Genotype-phenotype associations between chymase and angiotensin—converting enzyme gene polymorphisms in chronic systolic heart failure patients

PurposeAngiotensin II, which plays a crucial role in the myocardial remodeling process of heart failure, is generated via the angiotensin-converting enzyme and chymase pathways. We studied angiotensin-converting enzyme and chymase-1 polymorphisms in patients with systolic heart failure and the correlation with clinical status and left ventricular function.MethodsWe genotyped 195 patients with heart failure and systolic left ventricular dysfunction (ejection fraction <40%) for angiotensin-converting enzyme insertion (I)/deletion (D) and chymase-1 (−1903G/A) polymorphisms. Heart failure etiology and patients' clinical manifestations were analyzed in relation to genotype subtypes.ResultsThe chymase-1 −1903 GG genotype was associated with a nonischemic heart failure etiology (χ² = 6.67, P = 0.009). In the group of heart failure patients, the odds ratio of chymase-1 GG genotype having a nonischemic etiology was 2.48 (95% CI 1.23–5.00). The chymase-1 GG genotype was associated with lower ejection fraction (P = 0.005). Conversely, the angiotensin-converting enzyme D allele had no detectable impact on systolic heart failure phenotype.ConclusionsIn patients with chronic systolic heart failure, the chymase-1 polymorphism was related to nonischemic etiology of heart failure. Patients homozygous for the G allele had a significantly greater reduction in systolic left ventricular function.     

Apolipoprotein E and α-1-antichymotrypsin allele polymorphism in sporadic and familial Alzheimer's disease

Alzheimer disease (AD) patients with both sporadic and familial forms of AD and non-demented controls were genotyped for common polymorphisms in the signal peptide for α-1-antichymotrypsin (ACT) gene and in two different regions of apolipoprotein E (APOE) gene. The ACT TT genotype was over-represented (P=0.025) in patients with early onset of sporadic AD. In this patient's group ACT TT genotype conferred a significant crude odds ratio for the disease (OR=2.09; 95% CI=1.09–4.00, P=0.025). After adjustment for the APOE ε4 and APOE −491 genotypes, logistic regression analysis confirmed that the ACT TT genotype resulted independently associated with early onset AD (adjusted OR=2.56; 85% C.I.=1.3–5.2, P=0.009). The frequency of APOE ε4 allele was increased in AD, as expected (OR=5.92, 95% CI=3.60–9.70, P=0.0001). On the contrary, the APOE −491 A/T genotypes were not associated with AD. No preferential association of the APOE ε4 allele or APOE −491 A/T genotypes with ACT A/T alleles was observed in AD. Present findings indicated that subjects with ACT TT genotype had an increased risk of developing AD and suggested that this genotype influenced the risk of an early onset of the disease by affecting the production of ACT molecules.     

Increased D allele frequency of the angiotensin-converting enzyme gene in pulmonary fibrosis

An insertion/deletion (I/D) polymorphism of the angiotensin-converting enzyme has previously been studied extensively in relationship to cardiovascular and renal disease. The deletion/deletion (D/D) genotype is associated with a poor outcome in immunoglobulin (Ig) A nephropathy. However, the association of this genetic marker in cardiovascular and renal disease has generated controversy, with the exception of the rate of progression and therapeutic responsiveness in IgA nephropathy. Many of the same cytokines and polypeptide mediators involved in fibrosis of the cardiovascular and renal systems have been shown to be involved in pulmonary fibrosis. We examined the I/D polymorphism of the angiotensin-converting enzyme in a group of 24 patents with interstitial pneumonia and moderate to severe pulmonary fibrosis defined by radiographic studies, pulmonary function tests, and histologic findings. The incidence of the D allele in this study population was 69.0%, which is approximately 15.0% higher than the incidence in the general population of 54.0%. The incidence of the D/D genotype was 42.0%, which is approximately 11.0% greater than that in the general population (31.0%). The distribution of the D/D, I/D, and insertion/insertion genotypes of these 24 patients was not significantly different from that of historical controls (P =.1; chi(2) test); there were marginally significantly more D alleles among the 48 observed alleles than would be expected (P =.04).     

Association of angiotensin-converting enzyme insertion/deletion polymorphism with obesity,cardiovascular risk factors and exercise-mediated changes in Korean women

This study examined whether the angiotensin-converting enzyme (ACE) insertion (I)/deletion (D) polymorphism is associated with obesity, cardiovascular risk factors and 12-week exercise-mediated changes in Korean women. A total of 105 subjects were divided into three groups as II, ID and DD genotype groups based upon ACE I/D genotypes. Body composition and cardiovascular risk factors were compared among the three groups, and the association of ACE I/D genotypes with obesity and hypertension was evaluated. Total cholesterol (TC) and low density lipoprotein cholesterol (LDL-C) levels were higher (P < 0.05) in the DD genotype than in II or ID genotypes. D allele frequency in ACE I/D gene had a higher (P = 0.063) trend in the hypertensive group than the normotensive group. The DD genotype had a trend to develop (odds ratio 4.032, P = 0.086) more hypertension than the II genotype. The II and ID genotypes showed a significant (P < 0.05) decrease in intima media thickness of the carotid artery after an exercise intervention, whereas the DD genotype showed an increase. In conclusion, there is a trend towards association of ACE I/D polymorphism with hypertension but not with obesity. Exercise-mediated changes did not differ significantly among genotypes except IMTCA.     

Dipeptidyl carboxypeptidase 1 (DCP1) and butyrylcholinesterase (BCHE) gene interactions with the apolipoprotein E epsilon4 allele as risk factors in Alzheimer's disease and in Parkinson's disease with coexisting Alzheimer pathology

Alzheimer's disease (AD) and Parkinson's disease (PD) are genetically heterogeneous. Dipeptidyl carboxypeptidase 1 (DCP1) and butyrylcholinesterase (BCHE) genes may modify the risk of these disorders. We investigated whether common polymorphisms present in these genes operate as risk factors for AD and PD in Finnish subjects, independently or in concert with the apolipoprotein E ε4 allele (APOE ε4). Eighty late onset sporadic AD patients, 53 PD patients (34 of whom had concomitant AD pathology), and 67 control subjects were genotyped for the insertion (I)/deletion (D) polymorphism of DCP1 and the K variant of BCHE. In logistic regression analysis, the DCP1 *I allele in combination with APOE ε4 significantly increased the risk of AD (OR 30.0, 95% CI 7.3-123.7), compared to subjects carrying neither of the alleles. Similar analysis showed that the risk of AD was significantly increased in subjects carrying both the BCHE wild type (*WT/*WT) genotype and ε4 (OR 9.9, 95% CI 2.9-33.8), compared to those without this BCHE genotype and ε4. Further, the risk of PD with AD pathology was significantly increased for carriers of DCP1 *I and ε4 (OR 8.0, 95% CI 2.1-31.1). We thus conclude that, in Finns, interaction between DCP1 *I and ε4 increases the risk of AD as well as of PD with coexisting Alzheimer pathology, which underlines the importance of the DCP1 I/D polymorphism in the development of Alzheimer neuropathology, whereas the wild type BCHE genotype in combination with ε4 had a combined effect with regard to the risk of AD.


Keywords: Alzheimer's disease; Parkinson's disease; dipeptidyl carboxypeptidase 1; butyrylcholinesterase     

Effects of captopril treatment versus placebo on renal function in type 2 diabetic patients with microalbuminuria: a long-term study

We evaluated the renal effect of long-term antihypertensive treatment (12 months) with the angiotensin-converting enzyme inhibitor captopril compared to placebo in 15 type 2 diabetic patients with microalbuminuria. The patients were randomly allocated to captopril (n = 9) or placebo (n = 6). After 1-year therapy no significant decrease in blood pressure was demonstrated with captopril (139 ± 17/80 ± 9 versus 138±13/76±6 mmHg) or placebo (138 ± 9/75 ± 6 versus 135 ± 14/79 ±10 mmHg). Only in a small hypertensive subgroup (n = 4) treated with captopril did we find a significant reduction in blood pressure (154 ± 2/88 ± 1 versus 142 ± 7/78 ± 5 mmHg,P < 0.05). The urinary albumin excretion rate did not change significantly either in the captopril group (95.6 mg/24 h, 25th percentile 138.4, 75th percentile 25.1; versus 127.8 mg/24 h, 25th percentile 29.3, 75th percentile 222) or in the placebo group (99.2 mg/24 h, 25th percentile 58.5, 75th percentile 125.8; versus 120.9 mg/24 h, 25th percentile 62.1, 75th percentile 179.7). There were also no alterations in renal blood flow or filtration rate. In the hypertensive subgroup treated with captopril a reduction in urinary albumin excretion rate after 3 and 6 months of treatment was observed (captopril 73.4 versus 24 and 41 mg/24 h,P < 0.05), but not after 12 months. Triglyceride and cholesterol levels remained constant before and after treatment while glycosylated hemoglobin decreased significantly after 12 months captopril (7.8 ± 0.9 versus 6.9 ± 0.7 mg%,P < 0.03). We conclude that in patients with type 2 diabetes with microalbuminuria angiotensin-converting enzyme inhibitors may have protective renal effects in so far as a lack of increase in urinary albumin excretion is equivalent to low progression in renal disease.Abbreviations ACE angiotensin-converting enzyme - GFI glomerular filtration rate - HbA glycosylated hemo globin - RPF renal plasma flow - UAER urinary albumin excretion rate Correspondence to: R. Prager     

Deletion polymorphism in the gene for angiotensin-converting enzyme is associated with essential hypertension in men born during the Pacific War

Age is a strong risk factor for hypertension in relation to vascular aging. Additional etiological factors include: lifestyle, genetic factors, and their interactions. The aim of this study is to examine whether an insertion/deletion (I/D) polymorphism in the angiotensin-converting enzyme (ACE) gene is associated with essential hypertension in Korean born during the Pacific War. A total of 13,914 healthy subjects (8261 men, 5653 women) aged 20-79 years were examined. Subjects with abnormal renal, thyroid dysfunction, or electrolyte levels were excluded. Logistic regression analysis showed increased risk (OR=1.15; 95% CI, 1.01-1.31) in men, but not in women (OR, 1.06; 95% CI, 0.89-1.26). However, after adjustment for age, obesity, cholesterol, alcohol consumption, and diabetes mellitus, increased risk in men was not significant (OR, 1.13; 95% CI, 0.98-1.42). Analyzed according to birth-year, DD genotype showed increased risk for hypertension in only a subgroup of men (adjusted OR, 1.56; 95% CI, 1.16-2.09; p = 0.001), born during the Pacific War (1941-1945 year). Findings suggest that the ACE DD genotype plays a role in the pathogenesis of essential hypertension, in conjunction with adverse environmental conditions in early life, with sex-related difference.     

ACE (I/D) polymorphism and response to treatment in coronary artery disease: a comprehensive database and meta-analysis involving study quality evaluation

Background  

The role of angiotensin-converting enzyme (ACE) gene insertion/deletion (I/D) polymorphism in modifying the response to treatment modalities in coronary artery disease is controversial.     

The angiotensin-converting enzyme insertion/deletion polymorphism modifies the clinical outcome in patients with Pompe disease

PurposeThe insertion/deletion polymorphism of angiotensin-converting enzyme may influence muscle properties. We examined whether Pompe disease clinical manifestations, which are known to be highly variable among late-onset patients, may be modulated by angiotensin-converting enzyme polymorphism.MethodsWe included 38 patients with late-onset Pompe disease, aged 44.6 ± 19.8 years. We compared the distribution of angiotensin-converting enzyme polymorphism according to demographic and disease parameters.ResultsThe distribution of angiotensin-converting enzyme polymorphism was in line with the general population, with 16% of patients carrying the II genotype, 37% carrying the DD genotype, and the remaining patients with the ID genotype. The three groups did not differ in mean age, disease duration, Walton score, and other scores used to measure disease severity. The DD polymorphism was associated with earlier onset of disease (P = 0.041), higher creatine kinase levels at diagnosis (P = 0.024), presence of muscle pain (P = 0.014), and more severe rate of disease progression (P = 0.037, analysis of variance test for interaction).DiscussionThese findings suggest a potential role of angiotensin-converting enzyme polymorphism in modulating Pompe disease phenotype and prognosis.     

The angiotensin-I converting enzyme I/D polymorphism is not associated with type 2 diabetes in individuals undergoing coronary angiography. (The Ludwigshafen Risk and Cardiovascular Health Study)

The deletion (D) allele of the angiotensin-I converting enzyme (ACE) is associated with higher ACE activity and has been implicated only recently in the pathogenesis of type 2 diabetes in Caucasian subjects. We have studied the ACE I/D polymorphism in 1054 patients with type 2 diabetes and in 2251 individuals without type 2 diabetes in Caucasians persons undergoing coronary angiography. Further parameters of glucose metabolism (fasting glucose, HbA1c, insulin, C-peptide, pro-insulin, and pancreatic beta-cell function) were analyzed according to the ACE I/D genotype in a subgroup of 2000 individuals in whom an oral glucose challenge was performed. The genotypes ACE II, ID, DD occurred at similar frequencies in patients with type 2 diabetes mellitus (21.0, 50.8, and 28.3%, respectively) compared to non-diabetic individuals (23.3, 49.2, and 27.5%, respectively). There was no association of the ACE D allele with all type 2 diabetes mellitus (OR 1.16, 95%CI, 0.94-1.43), nor with known (OR 1.28, 95% CI, 0.99-1.68) or newly diagnosed diabetes (OR 1.00, 95% CI, 0.75-1.32). These findings were not materially altered when we adjusted for age and gender, cardiovascular risk factors and anti-diabetic or cardiovascular medication. Further the ACE D-allele was not associated with angiographic coronary heart disease or myocardial infarction. The ACE I/D genotype is not associated with type 2 diabetes mellitus, glucose metabolism, coronary heart disease, or myocardial infarction.     

Relation between angiotensin-converting enzyme II genotype and atrial fibrillation in Japanese patients with hypertrophic cardiomyopathy

Atrial fibrillation (AF) occurs in about 20% of patients with hypertrophic cardiomyopathy (HCM). HCM patients with AF have an increased risk for clinical decline and thromboembolism. In addition, AF is known to be associated with the atrial renin-angiotensin system (RAS). However, the relation between AF and the RAS in HCM has not been investigated. We genotyped the insertion/deletion (I/D) polymorphism of the angiotensin-converting enzyme (ACE) gene in 138 HCM patients (26 with AF, 112 with sinus rhythm). Distribution of the ACE genotypes (DD, ID, and II) among the total HCM patients was 15%, 46%, and 38%. AF was documented in 3 patients with the DD genotype, 7 with the ID genotype, and 16 with the II genotype (P < 0.03 vs. sinus rhythm group). The odds of AF were 3.2-fold greater in patients with the II genotype than in those with the other genotypes (P = 0.009, 95% confidence interval = 1.3–7.8). Kaplan-Meier curves examining the time to the first documented AF event showed a significant difference between genotypes during the follow-up period (mean 116 months, P < 0.05). These findings suggest that the II genotype of the ACE gene is a significant risk factor for AF in patients with HCM. Received: December 10, 2001 / Accepted: January 25, 2002     

脑卒中患者血管紧张素转换酶基因多态性与心率变异性的关联研究

目的　探讨脑卒中患者血管紧张素转换酶 (angiotensin- converting enzyme,ACE)基因多态性和心脏心率变异性的关系。方法　应用聚合酶链反应方法检测 4 3名正常人、4 6例脑梗塞患者、4 0例脑出血患者 ACE基因的插入 /缺失多态性 (insertion/deletion,I/D) ,并用心率变异性 (heart rate variability,HRV)分析方法观察其 HRV的时域、频域和混沌参数。结果　缺血性、出血性脑卒中患者的 ACE基因缺失型 (DD)及 D等位基因频率明显高于正常对照组 (P<0 .0 1) ,DD型患者的 HRV的参数值升高 ,即相邻心搏间期的均方根值、相邻心搏间期差大于 10 ms的心搏间期数占心搏间期总数的百分比、总功率谱、高功率谱、低频功率谱、混沌参数 ,明显高于 ACE基因插入型 (II)、ACE基因插入 /缺失混合型 (ID)患者 ,差异有显著性 (P<0 .0 5 )。结论　 HRV的相关参数和遗传相关 ,提示脑卒中患者有 ACE DD基因型的人 ,有脑源性心脏自主神经功能紊乱发生的危险性。     

The D-allele of ACE insertion/deletion polymorphism is associated with regional white matter volume changes and cognitive impairment in remitted geriatric depression

Prior studies suggested that angiotensin-converting enzyme (ACE) affected vascular homeostasis and degradation of amyloid β (Aβ). It is associated with the therapeutic outcome in major depression. The aim of this study was to investigate the association between angiotensin-converting enzyme (ACE) insertion/deletion (I/D) polymorphism and structural abnormalities in remitted geriatric depression (RGD), and test the relationship of neuropsychological performances and regional white matter volumes. 31 RGD patients were recruited and neuropsychological tests, magnetic resonance imaging (MRI) and genotype of ACE I/D were examined for each subject. The differences in regional white matter volume were tested between I homozygotes and D-allele carriers (I/D or D/D genotype) by optimized VBM. D-allele carriers exhibited significantly smaller white matter volumes of right superior frontal gyrus (SFG) and right anterior cingulated gyrus (ACG), but had larger volumes of left middle temporal gyrus (MTG) and right middle occipital gyrus (MOG) than I homozygotes (P < 0.001). Meanwhile, there was a significant positive correlation between white matter volume enlargement of left MTG and Symbol Digit Modalities Test (SDMT) (r = 0.456, P = 0.043), and the reduction of right ACG was negatively related to Clock Drawing Test (CDT) performance (r = −0.445, P = 0.050) in D-allele carriers. The finding suggests that ACE can modulates the pathology of RGD, the left MTG and right ACG might be involved in the pathophysiology of cognitive dysfunction in RGD patients.     

ACE genotype and cognitive decline in an African-Caribbean population

The insertion/deletion (I/D) polymorphism of the angiotensin I converting enzyme (ACE) gene is believed to influence risk of cerebrovascular disease. However, associations with cognitive outcomes remain controversial. As far as we are aware, all studies to date have been carried out in white American or European populations. African-Caribbean populations have high prevalence rates of hypertension, diabetes and cerebrovascular disease but risk factors for cognitive outcomes remain under-researched. In a UK community sample of 148 African-Caribbean people aged 55–75 years, we investigated the association between ACE genotype and cognitive decline over 3 years using a battery of repeated tests. No direct association was found between ACE genotype and decline. However, the association between increased age and cognitive decline was significantly stronger in people with the ACE DD genotype (odds ratio 3.6 per 5-year increase, 95% CI: 1.9–6.7) compared to those with ID/II genotype (odds ratio 0.7, 95% CI 0.4–1.2). This interaction was particularly strong for decline in verbal memory and was not apparently mediated by vascular risk factors measured at baseline.     

GATA4 mutations in 486 Chinese patients with congenital heart disease

Recent studies have reported germline mutations in GATA4 gene in some types of congenital heart disease (CHD). However, the prevalence of GATA4 mutations in CHD and the correlation between the GATA4 genotype and CHD phenotype have not been extensively studied. We screened germline mutations in the coding exons and the flanking intron sequences of the GATA4 gene in 486 CHD patients by denaturing high-performance liquid chromatography (DHPLC), and confirmed the mutations by sequencing. Nine distinct mutations including one small deletion mutation (46delS), two small insertion mutations (118–119insA and 125–126insAA), and six non-synonymous mutations (A6V, P163S, E359K, P407Q, S429T and A442V) were identified in 12 of the 486 patients (nine with ventricular septal defect, two with Tetralogy of Fallot, and one with endocardial cushion defect). Of them, two patients carrying E359K mutation were from two generations in one family with ventricular septal defect (VSD). Interestingly, a nucleotide insertion of c.1146 + 25insA in exon 6 was detected in five VSD patients, but not in 486 normal healthy controls. Our findings are useful in understanding the prevalence of GATA4 mutations and the correlation between the GATA4 genotype and the CHD phenotype in Chinese patients.     

Exploration of myostatin polymorphisms and the angiotensin-converting enzyme insertion/deletion genotype in responses of human muscle to strength training

This study explores the associations between polymorphisms in two candidate genes—myostatin gene (MSTN or GDF8) and angiotensin-converting enzyme (ACE) gene—with interindividual differences in human muscle mass and strength responses to strength training. The MSTN AluI A55T (exon 1), BanII K153R, TaqI E164 K and BstNI P198A (all in exon 2) markers and the ACE insertion (I)/deletion (D) polymorphism were typed in 57 males [22.4 (3.7) years] who participated in a 10-week, high-resistance training program for the elbow flexors. Maximal strength, and maximal isometric and concentric elbow flexor torques were measured at baseline and after training. Information on muscle cross-sectional area of the upper arm was obtained by computer tomography scans. Only one individual was heterozygous for the MSTN BanII K153R variant. No allelic variant was detected at the other MSTN sites in this population. For the ACE I/D polymorphism, no evidence was found for an association of the D or I allele with baseline strength, isometric and concentric torque or arm muscle cross-sectional area [analysis of covariance (ANCOVA) 0.25<P<0.97]. Responses to the strength-training program were not associated with the ACE I/D genotype (ANCOVA 0.057<P<0.70). Borderline significance was found for larger strength gains in dynamic flexion torques for I/I genotypes. This study therefore does not support the hypothesis that an increased muscle fiber hypertrophic effect of strength training is present in D-allele carriers.     

The serum angiotensin-converting enzyme and angiotensin II response to altered posture and acute exercise, and the influence of ACE genotype

The deletion (D) rather than insertion (I) allele of the angiotensin-converting enzyme (ACE) gene is associated with greater ACE activity. We examined: (1) the influence of posture change (recumbent to seated) and acute exercise on serum ACE and angiotensin II (Ang II) activity; (2) the relationship between ACE and Ang II levels; and (3) the influence of ACE genotype on changes in ACE and Ang II levels with posture and exercise. Recreationally active young male Caucasians (10 each of II, ID and DD genotypes) rested for 35 min supine then 15 min upright, took 20 min bicycle ergometric exercise at 70% maximum oxygen uptake, then rested for 40 min. Samples were taken throughout for ACE activity and Ang II levels. Supine ACE levels were dependent upon ACE genotype [24.8 (5.7), 26.9 (4.5), 45.5 (6.4) nmol His-Leu ml^–1 min^–1; II, ID, DD, respectively; P<0.00005] and thereafter. ACE activity rose with assumption of a seated posture [from 32.4 (10.9) nmol His-Leu ml^–1 min^–1 to 35.0 (11.5) nmol His-Leu ml^–1 min^–1, P<0.00001], the absolute rise being independent of genotype [3.22 (1.92), 1.6 (1.6), 2.4 (2.3) nmol His-Leu ml^–1 min^–1; II, ID, DD; P=0.22], unlike percentage change [12.8 (6.8), 5.6 (5.5), 5.3 (5.0)%; II, ID, DD; P<0.01, and P=0.004 for II vs presence of the D allele]. A further genotype-independent rise occurred with exercise [+2.9 (3.7) units, P<0.0003]. An associated rise in Ang II levels [30.3 (15.9), or 2587.9 (489.76)%, P<0.00001] was independent of ACE genotype or activity. Upright posture increases ACE activity, and this may be influenced by ACE genotype. ACE activity and Ang II levels rise independently with exercise in a non-genotype-dependent fashion.     

四川南部汉族人群血管紧张素转换酶基因多态性对血管紧张素转换酶抑制剂抗蛋白尿作用的影响

目的　探讨四川南部汉族人群血管紧张素转换酶(angiotensin- coverting enzyme,ACE)基因多态性与血管紧张素转换酶抑制剂治疗原发性慢性肾小球肾炎蛋白尿疗效的相关性。方法　用苯那普利治疗99例伴有蛋白尿的原发性慢性肾小球肾炎患者,疗程为3个月。用PCR方法检测ACE基因第16内含子的插入/缺失(insertion/ deletion,I/ D)多态性,比较血管紧张素转换酶抑制剂治疗前后各基因型患者尿蛋白定量下降程度的差异。结果　治疗前ACE基因DD型组尿蛋白显著高于II型组(P<0 .0 5 ) ;苯那普利治疗3月后,DD、ID型组的尿蛋白定量下降幅度明显高于II型组(P<0 .0 5 )。结论　苯那普利可以改善原发性慢性肾小球肾炎患者的尿蛋白,且降低尿蛋白的疗效与患者的ACE基因型有明显的相关性。     

Association between the angiotensin I-converting enzyme gene insertion/deletion polymorphism and endurance running speed in Japanese runners

We investigated the association between the angiotensin I-converting enzyme (ACE) gene insertion (I)/deletion (D) polymorphism and endurance running performance in Japanese elite runners, including several Olympic athletes. The frequency of the I/I genotype was not significantly higher and the frequency of the D/D genotype was not significantly lower in elite runners compared with non-athletes. However, the frequency of the I/D genotype tended to be lower in elite runners than in non-athletes. The best performance was significantly higher for runners with the D/D genotype than for those with the I/I genotype, and the average running speed was significantly higher for those with the combined D/D + I/D genotypes than for those with the I/I genotype. There were no I/I genotypes among the five fastest marathon runners. These results suggest that the D allele of the ACE gene I/D polymorphism is associated with a high level of human endurance.