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

Abstract

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.

Linkage Analysis of Albuminuria

“…46 Our locus on 7q has been isolated by three other genome scans. 15,18,19 The paraoxonase gene cluster (PON1 through 3) lies on 7q21.3. Paraoxonase is an HDL-associated enzyme that decreases oxidation of lipids and is a plausible candidate gene influencing the progression of kidney disease.…”

“…An increase in the prevalence of albuminuria with increasing percentage of selfidentified American Indian heritage has been reported. 8,10 The heritability for albuminuria ranges from approximately 0.17 to 0.20 in general populations, 11,12 0.20 in families with diabetes, 13 and 0.12 to 0.49 in families with hypertension, 14,15 depending on ethnicity. Genome-wide scans for albuminuria have mostly yielded regions with suggestive evidence for linkage.…”

Integrating Human and Rodent Data to Identify the Genetic Factors Involved in Chronic Kidney Disease

“…Evidence of familial aggregation and the heritability of biomarkers, such as albuminuria, for the development and progression of CKD, as well as various indices of renal function, provide a foundation for investigating the genetic predisposition of CKD. [3][4][5][6][7][8][9][10][11][12] Efforts to map loci contributing to CKD susceptibility often rely on family-based linkage approaches, which look to establish statistical associations using genetic markers with a given dichotomous (affected versus unaffected) or quantitative (GFR or degree of albuminuria) phenotypic trait. 13 The identification of genomic locations demonstrating linkage provides the first line of evidence suggesting where disease-associated genes are likely to reside.…”

Genotype by Diabetes Interaction Effects on the Detection of Linkage of Glomerular Filtration Rate to a Region on Chromosome 2q in Mexican Americans

“…In fact, in recent years, various linkage studies have been performed to localize susceptibility genes related to ESRD and diabetic nephropathy in populations such as Caucasians, Mexican Americans, African Americans, and Pima Indians (5)(6)(7)(8)(9)(10)(11). In addition, linkage studies have also been conducted to map loci that influence variation in renal function, using data from various ethnic groups and several measures of GFR such as serum creatinine, serum cystatin C, creatinine clearance, and formulae estimating GFR (Cockcroft-Gault [GFR-CG] and Modification of Diet in Renal Disease [GFR-MDRD] study equations) (12)(13)(14)(15)(16)(17)(18).…”