scholarly journals Whole-genome sequencing identifies complex contributions to genetic risk by variants in genes causing monogenic systemic lupus erythematosus

2019 ◽  
Vol 138 (2) ◽  
pp. 141-150 ◽  
Author(s):  
Jonas Carlsson Almlöf ◽  
Sara Nystedt ◽  
Dag Leonard ◽  
Maija-Leena Eloranta ◽  
Giorgia Grosso ◽  
...  
Keyword(s):  
Systemic Lupus Erythematosus ◽  
Whole Genome Sequencing ◽  
Genome Sequencing ◽  
Lupus Erythematosus ◽  
Genetic Risk ◽  
Whole Genome ◽  
Systemic Lupus

scholarly journals Contributions of de novo variants to systemic lupus erythematosus

2020 ◽  
Vol 29 (1) ◽  
pp. 184-193 ◽  
Author(s):  
Jonas Carlsson Almlöf ◽  
Sara Nystedt ◽  
Aikaterini Mechtidou ◽  
Dag Leonard ◽  
Maija-Leena Eloranta ◽  
...  
Keyword(s):  
Systemic Lupus Erythematosus ◽  
Whole Genome Sequencing ◽  
Genome Sequencing ◽  
Lupus Erythematosus ◽  
De Novo ◽  
Whole Genome ◽  
Gene Promoters ◽  
Single Nucleotide Variants ◽  
Systemic Lupus ◽  
Promoter Regions

AbstractBy performing whole-genome sequencing in a Swedish cohort of 71 parent-offspring trios, in which the child in each family is affected by systemic lupus erythematosus (SLE, OMIM 152700), we investigated the contribution of de novo variants to risk of SLE. We found de novo single nucleotide variants (SNVs) to be significantly enriched in gene promoters in SLE patients compared with healthy controls at a level corresponding to 26 de novo promoter SNVs more in each patient than expected. We identified 12 de novo SNVs in promoter regions of genes that have been previously implicated in SLE, or that have functions that could be of relevance to SLE. Furthermore, we detected three missense de novo SNVs, five de novo insertion-deletions, and three de novo structural variants with potential to affect the expression of genes that are relevant for SLE. Based on enrichment analysis, disease-affecting de novo SNVs are expected to occur in one-third of SLE patients. This study shows that de novo variants in promoters commonly contribute to the genetic risk of SLE. The fact that de novo SNVs in SLE were enriched to promoter regions highlights the importance of using whole-genome sequencing for identification of de novo variants.

scholarly journals Genetic Risk Factors for Thrombosis in Systemic Lupus Erythematosus

2012 ◽  
Vol 39 (8) ◽  
pp. 1603-1610 ◽  
Author(s):  
RACHEL KAISER ◽  
YONGHONG LI ◽  
MONICA CHANG ◽  
JOSEPH CATANESE ◽  
ANN B. BEGOVICH ◽  
...  
Keyword(s):  
Risk Factors ◽  
Systemic Lupus Erythematosus ◽  
Venous Thrombosis ◽  
Lupus Erythematosus ◽  
Genetic Risk ◽  
Genetic Risk Factors ◽  
Antiphospholipid Antibody ◽  
Systemic Lupus ◽  
Discovery Cohort ◽  
Thrombosis Risk

Objective.Thrombosis 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.Methods.Our 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.Results.In 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.Conclusion.Our results implicate specific genetic risk factors for thrombosis in patients with SLE and suggest that genetic risk for thrombosis differs across ethnic groups.

scholarly journals Genome-wide assessment of genetic risk for systemic lupus erythematosus and disease severity

2019 ◽  
Author(s):  
Lingyan Chen ◽  
Yong-Fei Wang ◽  
Lu Liu ◽  
Adrianna Bielowka ◽  
Rahell Ahmed ◽  
...  
Keyword(s):  
Systemic Lupus Erythematosus ◽  
Renal Disease ◽  
Disease Severity ◽  
Lupus Erythematosus ◽  
Genetic Risk ◽  
Age Of Onset ◽  
Genome Wide Association Studies ◽  
Systemic Lupus ◽  
Chinese Populations ◽  
Genome Wide

AbstractObjectiveUsing three European and two Chinese genome-wide association studies (GWAS), we investigated the performance of genetic risk scores (GRS) for predicting the susceptibility and severity of Systemic lupus erythematosus (SLE), using renal disease as a proxy for severity.MethodsWe used four GWASs to test the performance of GRS both cross validating within the European population and between European and Chinese populations. The performance of GRS in SLE risk prediction was evaluated by Receiver Operating Characteristic (ROC) curves. We then analyzed the polygenic nature of SLE statistically. We also partitioned patients according to their age-of-onset and evaluated the predictability of GRS in disease severity in each age group.ResultsWe found consistently that the best GRS in the prediction of SLE used SNPs associated at the level of P<1e-05 in all GWAS datasets and that SNPs with P-values above 0.2 were inflated for SLE true positive signals. The GRS results in an area under the ROC curve ranging between 0.64 and 0.72, within European and between the European and Chinese populations. We further showed a significant positive correlation between a GRS and renal disease in two independent European GWAS (Pcohort1=2.44e-08; Pcohort2=0.00205) and a significant negative correlation with age of SLE onset (Pcohort1=1.76e-12; Pcohort2=0.00384). We found that the GRS performed better in prediction of renal disease in the ‘later onset’ compared to the ‘earlier onset’ group.ConclusionThe GRS predicts SLE in both European and Chinese populations and correlates with poorer prognostic factors: young age of onset and lupus nephritis.

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

2019 ◽  
Vol 79 (3) ◽  
pp. 363-369 ◽  
Author(s):  
Sarah Reid ◽  
Andrei Alexsson ◽  
Martina Frodlund ◽  
David Morris ◽  
Johanna K Sandling ◽  
...  
Keyword(s):  
Systemic Lupus Erythematosus ◽  
Risk Score ◽  
Lupus Erythematosus ◽  
Genetic Risk ◽  
Genetic Risk Score ◽  
Disease Onset ◽  
Organ Damage ◽  
Systemic Lupus ◽  
Discovery Cohort ◽  
Damage Accrual

ObjectivesTo investigate associations between a high genetic disease risk and disease severity in patients with systemic lupus erythematosus (SLE).MethodsPatients with SLE (n=1001, discovery cohort and n=5524, replication cohort) and healthy controls (n=2802 and n=9859) were genotyped using a 200K Immunochip single nucleotide polymorphism array. A genetic risk score (GRS) was assigned to each individual based on 57 SLE risk loci.ResultsSLE was more prevalent in the high, compared with the low, GRS-quartile (OR 12.32 (9.53 to 15.71), p=7.9×10–86 and OR 7.48 (6.73 to 8.32), p=2.2×10–304 for the discovery and the replication cohorts, respectively). In the discovery cohort, patients in the high GRS-quartile had a 6-year earlier mean disease onset (HR 1.47 (1.22 to 1.75), p=4.3×10–5), displayed higher prevalence of damage accrual (OR 1.47 (1.06 to 2.04), p=2.0×10–2), renal disorder (OR 2.22 (1.50 to 3.27), p=5.9×10–5), anti-dsDNA (OR 1.83 (1.19 to 2.81), p=6.1×10–3), end-stage renal disease (ESRD) (OR 5.58 (1.50 to 20.79), p=1.0×10–2), proliferative nephritis (OR 2.42 (1.30 to 4.49), p=5.1×10–3), anti-cardiolipin-IgG (OR 1.89 (1.13 to 3.18), p=1.6×10–2), anti-β2-glycoprotein-I-IgG (OR 2.29 (1.29 to 4.06), p=4.8×10–3) and positive lupus anticoagulant test (OR 2.12 (1.16 to 3.89), p=1.5×10–2) compared with patients in the low GRS-quartile. Survival analysis showed earlier onset of the first organ damage (HR 1.51 (1.04 to 2.25), p=3.7×10–2), first cardiovascular event (HR 1.65 (1.03 to 2.64), p=2.6×10–2), nephritis (HR 2.53 (1.72 to 3.71), p=9.6×10–7), ESRD (HR 6.78 (1.78 to 26.86), p=6.5×10–3) and decreased overall survival (HR 1.83 (1.02 to 3.30), p=4.3×10–2) in high to low quartile comparison.ConclusionsA high GRS is associated with increased risk of organ damage, renal dysfunction and all-cause mortality. Our results indicate that genetic profiling may be useful for predicting outcomes in patients with SLE.

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