A Genome-Wide Search for Linkage to Renal Function Phenotypes in West Africans With Type 2 Diabetes
Received 16 March 2006; accepted 11 December 2006. published online 03 February 2007.
Background
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.
Methods
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.
Results
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.
Conclusion
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).
1National Human Genome Center at Howard University, College of Medicine, Washington, DC
2Department of Medicine, University of Ghana Medical School, Accra
3Department of Medicine, University of Science and Technology, Kumasi, Ghana
4Department of Medicine, University of Nigeria Teaching Hospital, Enugu
5University of Ibadan, College of Medicine, Ibadan
6Endocrine and Metabolic Unit, University of Lagos, College of Medicine, Lagos, Nigeria.
Address reprint requests to Guanjie Chen, MD, National Human Genome Center, Howard University, Genetic Epidemiology Unit, College of Medicine, 2216 6th St NW, Washington, DC 20059.
Originally published online as doi:10.1053/j.ajkd.2006.12.011 on February 1, 2007.
Support: Support for the Africa America Diabetes Mellitus (AADM) study is provided by NIH grant no. 3T37TW00041-03S2 from the Office of Research on Minority Health. This project also is supported in part by the National Center for Research Resources (NCRR), National Human Genome Research Institute (NHGRI), and by the NIDDK grant DK-54001. Genotyping services were provided by the Center for Inherited Disease Research (http://www.cidr.jhmi.edu). The Center for Inherited Disease Research is fully funded through a federal contract from the NIH to Johns Hopkins University, Contract No. N01-HG-65403. Potential conflicts of interest: None.
ABSTRACT