Sivils, Kathy L.

Objective Lupus nephritis (LN) is a severe manifestation of systemic lupus erythematosus (SLE) that exhibits familial aggregation and may progress to end‐stage renal disease (ESRD). LN is more prevalent among African Americans than among European Americans. This study was undertaken to investigate the hypothesis that the apolipoprotein L1 gene ( APOL1 ) nephropathy risk alleles G1/G2, common in African Americans and rare in European Americans, contribute to the ethnic disparity in risk. Methods APOL1 G1 and G2 nephropathy alleles were genotyped in 855 African American SLE patients with LN‐ESRD (cases) and 534 African American SLE patients without nephropathy (controls) and tested for association under a recessive genetic model, by logistic regression. Results Ninety percent of the SLE patients were female. The mean ± SD age at SLE diagnosis was significantly lower in LN‐ESRD cases than in SLE non‐nephropathy controls (27.3 ± 10.9 years versus 39.5 ± 12.2 years). The mean ± SD time from SLE diagnosis to development of LN‐ESRD in cases was 7.3 ± 7.2 years. The G1/G2 risk alleles were strongly associated with SLE‐ESRD, with 25% of cases and 12% of controls having 2 nephropathy alleles (odds ratio [OR] 2.57, recessive model P = 1.49 × 10 −9 ), and after adjustment for age, sex, and ancestry admixture (OR 2.72, P = 6.23 × 10 −6 ). The age‐, sex‐, and admixture‐adjusted population attributable risk for ESRD among patients with G1/G2 polymorphisms was 0.26, compared to 0.003 among European American patients. The mean time from SLE diagnosis to ESRD development was ∼2 years earlier among individuals with APOL1 risk genotypes ( P = 0.01). Conclusion APOL1 G1/G2 alleles strongly impact the risk of LN‐ESRD in African Americans, as well as the time to progression to ESRD. The high frequency of these alleles in African Americans with near absence in European Americans explains an important proportion of the increased risk of LN‐ESRD in African Americans.

Systemic lupus erythematosus (SLE) patients frequently have high circulating tumor necrosis factor alpha (TNF-α) levels. We explored circulating TNF-αlevels in SLE families to determine whether high levels of TNF-αwere clustered in a heritable pattern. We measured TNF-αin 242 SLE patients, 361 unaffected family members, 23 unaffected spouses of SLE patients, and 62 unrelated healthy controls. Familial correlations and relative recurrence risk rates for the high TNF-αtrait were assessed. SLE-affected individuals had the highest TNF-αlevels, and TNF-αwas significantly higher in unaffected first degree relatives than healthy unrelated subjects(P=0.0025). No Mendelian patterns were observed, but 28.4% of unaffected first degree relatives of SLE patients had high TNF-αlevels, resulting in a first degree relative recurrence risk of 4.48(P=2.9×10-5). Interestingly, the median TNF-αvalue in spouses was similar to that of the first degree relatives. Concordance of the TNF-αtrait (high versus low) in SLE patients and their spouses was strikingly high at 78.2%. These data support a role for TNF-αin SLE pathogenesis, and TNF-αlevels may relate with heritable factors. The high degree of concordance in SLE patients and their spouses suggests that environmental factors may also play a role in the observed familial aggregation.