Linkage of creatinine clearance to chromosome 10 in Utah pedigrees replicates a locus for end-stage renal disease in humans and renal failure in the fawn-hooded rat

Abstract

Renal failure is an important health concern for persons with hypertension and diabetes. In the fawn-hooded rat, a renal failure locus, Rf-1, has been identified on rat chromosome 1. A study of African American sibpairs with end-stage renal disease (ESRD) replicated this finding on the orthologous region in humans, chromosome 10, with a maximum logarithm of odds (LOD) score of 3.4. An important question is whether this region can be detected in healthy subjects prior to onset of ESRD by examining creatinine clearance as an indicator of early renal damage. We analyzed 49 Utah Caucasian pedigrees and performed quantitative nonparametric linkage analysis using 21 markers spanning chromosome 10. Pedigree members (mean age of 40 +/- 17) were examined up to three different times over 10 years, with creatinine clearance measured at each exam. For examination 1, three overnight, timed, 12-hour urine samples were obtained and averaged. One 12-hour sample was obtained for examinations 2 and 3. Heritabilities of creatinine clearance were 0.33 (N = 1360), 0.36 (N = 1196), and 0.53 (N = 718) for the three examinations, respectively. The nonparametric LOD score for examination 1 was 1.4 at marker D10S677 (approximately 117 cM). The LOD score at examination 2, an average of 21/2 years later, was 1.8 at marker D10S1239 (approximately 123 cM) and 1.9 at marker D10S1425 (approximately 137 cM). The LOD score at examination 3, an average of 10 years from baseline, was 2.1 at marker D10S2470 (approximately 113 cM). Thus, there is consistent evidence of linkage to this region from three different examinations spanning a period of 10 years. These linkage results confirm the ESRD linkage and the rat renal failure linkage to this region even though the LOD score is somewhat weaker, probably due to the less severe phenotype that was analyzed. It also suggests that there may be a locus on chromosome 10 that leads to reduced renal function that can be detected while subjects are still healthy. Identification of the responsible gene may help in predicting renal disease progression in susceptible patients.