A Genome-Wide Search for Linkage to Renal Function Phenotypes in West Africans With Type 2 Diabetes

Abstract

Reduced renal function often is a major consequence of diabetes and hypertension. Although several indices of renal function (eg, creatinine clearance) are clearly heritable and show linkage to several genomic regions, the specific underlying genetic determinants are still being sought. The purpose of this study is to conduct a genome-wide search for regions linked to 3 renal function phenotypes, serum creatinine, creatinine clearance, and glomerular filtration rate (GFR), in persons with type 2 diabetes. A genome-wide panel of 372 autosomal short tandem repeat markers at an average spacing of 9 centimorgan were typed in 691 patients with type 2 diabetes (321 sib pairs and 36 half-sib pairs) in an affected sib pair study in West Africa. Linkage analysis was conducted with the 3 phenotypes by using a multipoint variance components linkage method. Creatinine clearance showed higher logarithm of odds (LOD) score than the other 2 phenotypes. Linkage to creatinine clearance was observed on chromosomes 16 (marker D16S539, LOD score of 3.56, empirical P = 0.0001), 17 (D17S1298, LOD score of 2.08, empirical P = 0.0018), and 7 (D7S1818, LOD score of 1.84, nominal P = 0.00181, empirical P = 0.0022). Maximum LOD scores for serum creatinine were observed on chromosomes 10 (D10S1432, LOD score of 2.53, empirical P = 0.0001) and 3 (D3S2418, LOD score of 2.21, empirical P = 0.0003) and for GFR on chromosomes 6 (D6S1040, LOD score of 2.08, empirical P = 0.0001) and 8 (D8S256, LOD score of 1.80, empirical P = 0.0001). Several of these results are replications of significant findings from other genome scans. A genome-wide scan for serum creatinine, creatinine clearance, and GFR in a West African sample showed linkage regions that may harbor genes influencing variation in these phenotypes. Potential candidate genes in these regions that have been implicated in diabetic nephropathy and/or renal damage in models of hypertension include CYBA (or P22PHOX) (16q24), NOX1 (10q22), and NOX3 (6q25.1-q26).