Abstract
BACKGROUND: Although MYH9 is strongly associated with biopsy-proven idiopathic and HIV-associated focal segmental glomerulosclerosis (FSGS) and clinically diagnosed 'hypertension-associated' end-stage renal disease (ESRD) in African Americans, its role in type 2 diabetes mellitus (T2DM)-associated ESRD is unclear. METHODS: To assess whether MYH9 was associated with T2DM-ESRD, 751 African Americans with T2DM-ESRD, 227 with T2DM lacking nephropathy and 925 non-diabetic non-nephropathy controls were genotyped for 14 MYH9 SNPs. Association analyses used SNPGWA and Dandelion. RESULTS: Comparing T2DM-ESRD cases with non-diabetic controls, single SNP associations were detected with 8 of 14 SNPs, gender- and admixture-adjusted P-values 0.047-0.005 [recessive model, odds ratio (OR) range 1.30-1.55]. The previously associated MYH9 E1 and L1 haplotypes were associated with T2DM-ESRD (E1: OR 1.27, 95% CI 1.04-1.56, P = 0.021 recessive and L1: OR 1.43, 95% CI 1.09-1.87, P = 0.009 dominant). Contrasting the 751 T2DM-ESRD cases with 227 T2DM non-nephropathy controls revealed that E1 haplotype SNPs rs4821480, rs2032487 and rs4821481 were associated with kidney failure (OR 1.38-1.40 recessive, all P < 0.048). Among E1 and L1 risk homozygotes, respectively, mean (SD) diabetes duration prior to renal replacement therapy was 16.6 (9.7) and 16.4 (10.0) years, and 65% had diabetic retinopathy. CONCLUSIONS: Genetic dissection of T2DM-associated ESRD reveals that MYH9 underlies a portion of this clinically diagnosed disorder in African Americans. It is likely that a subset of African Americans with T2DM and coincident nephropathy have primary MYH9-related kidney disease (e.g. FSGS or global glomerulosclerosis), although renal biopsy studies need to be performed.