A total of 647 participants were evaluated for inclusion. Of these, 5 recovered renal function, 4 had temporary discontinuation of dialysis, 2 were transplanted within 6 months of dialysis onset, and 26 did not have the date of first dialysis recorded; these patients were withdrawn. The remaining 610 subjects were included in the final analysis. Table summarizes the baseline characteristics of participants. Hemodialysis was the predominant initial mode of renal replacement therapy (93% of patients), and we observed an overall 10% rate of modality conversion from any initial to an alternative renal replacement modality during the period of follow-up. After mean follow-up of 5.4 ± 3.5 years, 434 deaths, 44 kidney transplants, and 2 cases lost to follow-up were recorded (table ). The mean survival on dialysis for the 434 subjects who died was 5.2 ± 3.1 years. A total of 130 subjects remained alive at the last follow-up. Table summarizes the major causes of death. Sex, BMI, incident albumin, incident hemoglobin, and admixture were not individually significantly associated with survival, while age at dialysis inception (5-year HR = 1.2; p < 0.0001) and incident year of dialysis (dialysis vintage, 5-year HR = 1.16; p= 0.0008) were significantly associated with mortality (data not shown).
Demographics at dialysis inception
A number of genomic regions showed evidence of association with survival at p < 1.00 × 10−5, with 5 of the landmark SNPs associated at p < 1.00 × 10−6 (fig. ). Overall, there was no evidence of inflation of the tests of association, and there was appropriate fit to the expected overall distribution of association (fig. ).
Fig. 1 GWAS results for death on dialysis. The genome-wide distribution of –log10 p values from the adjusted trend is shown across the chromosomes. The dotted line indicates the genome-wide significance threshold (p < 1 × 10−6 (more ...)
Q-Q plot from the genome-wide association with dialysis survival analysis. The black bold line represents the observed p values; the red line is the expected line under the null distribution.
After adjustment for ancestry, age at dialysis, sex, BMI, diabetes duration, and incident year factor (model 1), 30 SNPs provided evidence for association (p < 1.00 × 10−5), 12 were located in 10 genes (table ), and 18 SNPs were located in intergenic regions (table ). One of the top hits (rs2412980, chr22q12.2, HR = 1.65, p = 3.67 × 10−6) was located in LOC729980, a gene encoding a protein with unknown function. Two of the top hits (rs6546886, chr2p13.1, HR = 2.13, p = 3.28 × 10−6; rs9921518, chr16q12.2, HR = 2.11, p = 8.62 × 10−6) were located in regions of reported copy number variation. Of note, several SNPs clustered around A Disintegrin And Metalloproteinase with Thrombospondin Motifs (ADAMTS) and Iroquois (IRX) genes (rs6816344, chr4q13.3, HR = 1.7, p = 1.37 × 10−6; rs1452093, chr21q21.3, HR = 1.59, p = 2.31 × 10−6; rs9977499, chr21q21.3, HR = 1.57, p = 4.36 × 10−6; rs1817114, chr21q21.3, HR = 1.57, p = 4.36 × 10−6; rs2830881, chr6q22.31, HR = 1.57, p = 4.67 × 10−6; and rs9921518, chr16q12.2, HR = 2.11, p = 8.62 × 10−6).
Summary results for top gene SNPs associated with all-cause death on dialysis
Summary results for top intergenic SNPs associated with all-cause death on dialysis
Additional covariate adjustments in model 2 (incident serum albumin and hemoglobin) maintained comparable HRs, but diminished the p values modestly (data not shown).