A Genome-Wide Scan for Urinary Albumin Excretion in Hypertensive Families

Freedman, Barry I.; Beck, Stephanie R; Rich, Stephen S.; Heiss, Gerardo; Lewis, Cora E.; Turner, Stephen T.; Province, Michael A.; Schwander, Karen; Arnett, Donna K.; Mellen, Beverly G.

doi:10.1161/01.hyp.0000087890.33245.41

Cited by 67 publications

(57 citation statements)

References 22 publications

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“…Moreover, we found no evidence of linkage for serum creatinine or for albuminuria in the chromosome 10q24-q26 region that corresponds to the rodent renal failure locus, RF-1 (42). This region had been implicated in early linkage analyses of small samples of black siblings with ESRD (43) and in white pedigrees with repeated measurements of creatinine clearance (44) but not in subsequent linkage analyses for serum creatinine or albuminuria reported in the larger HyperGen cohorts (14). A major limitation of this and previous linkage studies to localize CKD genes relates to measurement of the disease phenotype(s).…”

Section: Discussionmentioning

confidence: 99%

“…Serum creatinine, glucose, total cholesterol, HDL cholesterol, and triglyceride concentrations and urine albumin, total protein, and creatinine concentrations were measured by standard methods on a Hitachi 911 Chemistry Analyzer (Roche Diagnostics, Indianapolis, IN) (13,14). The eGFR was calculated using the Modification of Diet in Renal Disease (MDRD) equation: eGFR ϭ 186.3 ϫ (serum creatinine)…”

Section: Laboratory Measurementsmentioning

confidence: 99%

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

Turner¹,

Kardia²,

Mosley³

et al. 2006

Journal of the American Society of Nephrology

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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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Section: Discussionmentioning

confidence: 99%

Section: Laboratory Measurementsmentioning

confidence: 99%

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

Turner¹,

Kardia²,

Mosley³

et al. 2006

Journal of the American Society of Nephrology

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“…A heritability (h 2 ) ϭ 1 suggests the presence of a Mendelian disorder (e.g., autosomal dominant polycystic kidney disease), whereas h 2 ϭ 0 reveals the contribution of environmental factors. Heritability estimates for albuminuria were significant, ranging from 0.3 to 0.44 in Finnish (9), New England (10), and southeastern US (11) families enriched for members with type 2 diabetes, and the estimate was higher (h 2 ϭ 0.49) in Hypertension Genetic Epidemiology Network (Hyper-GEN) families enriched for multiple siblings with hypertension (12). Similarly, GFR was significantly heritable in families with diabetes and hypertension, ranging from 0.36 to 0.75 (11,13,14).…”

Section: Familial Aggregation Of Dnmentioning

confidence: 99%

Genetic Factors in Diabetic Nephropathy

Freedman

Bostrom

Daeihagh

et al. 2007

Clinical Journal of the American Society of Nephrology

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125

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Several genes that predispose to type 2 diabetes have recently been identified. In addition to the recognized and powerful effects of environmental factors, there is abundant evidence in support of genetic susceptibility to the microvascular complication of nephropathy in individuals with both type 1 and type 2 diabetes. Familial aggregation of phenotypes such as end-stage renal disease, albuminuria, and chronic kidney disease have routinely been reported in populations throughout the world, and heritability estimates for albuminuria and glomerular filtration rate demonstrate strong contributions of inherited factors. Recent genome-wide linkage scans have identified several chromosomal regions that likely contain diabetic nephropathy susceptibility genes, and association analyses have evaluated positional candidate genes under these linkage peaks. These complimentary approaches have demonstrated that polymorphisms in the carnosinase 1 gene on chromosome 18q, the adiponectin gene on 3q, and the engulfment and cell motility gene on 7p are likely associated with susceptibility to diabetic nephropathy. Additional genes that seem to be of importance in renal phenotypes include manganese superoxide dismutase and angiotensin 1-converting enzyme, with nitric oxide synthase implicated in albuminuria. This article reviews the inherited aspects of diabetic kidney disease with particular emphasis on recently implicated genes and pathways. It seems likely that the risk for diabetes-associated kidney disease is magnified by inheriting risk alleles at several susceptibility loci, in the presence of hyperglycemia.Clin J Am Soc Nephrol 2: 1306 -1316, 2007. doi: 10.2215/CJN.02560607 I t was previously thought that individuals who had diabetes and developed progressive diabetic nephropathy (DN) and/or ESRD were simply exposed to long durations of diabetes with relatively poor glycemic control. In other words, all individuals with diabetes were assumed to be at essentially equivalent risk for developing nephropathy, allowing for differences in their ambient serum glucose concentration. In support of the concept that exposure to a hyperglycemic environment led to DN (often with coexisting obesity, metabolic syndrome, hypertension, and hyperlipidemia), clinical trials have conclusively demonstrated that improving glycemic control delays and, in some cases, may prevent the subsequent development of albuminuria, DN, and macrovascular complications such as coronary artery disease (1,2). The concept that select individuals with diabetes were at differential risk for developing nephropathy on the basis of familial aggregation of kidney disease was initially reported in 1989 but has only recently gained broad acceptance among nephrologists and diabetologists (3). Familial Aggregation of DNThe notion that genetic factors contribute to any complex disease rests on the demonstration of familial aggregation. Familial clustering of nephropathy could result from shared genes, environmental exposures, or their combination.After repeated demonstra...

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“…Urine albumin, total protein and creatinine concentrations were measured by standard methods on a Hitachi 911 Chemistry Analyzer (Roche Diagnostics, Indianapolis, IN, USA). 18 Urinary albumin excretion was expressed in terms of urinary albumin/creatinine ratio (UACR, mg/g). Spot UACR correlates well with urinary albumin excretion 19 and is commonly used in large epidemiological studies.…”

Section: Urinary Albuminmentioning

confidence: 99%

Urinary albumin excretion is associated with impaired flow- and nitroglycerin-mediated brachial artery dilatation in hypertensive adults

et al. 2007

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We investigated whether the urinary albumin/creatinine ratio (UACR), a measure of albuminuria, is associated with non-invasive measures of arterial function in hypertensive adults without known coronary heart disease (CHD) or stroke. UACR was measured in the first voided morning urine sample in 469 non-Hispanic white hypertensive individuals (mean age 62.279.8 years, 41% men) belonging to hypertensive sibships. High-resolution ultrasonography of the brachial artery was used to assess flow-mediated dilatation (FMD) -an endothelium-dependent response -and nitroglycerin-mediated dilatation (NMD) -an endothelium-independent response. Because of skewed distribution, UACR was log transformed after addition of 0.1. The association of log (UACR þ 0.1) with FMD and NMD, before and after adjustment for CHD risk factors, serum creatinine, and hypertension medication and statin use was assessed using linear regression analyses. In univariable analyses, variables associated with lower FMD were greater age, male sex, history of smoking, lower high-density lipoprotein (HDL) cholesterol, higher serum creatinine and higher log (UACR þ 0.1); variables associated with lower NMD were greater age, male sex, higher systolic blood pressure, lower HDL cholesterol, higher serum creatinine and higher log (UACR þ 0.1). In separate stepwise multivariable regression analyses that adjusted for conventional CHD risk factors, serum creatinine and hypertension medication and statin use, higher log (UACR þ 0.1) was associated with lower brachial artery FMD (P ¼ 0.035) and NMD (P ¼ 0.0002). These findings highlight the association of increased urinary albumin excretion with impaired vascular reactivity in hypertensive individuals.

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A Genome-Wide Scan for Urinary Albumin Excretion in Hypertensive Families

Cited by 67 publications

References 22 publications

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

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

Genetic Factors in Diabetic Nephropathy

Urinary albumin excretion is associated with impaired flow- and nitroglycerin-mediated brachial artery dilatation in hypertensive adults

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