Genetic linkage analysis of growth factor loci and end-stage renal disease in African Americans

Abstract

Hypertension, diabetes mellitus and chronic glomerular diseases reportedly cause in excess of 80% of the incident cases of end-stage renal disease (ESRD) in the U.S. The factors that initiate progressive renal failure in patients with these disorders remain unknown. Several investigators have reported enhanced synthesis and activity of cytokines in the kidneys of patients with renal failure. The ensuing inflammation and fibrosis have been postulated to contribute to the development of progressive renal failure. There is also abundant evidence supporting the contribution of genetic factors in ESRD susceptibility based upon the strong familial clustering of ESRD, particularly in African Americans. Therefore, genetic linkage analysis may be useful to evaluate the role of candidate genes in several cytokine cascades that could contribute to the pathogenesis of chronic renal failure. We tested for genetic linkage between eight cytokine candidate genes and chronic renal failure in a collection of African American sibling pairs concordant for ESRD. Epidermal growth factor (EGF), platelet-derived growth factor (PDGF), transforming growth factor (TGF) beta 1, TGF-beta 2 and TGF-beta 3, and tumor necrosis factor (TNF)-alpha and TNF-beta candidate genes were selected for analysis due to their putative roles in diabetic renal disease and chronic glomerulonephritis. The interleukin-1 receptor antagonist gene (IL1RN) was also genotyped due to its reported association with diabetic nephropathy. Non-parametric (genetic model independent) affected sib pair linkage analysis was used to evaluate evidence for linkage. In order to genotype TGF-beta 3, we identified four closely linked, previously unidentified, highly polymorphic microsatellite loci near the TGF-beta 3 gene. Linkage of ESRD and transforming growth factor beta 2 polymorphisms on human chromosome 1 approached significance for non-diabetic nephropathy (predominantly chronic glomerular disease, hypertensive nephrosclerosis and unknown etiology) (P = 0.08), but showed no linkage to diabetic nephropathy. The other candidate loci did not demonstrate linkage to ESRD in the total population or in the subgroups with diabetic or non-diabetic etiologies of ESRD. The IL1RN gene did not show significant evidence for linkage to ESRD; however, we did confirm an association between allele 2 of IL1RN and ESRD (as reported in diabetic nephropathy). Overall, these results suggest that these growth factor loci do not make major contributions to the pathogenesis of ESRD in African Americans.

Variants of the Transcription Factor 7-Like 2 (TCF7L2) Gene Are Associated With Type 2 Diabetes in an African-American Population Enriched for Nephropathy

“…Recruitment of African-American and EuropeanAmerican patients and control subjects has previously been described (16). Briefly, 577 unrelated African-American patients with type 2 diabetes, born in North Carolina, South Carolina, Georgia, Tennessee, or Virginia, were recruited from dialysis facilities.…”

Loci Contributing to Adult Height and Body Mass Index in African American Families Ascertained for Type 2 Diabetes

“…DNA samples were collected from self-described African American families with multiple T2DM-affected members. Recruitment strategies and selection criteria have been described in detail previously (Yu et al 1996(Yu et al , 1998(Yu et al , 2000Freedman et al 1997Freedman et al , 2000Freedman et al , 2002. Briefly, families were originally identified through a proband with impaired renal function, either with end-stage renal disease (ESRD) and on dialysis, or nephropathy (defined as urinalysis with ≥ 100 mg/dl protein, urine albumin:creatinine ratio (ACR) ≥ 0.50 g/g, and/or serum creatinine concentration >1.5 mg/dl), associated with T2DM.…”

Association of variable number of tandem repeats polymorphism in the IL-4 gene with end-stage renal disease in Malaysian patients

“…The VNTR polymorphism located in the third intron consists of three 70-bp repeats, with two repeats and four repeats of rare alleles, which are the candidate genes for this disease (Kirchheiner et al, 2006;Mittal and Manchanda, 2007;Konwar and Bid, 2008). Many studies have reported that gene polymorphism of IL-4 is associated with ESRD (Freedman et al, 1997;Nordfors et al, 2005;Wetmore et al, 2005).…”