outcomes has not been described. Accordingly, this prospective longitudinal cohort study tested the associations between APOL1 high-risk genotypes and kidney outcomes, organ damage accrual, and death in 100 Ghanaian SLE patients.Methods: A prospective cohort of 100 SLE outpatients met four 1982 American College of Rheumatology SLE criteria. Patients were assessed for demographics, SLE activity, and organ injury as measured by the Systemic Lupus International Collaborating Clinics Damage Index (SDI) at baseline and every 6 months for 1 year. Serum, plasma, and saliva samples were taken for serologic testing and APOL1 genotyping. Outcomes of interest were kidney function, SDI, and case fatality. Results: Assuming a recessive model of inheritance, the APOL1 high-risk genotype (2RV) associated with developing end stage renal disease (ESRD) at an odds ratio of 14 (p=0.008). These patients accrued more SDI points particularly in renal, neurologic, and cardio/pulmonary domains. The SDI was 81.3% higher in 2RV patients compared to 0RV or 1RV patients despite no difference in SLE activity (p=0.02). After a 12 month period of observation, 3/12 (25%) of the 2RV patients died compared to 2/88 (2.3%) of the 0RV or 1RV carriers (odds ratio=13.6, p=0.01). Deaths were due to end stage kidney disease and heart failure. Conclusion: Our results suggest that in Ghanaian SLE patients, APOL1 risk variants are heritable risk factors for morbidity and mortality. Despite no appreciable differences in SLE severity, APOL1 high-risk patients exhibited progressive renal disease, organ damage accrual, and a 13-fold higher case fatality rate.

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Section: Apol1 Genotype Is Associated With Case Fatalitymentioning

confidence: 76%

Section: Apol1 Genotype Is Associated With Case Fatalitymentioning

confidence: 99%

Apolipoprotein L1 Risk Genotypes in Ghanaian Systemic Lupus Erythematosus Patients: A Prospective Cohort Study

Blazer

Dey

Nwaukoni

et al. 2020

Preprint

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“…In this gene–environment interaction study of SLE risk, the largest conducted to date and the first, to our knowledge, to employ GWAS results rather than to investigate individual candidate polymorphisms, we created an updated, weighted GRS based on existing GRS studies of SLE (28,29), and tested for interactions between SLE genetic factors and smoking status in relation to their potential influence on SLE risk. We found that having a high wGRS and being a current or recent smoker were each individually strongly associated with SLE risk: each standard deviation increase in the wGRS more than doubled the risk of SLE, while current smokers and those who had recently quit smoking had an increased SLE risk of ~50% compared to never and more distant past smokers.…”

Section: Discussionmentioning

confidence: 99%

Interactions Between Genome‐Wide Genetic Factors and Smoking Influencing Risk of Systemic Lupus Erythematosus

Cui

Raychaudhuri

Karlson

et al. 2020

Arthritis & Rheumatology

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Objective To identify interactions between genetic factors and current or recent smoking in relation to risk of developing systemic lupus erythematosus (SLE). Methods For 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. Results The 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. Conclusion The 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.

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“…Recently, the GRS (genetic risk score) has been widely adopted to predict disease outcomes from genetic variants [66]. The previous studies in SLE showed that overall mortality was higher in the striking GRS SLE patients; also, the high cumulative genetic risk could predict the speci c organ damages such as proliferative nephritis and cardiovascular disease [67].…”

Section: Discussionmentioning

confidence: 99%

Meta-analysis of genome-wide association study identifies FBN2 as a novel locus associated with Systemic Lupus Erythematosus in Thai population

Tangtanatakul

Thumarat

Satproedprai³

et al. 2020

Preprint

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Background: Differences in the expression of variants across ethnic groups in the Systemic Lupus Erythematosus (SLE) patients have been well documented. However, the genetic architecture in the Thai population has not been thoroughly examined. In this study, we carried out genome-wide association study (GWAS) in the Thai population. Methods: Two GWAS cohorts were independently collected and genotyped: discovery dataset (487 SLE cases and 1,606 healthy controls) and replication dataset (405 SLE cases and 1,590 unrelated-disease controls). Data were imputed to the density of the 1,000 Genomes Project Phase 3. Association studies were performed based on different genetic models, and pathway enrichment analysis was further examined. In addition, the performance of disease risk estimation for individuals in Thai GWAS was assessed based on the polygenic risk score (PRS) model trained by other Asian populations. Results: Previous findings on SLE susceptible alleles were well replicated in the two GWAS. The SNPs on HLA-class II (rs9270970, A>G, OR=1.82, p-value = 3.61E-26), STAT4 (rs7582694, C>G, OR=1.57, p-value = 8.21E-16), GTF2I (rs73366469, A>G, OR=1.73, p-value = 2.42E-11) and FAM167A-BLK allele (rs13277113, A>G, OR=0.68, p-value = 1.58E-09) were significantly associated with SLE in Thai population. Meta-analysis of the two GWAS identified a novel locus at the FBN2 that was specifically associated with SLE in the Thai population (rs74989671, A>G, OR=1.54, p-value = 1.61E-08). Functional analysis showed that rs74989671 resided in a peak of H3K36me3 derived from CD14+ monocytes and H3K4me1 from T-lymphocytes. In addition, we showed that the PRS model trained from the Chinese population could be applied in individuals of Thai ancestry, with the area under the receiver-operator curve (AUC) achieving 0.76 for this predictor. Conclusions: We demonstrated the genetic architecture of SLE in the Thai population and identified a novel locus associated with SLE. Also, our study suggested a potential use of the PRS model from the Chinese population to estimate the disease risk for individuals of Thai ancestry.

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High genetic risk score is associated with early disease onset, damage accrual and decreased survival in systemic lupus erythematosus

Cited by 93 publications

References 46 publications

Apolipoprotein L1 Risk Genotypes in Ghanaian Systemic Lupus Erythematosus Patients: A Prospective Cohort Study

Apolipoprotein L1 Risk Genotypes in Ghanaian Systemic Lupus Erythematosus Patients: A Prospective Cohort Study

Interactions Between Genome‐Wide Genetic Factors and Smoking Influencing Risk of Systemic Lupus Erythematosus

Meta-analysis of genome-wide association study identifies FBN2 as a novel locus associated with Systemic Lupus Erythematosus in Thai population

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