Beta2-adrenoceptor polymorphisms relate to obesity through blunted leptin-mediated sympathetic activation.

BACKGROUND: Obesity is a growing public health problem. It has been reported that beta2-adrenoceptor polymorphisms are associated with obesity. This study examines the associations of beta2-adrenoceptor polymorphism with relationships between plasma norepinephrine (NE) and leptin to evaluate further the mechanisms of obesity. METHODS: In 329 normotensive (BP <140/90 mm Hg) men with a wide range of BMI (17.0 to 36.5 kg/m2), we measured BMI, total body fat mass, waist-to-hip ratio (W/H), BP, plasma NE, leptin, and the beta2-(Arg16Gly, Gln27Glu) adrenoceptor polymorphisms. The subjects consisted of 206 nonobese (BMI <25 kg/m2) and 123 overweight or obese (BMI >or=25 kg/m2) men. RESULTS: Overweight or obese subjects had a significantly higher frequency of Gly16 and Glu27 alleles compared with nonobese subjects. The subjects carrying Gly16 or Glu27 alleles regardless of BMI had greater total fat mass, W/H and plasma leptin compared with those without the Gly16 or Glu27 alleles, indicating that Gly16 and Glu27 alleles of the beta2-adrenoceptor gene are related to obesity and fat mass. Only in the nonobese subjects who carried the Gly16 and Glu27 alleles was there a high plasma NE level, but similar in overweight or obese subjects. To evaluate leptin-mediated sympathetic activation, we performed linear regression analyses between plasma leptin and NE. In groups with and without the Gly16 or Glu27 alleles, plasma leptin correlated with NE, but the slope in the group carrying the Gly16 or Glu27 allele was significantly lower than that without the Gly16 or Glu27. CONCLUSIONS: The findings demonstrate a strong and significant association of the Gly16 and Glu27 alleles with obesity. Lower slopes between leptin and NE in the subjects carrying these beta2-adrenoceptor polymorphisms indirectly indicate a blunted leptin-mediated sympathetic nerve activity. We propose that the beta2-adrenoceptor polymorphisms related to blunted leptin-mediated sympathetic activation offers further proof for the mechanisms of obesity.

Effects of angiotensin II type 1 receptor gene polymorphisms on insulin resistance in a Japanese general population: the Tanno-Sobetsu study.

Although gene polymorphisms in the renin-angiotensin system (RAS) are predisposing factors for cardiovascular diseases, the precise mechanisms and interactions among confounding factors have not been clarified. We investigated whether genetic variants of RAS are involved in insulin sensitivity in a Japanese general population. During a medical checkup in 2001, participants (n=550) were recruited from among the residents of the towns of Tanno and Sobetsu, and written informed consent was obtained to participate in the genetic analysis and the epidemiological study. The insertion/deletion (lID) polymorphism of the angiotensin-converting enzyme gene (ACE), the Met235Thr polymorphism of the angiotensinogen gene (AGT), and the A1166C polymorphism of the angiotensin II type 1 receptor gene (AGTR1) were determined by gel electrophoresis or the TaqMan PCR method. We assessed insulin sensitivity using the homeostasis model assessment insulin resistance (HOMA-IR). The RAS gene polymorphisms were not associated with log-transformed values of HOMA-IR, whereas borderline association (p=0.02) was found between the A1166C polymorphism and dichotomous categorization of insulin resistance (defined as HOMA-IR > or =1.73). Our results suggested that the A1166C polymorphism of AGTR1 might affect insulin resistance by altering the responsiveness to angiotensin II signaling, though this mechanism is as yet inconclusive. Further study is required to confirm these findings in a larger, multi-ethnic population.

Rebound weight gain as associated with high plasma norepinephrine levels that are mediated through polymorphisms in the beta2-adrenoceptor.

BACKGROUND: A successful weight loss program is essential treatment for obesity-related diseases, but it is well known that the majority of individuals do not succeed in weight loss maintenance. The present study evaluates hormonal mechanisms and the relationship of beta2-adrenoceptor polymorphisms involved in individuals who regain weight after initially successful weight loss. METHODS: Overweight Japanese men (n = 154) were enrolled in a 24-month weight loss program. Body mass index (BMI), total body fat mass, plasma norepinephrine (NE) and leptin levels, and beta2-adrenoceptor polymorphisms (Arg16Gly, Gln27Glu) were measured every 6 months for the 24-month period. Maintenance of weight loss was defined as significant weight loss (>or=10% reduction) from entry weight at 6 months and maintenance of the weight loss for an additional 18 months. Rebound weight gain was defined as significant weight loss at 6 months but subsequent regain of body weight during the next 18 months. RESULTS: The results showed that 37 subjects maintained weight loss during 24 months, whereas 36 subjects had rebound weight gain. The BMI at entry and calorie intake and physical activity at each period were similar between the two groups. Subjects who maintained weight loss had at entry a significantly lower fat mass and plasma NE levels compared to those with rebound weight gain. Body fat mass, NE, and leptin levels at entry predicted the degree of change in body weight during the 24-month study period. Subjects with rebound weight gain had a significantly higher frequency of the Gly16 allele for the beta2-adrenoceptor polymorphism compared to subjects who had a 24-month maintenance of weight loss. Subjects carrying the Gly16 allele also had significantly higher plasma NE, leptin, and body fat mass levels and a greater waist-to-hip ratio both at entry and throughout the study. CONCLUSIONS: A high initial degree of body fat mass and high plasma NE levels as determined by the Gly16 allele for the beta2-adrenoceptor polymorphisms predict those individuals who will have rebound weight gain after their initial successful weight loss.

Beta2-adrenoceptor polymorphisms relate to insulin resistance and sympathetic overactivity as early markers of metabolic disease in nonobese, normotensive individuals.

BACKGROUND: The genes responsible for insulin resistance are also candidate genes for insulin resistance-related diseases, such as obesity and hypertension. Functional polymorphisms in the beta2- and beta3-adrenergic receptors have been reported to be associated with diabetes, hypertension, and obesity. To clarify the relevance of the beta-adrenergic receptor polymorphisms to insulin resistance, we studied their association with polymorphisms of beta2 (Arg16Gly, Gln27Glu) and beta3 (Trp64Arg) adrenoceptor genes. METHODS: We studied 155 young, nonobese Japanese men using the homeostasis model assessment of insulin resistance (HOMA-IR) to divide individuals into insulin-sensitive and insulin-resistant groups. Insulin resistance in the participants was defined as HOMA-IR equal to or greater than the average plus 1 SD of 3.1. There were 69 men who were insulin resistant and 86 men who were insulin sensitive. Body mass index (BMI), blood pressure (BP), plasma glucose, insulin, leptin, norepinephrine (NE) levels, and the polymorphisms of Arg16Gly and Gln27Glu of the beta2- and Trp64Arg of the beta3-adrenoceptor polymorphisms were measured in all participants. RESULTS: The insulin-resistant group had higher frequency of the Gly16 allele of Arg16Gly compared with the insulin-sensitive group, whereas the frequencies of genotypes or alleles of Gln27Glu and Trp64Arg were similar. The insulin-resistant group had a higher mean HOMA-IR, fasting insulin, NE, and total fat mass compared with levels in the insulin-sensitive group, but the BMI and leptin levels were similar. The subjects carrying the Gly16 allele of the beta2-adrenoceptor gene had a higher mean HOMA-IR, fasting insulin, NE, body fat mass, and BP than those without the Gly16 allele. CONCLUSIONS: The Gly16 mutation of the beta2-adrenoceptor gene is associated with increased insulin resistance, adiposity, and BP accompanied by higher plasma NE levels early in the metabolic disease in developing obesity. These findings show an important role of beta2-adrenoceptor gene polymorphisms in the association of insulin resistance in hypertension and obesity.

Beta2- and beta3-adrenergic receptor polymorphisms are related to the onset of weight gain and blood pressure elevation over 5 years.

BACKGROUND: The genes responsible for obesity are candidate genes for obesity-related diseases, such as hypertension. Functional polymorphisms in the beta2- and beta3-adrenergic receptors have been reported to be associated with hypertension and obesity. METHODS AND RESULTS: To longitudinally clarify the relevance to alterations in beta-adrenergic receptor polymorphisms related to weight gain, blood pressure (BP) elevation, and sympathetic nerve activity as measured by plasma norepinephrine level, we studied 160 young, nonobese, normotensive men. Changes in body weight, BP, plasma norepinephrine levels, and beta2-adrenergic (Arg16Gly, Gln27Glu) and beta3-adrenergic (Trp64Arg) receptor polymorphisms were measured periodically over a 5-year period. Weight gain and BP elevation were defined as > or =10% increases from entry levels over 5 years in body mass index or mean BP. The presence of the Gly16 allele of Arg16Gly was associated with a higher frequency of weight gain and BP elevation over the 5-year period. The subjects carrying the Glu27 allele of Gln27Glu and the Trp64 allele of Trp64Arg had a higher frequency of BP elevation. Significantly higher levels of plasma norepinephrine at entry and at year 5 were observed in the subjects with the Gly16 allele of Arg16Gly and the Glu27 allele of Gln27Glu compared with those without the Gly16 or the Glu27 alleles. CONCLUSIONS: These results demonstrate that the Gly16 allele is related to greater weight gain and BP elevation. Additionally, Glu27 and Trp64 alleles are linked to BP elevation. The subjects carrying the beta2-polymorphisms linked to weight gain and BP elevation also have higher plasma norepinephrine levels that are present at entry before weight gain and BP elevation. These findings suggest that beta2-adrenergic receptor polymorphisms in association with a heightened sympathetic nerve activity could predict the future onset of obesity and hypertension, as shown in the 5-year longitudinal study.

Lys418Asn polymorphism of the alpha2-adrenoceptor gene relates to serum uric acid levels but not to insulin sensitivity.

Hyperuricemia is associated with cardiovascular risk. The present study examines the association between serum uric acid (UA) elevation and the alpha2-, beta2-, and beta3-adrenoceptor polymorphisms. In 219 nonobese, normotensive, normouricemic (serum UA <6.5 mg/dL at entry) men, serum UA, plasma norepinephrine (NE), the homeostasis model assessment of insulin resistance (HOMA-IR), body mass index, total body fat mass, the alpha2A(Lys418Asn)-, beta2(Arg16Gly, Gln27Glu)-, and beta3(Trp64Arg)-adrenoceptor polymorphisms were measured annually over 5 years. Hyperuricemia was defined as a serum UA level of > or =mean+1 SD of 5.0 mg/dL in the participants. At entry, there were 36 subjects who had hyperuricemia and 183 who had normal UA levels. A significant UA elevation for 5 years was defined as an increase in > or =10% in UA levels. There were 82 subjects who had significant UA elevations. The subjects who had hyperuricemia at entry in addition to the subjects who had significant UA elevations over the 5-year period carried a significantly higher frequency of the Asn418 allele of Lys418Asn. Additionally, subjects carrying the Asn418 allele had higher UA and plasma NE and greater elevations in UA over the study period, but HOMA-IR was similar. Insulin resistance at entry and during the study was associated with Arg16Gly polymorphisms but not with Lys418Asn polymorphisms. In conclusion, the Asn418 allele of Lys418Asn is associated with either established hyperuricemia or the progressive elevation of UA over time. This polymorphism was not associated with insulin resistance in nonobese, normotensive individuals. Although hyperuricemia is of known relevance to insulin resistance, it appears to have different genetic determinants from insulin resistance in terms of adrenoceptor polymorphisms.

Association between hepatocyte growth factor gene polymorphism and essential hypertension.

Hepatocyte growth factor (HGF) is a growth factor which contributes to protection and/or repair of vascular endothelial cells. Serum HGF level is elevated in response to hypertensive organ damage, which suggests that blood pressure regulation may be affected by HGF gene polymorphisms via serum HGF. To examine the interaction between a HGF gene polymorphism and hypertension, we carried out a case-control study. The present study was conducted in outpatients of Osaka University Hospital. Subjects (n=654) who gave informed consent to the study protocol and genetic analysis were recruited. A C to A nucleotide substitution in intron 13 of the HGF gene was determined by the TaqMan polymerase chain reaction (PCR) method using an MGB (Minor Groove Binder) probe. The genotype distribution of the C/A polymorphism of the HGF gene in total subjects was as follows: CC, 83%; CA, 16%; and AA 1%. This distribution was not significantly different from the predicted by Hardy-Weinberg's equilibrium. The prevalence of hypertension was significantly higher in subjects with the CC genotype than in those with an A allele, and the positive association remained after adjustment for confounding factors, with the estimated odds ratio for hypertension (CC vs. CA+AA) being 1.71 (95% confidence interval: 1.02-2.93). A significant association with hypertension was observed in lean or female subjects but not in obese or male subjects. In conclusion, our data suggested that C/A polymorphism in intron 13 of the HGF gene is associated with susceptibility to essential hypertension in lean or female subjects.

Hypoadiponectinemia is an independent risk factor for hypertension.

Adiponectin is one of the key molecules in the metabolic syndrome, and its concentration is decreased in obesity, type-2 diabetes, and coronary artery disease. Genetic investigation has revealed that 2 polymorphisms (I164T and G276T) are related to adiponectin concentration and diabetes. To examine whether adiponectin affects hypertension genetically or biologically, we performed a case-control study. A total of 446 diagnosed cases of hypertension (HT) in men and 312 normotensive (NT) men were enrolled in this study. Plasma adiponectin concentration was measured using an enzyme-linked immunosorbent assay system. Single nucleotide polymorphisms were determined by TaqMan polymerase chain reaction method. After adjustment for confounding factors, adiponectin concentration was significantly lower in HT (HT: 5.2+/-0.2 microg/mL; NT: 6.1+/-0.2 microg/mL; P<0.001). Furthermore, multiple regression analysis indicated that hypoadiponectinemia was an independent risk factor for hypertension (P<0.001). Blood pressure was inversely associated with adiponectin concentration in normotensives regardless of insulin resistance. In subjects carrying the TC genotype of the I164T polymorphism, adiponectin concentration was significantly lower (TC: 2.6+/-0.9 microg/mL; TT: 5.5+/-0.1 microg/mL; P<0.01), and most of them had hypertension. In contrast, the G276T polymorphism was not associated with adiponectin concentration or hypertension. In conclusion, hypoadiponectinemia is a marker for predisposition to hypertension in men.

Relationship of bradykinin B2 receptor gene polymorphism with essential hypertension and left ventricular hypertrophy.

The bradykinin B2 receptor shows a protective role in the development of hypertension and renal and cardiovascular complications. It was recently reported that a polymorphism of the bradykinin B2 receptor gene (BDKRB2) is a genetic predisposing factor for hypertension and cardiovascular disease. The aim of this study was to examine the relationship of a polymorphism (-58 T/C and exon 1 +9/-9) of BDKRB2, and an insertion/deletion polymorphism (I/D) of the angiotensin converting enzyme gene (ACE) with essential hypertension and cardiovascular mortality in the Japanese population. Genotyping was carried out in 275 hypertensive and 441 normotensive subjects. Left ventricular hypertrophy (LVH) was detected by ECG in 242 untreated patients with hypertension. All participants were Japanese and gave their written informed consent. The polymorphism (-58 T/C) in the promoter region of the BDKRB2 was determined using the TaqMan-polymerase chain reaction (PCR) method, the exon 1 +9/-9 polymorphism of the BDKRB2 and I/D polymorphism of the ACE were monitored by PCR and gel electrophoresis. The genotypes and allelic frequencies were in Hardy-Weinberg equilibrium. The polymorphism (-58 T/C) in the promoter of the BDKRB2 was associated with LVH in the hypertensive group (n =242) (p =0.048; chi2 =3.9; odds ratio: 1.8; 95% confidence interval (CI): 1.0-3.3). Furthermore, the frequency of LVH in hypertensives was significantly higher in the subjects with both the BDKRB2 CC and ACE D allele than those with other genotypes (p =0.002, chi2 =9.4). However, no relationship could be found between polymorphism of the BDKRB2 (p =0.86, chi2 =0.3) or the ACE (p =0.21, chi2 =3.1) and hypertension in this group of subjects. These results suggest that the polymorphism (-58 T/C) in the promoter region of BDKRB might be a risk factor and might have a synergetic effect with the ACE for LVH in hypertensives, but it is not associated with hypertension in the Japanese population.

Epsilon 4 allele of apolipoprotein E gene associates with lower blood pressure in young Japanese subjects: the Suita Study.

OBJECTIVES: The apolipoprotein epsilon 4 allele (APOE/epsilon 4) increases plasma cholesterol level and the risk for the late onset type of Alzheimer's disease. However, the correlation between hypertension and APOE/epsilon 4 has not yet been clarified. To examine the APOE/epsilon 4 effect in the general population of Japan, we performed a large genetic epidemiological survey (the Suita Study). DESIGN AND METHODS: The Suita Study was a cohort study based on a random sample of 14,200 Japanese residents of Suita city. Subjects who gave informed consent for genetic analysis were recruited in the current study ( = 3997). APOE polymorphism was clearly determined by the TaqMan polymerase chain reaction method. RESULTS: Subjects with APOE/epsilon 4 were significantly ( P < 0.03) more frequent (19.7%) in normotensives than in hypertensives (16.9%), the estimated odds ratio for hypertension (with APOE/epsilon 4 versus without APOE/epsilon 4) being 0.83 [95% confidence interval (CI), 0.70-0.98]. The significance of the association (OR = 0.64; 95% CI, 0.48-0.86) was increased in young subjects ( < or = 60 years old) but disappeared in old subjects. APOE/epsilon 4 also significantly contributed to a 2.9% increase of total cholesterol, 11.8% increase of triglyceride and 3.2% of decrease of high-density lipoprotein-cholesterol. CONCLUSIONS: We concluded that APOE/epsilon 4 was associated with an increase of plasma lipid levels and with a decrease of systolic blood pressure. The final conclusion on whether APOE/epsilon 4 contributes to the risk for cardiovascular disease will be clarified by analysis of the cumulative incidence, which will be obtained in the future Suita Study.