Brief Report: Whole-Exome Sequencing to Identify Rare Variants and Gene Networks That Increase Susceptibility to Scleroderma in African Americans.

OBJECTIVE: Whole-exome sequencing (WES) studies in systemic sclerosis (SSc) patients of European American (EA) ancestry have identified variants in the ATP8B4 gene and enrichment of variants in genes in the extracellular matrix (ECM)-related pathway that increase SSc susceptibility. This study was undertaken to evaluate the association of the ATP8B4 gene and the ECM-related pathway with SSc in a cohort of African American (AA) patients. METHODS: SSc patients of AA ancestry were enrolled from 23 academic centers across the US under the Genome Research in African American Scleroderma Patients consortium. Unrelated AA individuals without serologic evidence of autoimmunity who were enrolled in the Howard University Family Study were used as unaffected controls. Functional variants in genes reported in the 2 WES studies in EA patients with SSc were selected for gene association testing using the optimized sequence kernel association test (SKAT-O) and pathway analysis by Ingenuity Pathway Analysis in 379 patients and 411 controls. RESULTS: Principal components analysis demonstrated that the patients and controls had similar ancestral backgrounds, with roughly equal proportions of mean European admixture. Using SKAT-O, we examined the association of individual genes that were previously reported in EA patients and none remained significant, including ATP8B4 (P = 0.98). However, we confirmed the previously reported association of the ECM-related pathway with enrichment of variants within the COL13A1, COL18A1, COL22A1, COL4A3, COL4A4, COL5A2, PROK1, and SERPINE1 genes (corrected P = 1.95 × 10-4 ). CONCLUSION: In the largest genetic study in AA patients with SSc to date, our findings corroborate the role of functional variants that aggregate in a fibrotic pathway and increase SSc susceptibility.

Erythrocyte C3d and C4d for monitoring disease activity in systemic lupus erythematosus.

OBJECTIVE: Disease activity in systemic lupus erythematosus (SLE) is typically monitored by measuring serum C3 and C4. However, these proteins have limited utility as lupus biomarkers, because they are substrates rather than products of complement activation. The aim of this study was to evaluate the utility of measuring the erythrocyte-bound complement activation products, erythrocyte-bound C3d (E-C3d) and E-C4d, compared with that of serum C3 and C4 for monitoring disease activity in patients with SLE. METHODS: The levels of E-C3d and E-C4d were measured by flow cytometry in 157 patients with SLE, 290 patients with other diseases, and 256 healthy individuals. The patients with SLE were followed up longitudinally. Disease activity was measured at each visit, using the validated Systemic Lupus Activity Measure (SLAM) and the Safety of Estrogens in Lupus Erythematosus: National Assessment (SELENA) version of the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI). RESULTS: At baseline, patients with SLE had higher median levels of E-C3d and E-C4d (P < 0.0001) in addition to higher within-patient and between-patient variability in both E-C3d and E-C4d when compared with the 2 non-SLE groups. In a longitudinal analysis of patients with SLE, E-C3d, E-C4d, serum C3, and anti-double-stranded DNA (anti-dsDNA) antibodies were each significantly associated with the SLAM and SELENA-SLEDAI. In a multivariable analysis, E-C4d remained significantly associated with these SLE activity measures after adjusting for serum C3, C4, and anti-dsDNA antibodies; however, E-C3d was associated with the SLAM but not with the SELENA-SLEDAI. CONCLUSION: Determining the levels of the erythrocyte-bound complement activation products, especially E-C4d, is an informative measure of SLE disease activity as compared with assessing serum C4 levels and should be considered for monitoring disease activity in patients with SLE.

Association between depression and coronary artery calcification in women with systemic lupus erythematosus.

OBJECTIVES: To determine the associations between depression, cardiovascular risk factors and coronary artery calcification (CAC) in women with SLE and controls. METHODS: CAC was measured using electron-beam CT (EBCT). Traditional, inflammatory and lupus-related risk factors as well as depressive symptoms (Center for Epidemiologic Studies Depression Scale-CES-D) were measured at a single study visit in 161 women with SLE and 161 age- and race frequency-matched female healthy controls. RESULTS: Women with SLE reported more depressive symptoms than controls, with 27% of SLE and 15% of controls having CES-D scores suggestive of clinical depression. SLE women were more likely to have CAC, as well as more severe CAC compared with controls. Among the SLE women, depression was associated with greater than 2-fold odds of having any CAC [odds ratio (OR) 2.48; 95% CI 1.05, 5.87; P = 0.04], independent of traditional risk factors (age, hypertension and triglycerides) and inflammatory markers. However, when BMI was included among the covariates, the association between depression and CAC was attenuated, indicating the potential mediating role of BMI. Depression was not a risk factor for CAC in controls. CONCLUSIONS: In women with SLE, depression was associated with CAC. This association was mediated by BMI. Depression and adiposity may add to the inflammatory burden of SLE, thus contributing to cardiovascular disease risk.