Notes: I   insertion; D   deletion. Populations are in Hardy-Weinberg equilibrium for the ACE gene.

arising from genetic drift and a founder effect or from a se- lection process. The D allele has been associated with pre- mature coronary artery disease, cardiac hypertrophy, rela- tively 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 as- sumptions, and divergent populations. For instance, the Ca- nadian Inuit population, an endogenous native people, has a much lower rate of heart disease than do non-native popula- tions. Hegele and colleagues tested the possibility of a genetic basis for this by examining five different gene polymorphisms previously associated with the risk of car- diovascular disease, namely ACE, angiotensinogen, intesti- nal fatty acid binding protein, paraoxnase, and the apolipo- protein 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 predomi- nance 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” at- tributes is likely to become increasingly important.

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 Ger- EN >8 man 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 popula- tion 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 re- ported 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 exam- ples 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 be- tween natural longevity and race among individuals in the autonomous Xin Jiang region of China and also inform fu- ture study of the relation between the ACE gene I/D poly- morphism and cardiovascular disease.

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 fac- tor 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

Acknowledgments

This study was supported by a Nihon University President’s Grant for Specified Interdisciplinary Research and Health Organization of Hotan dis- trict, Xin Jiang autonomous region, China.

Address correspondence to Dolkun Rahmutula, MD, PhD, Metabolic Research Unit, University of California at San Francisco, 513 Parnassus, HSW 1119, San Francisco, CA 94143. E-mail: dolkunr@itsa.ucsf.edu

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