Time of Onset of Non-Insulin-Dependent Diabetes Mellitus and Genetic Variation in the β<sub>3</sub>-Adrenergic–Receptor Gene

Walston, Jeremy D.; Silver, Kristi; Bogardus, Clifton; Knowler, William C.; Celi, Francesco S.; Austin, Sharon; Manning, Brian S.; Strosberg, A. Donny; Stern, Michael P.; Raben, Nina; Sorkin, John D.; Roth, Justine P.; Shuldiner, Alan R.

doi:10.1056/nejm199508103330603

Cited by 585 publications

(458 citation statements)

References 29 publications

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“…Thus, it can be inferred that these genetic variants and modifiable risk factors may interact in a multiplicative manner to establish a vicious cycle involving obesity, dyslipidaemia, hypertension and renal dysfunction. The interaction term of lipid × ADRB on obesity, especially in the highrisk model, is consistent with known risk associations of genetic variants of ADRB2 and ADRB3 with diabetes, obesity, fatty liver, dyslipidaemia, hypertension and reduced metabolic rate in multiple populations [42][43][44][45][46]. Since sympathetic adrenergic activity is a major determinant of lipolysis and energy metabolism, it is plausible that a combination of genetic factors that promote lipogenesis and/or reduce lipolysis may facilitate energy storage during times of deprivation but predispose to obesity during times of plenty [47].…”

Section: Effects Of Genotypes and Phenotypes On Renal Functionsupporting

confidence: 79%

Phenotype–genotype interactions on renal function in type 2 diabetes: an analysis using structural equation modelling

Song

Lee

et al. 2009

Diabetologia

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Aims/hypothesis Cardiovascular and renal diseases share common risk factors. We used structural equation modelling (SEM) to evaluate the independent and combined effects of phenotypes and genotypes implicated in cardiovascular diseases on renal function in type 2 diabetes.Methods 1,188 type 2 diabetic patients were stratified into high-risk and low-risk groups according to bimodal distributions of the logarithmically transformed (log e ) urinary albumin:creatinine ratio and plasma creatinine levels. Models for these groups, comprising continuous and non-ranking categorical data, were developed separately to evaluate the inter-relationships among measured variables and latent factors using non-linear SEMs, Bayesian estimation and model selection as assessed by a goodness-of-fit statistic. Results Inter-correlated measured variables (obesity, glycaemia, lipid, blood pressure) and variants of the genes encoding endothelial nitric oxide synthase (NOS), β-adrenergic receptor (ADRB), components of the reninangiotensin system (RAS) and lipid metabolism were loaded onto their respective latent factors of phenotypes and genotypes. In addition to direct and indirect effects, latent factors of obesity, lipid and BP interacted with latent factors of ADRB and RAS genotypes to influence renal function. Together with variants of the genes encoding peroxisome proliferator-activated receptor γ, atrial natriuretic peptide, adducin, G protein β 3 subunit, epithelial sodium channel α subunit and matrix metallopeptidase 3, these parameters explained 39-80% of the variance in renal function in the high-risk and low-risk models. Conclusions/interpretation SEM is a useful tool for confirming and quantifying multiple interactions of biological pathways with genetic determinants. The combined and interactive effects of blood pressure, lipid and obesity on renal function may have therapeutic implications, especially in type 2 diabetic individuals with genetic risk factors.

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Section: Effects Of Genotypes and Phenotypes On Renal Functionsupporting

confidence: 79%

Phenotype–genotype interactions on renal function in type 2 diabetes: an analysis using structural equation modelling

Song

Lee

et al. 2009

Diabetologia

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“…24 In previous epidemiologic studies, the association between the ADRB3 variant and obesity-related phenotypes has been investigated among individuals from several racial/ ethnic groups and nationalities, including Caucasians, 13 Japanese, 12,25,26 Pima Indians, 24 Mexican Americans, 14 African Americans 27,28 and Jamaicans. 29 Previous studies of white or Japanese populations found the variant allele of the ADRB3 receptor to be associated with elevated measures of obesity, 13 whereas two previous studies of African Americans reported associations with the wild-type receptor.…”

Section: Adrb3 and Obesity R Mckean-cowdin Et Almentioning

confidence: 99%

“…31 The tryptophan-toarginine substitution at codon 64 of ADRB3 was initially reported in 1995. 13,15,24 The substitution is located in the first coding exon, at the junction of the first transmembrain domain and the first intracellular loop of the receptor. 32,33 The impact of the missense change is not known; it has been suggested that the substitution could impact receptorprotein folding or alter functional properties such as ligand binding or receptor activation.…”

Section: Adrb3 and Obesity R Mckean-cowdin Et Almentioning

confidence: 99%

The ADRB3 Trp64Arg variant and obesity in African-American breast cancer cases

McKean‐Cowdin

Bernstein

et al. 2007

Int J Obes

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Objective: To determine if a missense change at codon 64 of ADRB3 (Trp64Arg), a candidate obesity gene, is associated with obesity and levels of subcutaneous or visceral fat in African-American breast cancer cases. Several observational studies have found that women, who are overweight or obese at the time of diagnosis, as well as those who gain weight after diagnosis, are at greater risk for breast cancer recurrence and death than non-overweight women. Design: Prospective cohort of breast cancer cases. Subjects: 219 African-American breast cancer patients participating in the Los Angeles component of the Health, Eating, Activity and Lifestyle Study. Measures: ADRB3 Trp64Arg genotype, measures of weight including body mass index (BMI), weight gain (weight 5 years before diagnosis compared with weight at 30 months after diagnosis), obesity (BMIX30 kg/m 2 ), waist/hip circumference and visceral or subcutaneous fat were determined by magnetic resonance imaging. Results: African-American women who were homozygous for the ADRB3 wild-type allele had significantly higher mean visceral fat levels than women who carried the variant (P ¼ 0.04), and were significantly more likely to be obese (odd ratios (OR) ¼ 2.1, 95% confidence interval (CI) ¼ 1.1-4.2). The association with obesity was most pronounced among women who were premenopausal (OR ¼ 4.8, 95% CI ¼ 1.3-18), who received chemotherapy for their breast cancer (OR ¼ 6.1, 95% CI ¼ 1.8-20), or who were not physically active (OR ¼ 3.9, 95% CI ¼ 1.5-9.7). Conclusion: The wild-type allele of the ADRB3 missense change was associated with measures of obesity in our sample of African-American women. The association was modified by menopausal status, history of chemotherapy and modest levels of physical activity. These results will need to be confirmed in an independent sample.

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“…In most cases, the clinical expression of the disease can be prevented by dietary and lifestyle modification [1]. On the other hand, the genetic base of Type II diabetes is very heterogeneous and has been related to various genetic mutations that codify proteins linked to glucose and insulin metabolism, such as the insulin receptor [2], the insulin receptor substrate-1 [3], the Rad protein [4], the glycogen synthase [5] and the β-3-adrenergic receptor [6]. However, the genetic background of insulin resistance and Type II diabetes is more complex and it can also involve other genes seemingly unrelated to carbohydrate metabolism.…”

mentioning

confidence: 99%

The SstI polymorphism of the apo C-III gene is associated with insulin sensitivity in young men

Pérez‐Jiménez

Gomez

et al. 2002

Diabetologia

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Aims/hypothesis. Insulin resistance is considered to be a risk factor for diabetes and coronary heart disease and is determined by the interaction between genetic and environmental factors. The SstI polymorphism in the apolipoprotein C-III gene has been related to the presence of different features of the insulin resistance syndrome. We investigate if this mutation influences the peripheral effect of insulin in healthy young subjects (30 men and 29 women) eating a westernised diet. Methods. We investigated peripheral insulin sensitivity with the insulin suppression test after a 28-day westernised high-saturated fat diet (38% total fat and 18% saturated fat with 115 mg of cholesterol per 1000 Ju). Results. Steady state plasma glucose values were lower in S1-S1 compared with S1-S2 men (p=0.018 by ANOVA), but not in women (p=0.723). Conclusion/interpretation. There was no difference between carriers and non-carriers of the S2 allele in relation to incidence and sensitivity; although on subgroup analysis there was an effect in men but not in women. [Diabetologia (2002[Diabetologia ( ) 45:1196[Diabetologia ( -1200 Keywords High-saturated fat diet, insulin sensitivity, glucose metabolism, non-esterified fatty acids.

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Time of Onset of Non-Insulin-Dependent Diabetes Mellitus and Genetic Variation in the β₃-Adrenergic–Receptor Gene

Abstract: Pima subjects homozygous for the Trp64Arg beta 3-adrenergic-receptor mutation have an earlier onset of NIDDM and tend to have a lower resting metabolic rate. This mutation may accelerate the onset of NIDDM by altering the balance of energy metabolism in visceral adipose tissue.

Cited by 585 publications

References 29 publications

Phenotype–genotype interactions on renal function in type 2 diabetes: an analysis using structural equation modelling

Phenotype–genotype interactions on renal function in type 2 diabetes: an analysis using structural equation modelling

The ADRB3 Trp64Arg variant and obesity in African-American breast cancer cases

The SstI polymorphism of the apo C-III gene is associated with insulin sensitivity in young men

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Time of Onset of Non-Insulin-Dependent Diabetes Mellitus and Genetic Variation in the β3-Adrenergic–Receptor Gene

Abstract: Pima subjects homozygous for the Trp64Arg beta 3-adrenergic-receptor mutation have an earlier onset of NIDDM and tend to have a lower resting metabolic rate. This mutation may accelerate the onset of NIDDM by altering the balance of energy metabolism in visceral adipose tissue.

Cited by 585 publications

References 29 publications

Phenotype–genotype interactions on renal function in type 2 diabetes: an analysis using structural equation modelling

Phenotype–genotype interactions on renal function in type 2 diabetes: an analysis using structural equation modelling

The ADRB3 Trp64Arg variant and obesity in African-American breast cancer cases

The SstI polymorphism of the apo C-III gene is associated with insulin sensitivity in young men

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Time of Onset of Non-Insulin-Dependent Diabetes Mellitus and Genetic Variation in the β₃-Adrenergic–Receptor Gene