Relationship of the angiotensin-converting enzyme gene polymorphism to glucose intolerance, insulin resistance, and hypertension in NIDDM

The deletion (D) allele of the angiotensin-converting enzyme (ACE) gene insertion/deletion (I/D) polymorphism has been shown to be associated with cardiovascular and renal diseases in diabetes mellitus, but the mechanism underlying this association is not known. In addition, recent studies of the effect of the ACE gene on blood pressure have yielded conflicting results. Therefore, we studied the association of the ACE gene I/D polymorphism with glucose intolerance and insulin resistance, and the contribution of this locus to genetic susceptibility to hypertension in non-insulin-dependent diabetic mellitus (NIDDM). We analysed the ACE genotype in 84unrelated NIDDM patients with a known disease duration of less than 1year and in 115age- and sex-matched controls. The I/D polymorphism was determined by the polymerase chain reaction. There were no differences in ACE genotype distribution and allele frequencies between patients with NIDDM and nondiabetic controls. The frequencies of the D and Ialleles in both groups were identical, viz., 0.65 and 0.35, respectively. The NIDDM patients with the DD genotype had significantly higher blood glucose levels in the oral glucose tolerance test than those with the other genotypes; the incremental glucose area under the curve in the order of II, ID, and DD was 7.2 ± 2.4, 9.2 ± 4.0, and 10.7 ± 2.7mmol/l · h (II vs ID vs DD, P=0.0066 by ANOVA). No significant difference was found between the ACE genotype and serum insulin values. Similarly, there were no differences in body mass index, blood pressure, or serum lipids between the three genotypes. Among the nondiabetic controls, there was no statistically significant association of the I/D polymorphism with serum lipids, blood glucose levels, serum insulin concentrations, or blood pressure values. In conclusion, NIDDM patients with the DD genotype have higher blood glucose levels and are more glucose intolerant; this may help to explain the reported association between the Dallele and vascular complications in NIDDM. Received: 15 September 1997 / Accepted: 13 November 1997     

Association of angiotensin converting enzyme gene I/D polymorphism of vitiligo in Korean population

Vitiligo (leukoderma) is an acquired idiopathic hypomelanotic disorder characterized by the circumscribed depigmented patches. Vitiligo is a polygenic disease. The exact pathogenesis is not yet known. The angiotensin converting enzyme (ACE) gene was selected as a candidate gene as ACE plays an important role in the physiology of the vasculature, blood pressure and inflammation, and its relationship with various diseases, including autoimmune diseases, has been widely investigated. The I/D polymorphism of ACE gene in vitiligo patients has not been reported. In this study, we investigated ACE gene polymorphism in 120 vitiligo patients and in 429 healthy volunteers in Korea. The ACE gene genotype distribution (P = 0.032) and allele frequency (P = 0.012) were significantly different between vitiligo patients and healthy controls. This study suggests that the ACE gene polymorphism has a strong association with the development of vitiligo in Korean patients.     

ACE I/D polymorphism in Alzheimer’s disease

Angiotensin-converting enzyme (ACE) has been reported to show altered activity in patients with neurological diseases. The recent studies found that a 287 bp insertion/deletion (I/D) polymorphism of the ACE gene may be associated with susceptibility to Alzheimer’s disease (AD) but the results have been heterogenous between studies in Europe. In the present study we examined for the first time the association of ACE I/D polymorphism along with APOE genotype in 70 sporadic AD and 126 control subjects in Slovak Caucasians (Central Europe). An increased risk for AD was observed in subjects with at least one APOE*E4 allele (OR=3.99, 95% CI=1.97–8.08). No significant differences for the genotype distribution or the allele frequency were revealed comparing controls and patients for ACE gene. Gene-gene interaction analysis showed increase of the risk to develop AD in subjects carrying both the ACE DD genotype and the APOE*E4 allele (OR=10.32, 95% C.I. 2.67–39.81).     

ACE基因多态性与高血压肾脏损害及PAI-1的关系

为探讨血管紧张素转换酶（ACE）基因多态性与高血压肾损害和纤溶酶原激活物抑制物-1（PAI-1）的关系,应用聚合酶链反应（PCR）检测96例正常人、67例高血压无肾脏损害患者和70例高血压伴肾损害患者的ACE基因型,采用ELISA法检测血浆PAI-1。ACE基因I/D多态性与高血压病无明显相关,但高血压肾损害患者DD基因型频率及D等位基因频率显著高于对照组和高血压无肾脏损害组,χ2值分别为6.8589、5.6162 和5.9085、5372。血浆PAI-1在DD型、ID型、II型高血压患者之间亦有显著性差异（P＜0.05）。ACE基因DD型可能是高血压肾损害的危险因素;ACE基因多态性与血浆PAI-1水平相关。 Abstract:The work is to explore the relationship between the polymorphism of angiotensin converting enzyme(ACE) gene and hypertensive kidney lesion/PAI-1 in hypertension patients.ACE genotyping with polymorase chain reaction (PCR) was performed in 96 unrelated healthy controls,67 hypertensives without kidney lesion and 70 hypertensives complicated with kidney lesion.The plasma PAI-1 were determined with ELISA.No significant differences could be detected between ACE gene I/D polymorphism and hypertension.However,the frequencies of DD genotype and deletion allele among the hypertensives complicated with kidney lesion were higher than those among the healthy controls and those among the hypertensives without kidney lesion."χ2" values were 6.8589,5.6162 and 5.9085,5.372 respectively.The plasma PAI-1 level showed significant differences among DD genotype,ID genotype and II genotype(P＜0.05).The DD genotype of ACE gene may be a risk for hypertensive kidney lesion.The plasma PAI-1 level is associated with ACE gene polymorphism.     

Insertion/deletion polymorphism of angiotensin-converting enzyme gene--risk factor for coronary artery disease in the Tuzla region population (Bosnia and Herzegovina)

Angiotensin II is the major effector molecule of renin-angiotensin system; its production can be conveniently interrupted by angiotensin-converting enzyme (ACE). Typical plasma levels of ACE accompany the I/D polymorphism; however, a controversy exists as to whether the DD genotype of the ACE polymorphism affects the risk for the development of coronary artery disease (CAD) and to what extent the ACE polymorphism is associated with CAD in different populations. We compared the I/D polymorphism in 212 CAD patients younger than 50 years with 165 healthy control individuals. They were all from the Tuzla region in Bosnia and Herzegovina. Patients with CAD had a higher prevalence of the DD genotype (36.3%) than controls (25.6%). The odds ratio for the ACE DD genotype in CAD patients was 1.7 (95% confidence interval 1.0-2.7; p < 0.05). We may conclude that the D/D genotype of the ACE gene polymorphism is associated with an increased risk for CAD in the Bosnian population.     

Insertion/deletion polymorphism of the angiotensin converting enzyme gene in coronary artery disease in southern Turkey

Genetic factors are important in the pathogenesis of coronary artery disease (CAD). Angiotensin converting enzyme (ACE) gene insertion(I)/deletion(D) polymorphism is one of the genetic factor found to be related with CAD. We investigated the association between I/D polymorphism of the ACE gene and the presence of CAD. Three hundred and seven patients (187 males and 120 females, aged between 35-80, mean 54.3 +/-9.8 years) who underwent diagnostic coronary angiography were included in the study. ACE I/D polymorphism was detected by polymerase chain reaction. Of the 307, 176 had CAD. The most frequently observed genotype in all subjects was ID (47.9 %). However, in patients with CAD the frequency of II genotype was lower whereas DD genotype was higher compared to the controls (p < 0.05). The number of D allele carrying subjects were also higher (p < 0.05) in CAD patients. The logistic regression analysis indicated that the ACE D allele is an independent risk factor (odds ratio = 1.48, 95 % CI = 1.01-2.18, p < 0.05). In conclusion, the I/D polymorphism of ACE gene (carrying D allele) is an independent risk factor for CAD in the studied Turkish population.     

Angiotensin converting enzyme gene polymorphism and myocardial infarction a large association and linkage study

The DD genotype of the angiotensin converting enzyme (ACE) polymorphism has been associated with myocardial infarction (MI). However, sample sizes of many case-control studies showing positive association were small and data were inconsistent. Furthermore, no family-based study is available.In a case-control study frequencies of the ACE genotypes were compared in 1319 unrelated patients with previous MI before 60 years of age (616 from the MONICA Augsburg region and 703 from rehabilitation centers in south Germany) and in 2381 population controls from the MONICA Augsburg study region). Furthermore, linkage and association of the ACE I/D polymorphism with MI were tested in 246 informative families using the sib-transmission/disequilibrium test (S-TDT).Overall, no excess of the D allele was found in MI patients (frequency 0.53 versus 0.57 in the general population; P=0.2). The ACE DD genotype was even slightly less frequent in groups with MI compared to the general population controls (0.26 versus 0.33 in women and 0.28 versus 0.33 in men). Similar results were also obtained in 247 men with low cardiovascular risk. In the family-based study, the frequency of the D allele was not different in siblings with or without previous MI (0.53 versus 0.50, respectively; S-TDT P=0.15) indicating no linkage or association of the D allele with MI.In a case-control study of MI patients and controls from the general population as well as a family study neither association nor linkage of the ACE D allele with MI was detected despite sample sizes that were among the largest samples studied so far.     

Association of angiotensin-converting enzyme (ACE) gene insertion–deletion polymorphism with spondylarthropathies

Summary Low back pain (LBP) is a common medical problem. Interaction between genetic and environmental factors predisposes individuals to LBP even at an early age. Inflammatory back pain or spondylarthropathies include ankylosing spondylitis (AS), psoriatic arthritis (PSA), reactive arthritis enteropathic and undifferentiated arthropathies. Angiotensin-converting enzyme (ACE) plays an important role in circulatory homeostasis, physiology of vasculature and inflammation. The insertion–deletion (I/D) polymorphism of the ACE gene has been shown to determine the plasma and tissue levels of ACE especially in the synovial fluid. The aim of this study was to investigate an association between ACE gene I/D polymorphism and inflammatory back pain (spondylarthropathies) secondary to ankylosing spondylitis (AS), psoriatic arthritis, inflammatory bowel disease and undifferentiated spondylarthropathies. The prevalence of ACE gene I/D polymorphism genotypes was determined in 63 patients with inflammatory back pain by polymerase chain reaction (PCR) and compared with that in 111 healthy controls. Of the 63 patients studied, 45 (71.4%) were with AS, 13 (20.6%) were with PSA, 4 (6.3%) were with reactive arthropathy and 1 (1.6%) manifested undifferentiated arthropathy. There were 43 males and 20 females. Mean age of patients was 39.0 ± 11.36 years, age at onset of spondylarthropathy was 27.7 ± 7.49 years and disease duration was 10.3 ± 7.74 months. The controls were selected to match with the patients group in terms of gender ratio, age and ethnicity. The ACE gene polymorphism showed an overall significant difference between patients and controls (p = 0.050). When the ID and II genotype frequency was combined and compared with that for DD genotype amongst patient and control groups, a considerably higher incidence was detected for ID and II genotypes than the DD genotype in spondylarthropathy patients compared to that in the controls (p = 0.036). This study showed a significant association of the I-allele of ACE gene I/D polymorphism with spondylarthropathy in Kuwaiti Arabs.     

Deletion/Deletion genotype of angiotensin-I converting enzyme gene is not associated with coronary artery disease in caucasians with type 2 diabetes

In this study we analyzed the contribution of genetic variability of the insertion/deletion (I/D) polymorphism of the angiotensin-I converting enzyme (ACE) gene to the predisposition for coronary artery disease (CAD) in a group of patients with type 2 diabetes. The I/D ACE gene polymorphism was tested in 366 Caucasians with type 2 diabetes: 148 cases with CAD and 218 subjects with no history of CAD. We failed to demonstrate that the ACE DD genotype was a risk factor for CAD in Caucasians with type 2 diabetes (OR 2.0, 95% CI 0.9-4.7; p = 0.1). In conclusion, we provide evidence that the ACE deletion/deletion genotype is not a risk factor for CAD in Caucasians with type 2 diabetes.     

Association between insertion-deletion polymorphism of the angiotensin-converting enzyme gene and development of angiopathies in patients with non-insulin dependent diabetes mellitus from the Chuvash Republic

Insertion/deletion polymorphism of the angiotensin-converting enzyme (ACE) gene was analyzed in patients with non-insulin-dependent diabetes mellitus (NIDDM) and in the control group consisting of healthy subjects. The insertion allele (I) and genotype II were found to be associated with NIDDM. The frequencies of diabetic retinopathy and nephropathy in NIDDM patients were not associated with this polymorphism. However, an association was found between the DD genotype of the ACE gene and diabetic angiopathy in lower extremities.     

Association between angiotensin I-converting enzyme gene polymorphism and hypertension in selected individuals of the Bangladeshi population

The genetic factors that contribute to the development of coronary artery disease (CAD) are poorly understood. It is likely that multiple genes that act independently or synergistically contribute to the development of CAD and the outcome. Recently, an insertion/deletion (I/D) polymorphism of the human angiotensin I-converting enzyme (ACE) gene, a major component of the reninangiotensin system (RAS), was identified. The association of the ACE gene D allele with essential hypertension and CAD has been reported in the African-American, Chinese, and Japanese populations. However, other studies have failed to detect such an association. It has been suggested that these inconsistencies may be due to the difference in backgrounds of the population characteristics. In the present study, we investigated the I/D polymorphism of the ACE gene in 103 subjects of both sexes, consisting of 59 normal controls and 44 patients with hypertension. The allele and genotype frequency were significantly different between the hypertensive and control groups (p < 0.01). Among the three ACE I/D variants, the DD genotype was associated with the highest value of the mean systolic blood pressure [SBP] and mean diastolic blood pressure [DBP] (p = < 0.05) in men, but not in women. In the overall population, the mean SBP and DBP was highest in DD subjects, intermediate in I/D subjects, and the least in II subjects     

ACE I/D polymorphism in Indian patients with hypertrophic cardiomyopathy and dilated cardiomyopathy

Aim The study was carried to determine the association of angiotensin converting enzyme (ACE) insertion/deletion (I/D) polymorphism with the risk of hypertrophic cardiomyopathy (HCM), dilated cardiomyopathy (DCM), and restrictive cardiomyopathy (RCM). Methods and results A total of 174 patients diagnosed with cardiomyopathy (118 with HCM, 51 with DCM, and 5 with RCM) and 164 ethnically, age- and gender-matched controls were included in the study. ACE I/D genotyping was performed by PCR. In total, 25.86% of the patients were in New York Heart Association (NYHA) class III and IV at presentation. A total of 67.24% patients had dyspnea, 56.89% had angina pectoris, and 25.28% of the patients had at least one event of syncope. Frequency of occurrence of the disease was more in male patients compared to female patients (P < 0.05). After adjustment for age, sex, body mass index (BMI), and smoking habit, the prevalence of ACE DD genotype, and ACE ‘D’ allele was significantly higher in patients as compared to controls and was associated with increased risk (DD: OR 2.11, 95% CI 1.27–3.52, P < 0.05; ‘D’: OR 1.91, 95% CI 1.08–3.35, P < 0.05). The mean septal thickness was higher for DD and ID genotypes (20.40 ± 3.73 mm and 21.82 ± 5.35 mm, respectively) when compared with II genotype (18.63 ± 6.69 mm) in HCM patients, however, the differences were not significant statistically (P > 0.05). The DCM patients with ID genotype showed significantly decreased left ventricular ejection fraction (LVEF) at enrolment (26.50 ± 8.04%) (P = 0.04). Conclusion Our results suggest that D allele of ACE I/D polymorphism significantly influences the HCM and DCM phenotypes.     

Association between Angiotensin I-Converting Enzyme Insertion/Deletion Polymorphism and Prognosis of Kidney Transplantation: A Meta-Analysis

PurposeAngiotensin I-converting enzyme (ACE) is crucial in the renin–angiotensin–aldosterone system. ACE insertion/deletion (I/D) polymorphism is a common genetic variation of this gene and is associated with several disease phenotypes. However, the results of published studies on the influence of this polymorphism on renal transplantation are inconsistent. Therefore, a meta-analysis was performed to evaluate the association between ACE I/D polymorphism and prognosis of kidney transplantation.MethodsA meta-analysis was performed based on 21 case–control studies from 12 publications (1497 cases and 2029 controls) and 10 studies with quantitative values from 5 publications (814 patients). Pooled odds ratios (ORs) and weighted mean differences (WMDs) with their corresponding 95% confidence intervals (CIs) were used to estimate associations.ResultsACE I/D polymorphism was found to be associated with acute rejection (AR) in genotypes DD+ID versus II (OR = 1.62, 95% CI = 1.14–2.29) and with serum creatinine concentration after renal transplantation in genotypes DD versus ID (WMD = 13.12, 95% CI = 8.09–18.16). Stratified analysis revealed that recipients transplanted within a year had higher serum creatinine concentrations in the DD versus ID model. No significant association was found between hypertension and ACE I/D polymorphism.ConclusionACE I/D polymorphism is associated with AR and allograft function after kidney transplantation.     

Polymorphisms in the RAS and cardiac function

Since the discovery of the polymorphism in the angiotensin converting enzyme (ACE) and the consequences of this polymorphism on the activity levels of the enzyme, numerous association studies have been performed. However, these investigations do not often adhere to the most stringent criteria for such studies. The initial study reporting a positive association of the ACE polymorphism and myocardial infarction showed an increased risk of the DD genotype. This initial association was eventually refuted by a large, well conducted association study, which found a risk ratio of 1.02 after combining their own data with all published data. Although such large, well conducted association studies have not been performed in left ventricular (LV) hypertrophy, the association between DD genotype and hypertrophy is more convincing with a 192% excess risk of LV hypertrophy in untreated hypertensives. The role of ACE genotype in LV growth is well established, especially in athletes. In heart failure, large studies or meta-analyses have not been performed, because most studies have selected different end-points. This hampers a proper meta-analysis of the results obtained in associations with heart failure. As most association studies do not fulfill the criteria for good association studies and use too small sample sizes, it remains important to perform a meta-analysis to add meaning to the results of such studies. Above all, it is important to obey the rules set for association studies, large sample size, small P values, report associations that make biological sense and alleles that affect the gene product in a physiologically meaningful way.     

Angiotensinogen and angiotensin-I converting enzyme gene polymorphisms and the risk of coronary artery disease in Chinese

The homozygous deletion allele (DD) of the angiotensin-I converting enzyme (ACE) gene and the T235 homozygote of the angiotensinogen (AGT) gene have been reported to be correlated with an increased prevalence of coronary artery disease (CAD) and myocardial infarction (MI). The importance of the DD genotype and T235 homozygote as genetic risk factors for CAD in Chinese remains uncertain. This study included 426 patients who underwent coronary angiography and 180 healthy subjects without clinical evidence of CAD. Coronary angiography identified 268 patients with CAD (CAD group) and 158 patients without CAD. The healthy subjects and patients without angiographic evidence of CAD constituted the control group. Three polymorphisms were studied: an insertion/deletion (I/D) polymorphism of the ACE gene and the T174 M and M235T polymorphisms of the AGT gene. No association was found between any of the three studied polymorphisms and the risk of CAD or MI in Chinese using univariate or multivariate analysis. In multivariate analysis, the relative risks were 1.20 (95% confidence interval = 0.91–1.61, P = 0.20) for the DD genotype, 1.05 (95% CI = 0.82–1.35, P = 0.69) for the T174 homozygote, and 1.19 (95% CI = 0.91–1.55, P = 0.20) for the T235 homozygote. Similarly, no significant difference was found in the frequencies of the DD genotype and the T174 and T235 homozygotes between the control group, the CAD group, the non-MI group, and the MI group when analyzed according to sex, age, or degree of risk. Our data suggest that neither the DD genotype of the ACE I/D polymorphism nor the T174 and T235 homozygotes of the AGT gene confer significant risk for CAD or MI in Chinese. Received: 18 December 1996 / Accepted: 27 February 1997     

飞行(学)员ACE基因的多态性

血管紧张素转化酶 (ACE)第 16内含子的插入 缺失多态性与运动员耐力水平有关 .为了解这一多态性与飞行员飞行耐力的关系 ,对不同阶段飞行人员ACE第 16内含子基因型进行了分析和比较 .结果显示 ,ACEDD基因型百分率在招飞体检应征人员为 12 5 %、基础飞行学院学员 (未飞 )为 11 5 %、飞行学院初教机飞行学员为 10 0 %、歼击机飞行员为 3 0 % .歼击机飞行员组D等位基因频率及DD基因型明显低于其他 3组 (P <0 0 1) ,而后 3组之间无明显差异 (P >0 0 5 ) .进而观察到 ,飞行员体能测试成绩优者 ,无DD基因型 .提示 ,飞行员体能表现与ACE第 16内含子的插入 缺失多态性有关 ,具有I等位基因者 ,体能较好 ,飞行耐力也较好 .     

Polymorphism of genes of the renin-angiotensin system ACE, AT1R, and AT2R in patients with pulmonary tuberculosis

The goal of this work was to verify the hypothesis about the possible role of some genes of the renin-angiotensin system in the innate immunity to tuberculosis. The insertion/deletion polymorphism (I/D) of the gene of the angiotensin-converting enzyme (ACE) is known to have an effect on the concentration of the angiotensin II in human body and also an indirect effect on various branches of metabolism. On the one hand, people with homozygote deletion of the ACE gene (DD genotype) are vulnerable to adiposity, arterial hypertension, hypercholesterolemia, and a number of other pathological conditions. On the other hand, it was shown that hypocholesterolemia is the general phenomenon for the patients with pulmonary tuberculosis (Perez-Guzman C. et al., Chest (2005)). In this work, we studied the I/D polymorphism of the gene ACE (genotypes DD, ID, and II), single nucleotide polymorphism (SNP) of the gene AT1R (1166 A/C), and SNP in 3123 positions of the gene AT2R (3123 A/C) in 200 patients with tuberculosis, 202 patients with essential hypertension, and 208 apparently healthy subjects. A group of patients with essential hypertension was used as a contrast group. According to the hypothesis stated above, the excess in the number of patients with the DD genotype (ACE) should be statistically significant in the group of patients with hypertension as compared to the group of patients with tuberculosis (chi2 = 9.64; chi2 = 0.0019; OR = 2.0; CI 1.2-3.3). There was a trend toward an increase in the rate of the DD genotype in the group of patients with tuberculosis relative to healthy subjects. Similar trend was observed in healthy subjects relative to the group of patients with hypertension. However, this difference was found to be statistically insignificant. The genotypes and allelotypes were compared in the group of patients with tuberculosis versus both the two control groups (healthy subjects and patients with hypertension). The significant difference from control was observed only in male rather than female patients with tuberculosis. It was shown that the greatest contribution to the distinction between groups was due to the genes ACE and AT2R. The combination of the genotypes of genes ACE and AT2R (ID+3123C) was met significantly more frequently in male patients with tuberculosis as compared to control group of healthy subjects (chi2 = 9.70; chi2 = 0.002; OR = 2.3; CI 1.2-4.3). The results obtained in this work are discussed in terms of the hypothesis stated above.     

在中国北方汉族人群中血管紧张素转换酶基因I/D多态与G蛋白beta3亚基基因C825T多态对原发性高血压的联合作用

原发性高血压是一种复杂的多基因疾病,被认为是多个变异了的基因遗传交互以及环境因素共同作用的结果.证据表明,血管紧张素转换酶基因和G蛋白beta3亚基基因各自都是重要的原发性高血压的易感基因,并且可能存在共同的通路来导致高血压疾病的发展.为了探索这两个基因在中国北方汉族人群中是否对高血压有影响,挑选血管紧张素转换酶基因I/D多态与G蛋白beta3亚基基因C825T多态,在一个包含502个高血压病例和490个健康对照的样本中做了关联研究.连锁不平衡分析揭示,仅仅在男性中有显著性的非随机性分布,表明血管紧张素转换酶基因与G蛋白beta3亚基基因倾向在男性中造成高血压.调整了的单位点的多变量逐步回归分析展示,在男性显性模型中DD/ID对Ⅱ的比值比达到显著性水平(OR1.57;95%CI,1.09～2.27;P=0.016).在对性别进行分层后的联合分析中,在男性中经过调整后的比值比具有弱显著性水平:在血管紧张素转换酶基因的DD基因型中,TT对CC的比值比是0.11;95%CI,0.01～0.99;P=0.049;在G蛋白beta3亚基基因的CC CT基因型中,DD/ID对Ⅱ的比值比是1.52;95%CI,1.01～2.29;P=0.047.结果暗示,血管紧张素转换酶基因或附近的某个基因是具有男性性别倾向的高血压易感侯选基因,同时,在血管紧张素转换酶基因基因的D等位基因和G蛋白beta3亚基基因的825C等位基因之间,可能存在具有上位效应的基因-基因相互作用.     

Human ACE I/D polymorphism is associated with individual differences in exercise heat tolerance.

We hypothesized that there is an association between the angiotensin I-converting enzyme (ACE) insertion (I)/deletion (D) polymorphism with the variability in exercise heat tolerance in humans. Fifty-eight Caucasian men were exposed to a 2-h exercise heat-tolerance test. We analyzed the association between their heat-tolerance levels with the ACE DD (n = 25) and I+ (n = 33) genotypes and with various anthropometrical parameters and aerobic fitness. It was found that the relative changes in body core temperature, heat storage, and heart rate during the 120-min exposure to exercise heat stress was consistently lower in the I+ genotype group compared with the DD genotype group (0.8 +/- 0.2 vs. 1 +/- 0.1 degrees C, P < 0.05; 17.7 +/- 1.8 vs. 19.8 +/- 1.3 W/M(2), P < 0.05; and 33 +/- 7 vs. 44 +/- 5 beats/min, respectively, P = 0.06). No significant association was found between heat strain response and the anthropometrical measurements or aerobic fitness in the various genotype groups. We suggest that the ACE I+ polymorphism may be considered as a possible candidate marker for increased heat tolerance.