A genome-wide linkage scan for genes controlling variation in urinary albumin excretion in type II diabetes

Królewski, Andrzej S.; Poznik, G. David; Placha, Grzegorz; Canani, Luís Henrique Santos; Dunn, Jonathon; Walker, William H.; Smiles, Adam M.; Krolewski, Bozena; Fogarty, Damian; Moczulski, Dariusz; Araki, Shin‐ichi; Makita, Yuichiro; Ng, Daniel; Rogus, John; Duggirala, Ravi; Rich, Stephen S.; Warram, James H.

doi:10.1038/sj.ki.5000023

Cited by 101 publications

(94 citation statements)

References 40 publications

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“…Several regions of linkage have been replicated among the various groups with type 2 DN, as well. The 18q22-23 linkage region was replicated in four populations (23,26,29), the 7q35-36 peak in three reports (25,26,31), and the 7p15 and 10q26 peaks in two each (14,23,32). Positional candidate genes for DN in these regions are now being sought and identified (Table 2).…”

Section: Genome-wide Linkage Scans For Dnmentioning

confidence: 99%

Genetic Factors in Diabetic Nephropathy

Freedman

Bostrom

Daeihagh

et al. 2007

Clinical Journal of the American Society of Nephrology

174

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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Section: Genome-wide Linkage Scans For Dnmentioning

confidence: 99%

Genetic Factors in Diabetic Nephropathy

Freedman

Bostrom

Daeihagh

et al. 2007

Clinical Journal of the American Society of Nephrology

174

125

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“…The other study 56 investigated four different variants of eNOS than those described earlier: C1067T, A26G, G894T, and A15G; none of these variants produced a significant transmission (OR ϭ 1.15, 95% CI: 0.63-2.09, OR ϭ 1.08, 95% CI: 0.63-1.84, OR ϭ 1.10, 95% CI: 0.61-1.98, and OR ϭ 1.14, 95% CI: 0.64 -2.05, respectively). Only one genome-wide linkage scan 60 provided evidence of linkage at the chromosomal region 7q36, which harbors the eNOS gene. None of the genome-wide association studies 69,70 showed association with eNOS gene polymorphisms.…”

Section: Evidence From Family-based and Genome-wide Study Designsmentioning

confidence: 99%

Endothelial nitric oxide synthase gene polymorphisms and diabetic nephropathy: A HuGE review and meta-analysis

Ζιντζαράς

Papathanasiou

Stefanidis

2009

Genetics in Medicine

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Candidate-gene association studies that examined the association between polymorphisms of endothelial nitric oxide synthase (NOS3) gene (G894T, 4b/a, and T786C) and diabetic nephropathy or diabetes leading to severe nephropathy produced inconclusive results. Thus, a meta-analysis of all candidate-gene association studies with endothelial nitric oxide synthase genotyping (7401 cases and 8046 controls) was conducted. Other study designs, such as family-based association studies and genome-wide linkage and association studies were also reviewed for supportive evidence of implication of endothelial nitric oxide synthase gene in diabetic nephropathy. The meta-analysis showed that G894T is significantly associated with diabetic nephropathy and diabetes leading to severe nephropathy in type 2 diabetics and in East Asians, respectively. Concerning the 4b/a polymorphism and its relationship to diabetes leading to severe nephropathy, a significant association was shown for East Asians. Heterogeneity between studies was in general high. There was no differential magnitude of effect in large versus small studies. One genome-wide linkage scan provided evidence of linkage nearby the endothelial nitric oxide synthase locus. Studies exploring gene and environment interactions with endothelial nitric oxide synthase polymorphisms may help understand better the genetics of diabetic nephropathy. Genet Key Words: eNOS, NOS3, G894T, 4b/a, T786C, diabetic nephropathy, diabetes, polymorphism, meta-analysis, genetic epidemiology Gene and gene variantsVascular endothelial nitric oxide (NO) regulates endothelial function and precipitates vasodilatory effects in multiple organs, including the kidney. 1 NO is produced by the oxidation of L-arginine to L-citrulline by NO synthase (NOS). There are three isoforms of NOS: endothelial NOS (eNOS), neuronal NOS, and inducible NOS. 2,3 Each isoform is coded by separate genes with a different pattern of expression. 4 The eNOS gene (NOS3) is located on chromosome 7q35-36, and it comprises 26 exons and 25 introns, with an entire length of 21kb. 4 Variants of eNOS gene contribute to endothelial dysfunction and attenuate the NO production. 5 Dysfunctional eNOS may play a critical role in the pathogenetic pathway, leading to diabetic vascular complications including diabetic nephropathy (DN). 6 Several polymorphisms of the eNOS gene have been identified, and their association with various diseases has been investigated, including coronary artery disease, myocardial infarction, coronary spasm, hypertension, end-stage renal disease (ESRD), and DN. 4,[7][8][9][10] The most clinically relevant polymorphisms that have been described in the eNOS gene 11 are the following: (i) a G894T substitution in exon 7 that results in a Glu to Asp substitution at codon 298, 7 (ii) an insertion-deletion in intron 4 consisting of two alleles (the a-deletion has 4 tandem 27-bp repeats, and the b-insertion has 5 repeats), 12 and (iii) a T786C substitution in the promoter region, which is strongly linked to 4b/a....

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“…These families belong to the Joslin Study on Genetics of Type 2 Diabetes -a collection of 104 extended families in which type 2 diabetes segregates as an autosomal dominant disorder. The ascertainment of these families and the recruitment procedures have been previously described [20]. The screening criteria were: 1) a proband and at least one sibling with type 2 diabetes diagnosed between ages 10 and 59 years; 2) three or more generations affected by diabetes; and 3) unilineal transmission of diabetes.…”

Section: Families With Type 2 Diabetesmentioning

confidence: 99%

Identification of a locus modulating serum C-reactive protein levels on chromosome 5p15

et al. 2008

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Objective: Individual propensity to chronic, low-grade inflammation -a determinant of atherosclerosis -is in part under the control of genetic factors. To identify genes involved in this modulation, we performed a 10 cM genome screen for linkage with plasma C-reactive protein in 38 extended families including 317 non-diabetic and 177 type 2 diabetic family members (2,547 relative pairs). Methods and results:In a variance component analysis, heritability of CRP values was significant (h 2 =0.39, p<0.0001). This effect was independent of BMI and was present in both diabetic (h 2 =0.42, p=0.003) and non-diabetic (h 2 =0.34, p=0.0015) relatives. The strongest evidence of linkage with CRP was on chromosome 5p15, where the LOD score reached genome-wide significance (LOD=3.41, genome-wide p=0.013). Both diabetic and non-diabetic family members contributed to linkage at this location. Smaller linkage peaks were detected on chromosomes 5q35 (LOD=1.35) and 17p11 (LOD=1.33). When the analysis was restricted to diabetic family members, another peak of moderate intensity (LOD=2.17) was evident at 3p21. Conclusions:A major gene influencing CRP levels appears to be located on chromosome 5p15, with an effect that is independent of diabetes. Another gene on 3p21 may control CRP variation but only in the presence of a diabetic or insulin-resistant environment.

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A genome-wide linkage scan for genes controlling variation in urinary albumin excretion in type II diabetes

Cited by 101 publications

References 40 publications

Genetic Factors in Diabetic Nephropathy

Genetic Factors in Diabetic Nephropathy

Endothelial nitric oxide synthase gene polymorphisms and diabetic nephropathy: A HuGE review and meta-analysis

Identification of a locus modulating serum C-reactive protein levels on chromosome 5p15

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