Evaluation of Markers on Human Chromosome 10, Including the Homologue of the Rodent Rf-1 Gene, for Linkage to ESRD in Black Patients Hongrun Yu, PhD, Michele Sale, PhD, Stephen S. Rich, PhD, Beverly J. Spray, PhD, Bong H. Roh, BS, Donald W. Bowden, PhD, and Barry I. Freedman, MD ● There is abundant evidence supporting the contribution of genetic factors to the development of end-stage renal disease (ESRD) in blacks. Two renal failure susceptibility genes, Rf-1 and Rf-2, have been identified in the fawn-hooded rat, an animal model of hypertension and nephrosclerosis. The human homologous region containing the rodent Rf-1 gene has been localized to chromosome 10q. We tested for genetic linkage between 21 polymorphic markers on human chromosome 10 and chronic renal failure in 129 black sibling pairs concordant for ESRD. Two adjacent markers on 10p, D10S1435 and D10S249 (4 centiMorgans from D10S1435), approached significance for linkage to ESRD in sibling pairs with nondiabetic causes of ESRD (P  0.035 pairwise, P  0.082 multipoint for D10S1435; P  0.074 pairwise, P  0.063 multipoint for D10S249). The markers spanning the homologous region of Rf-1 did not show evidence for linkage to ESRD in sibling pairs concordant for diabetic ESRD, sibling pairs concordant for nondiabetic causes of ESRD, or in the entire family set. These results suggest that the human homologue of Rf-1 is unlikely to contribute substantially to renal failure susceptibility from the common causes of kidney disease in blacks.  1999 by the National Kidney Foundation, Inc. INDEX WORDS: End-stage renal disease; blacks; renal failure-1 gene; genetic linkage analysis; fawn-hooded rat. T HE FAWN-HOODED rat (FHR) is an in- bred hypertensive strain that develops neph- rosclerosis early in life, with resultant chronic renal failure. 1,2 Clinical characteristics of the FHR include systemic and glomerular hyperten- sion with proteinuria, reduced urinary kallikrein activity, and glomerulosclerosis leading to prema- ture death. Renal histopathology consists of early mesangial matrix expansion and nonselective deposition of immunoglobulins and complement with progressive podocyte injury. 3,4 As in human renal disease, age-matched males are more se- verely affected than females. Renal failure in the FHR is regulated, in part, by two genes on rat chromosome 1. 5 These genes, termed renal failure-1 (Rf-1) and renal failure-2 (Rf-2), are responsible for nearly one half (46%) the genetic variance in proteinuria and nephrosclerosis. 5 Animals homozygous at both Rf-1 and Rf-2 have more severe renal impair- ment compared with animals heterozygous at either of these loci. 5 Importantly, Rf-1 and Rf-2 appear to be inherited independently from any of the identified loci that determine blood pressure. Striking similarities exist between renal fail- ure in the FHR and end-stage renal disease (ESRD) in humans. Human renal failure appears to have a strong genetic component, 6,7 and suscep- tibility is independent from, but appears to inter- act with, hypertension, 8 diabetes mellitus, 9-11 and such systemic diseases as lupus erythematosus. 12 Additionally, black multiplex families with ESRD often contain members with disparate causes of renal failure. 8,13 Recently, the human homologue for the rat Rf-1 gene has been assigned to the long arm of human chromosome 10. To establish homology between the rat Rf-1 region and the human homologus region, two genes (Cyp17G and s65119) were mapped from the rat onto the human using radiation hybrids. The results from the hybrid analysis indicated that the human homology should be between 10q24 and 10q26 (Howard J. Jacob, personal communication, Janu- ary 1997). The Rf-2 gene has been mapped to a chromosomal region in the rat that has multiple From the Departments of Biochemistry, Public Health Sciences, and Internal Medicine/Section on Nephrology, Wake Forest University Baptist Medical Center, Winston- Salem, NC. Received April 2, 1998; accepted in revised form August 28, 1998. Supported in part by grants no. RO1 HL56266 (B.I.F.) and RO1 DK47480 (D.W.B.) from the National Institutes of Health. Some results were obtained using the program package Statistical Analysis for Genetic Epidemiology, which is supported by the US Public Health Service resource grant no. 1 P41 RR03655 from the Division of Research Re- sources, National Institutes of Health. Address reprint requests to Barry I. Freedman, MD, Internal Medicine/Nephrology, Wake Forest University Bap- tist Medical Center, Medical Center Blvd, Winston-Salem, NC 27157-1053. E-mail: bfreedma@wfubmc.edu  1999 by the National Kidney Foundation, Inc. 0272-6386/99/3302-0010$3.00/0 294 American Journal of Kidney Diseases, Vol 33, No 2 (February), 1999: pp 294-300