Table contains demographic data in all cases and controls. Twenty-five unrelated AA cases with SLE preceding ESRD were recruited at the WFUSM, along with 735 controls lacking SLE. Available medical records, renal histopathology and laboratory data were reviewed in these 25 cases with ESRD and none had co-morbidities other than SLE felt likely to cause kidney disease (e.g. none had diabetes mellitus, HIV infection, hepatitis B or hepatitis C viral infection). ESRD cases were 88% female with mean (SD) age at ESRD 42.3 ± 12.6 years and 7 reportedly had renal-biopsy evidence of LN (4 of the renal biopsy reports were available; all revealed diffuse proliferative glomerulonephritis, 1 on a background of membranous nephropathy). Medical records in the 18 cases lacking kidney biopsies revealed 4 cases had anti-double-stranded DNA titers ≥1/160 with proteinuria exceeding 5.2 g/day (maximum 11.6 g/day). The causes of ESRD listed in the US Renal Data Systems may not always be accurate [15
]. In an attempt to clarify this question, we contacted surviving SLE patients with ESRD recruited at WFUSM, their families and physicians. The nephrologists caring for these 25 ESRD patients confirmed the clinical diagnosis of LN and we could not detect risk factors for non-SLE nephropathies in these cases.
Demographic data in patients with SLE
The second association analysis was performed in the 583 AA PROFILE participants. 93% of PROFILE LN cases and 94% of SLE controls were female (table ). Age at SLE onset was 29.7 ± 11.3 years in LN cases and 35.3 ± 11.5 years in non-nephropathy controls (p < 0.0001). Mean (median) ± SD SLE duration and number of ACR SLE diagnostic criteria in cases versus controls, respectively, were 9.5 (8.5) ± 6.8 vs. 7.3 (6.4) ± 5.0 years (p = 0.001), and 6.9 (7) ± 1.8 vs. 6.9 (7) ± 1.8 (p = 0.96), respectively. In PROFILE, 71.2% of LN cases and 66% of SLE controls, respectively, had longitudinal measures of renal parameters; 28.8% of cases and 34% of controls had a single measure.
The third association analysis was performed using 60 lupus cases at the NIH Clinical Center, of whom 39 manifested LN and 21 did not after a follow-up interval of 14.5 ± 9.4 and 13.7 ± 6.4 years, respectively. Among LN cases, 89% were female; among SLE controls, 85% were female. Mean ages at entry into the study cohort were 26.5 ± 9.7 and 33.5 ± 11.8 years, respectively. All SNPs met HWE expectations in the WFUSM, NIH and PROFILE cases and controls.
Tables and , respectively, contain association results with the seven MYH9 single SNPs and the E1 haplotype in Wake Forest SLE-ESRD cases and non-SLE controls. Despite the small sample, the a priori recessive model form of the E1 haplotype was associated with SLE-ESRD (OR 3.09; 95% CI 1.31–7.27; p = 0.010), as were 4 of 7 individual SNPs (OR 2.37–4.31; p values ranged from 0.022 to 0.05).
Haplotypes of MYH9 with association of LN in the Wake Forest sample: 25 SLE-ESRD cases vs. 735 non-SLE controls
Tables and , respectively, contain results of the single SNP and E1 haplotype replication analyses from the 300 PROFILE LN cases and 246 SLE non-nephropathy controls with data on principal components. No evidence of association was detected between MYH9
single SNPs (table ) or the E1 haplotype (OR 0.79; 95% CI 0.55–1.15; p = 0.22 recessive). In addition, analyses adjusting solely for age and gender in the full PROFILE sample of 318 LN cases and 265 SLE controls had similar results (data not shown). These results suggested that heterogeneity existed between the PROFILE LN cases and the Wake Forest SLE-ESRD cases, or that the different types of control groups contributed to results (non-SLE controls in Wake Forest and SLE non-nephropathy controls in PROFILE). PROFILE controls are felt to be the optimal sample for detecting nephropathy genes, because all had SLE. We note that there is no evidence that the MYH9
polymorphisms predispose to SLE itself (data not shown) based on genome-wide association data [17
MYH9 association analysis in PROFILE participants with principal component data (300 LN cases vs. 246 SLE non-nephropathy controls)
Haplotypes of MYH9 with association of LN in PROFILE: 300 LN cases vs. 246 SLE non-nephropathy controls
Among the smaller NIH lupus cohort, none of the seven MYH9 SNPs or E1 haplotype was independently associated with LN (data not shown). In addition, no evidence of E1 haplotype association was detected within the NIH cohort when contrasting the 8 LN patients with serum creatinine concentrations ≥2.5 mg/dl versus the 52 lupus patients with serum creatinine values <2.5 mg/dl (p = 0.98, additive model). Table contains the results of the MYH9 E1 haplotype association analysis in all LN cases and SLE non-nephropathy controls from the combined PROFILE and NIDDK samples. No evidence of association was observed in these well-phenotyped cases and controls, nor was association detected for any individual SNP (ancestry-adjustment was not performed due to the lack of AIMs in the NIH samples).
Haplotypes of MYH9 with association of LN in combined PROFILE and NIH samples: 357 LN cases vs. 286 SLE non-nephropathy controls
We next tested whether differences in genotype frequencies were present between the Wake Forest SLE-ESRD cases (n = 25) and PROFILE ESRD cases (n = 31) with LN-associated ESRD. Significant differences in MYH9 E1 haplotype frequencies were detected between these cases with ESRD (p = 0.037), suggesting that the renal diseases in each cohort were not homogeneous. Although combining SLE cases from Wake Forest and PROFILE revealed significant evidence of MYH9 association (compared to the PROFILE SLE non-nephropathy controls and separately to the Wake Forest non-SLE controls), the results were dominated by Wake Forest ESRD cases (data not shown).