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Phenome-wide association study identifies dsDNA as a driver of major organ involvement in systemic lupus erythematosus.

ABSTRACT: In systemic lupus erythematosus (SLE), dsDNA antibodies are associated with renal disease. Less is known about comorbidities in patients without dsDNA or other autoantibodies. Using an electronic health record (EHR) SLE cohort, we employed a phenome-wide association study (PheWAS) that scans across billing codes to compare comorbidities in SLE patients with and without autoantibodies. We used our validated algorithm to identify SLE subjects. Autoantibody status was defined as ever positive for dsDNA, RNP, Smith, SSA and SSB. PheWAS was performed in antibody positive vs. negative SLE patients adjusting for age and race and using a false discovery rate of 0.05. We identified 1097 SLE subjects. In the PheWAS of dsDNA positive vs. negative subjects, dsDNA positive subjects were more likely to have nephritis ( p?=?2.33?×?10-9) and renal failure ( p?=?1.85?×?10-5). After adjusting for sex, race, age and other autoantibodies, dsDNA was independently associated with nephritis and chronic kidney disease. Those patients negative for dsDNA, RNP, SSA and SSB negative subjects were all more likely to have billing codes for sleep, pain and mood disorders. PheWAS uncovered a hierarchy within SLE-specific autoantibodies with dsDNA having the greatest impact on major organ involvement.

SUBMITTER: Barnado A

PROVIDER: S-EPMC6389392 | biostudies-literature | 2019 Jan

REPOSITORIES: biostudies-literature

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Phenome-wide association study identifies dsDNA as a driver of major organ involvement in systemic lupus erythematosus.

Barnado A A Carroll R J RJ Casey C C Wheless L L Denny J C JC Crofford L J LJ

Lupus 20181126 1

In systemic lupus erythematosus (SLE), dsDNA antibodies are associated with renal disease. Less is known about comorbidities in patients without dsDNA or other autoantibodies. Using an electronic health record (EHR) SLE cohort, we employed a phenome-wide association study (PheWAS) that scans across billing codes to compare comorbidities in SLE patients with and without autoantibodies. We used our validated algorithm to identify SLE subjects. Autoantibody status was defined as ever positive for d ...[more]

PMID: 30477398

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Project description:IntroductionDisturbed lipid metabolism was observed in systemic lupus erythematosus (SLE) patients. This study aimed to evaluate the relationships between dyslipidemia and visceral organ involvement, disease severity, inflammatory factors, and drug intake in SLE patients.MethodInpatients with SLE (n = 105) and healthy controls (HC) (n = 75) were recruited in this study. Clinical and laboratory data were collected from patient records. The concentrations of tumor necrosis factor receptors superfamily member1A (TNFRSF1A), member1B (TNFRSF1B) and adipokine angiopoietin-like 4 (ANGPTL4) in plasma were measured by ELISA.ResultCompared to HC, serum levels of triglyceride (TG), total cholesterol (TC), low-density lipoprotein (LDL), and apolipoprotein B (ApoB) were significantly increased, while high-density lipoprotein (HDL) and apolipoprotein A1 (ApoA1) were decreased in SLE patients. Patients with higher disease activity and renal damage suffered from more severe dyslipidemia. Renal functional parameters were closely correlated with serum lipid levels. Inflammatory factors were associated with dyslipidemia. The levels of TNFRSF1A and TNFRSF1B were obviously increased and associated with kidney involvement in SLE patients. Patients with high-dose glucocorticoid intake showed more severe dyslipidemia.ConclusionsAttention should be paid to the dyslipidemia of SLE. Dyslipidemia is associated with inflammation and organ involvement in SLE. These findings might provide a new strategy for the treatment of SLE. Key Points • Serum levels of TG, TC, LDL, and ApoB were significantly increased, while HDL and ApoA1 were decreased in SLE patients. • Patients with higher disease activity and renal damage suffered from more severe dyslipidemia. Renal functional parameters and inflammatory factors were closely correlated with serum lipid levels. • Patients with high-dose glucocorticoid intake showed more severe dyslipidemia. • These findings might provide a new strategy for the treatment of SLE.

Project description:BACKGROUND:African Americans with systemic lupus erythematosus (SLE) have increased renal disease compared to Caucasians, but differences in other comorbidities have not been well-described. We used an electronic health record (EHR) technique to test for differences in comorbidities in African Americans compared to Caucasians with SLE. METHODS:We used a de-identified EHR with 2.8 million subjects to identify SLE cases using a validated algorithm. We performed phenome-wide association studies (PheWAS) comparing African American to Caucasian SLE cases and African American SLE cases to matched non-SLE controls. Controls were age, sex, and race matched to SLE cases. For multiple testing, a false discovery rate (FDR) p value of 0.05 was used. RESULTS:We identified 270 African Americans and 715 Caucasians with SLE and 1425 matched African American controls. Compared to Caucasians with SLE adjusting for age and sex, African Americans with SLE had more comorbidities in every organ system. The most striking included hypertension odds ratio (OR) = 4.25, FDR p = 5.49 × 10- 15; renal dialysis OR = 10.90, FDR p = 8.75 × 10- 14; and pneumonia OR = 3.57, FDR p = 2.32 × 10- 8. Compared to the African American matched controls without SLE, African Americans with SLE were more likely to have comorbidities in every organ system. The most significant codes were renal and cardiac, and included renal failure (OR = 9.55, FDR p = 2.26 × 10- 40) and hypertensive heart and renal disease (OR = 8.08, FDR p = 1.78 × 10- 22). Adjusting for race, age, and sex in a model including both African American and Caucasian SLE cases and controls, SLE was independently associated with renal, cardiovascular, and infectious diseases (all p <?0.01). CONCLUSIONS:African Americans with SLE have an increased comorbidity burden compared to Caucasians with SLE and matched controls. This increase in comorbidities in African Americans with SLE highlights the need to monitor for cardiovascular and infectious complications.

Project description:Systemic lupus erythematosus is a chronic autoimmune disease of complex clinical presentation and etiology and is likely influenced by numerous genetic and environmental factors. While a large number of susceptibility genes have been identified, the production of antibodies against a distinct subset of nuclear proteins remains a primary distinguishing characteristic in disease diagnosis. However, the utility of autoantibody biomarkers for disease sub-classification and grouping remains elusive, in part, because of the difficulty in large scale profiling using a uniform, quantitative platform. In the present study serological profiles of several known SLE antigens, including Sm-D3, RNP-A, RNP-70k, Ro52, Ro60, and La, as well as other cytokine and neuronal antigens were obtained using the luciferase immunoprecipitation systems (LIPS) approach. The resulting autoantibody profiles revealed that 88% of a pilot cohort and 98% of a second independent cohort segregated into one of two distinct clusters defined by autoantibodies against Sm/anti-RNP or Ro/La autoantigens, proteins often involved in RNA binding activities. The Sm/RNP cluster was associated with a higher prevalence of serositis in comparison to the Ro/La cluster (P?=?0.0022). However, from the available clinical information, no other clinical characteristics were associated with either cluster. In contrast, evaluation of autoantibodies on an individual basis revealed an association between anti-Sm (P?=?0.006), RNP-A (P?=?0.018) and RNP-70k (P?=?0.010) autoantibodies and mucocutaneous symptoms and between anti-RNP-70k and musculoskeletal manifestations (P?=?0.059). Serologically active, but clinically quiescent disease also had a higher prevalence of anti-IFN-? autoantibodies. Based on our findings that most SLE patients belong to either a Sm/RNP or Ro/La autoantigen cluster, these results suggest the possibility that alterations in RNA-RNA-binding protein interactions may play a critical role in triggering and/or the pathogenesis of SLE.

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Phenome-wide association study identifies dsDNA as a driver of major organ involvement in systemic lupus erythematosus.

Publications

Phenome-wide association study identifies dsDNA as a driver of major organ involvement in systemic lupus erythematosus.

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