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Influence of Genomic Loci on Measures of Chronic Kidney Disease in Hypertensive Sibships

Stephen T. Turner^*, Sharon L.R. Kardia, Thomas H. Mosley, Andrew D. Rule^*, Eric Boerwinkle and Mariza de Andrade^||

^* Division of Nephrology and Hypertension, Department of Internal Medicine, and ^|| Division of Biostatistics, Department of Health Sciences Research, Mayo Clinic and Foundation, Rochester, Minnesota; Department of Epidemiology, University of Michigan, Ann Arbor, Michigan; Department of Medicine, University of Mississippi Medical Center, Jackson, Mississippi; and Human Genetics Center and Institute of Molecular Medicine, University of Texas–Houston Health Science Center, Houston, Texas

Address correspondence to: Dr. Stephen T. Turner, Division of Nephrology and Hypertension, Mayo Clinic, 200 First Street SW, Rochester MN 55905. Phone: 507-284-8129; Fax: 507-266-1702; E-mail: turner.stephen{at}mayo.edu

Received for publication December 3, 2005. Accepted for publication May 1, 2006.

Genomewide linkage analyses were conducted of serum creatinine, estimated GFR (eGFR), and urine albumin-creatinine ratio (UACR) in search of genetic susceptibility loci for chronic kidney disease in 1351 black (median age 63 yr, 70% women, 79% hypertensive) and 1022 white individuals (median age 61 yr, 56% women, 75% hypertensive) from sibships in which two or more members had essential hypertension diagnosed before age 60 yr. After adjustment for gender, age, diabetes, and use of angiotensin inhibitors, the logarithm-transformed measure of serum creatinine was heritable in both ethnic groups (0.45 in black individuals [P < 0.001]; 0.39 in white individuals [P < 0.001]), as was eGFR (0.52 in black individuals [P < 0.001]; 0.39 in white individuals [P < 0.001]). Log UACR was heritable in black individuals (0.30, P < 0.001) but not in white individuals (0.12; P = 0.059). In black individuals, the univariate maximum multipoint logarithm of odds scores (MLS) were observed on chromosome 7 for log serum creatinine (MLS = 3.65, at 43 cM from pter; P = 0.00002) and eGFR (MLS = 2.52, at 45 cM from pter; P = 0.00033) and for log UACR (MLS = 2.91, at 112 cM from pter; P = 0.00012). In white individuals, only one MLS for log serum creatinine and one for eGFR achieved the logarithm of odds score criterion for "suggestive" evidence of linkage (2 MLS < 3), both on chromosome 3 (at 211 and 209 cM, respectively); however, none did so for log UACR. In black individuals, bivariate linkage analyses of log serum creatinine and pulse pressure (i.e., systolic–diastolic BP) provided "suggestive" evidence of a region on chromosome 5 with pleiotropic effects on both traits (MLS = 3.62, at 85 cM from pter; P = 0.00023). These findings support the utility of genetic linkage analyses for identification of novel risk factors that influence measures of chronic kidney disease, particularly among black individuals.

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