Association of a Genetic Variation in the β3-Adrenergic Receptor Gene with Coronary Heart Disease among Japanese

Higashi, Kenji; Ishikawa, Takahiro; Ito, Tsuyoshi; Yonemura, Atsushi; Shige, Hideki; Nakamura, Haruo

doi:10.1006/bbrc.1997.6339

Cited by 38 publications

(17 citation statements)

References 21 publications

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“…9 In 1995, a missense mutation that replaces tryptophan with arginine (Trp 64 Arg) of the human ␤3-AR gene was reported to be associated with increased capacity to gain weight in the French population, 10 the features of insulin resistance syndrome in Finns, 11 and the earlier onset of NIDDM in obese Pima Indians, 12 even in a heterozygous state. These observations were supported by subsequent reports in various ethnic populations, including Japanese, [13][14][15][16][17][18] Danes, 19 and Australians. 20 However, the role of this mutation in the pathogenesis of obesity is still controversial, and contradictory results have been reported with respect to the effects of the Trp 64 Arg mutation on obesity.…”

Section: ␤3-arsupporting

confidence: 85%

Clinical Features Associated With the Homozygous Trp ⁶⁴ Arg Mutation of the β3-Adrenergic Receptor

Sun

Ishibashi

Osuga

et al. 1998

ATVB

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Abstract-To characterize the clinical features associated with the Trp 64 Arg mutation of the ␤3-adrenergic receptor (␤3-AR), the effects of this mutation, in particular the homozygous state (Arg/Arg), on obesity, blood pressure, and plasma lipoproteins were investigated in 2 populations: subjects residing on a small isolated island (group 1; nϭ746) and patients residing in Tokyo who attend a clinic for metabolic diseases (group 2; nϭ371). The allelic frequency of the Trp 64 Arg mutation was 23.4% in group 1 and 18.3% in group 2. No significant difference in the body mass index was observed between subjects with 3 different genotypes in each group. There was a trend that the Arg/Arg had higher systolic blood pressure than the Trp/Trp in both groups, but the differences were not statistically significant. The plasma LDL cholesterol levels were significantly lower in Arg/Arg than in Trp/Trp in men from the group 1 cohort (2.82Ϯ0.84 versus 3.19Ϯ0.7 mmol/L, PϽ0.05). These results suggest that the homozygous Trp 64 Arg mutation is not a major contributing factor for obesity, but potentially contributed to higher systolic blood pressure and low plasma levels of LDL cholesterol in Japanese men. (Arterioscler Thromb Vasc Biol. 1998;18:941-946.)

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Section: ␤3-arsupporting

confidence: 85%

Clinical Features Associated With the Homozygous Trp ⁶⁴ Arg Mutation of the β3-Adrenergic Receptor

Sun

Ishibashi

Osuga

et al. 1998

ATVB

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“…Only four studies (two Japanese and two Caucasian) report increased allele frequency of the Arg variant in obesity; the increase in frequency is about two-fold [16,21,23,26]. In some studies there is no…”

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confidence: 97%

Adrenoceptor genes in human obesity

Arner

Hoffstedt

1999

Journal of Internal Medicine

109

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The genes causing obesity in rodent models have been characterized, but do not seem to be important for human obesity. Recently the putative association between obesity and polymorphism in human betaadrenergic receptor genes have been studied intensely in the light of the important role of these receptors in the regulation of energy mobilization and utilization. A polymorphism (Trp64Arg) in the beta 3 -adrenergic receptor gene is associated with obesity (relative risk < 2) in some but not all investigations on Caucasian and Japanese populations. When expressed in artificial cell systems, the polymorphism is associated with alterations of the beta 3 -adrenoceptor. The genetic allele variance influences also the native receptor function when measured in isolated human fat cells. The human beta 2 -adrenoceptor gene shows a high degree of polymorphism. The role of beta 2 -receptor gene polymorphism for obesity has so far only been investigaed in women. A Gln27Glu variant is markedly associated with obesity with a relative risk for obesity of < 7 and odds ratio of < 10. Women who are homozygous for 27Glu have < 20 kg higher fat mass than controls. Thus, polymorphism in genes coding for different beta-adrenoceptor subtypes may be important for the development of human obesity.

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“…Similarly, comparison of IMT cases and thin-walled controls by using logistic regression modeling suggested that the Arg64 allele was not a significant predictor of carotid artery wall thickness case status. In their study, Higashi et al (1997) have reported a higher frequency of the Trp64Arg mutation in CAD patients than in controls but caution that the frequency of this polymorphism in Japanese nationals is higher than in Caucasians, African Americans, and Hispanic Americans in the United States. Umekawa et al (1999) have recently reported that the Trp64Arg mutation is associated with lower lipolytic activities.…”

Section: Discussionmentioning

confidence: 87%

“…However, analyses involving Cox proportional hazards modeling to compare incident CHD cases and cohort individuals did not support the hypothesis that the Arg64 allele significantly predicts incident CHD. The Trp64Arg mutation has been reported to be positively associated with coronary artery disease (CAD) in a Japanese population (Higashi et al 1997). It has been suggested that even small decrements in resting metabolic rate and a reduced rate of fat oxidation may contribute to obesity (Ravussin et al 1988).…”

Section: Discussionmentioning

confidence: 99%

β3-Adrenergic receptor Trp64Arg polymorphism does not predict incident CHD or carotid intima-media thickness in a community-based sample of whites: the ARIC study

et al. 1999

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The beta3-adrenergic receptor (beta3-AR) is expressed in adipose tissue and plays a significant role in controlling energy expenditure through the regulation of lipolysis and thermogenesis. The possible clinical importance of the beta3-AR Trp64Arg polymorphism has prompted us to investigate the association between it and the extent of atherosclerosis and risk of incident coronary heart disease (CHD). The ability of the beta3-AR Trp64Arg polymorphism to predict the extent of atherosclerosis and incident CHD has been evaluated in participants of the Atherosclerosis Risk in Communities (ARIC) study. Incident CHD cases (n=271) were compared with a stratified random sample of the ARIC cohort (n=700). Comparisons were also made between a group with increased intimamedia thickness (IMT) of the carotid artery walls, but without prevalent CHD (n=324), and a thin-walled control group (n=407). The frequency of the Arg64 allele was 0.081 and 0.069 in the incident CHD cases and cohort sample, respectively, and 0.062 and 0.057 in the IMT cases and thin-walled controls, respectively. Comparison of incident CHD cases and the cohort sample by Cox proportional hazards modeling indicated that the Arg64 allele was not a significant predictor of incident CHD, either alone (RR=0.99, P=0.98) or after inclusion of body mass index (BMI) and fasting insulin and glucose measurements (RR=1.02, P=0.93). A comparison of IMT cases and thin-walled controls by multivariate logistic regression analysis suggested that the Arg64 allele was not a significant predictor of carotid artery intima-media thickness when evaluated alone (OR=1.32, P=0.29) or after BMI and fasting insulin and glucose measurements were added to the model (OR=1.28, P=0.35). We infer that the beta3-AR Trp64Arg polymorphism is not a major predictor of atherosclerosis or incident CHD in this sample of middle-aged white Americans.

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Association of a Genetic Variation in the β3-Adrenergic Receptor Gene with Coronary Heart Disease among Japanese

Cited by 38 publications

References 21 publications

Clinical Features Associated With the Homozygous Trp ⁶⁴ Arg Mutation of the β3-Adrenergic Receptor

Clinical Features Associated With the Homozygous Trp ⁶⁴ Arg Mutation of the β3-Adrenergic Receptor

Adrenoceptor genes in human obesity

β3-Adrenergic receptor Trp64Arg polymorphism does not predict incident CHD or carotid intima-media thickness in a community-based sample of whites: the ARIC study

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Association of a Genetic Variation in the β3-Adrenergic Receptor Gene with Coronary Heart Disease among Japanese

Cited by 38 publications

References 21 publications

Clinical Features Associated With the Homozygous Trp 64 Arg Mutation of the β3-Adrenergic Receptor

Clinical Features Associated With the Homozygous Trp 64 Arg Mutation of the β3-Adrenergic Receptor

Adrenoceptor genes in human obesity

β3-Adrenergic receptor Trp64Arg polymorphism does not predict incident CHD or carotid intima-media thickness in a community-based sample of whites: the ARIC study

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Clinical Features Associated With the Homozygous Trp ⁶⁴ Arg Mutation of the β3-Adrenergic Receptor

Clinical Features Associated With the Homozygous Trp ⁶⁴ Arg Mutation of the β3-Adrenergic Receptor