Enzyme Gene and Longevity in the Xin Jiang Uighur Autonomous Region of China: An Association Study

Dolkun Rahmutula,1,3 Tomohiro Nakayama,1 Yoichi Izumi,1 Yukio Ozawa,1 Hiroaki Shimabukuro,1 Hiroshi Kawamura,2 Shi Zhen-Wang,3 Jing Xiong-Wang,3 Muhupul Aisa,3 Chun Run-Yang,3 Masum Mahmut,3 Rena Mahsut,3 and Zhu Hen-Chen3

1The Second Department of Internal Medicine, Nihon University School of Medicine, Tokyo, 2Department of Medicine, Nippon Dental University School of Dentistry, Tokyo. 3Department of Medicine, Xin Jiang Medical University, Xin Jiang Uighur Autonomous Region, the People’s Republic of China.

Background. Longevity can be regarded as a multifactorial trait that results from an interaction between environ- mental 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 indi- viduals, and 89 Han individuals. All subjects in the latter two groups ranged in age from 65 to 70 years, whereas the Ui- ghur 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 Ui- ghur 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 ((cid:2)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 differ- ence among individuals in the Xin Jiang Uighur Autonomous region of China.

ACE occurs in intron 16 (9). The insertion (I) allele con- tains 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) (10–12), cardiomyopathy (13,14), left ventricular hypertro- phy (15), and coronary risk in noninsulin-dependent dia- betic patients (16). In some studies, elevated ACE levels were associated with the D allele (11,17,18). Although as- sociations 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 fre- quency of the ACE/D allele found in association with lon- gevity (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 lon- gevity, as well as that in control subjects.

mous region of China is a relatively isolated area and is well known for an ethnic group that displays marked lon- gevity, a group known as the Uighur (1–3). Angiotensin converting enzyme (ACE), one of the constituents of the renin-angiotensin system, has attracted attention in the pathogenesis of cardiovascular disease. Cardiovascular dis- ease is a multifactorial disease in which genetic and envi- ronmental factors play important roles. These factors may differ according to race or ethnic group. A number of stud- ies have suggested various risk factors in association with cardiovascular diseases (4). Because it modulates the pro- duction of angiotensin II and the catabolism of bradykinin, ACE is implicated in the development of cardiovascular disease. Plasma ACE levels are variable between individu- als (5,6). Furthermore, levels of plasma ACE are consid- ered 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

M ETHODS

DNAmarkerVD YD VD DD IA VD 

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 se- lection 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 di- vided into two groups, those aged 59 to 70 and those aged 90 and older. Those aged 90 and older were termed the Ui- ghur 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 con- firm general health and to prepare DNA.