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The Journals of Gerontology Series A: Biological Sciences and Medical Sciences 57:M57-M60 (2002)
© 2002 The Gerontological Society of America

Angiotensin-Converting Enzyme Gene and Longevity in the Xin Jiang Uighur Autonomous Region of China

An Association Study

Dolkun Rahmutulaa,c, Tomohiro Nakayamaa, Yoichi Izumia, Yukio Ozawaa, Hiroaki Shimabukuroa, Hiroshi Kawamurab, Shi Zhen-Wangc, Jing Xiong-Wangc, Muhupul Aisac, Chun Run-Yangc, Masum Mahmutc, Rena Mahsutc and Zhu Hen-Chenc

a The Second Department of Internal Medicine, Nihon University School of Medicine, Tokyo, Japan
b Department of Medicine, Nippon Dental University School of Dentistry, Tokyo
c Department of Medicine, Xin Jiang Medical University, Xin Jiang Uighur Autonomous Region, the People's Republic of China

Dolkun Rahmutula, Metabolic Research Unit, University of California at San Francisco, 513 Parnassus, HSW 1119, San Francisco, CA 94143 E-mail: dolkunr{at}itsa.ucsf.edu.

Decision Editor: John E. Morley, MB, BCh


   Abstract
Top
 Abstract
Methods
 Results
 Discussion
 References
 
Background. Longevity can be regarded as a multifactorial trait that results from an interaction between environmental factors and sets of epistatic alleles that have pleiotropic age-dependent effects. The Hotan district in the Xin Jiang Uighur Autonomous region of China is relatively isolated and is well known for an ethnic group that displays marked longevity.

Methods. We performed a correlation study between the insertion/deletion (I/D) polymorphism of the angiotensin-converting enzyme (ACE) gene and longevity by comparing distributions of the polymorphism between three different ethnic groups in this region. We obtained data from 424 subjects comprising 227 Uighur individuals, 108 Kazakh individuals, and 89 Han individuals. All subjects in the latter two groups ranged in age from 65 to 70 years, whereas the Uighur subjects actually comprised two different age groups: those ranging in age from 59 to 70 years (Uighur older group in Hotan [UOH]) and those ranging in age from 90 to 113 years (Uighur longevity group in Hotan [ULH]). Genomic DNA was extracted from peripheral white blood cells. Polymerase chain reaction was performed to amplify the I/D polymorphic region of the ACE gene.

Results. Frequencies of the insertion (I) and deletion (D) alleles were 0.596 (243/408) and 0.404 (165/408) in the Uighur group, 0.606 (130/216) and 0.394 (85/216) in the Kazakh group, and 0.657 (117/178) and 0.343 (61/178) in the Han group. The overall distributions of alleles in these three groups did not differ significantly ({chi}2 = 4.6, p = .33). Within the Uighur group, frequency of the D allele was significantly higher in the ULH group (0.448) than in the UOH group (0.355) (p < .04).

Conclusions. This association reflects a genetic influence on differential survival and may point to pleiotropic age-dependent effects on longevity. Our data may help elucidate the relationship between natural longevity and race difference among individuals in the Xin Jiang Uighur Autonomous region of China.

THE Hotan district in the Xin Jiang Uighur Autonomous region of China is a relatively isolated area and is well known for an ethnic group that displays marked longevity, a group known as the Uighur (1)(2)(3). Angiotensin converting enzyme (ACE), one of the constituents of the renin-angiotensin system, has attracted attention in the pathogenesis of cardiovascular disease. Cardiovascular disease is a multifactorial disease in which genetic and environmental factors play important roles. These factors may differ according to race or ethnic group. A number of studies have suggested various risk factors in association with cardiovascular diseases (4). Because it modulates the production of angiotensin II and the catabolism of bradykinin, ACE is implicated in the development of cardiovascular disease. Plasma ACE levels are variable between individuals (5)(6). Furthermore, levels of plasma ACE are considered to be under genetic control. The gene encoding human ACE has been cloned and assigned to chromosome 17q23 (7)(8). The insertion/deletion (I/D) polymorphism at the ACE occurs in intron 16 (9). The insertion (I) allele contains a 287 bp Alu repeat sequence, whereas the deletion (D) allele lacks the Alu sequence. The D allele of the ACE gene has been associated with myocardial infarction (MI) (10)(11)(12), cardiomyopathy (13)(14), left ventricular hypertrophy (15), and coronary risk in noninsulin-dependent diabetic patients (16). In some studies, elevated ACE levels were associated with the D allele (11)(17)(18). Although associations between ACE polymorphism and cardiovascular diseases have been elucidated in many studies, they are neither strong nor consistent in all populations. Also, the allelic frequencies of the ACE gene vary between racial and ethnic groups. More surprising is the increased frequency of the ACE/D allele found in association with longevity (19). In this study, we made a correlation between the I/D polymorphism of the ACE gene and longevity by comparing distributions of the polymorphism between three ethnic groups, one of which is characterized by longevity, as well as that in control subjects.


   Methods
Top
 Abstract
 Methods
Results
 Discussion
 References
 
Materials
We obtained data from 424 individuals comprising three races. Subjects were recruited from the Hotan (south Xin Jiang) and Balkun (north Xin Jiang) districts by random selection of resident cards (in a local government office). A total of 227 Uighur individuals and 38 Han individuals were recruited from Hotan. The Uighur subjects ranged in age from 59 to 113 years, and the Han subjects ranged in age from 65 to 70 years. One hundred eight Kazakh individuals and 51 Han individuals were recruited from Balkun. Both the Kazakh subjects and the Han subjects ranged in age from 65 to 70 years. The Hotan Uighur subjects were divided into two groups, those aged 59 to 70 and those aged 90 and older. Those aged 90 and older were termed the Uighur longevity group, and those aged 59 to 70 were used as a control group (Table 1 ). All subjects underwent a general physical examination. Blood samples were collected to confirm general health and to prepare DNA.


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  		Table 1. Characteristics of the Study Populations

 
DNA Analysis
We extracted genomic DNA from citrated whole-blood peripheral white blood cells by a modification of previously described methods (20). Polymerase chain reaction (PCR) was performed to amplify the I/D polymorphic region of the ACE gene as previously described (21). The sense primer was 5'-CTGCAGACCACTCCCATCCTTTCT-3, and the antisense primer was 5'-GATGTGGCCATCACATTCGTCAGAT-3'. The thermal cycling conditions were as follows: initial denaturation at 94°C for 3 minutes followed by 30 cycles at 94°C for 30 seconds, 63°C for 1 minute, 72°C for 1 minute, and a final extension at 72°C for 10 minutes. The PCR products were separated by electrophoresis on a 1.5% agarose gel (Fig. 1). Allele frequencies for each group were calculated by chi-square analysis on contingency tables.



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  		Figure 1. Angiotensin converting enzyme (ACE) genotypes. Polymerase chain reaction amplification of ACE alleles insertion (I) and deletion (D) showed the presence of 490-bp and 190-bp products on 1.5% agarose gel electrophoresis.

 

   Results
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 Abstract
 Methods
 Results
Discussion
 References
 
The frequencies of genotypes and alleles of the I/D polymorphism of the ACE gene in the three races are shown in Table 2 . There were no significant differences between the groups in the overall distribution of genotypes ({chi}2 = 4.6, p = .33) and alleles ({chi}2 = 1.3, p = .51). Frequencies of the I and D alleles were 0.645 (156/242) and 0.355 (86/242), respectively, in the control group and 0.552 (117/212) and 0.448 (95/212), respectively, in the Uighur longevity group ({chi}2 = 4.05, p = .04) (Table 3 ). These results are similar to those previously reported (D allele more frequent in centenarian than in control: p < .01) (16).


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  		Table 2. Distribution of the Insertion/Deletion Polymorphism of the Angiotensin-Converting Enzyme Gene in the Three Races Studied

 

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  		Table 3. Distribution of the Insertion/Deletion Polymorphism of the Angiotensin-Converting Enzyme Gene in Uighur Control and Longevity Groups

 

   Discussion
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 Abstract
 Methods
 Results
 Discussion
References
 
The genotypes and I/D allele polymorphism of the ACE gene have been reported at different frequencies in different races. The I allele of the ACE gene has a reported frequency of approximately 0.47 in Caucasians (22)(23). Barley and colleagues (23) reported a considerably higher I allele frequency of 0.91 in Polynesian (Samoan) and 0.85 in South American native (Yanomami) populations. The frequency of the I allele in healthy Korean subjects (0.58) was very similar to that in healthy Japanese subjects (0.59) (18)(24) and fell between the frequencies reported for Caucasians, Samoans, and Yanomami. In our study, there were no marked differences in genotype or allele frequencies between the three racial groups, and the frequency of the I allele (0.645) was closer to that of the Koreans and Japanese than that of the Caucasians, Samoans, or Yanomami. It is possible, though only speculative, that this may reflect a similarity among Asians in general.

The differences in the ACE polymorphism between populations may be due to differences in genetic background arising from genetic drift and a founder effect or from a selection process. The D allele has been associated with premature coronary artery disease, cardiac hypertrophy, relatively rapid progression of chronic renal disease, stroke, and coronary restenosis after stent placement. The association between MI and ACE polymorphism among westerners might be a consequence of linkage disequilibrium between neutral mutations and a significant cardiovascular allele of the ACE gene. Nevertheless, not all investigators have found an increased risk associated with the D allele (25). In fact, the D allele occurred more frequently in a group of 100-year-old individuals than would otherwise be expected. How are these divergent findings, a "bad" and "good" effect of a single mutation, to be reconciled? One possibility may be related to differing genetic methodologies, unrealistic assumptions, and divergent populations. For instance, the Canadian Inuit population, an endogenous native people, has a much lower rate of heart disease than do non-native populations. Hegele and colleagues tested the possibility of a genetic basis for this by examining five different gene polymorphisms previously associated with the risk of cardiovascular disease, namely ACE, angiotensinogen, intestinal fatty acid binding protein, paraoxnase, and the apolipoprotein E gene (26). Interestingly, the Inuit population features a predominance of the "bad" polymorphism for four of the genes. In the case of ACE, they had a predominance of the "good" I polymorphism in comparison with the non-Inuit control group who showed a predominance of the D allele. Predominance explaining "good" and "bad" attributes is likely to become increasingly important.

Our results support this finding, and it is interesting in view of its reported association with MI. Perhaps the risk conferred by the I/D allele is offset by some unknown long-term protective effect that appears to be unrelated to blood pressure and hypertension in adults (11)(17). However, the protective effect may arise during old age, which might then explain increased blood pressure as a positive survival factor for longevity. ACE activity has been related not only to the cardiovascular control system but also to the immune system (27). Further studies are needed to understand the role of ACE outside the cardiovascular system. Faure-Delanef and colleagues (28) found the D/D genotype to be more frequent in French centenarians than in controls; the D allele as well as increased serum ACE activity were also more frequent in centenarians. Similar results were reported by Baltes and colleagues: analysis revealed a significantly increased frequency of the D/D genotype in an elderly German group (age >80 years) (29). Interestingly, both of these groups were Caucasians. They are distinguished from our subjects in ethnicity, but the findings were similar.

These comparative studies of the ACE polymorphism demonstrate the importance of using a homogeneous population for the selection of study subjects, making possible more exact estimations of the distributions of ACE genotypes among racial groups. The I/D polymorphism frequencies reported in various populations are not conclusive. Studies of longevity in other racial or ethnic groups, such as South or Central Asians, North or South Americans, and Africans, will be of great interest. The associations we found provide examples of genetic influence on differential survival and may point to pleiotropic age-dependent effects on longevity rather than to a significant difference in the distribution of the ACE gene I/D polymorphism between our three ethnic groups.

The D allele frequency was significantly higher in our longevity group than in elderly subjects of the same ethnic background. This reflects a genetic influence on differential survival and may point to pleiotropic age-dependent effects on longevity. Our data may help to elucidate the relation between natural longevity and race among individuals in the autonomous Xin Jiang region of China and also inform future study of the relation between the ACE gene I/D polymorphism and cardiovascular disease.


   Acknowledgments
 
This study was supported by a Nihon University President's Grant for Specified Interdisciplinary Research and Health Organization of Hotan district, Xin Jiang autonomous region, China.

Received January 18, 2001

Accepted March 26, 2001


   References
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 Discussion
 References
 

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