Angiotensinogen gene polymorphism is associated with insulin resistance in nondiabetic men with or without coronary heart disease

Background Variants of the angiotensinogen gene may increase the risk of having arterial hypertension and coronary heart disease (CHD), but their effect on insulin resistance remains unknown.Methods We determined M235 and T174 allele status and fasting plasma glucose, insulin, and lipids values in nondiabetic men with CHD documented on angiography (n = 102) and in a control group (n = 145). Plasma glucose and insulin responses to 75 gm oral glucose tolerant test and insulin resistance as measured by an insulin suppression test were also carried out in 46 (45%) patients with CHD and in 73 (50%) members of a control group.Results We found no association between M235T status and blood pressure, fasting plasma glucose, insulin, most of the lipids values, and insulin resistance in patients with CHD and normal subjects. Nevertheless, compared with individuals with homozygotes T174, subjects with heterozygotes T174M were associated with greater glucose and insulin response to the oral glucose tolerance test and insulin resistance indicated by higher steady state plasma glucose concentrations in patients with CHD (14.7 ± 0.9 vs 11.3 ± 0.7 mmol/L, p < 0.04). Similar findings were found in the control group, with higher steady-state plasma glucose values in individuals with heterozygotes T174M than in those with homozygotes T174 (10.1 ± 1.4 vs 7.7 ± 0.4 mmol/L, p < 0.05).Conclusion We suggest that the angiotensinogen T174M allele might be associated with insulin resistance in nondiabetic men with and without CHD. (Am Heart J 1998;136:125-31.)     

The beta3-adrenergic receptor Trp64Arg mutation is not associated with coronary artery disease

There is some evidence that the Trp64Arg polymorphism of the beta3-adrenergic receptor (beta3-AR) is associated with atherogenic risk factors that include weight gain, insulin resistance, and diabetes. The objective of this cross-sectional study was to investigate the relationship between the Trp64Arg polymorphism and coronary artery disease (CAD). A total of 1,000 consecutive patients with angiographically confirmed CAD and 1,000 controls, carefully matched for age and sex, were genotyped for the Trp64Arg polymorphism by polymerase chain restriction and subsequent restriction fragment length polymorphism analysis. Among cases with CAD, 83.3% were wild-type Trp/Trp, 15.8% were heterozygotes, and 0.9% were homozygous Arg/Arg compared with 82.3%, 17.3%, and 0.4%, respectively, among controls (P = .27). The odds ratios for the presence of Trp/Arg and Arg/Arg in cases and controls were 0.90 (95% confidence interval [CI] 0.7 to 1.2; P = .40) and 2.2 (95% CI 0.7 to 7.2; P = .17), respectively. There was no effect modification by gender and atherogenic risk factors, including diabetes, hypercholesterolemia, hypertension, and smoking. Furthermore, there was no evidence of an association with premature disease onset (< 40 years) or extent of disease. In conclusion, the results of this study in a large sample of clinically well-characterized patients indicate that neither the Trp/Arg nor the Arg/Arg genotype represents a major risk factor for angiographically confirmed coronary artery disease.     

Lack of association between genetic variation in the beta3-adrenergic receptor gene and insulin resistance in patients with coronary heart disease.

The beta-adrenergic system plays a critical role in regulating lipolysis and thermogenesis. Recent studies have suggested that a missense Trp64Arg mutation in the beta3-adrenergic receptor gene is involved in visceral obesity and insulin resistance. We investigated the effect of this mutation on insulin resistance in patients with angiographically documented coronary heart disease ([CHD]n = 137) and normal subjects (n = 188). Plasma glucose and insulin responses to a 75-g oral glucose tolerance test and insulin resistance measured by the insulin suppression test, were determined in 58 (42%) patients with CHD and 121 (64%) controls. The genotype and allele frequency of the beta3-adrenergic receptor did not differ between patients with CHD and controls. The blood pressure, body mass index (BMI), waist to hip ratio, fasting plasma glucose, insulin, and lipid, and plasma glucose and insulin responses to the glucose load were relatively similar in subjects with and without the mutation in CHD and normal groups. The degree of insulin sensitivity, ie, the steady-state plasma glucose concentration, was not significantly different between subjects with and without the mutation in the CHD group (11.3 +/- 1.2, n = 11 v 11.9 +/- 0.6 mmol/L, n = 47, P = NS) and control group (8.4 +/- 0.7, n = 30 v 8.2 +/- 0.4 mmol/L, n = 91, P = NS). We conclude that Trp64Arg polymorphism of the beta3-adrenergic receptor gene does not likely play a major role in the development of CHD in the Chinese population. In addition, it appears to have no association with the insulin resistance syndrome in either CHD or non-CHD subjects.     

Association of beta3-adrenergic receptor gene polymorphism with insulin resistance in Japanese-American men

The Trp64Arg variant of the beta3-adrenergic receptor (beta3-AR) gene is relatively common in Japanese people. We hypothesized that this variant may be associated with obesity and insulin resistance when combined with a westernized lifestyle. To test this hypothesis, we investigated the relationships between the beta3-AR gene variant and obesity and insulin resistance in Japanese-American men, who are known to have a higher prevalence of type 2 diabetes mellitus (DM). The subjects were 152 Japanese-American men living in Hawaii, 83 with normal glucose tolerance (NGT), 40 with impaired glucose tolerance (IGT), and 29 with DM. The frequency of the Trp64Arg allele of the beta3-AR gene was 0.18, almost identical to that of the mainland Japanese. The prevalence of the Trp64Arg allele was 30.1% in NGT, 35.0% in IGT, and 41.4% in DM subjects (nonsignificant). The Trp64Arg variant of the beta3-AR gene showed no significant relationship with obesity or insulin resistance in NGT subjects. However, fasting and 2-hour insulin levels and insulin resistance as determined by homeostasis model assessment (HOMA) were significantly higher in IGT subjects with the Trp64Arg variant. Although indices of obesity were the same in IGT subjects with and without the Trp64Arg variant, differences in the body mass index (BMI) and percent body fat between NGT and IGT subjects were greater for individuals with the Trp64Arg variant. Thus, there is an association between the Trp64Arg variant of the beta3-AR gene and insulin resistance in Japanese-Americans with IGT.     

T64A polymorphism in beta3-adrenergic receptor gene (ADRB3) and coronary heart disease: a case-cohort study and meta-analysis

Objectives. A missense mutation of the human ADRB3 gene replacing tryptophan with arginine at codon 64 (Trp64Arg) has been related to obesity, insulin resistance, earlier onset of noninsulin‐dependent diabetes mellitus and hypertension. These findings may also suggest an increased risk of coronary heart disease (CHD). We therefore investigated the role of this polymorphism on the occurrence of acute myocardial infarction (AMI) and CHD in a population of healthy Dutch women. Design. We performed a case‐cohort study in a prospective cohort of 15 236 initially healthy Dutch women. We applied a Cox proportional hazards model with an estimation procedure adapted for case‐cohort designs to study the relationship between the polymorphism and AMI (n = 71) and CHD (n = 211). In addition, a meta‐analysis of published studies was performed using a random effect model. Results. Using the dominant model, carriers of the arginine allele (n = 222) compared to those with the more common genotype (n = 1508) were not at increased risk of AMI (hazard ratio = 1.60; 95% CI, 0.86–2.96) and for CHD (HR = 1.36; 95% CI, 0.92–2.02). We did not find any relationship using recessive and additive models, either. Our meta‐analysis corroborated these findings by showing no significant association between the polymorphism and risk of CHD using different genetic models. Conclusions. Our study in combination with a meta‐analysis of previous reports do not provide support for a role of missense mutation replacing tryptophan with arginine at codon 64 (Trp64Arg) at the human ADRB3 gene in CHD risk.     

The polymorphism of the beta3-adrenergic receptor gene is associated with reduced low-density lipoprotein particle size

People with a predominance of small, dense low-density lipoprotein (LDL) particles appear to be at increased risk for coronary disease, independent of LDL cholesterol levels. The Trp64Arg variant of the beta3-adrenergic receptor gene is reported to be associated with abdominal obesity and resistance to insulin, and as a consequence, this variant may be a genetic factor in the development of atherosclerosis. Therefore, we investigated whether the beta3-adrenergic receptor polymorphism contributes to the distribution of LDL particle size in 136 Japanese subjects, aged 33 to 59 years, who visited for a routine annual checkup. None of these subjects were taking any medication. The diameter of LDL particles was determined at their peak size using nondenaturing 2% to 16% polyacrylamide gradient gels using fresh plasma samples. The genotype frequencies were: Trp/Trp, 71.3%; Try/Arg, 22.1%; and Arg/Arg, 6.6%, with allele frequencies of 0.82 for Trp64 and 0.18 for Arg64. The subjects with the Arg/Arg genotype had significantly higher levels of fasting plasma insulin and triglycerides and an insulin resistance index of homeostasis model assessment (HOMA-R), and significantly smaller LDL particle size than did the subjects with the Trp/Trp genotype. After adjusting for fasting insulin, body mass index (BMI), and HOMA-R index, there was no longer an observed difference in LDL particle size. The number of the Arg64 allele in individuals was significantly related with fasting insulin, BMI, triglycerides, glycosylated hemoglobin (HbA1c), and fasting glucose, and it was inversely related with LDL particle size. After adjusting for triglyceride, fasting insulin levels, and HOMA-R index, LDL particle size was no longer inversely correlated with the Arg allele. These findings suggest that the Trp64Arg variant in the beta3-adrenergic receptor gene may be associated with reducing LDL particle size, probably due to insulin resistance.     

The Trp64Arg polymorphism of the beta3-adrenergic receptor gene is associated with hypertension in men with type 2 diabetes mellitus

A missense mutation of the beta3-adrenergic receptor gene (ADRB3) resulting in a tryptophan/arginine exchange at position 64 (Trp64Arg polymorphism) has recently been associated with greater capacity to gain weight, a low resting metabolic rate, higher blood pressure, and an early onset of type 2 diabetes. These findings prompted us to examine the relationship between this mutation, blood pressure, and vascular complications in German patients with type 2 diabetes. White patients with type 2 diabetes mellitus (n = 417) were enrolled in the study. The Trp64Arg polymorphism of the ADRB3 gene was detected by polymerase chain amplification and subsequent restriction digest with BstN I. Stepwise logistic regression analysis of the entire study population revealed a significant interaction between gender and genotype (P = .019). We therefore performed separate analyses for men and women. There was a significant relationship between hypertension and the ADRB3 Trp64Arg variant in men (P = .015), but not in women. Furthermore, blood pressure levels in male patients with the minor allele had higher blood pressure levels (P < .05), despite a significantly greater number of antihypertensive medications (P = .01). There was no association between ADRB3 genotype and vascular complications in these patients. In conclusion, our data are compatible with a contribution of this genetic variant of ADRB3 to hypertension in male patients with type 2 diabetes. Further studies will be needed to determine the role of this polymorphism as a predictor of hypertension or vascular complications in patients with type 2 diabetes.     

Arg16Gly polymorphism in beta2-adrenergic receptor gene is not associated with thyrotoxic periodic paralysis in Korean male patients with Graves' disease

BACKGROUND: Thyrotoxic periodic paralysis (TPP) occurs most frequently in Asian males and present with an acute episode of proximal muscle weakness in the setting of thyrotoxicosis. Despite the fact that mutations were described in genes encoding ion channels in familial hypokalaemic periodic paralysis, no definite genetic variants were found in TPP. beta2-adrenergic receptors (ADRB2s) are expressed in skeletal muscle and stimulate the sodium pump. Single nucleotide polymorphisms in ADRB2 gene were identified and may act as disease modifiers in various diseases. OBJECTIVE: We were to demonstrate that ADRB2 gene might be a susceptibility gene for TPP in Korean male patients with Graves' disease. DESIGN AND PATIENTS: In a series of 28 male TPP patients and 31 control patients, three polymorphisms in ADRB2 gene have been studied: a T to C substitution at -47 (-47T/C), Arg16Gly and Gln27Glu. Control patients were male Graves' patients without history of paralysis. RESULTS: The distributions of the -47C, Gly16 and Glu27 alleles in all patients were 0.02, 0.34 and 0.02, respectively. The genotype Arg16/Arg16 was not significantly associated with TPP (odds ratio 0.53; 95% confidence interval, 0.19-1.50; corrected P = 0.897). Also, the frequency of genotype Gly16/Gly16 was not significantly different in TPP patients than in controls (0.07 vs. 0.23; odds ratio, 0.26; 95% confidence interval, 0.05-1.40; corrected P = 0.45). Allele frequencies of ADRB2 in patients with TPP did not differ from controls. CONCLUSIONS: The polymorphism of the ADRB2 gene may not confer genetic susceptibility to TPP in Korean male patients with Graves' disease.     

Arg64 variant of the beta3-adrenergic receptor is associated with gallstone formation

OBJECTIVES: The beta3-adrenergic receptor (ADRB3) is a transmembrane receptor highly expressed in adipose tissue and thought to be involved in the regulation of lipolysis. ADRB3 is also highly expressed in gallbladder tissue where it may be involved in gallbladder contraction. Because polymorphisms of ADRB3 are present in populations with a high prevalence of gallstones (e.g., Pima-Indians, obese subjects), we hypothesized that known polymorphisms for ADRB3 (Trp64Arg) may represent an independent risk factor for gallstone disease. METHODS: The EMIL cross-sectional study investigated the health behavior and prevalence of chronic diseases in a small Southwestern German town of 12,475 inhabitants. From 3,893 randomly selected citizens 2,147 subjects were enrolled and screened for gallstones employing ultrasonography. Blood samples were drawn for biochemical analysis and isolation of genomic DNA. ADBR3 genotypes were determined by TaqMan SNP Assay. RESULTS: We identified 171 (8%) gallstone carriers of whom 143 participated (46 male, 97 female), with a mean age of 51.4, and mean BMI of 29.3 kg/m2. For these subjects an age, gender and BMI matched partner without gallstones was recruited from the study population. Genotyping for ADRB3 revealed an Arg64 allele frequency of 5.9 versus 0.7% (HR = 11.9, P < 0.05) compared with controls. CONCLUSIONS: Our results indicate that the ADRB3 Trp64Arg polymorphism is associated with gallstone disease thereby representing a genetic marker that identifies subjects at higher risk for gallstone formation.     

The Trp(64)Arg polymorphism of the beta(3)-adrenergic receptor gene is not associated with body weight or body mass index in Japanese: a longitudinal analysis

The beta(3)-adrenergic receptor (ADRB3) is expressed mainly in visceral adipose tissue and is thought to contribute to lipolysis and the delivery of free fatty acids to the portal vein. Although many studies have examined the relationship between the Trp(64)Arg mutation of ADRB3 and obesity, the results have been inconsistent. We examined the cross-sectional relationship of ADRB3 variants with indexes of obesity, and their longitudinal changes over 10 yr, in men and women, aged 40-69 yr, who were randomly selected from the Japanese rural population. The study considered both dietary energy intake and physical activity levels. Among the 746 participants, the genotype frequencies of the Trp(64)Trp, Trp(64)Arg, and Arg(64)Arg variants were 483, 224, and 39, respectively. The cross-sectional analysis showed no significant differences in height, weight, body mass index, blood pressure, serum total and high density lipoprotein cholesterols, and hemoglobin A(1c) among the genotype groups even after adjustments for gender, age, smoking, alcohol drinking, physical activity, and energy intake. No significant differences in the weight changes between the genotype groups were evident in the longitudinal analysis. We conclude that the Trp(64)Arg mutation of ADRB3 has little or no influence on either body weight or body mass index in the general Japanese population.     

The Trp64Arg polymorphism of the beta3-adrenergic receptor gene and obesity in Chinese subjects with components of the metabolic syndrome

BACKGROUND: In regions such as Hong Kong, rapid economic development has led to lifestyle alterations characterized by increases in energy and fat intake and reduction in physical activity. These changes have been associated with a dramatic increase in the prevalence of diabetes and related diseases of the metabolic syndrome. OBJECTIVE: To investigate if a common polymorphism (Trp64Arg) of the beta3-adrenergic receptor gene, previously implicated as predisposing to type 2 diabetes mellitus or obesity in other populations, has a role in the apparent susceptibility of Hong Kong Chinese to diabetes and related disorders. METHOD: A PCR-based protocol was used to genotype 802 Southern Chinese subjects who were either healthy or had one or more of the metabolic disorders including diabetes, hypertension or dyslipidaemia. RESULTS: The frequencies of the mutant A allele (12.7%) and AA genotype (1.7%) did not differ, by the chi2 test, in any patient group with diabetes, hypertension or dyslipidaemia, alone or in combination, compared to healthy controls. Using the t-test in the 802 subjects, those carrying the mutant A allele had evidence of increased obesity with a significantly (all P<0.05) higher body mass index (BMI, kg/m2) and also lower HDL-cholesterol. BMI was also elevated in subjects with the A allele in the separate groups with diabetes, dyslipidaemia or hypertension. Stepwise multiple regression showed this polymorphism to be an independent predictor of BMI. CONCLUSION: These data do not support any direct involvement of the Trp64Arg polymorphism in the development of diabetes, hypertension or dyslipidaemia in Chinese subjects, but do suggest a relationship with obesity.     

Variant of the beta3-adrenergic receptor gene and coronary atherosclerosis in Japanese subjects.

In the present study, we assessed the significance of the Trp64Arg mutation in the beta3-adrenergic receptor gene in 428 Japanese subjects, including 198 subjects who underwent coronary angiography for possible ischemic heart diseases (IHD group) and 230 non-IHD subjects (control group). We conclude that the Trp64Arg polymorphism of the beta3-adrenergic receptor gene did not appear to have any pathophysiological significance in Japanese subjects.     

Elevated serum leptin in patients with coronary artery disease: no association with the Trp64Arg polymorphism of the beta3-adrenergic receptor

BACKGROUND: Serum leptin is associated with the occurrence of cardiovascular risk factors but it is unknown whether leptin is also associated with cardiovascular disease. Another open question is whether the Trp64Arg polymorphism of the beta3-adrenergic receptor (beta3-AR) is a determinant of circulating leptin. OBJECTIVES: We measured serum leptin concentrations in a large group of patients with angiographically assessed coronary artery disease (CAD) and investigated the relationship between the Trp64Arg polymorphism of the beta3-adrenergic receptor (AR) and serum leptin. PATIENTS AND METHODS: Leptin was measured in the fasting state in 1000 consecutive patients with angiographically confirmed CAD by radioimmunoassay. The codon 64 T/C polymorphism of the beta3-AR gene was analysed by the polymerase chain reaction/restriction fragment length polymorphism (PCR/RFLP) technique. Controls were 1000 age-, gender- and weight-matched subjects without clinical signs of CAD. RESULTS: Serum leptin concentrations were significantly higher in patients with CAD than in those without CAD (median: 6.8 vs 6.1 ng/ml, P < 0.001). In a multiple regression analysis leptin was found to be a determinant of CAD (P = 0.005) along with established risk factors. No differences in serum leptin were observed between wild-type and heterozygous carriers of the Trp64Arg mutation of the beta3-AR gene, whereas the small group of homozygous carriers had higher leptin due to their higher BMI. In a multiple linear regression analysis, body mass index, gender and fasting insulin were the main significant determinants of serum leptin, whereas the beta3-AR polymorphism had no effect. CONCLUSIONS: Patients with coronary artery disease exhibit higher serum leptin concentrations than age- and gender-matched controls of comparable BMI, indicating that leptin could contribute to the development of cardiovascular disease, possibly via activation of the sympathetic nervous system. The Trp64Arg variant of the beta3-adrenoceptor did not influence serum leptin.     

The Gln27Glu polymorphism in the beta2-adrenergic receptor gene is not associated with morbid obesity in Austrian women

OBJECTIVE: Beta-adrenergic receptors (betaARs) play an important role in the regulation of energy expenditure and lipid mobilization. A Gl-27Glu polymorphism in the beta2-adrenergic receptor (beta2AR) gene has recently been associated with several indices of obesity in a female Caucasian population, while the same polymorphism exhibited no association with obesity in another, albeit male, population. METHODS: We have therefore studied possible associations of the Gln27Glu and the Gly16Arg polymorphisms in the beta2AR with BMI, plasma leptin and UCP-1 mRNA expression in the intraperitoneal adipose tissue in a population of Caucasian women. RESULTS: The frequencies of the Gln27 and the Gly16 alleles as well as the beta2AR haplotypes were similar in our morbidly obese and lean subjects. Furthermore, no association was found between the Gln27Glu or the Gly16Arg polymorphisms and plasma leptin or adipose tissue UCP-1 gene expression in either group. CONCLUSIONS: We conclude that the two polymorphisms in the beta2AR gene studied are not a major factor contributing to obesity in our population.     

The Trp64Arg beta3-adrenergic receptor amino-acid variant is not associated with overweight and type 2 diabetes mellitus in Polish population.

The Trp64Arg amino-acid variant of the beta3 adrenoreceptor gene may be associated with a genetic predisposition to human obesity and related disorders, including type 2 diabetes mellitus. This relationship has been reported in various ethnic groups, however it was not extensively studied in Polish population. Therefore, the aim of the study was to investigate the association of Trp64Arg polymorphism of the beta3 adrenergic receptor gene with overweight and type 2 diabetes mellitus in polish subjects. The Trp64Arg polymorphism was determined by PCR-based MspI restriction fragment length polymorphism (PCR-RFLP). The study population consisted of 358 subjects, among whom 200 were diagnosed as overweight (BMI > 27 kg/m (2)). Among overweight subjects 111 presented with type 2 diabetes mellitus and 89 with normal glucose metabolism. All study participants were unrelated Caucasians and inhabited the city of Lodz, Poland. The frequency of the Arg allele did not differ significantly between overweight and normal weight patients (13 % vs. 11 %, OR 1.17, CI 0.74 - 1.85). The same applied to overweight diabetic patients vs. overweight patients without diabetes mellitus (13 % vs. 13 %, OR 0.97, CI 0.54 - 1.76). The obtained results suggest no association between Trp64Arg polymorphism of the beta3-AR gene and the incidence of overweight and type 2 diabetes mellitus in Polish population.     

Insertion/deletion polymorphism of the angiotensin-converting enzyme gene is strongly associated with coronary heart disease in non-insulin-dependent diabetes mellitus.

Non-insulin-dependent diabetes mellitus (NIDDM) is considered a model of premature atherosclerosis with a strong genetic component. We have investigated the role of angiotensin-converting enzyme (ACE; EC 3.4.15.1) gene in 316 unrelated NIDDM individuals, 132 who had myocardial infarction or significant coronary stenoses and 184 with no history of coronary heart disease (CHD). A deletion-polymorphism in the ACE gene was recently reported to be associated with myocardial infarction especially in people classified as low risk. Here we report that the D allele of the ACE gene is a strong and independent risk factor for CHD in NIDDM patients. The D allele is associated with early-onset CHD in NIDDM, independently of hypertension and lipid values. A progressively increasing relative risk in individuals heterozygous and homozygous for the D allele was observed (odds ratios of 1.41 and 2.35, respectively; P < 0.007), suggesting a codominant effect on the cardiovascular risk. The percentage of CHD attributable to the ACE deletion allele was 24% in this NIDDM population. Identification of NIDDM patients carrying this putative CHD-susceptibility genotype would help early detection and treatment of CHD.     

Phenotypic characterization of the Trp64Arg polymorphism in the beta3-adrenergic receptor gene in normal weight and obese subjects

Summary The beta₃-adrenergic receptor, located mainly in fat cells of visceral adipose tissue, is involved in the regulation of lipolysis and thermogenesis. Recently, a mutation in the corresponding gene resulting in the replacement of tryptophan by arginine in position 64 (Trp64Arg) has been demonstrated, which associated with obesity and metabolic complications of obesity. We have investigated whether this polymorphism is associated with changes in beta₃-adrenergic receptor function or clinical characteristics in 40 non-obese and 43 obese non-diabetic subjects who underwent elective abdominal surgery. The beta-adrenergic receptor gene polymorphism was examined by restriction-enzyme cleavage conformation. Beta₃-adrenergic receptor function was investigated by measuring lipolysis in isolated visceral white fat cells incubated with noradrenaline (natural ligand) or (CGP) 12177 (selective beta₃-agonist). No homozygotes for the mutation were found. The allelic frequency of Trp64Arg was similar in obese and non-obese subjects (9.4 and 12.5 %, respectively). In obese and non-obese subjects there was no change in body mass index, body fat distribution, fat cell size, fasting circulating levels of insulin, glucose or lipids, blood pressure or adipocyte lipolysis induced by noradrenaline or CGP 12177 when Trp64Arg heterozygotes were compared with Trp64 homozygotes. Our results suggest that the Trp64Arg mutation in its heterozygous form is not a major determinant of beta₃-adrenergic receptor function (when assessed by lipolysis in white adipose tissue) or of the pathophysiology of obesity. [Diabetologia (1996) 39: 857–860] Received: 21 February 1996 and in revised form: 22 March 1996     

Insertion/deletion polymorphism in the angiotensin-l-converting enzyme gene is associated with coronary heart disease in IDDM patients with diabetic nephropathy

Summary Insulin-dependent diabetic (IDDM) patients with diabetic nephropathy have a highly increased morbidity and mortality from coronary heart disease. An insertion (I) /deletion (D) polymorphism in the angiotensin-I-converting enzyme (ACE) gene has been shown to be associated with coronary heart disease. Therefore, we have investigated the role of this ACE/ID polymorphism in 198 IDDM patients with diabetic nephropathy and 190 normoalbuminuric IDDM patients. The prevalence of myocardial infarction and other coronary heart disease was significantly elevated in patients with nephropathy, 19 % (38/198) vs 8 % (15/190), p < 0.001. In the nephropathic group 12 of 63 (19 %), 23 of 95 (24 %), and 3 of 40 (7.5 %) patients with the DD, ID and II genotypes, respectively had a history of coronary heart disease, II vs DD and ID, p < 0.05 when compared to nephropathic patients without coronary heart disease. Multiple logistic regression analysis of the risk factors associated with coronary heart disease in univariate analysis revealed that the II genotype acts as an independent protective factor against coronary heart disease, odds ratio II/DD + ID 0.27 (95 % confidence interval 0.07–0.97, p < 0.05). There was no difference in genotype or allele frequency (D/I) between patients with and without nephropathy, 0.56/0.44 in both groups, but plasma ACE concentration was elevated in patients with nephropathy 609 (151–1504) ng/ml as compared to patients with normoalbuminuria, 428 (55–1630) ng/ml, p < 0.001. We suggest that ACE/ID polymorphism may influence the frequency of life-threatening cardiac complications in IDDM patients suffering from diabetic nephropathy, a condition characterized by increased plasma ACE concentration. [Diabetologia (1995) 38: 798–803] Received: 10 October 1994 and in revised form: 20 December 1994     

2 型糖尿病与正常人群中肾上腺素能受体基因Trp 6 4Arg多态性表型特征

目的　研究中国人群 β3 肾上腺素能受体基因 Trp64 Arg错义突变频率 ,并了解该突变对 2型糖尿病临床特征的影响。方法　应用 PCR RFLP技术检测了相互间无一级亲属关系的 12 4例 2型糖尿病患者及 13 8例非糖尿病对照人群中 β3 肾上腺素能受体基因 Trp64 Arg错义突变 ;同时检查体重指数、腰臀比例、血压 ,测定血脂及 OGTT或馒头餐试验中 0分钟及 12 0分钟血糖及胰岛素。结果　非糖尿病人群中 Trp64 Arg等位基因频率为 0 17;突变频率在糖尿病与非糖尿病之间相比无显著性差异 (P >0 0 5 ) ;突变与否间上述临床特征相比无显著性差异 (P >0 0 5 )。结论　该突变至少在其杂合子型可能不是中国人散发 2型糖尿病的主要决定因素 ;纯合子突变型可能导致 2型糖尿病早发 ,有待今后积累资料深入研究。