Title: ACE and APOE Polymorphisms and Their Relationship with Dementia Status in Korean Centenarians

Authors: Yoon-Ho Choi, Ji-Hae Kim, Doh Kwan Kim, Jong-Won Kim, Duk-Kyung Kim, Mee Sook Lee, Cheol Ho Kim, and Sang Chul Park

Affiliations: 1 Department of Clinical Pathology, Sungkyunkwan University School of Medicine, Seoul, Korea. 2 Department of Food and Nutrition, Hannam University, Daejeon, Korea. 3 Department of Biochemistry, Aging and Apoptosis Research Center, Seoul National University College of Medicine, Seoul, Korea.

Background:
Genetic polymorphisms of angiotensin-converting enzyme (ACE) and apolipoprotein E (APOE) have been associated with human longevity and dementia in the elderly. However, it is not well known whether such putative longevity genes exert the same effects on different ethnic groups living in different environments.

Methods:
We conducted a cross-sectional study to investigate the distributions of ACE and APOE genotypes and their relations with dementia status in Korean centenarians. A total of 103 centenarians (13 men and 90 women, mean age 102.4 ± 2.6 years) were included in this study. The allele frequencies of the genes were compared with those of two control groups: 7232 apparently healthy adults (4100 men and 3132 women) of mean age 48.5 ± 9.6 years for the ACE genotyping, and 6435 adults (5008 men and 1427 women) of mean age 50.7 ± 7.9 years for the APOE genotyping. The dementia status of the centenarians was assessed by a clinical psychologist using the Clinical Dementia Rating (CDR) score.

Results:
The frequencies of genotypes and alleles of the ACE and APOE genes of the centenarians were not significantly different from those of the control groups. There was a lack of association between presence of the D allele on the ACE gene and dementia status. However, the frequency of the e4 allele of the APOE gene was significantly higher in centenarians with dementia than in centenarians without definitive dementia (9.1% versus 1.5%, p < .05).

Conclusions:
These results suggest that neither the ACE nor the APOE gene is significantly associated with longevity in the Korean population, but that the APOE e4 allele is still related to dementia even at age 100 and older.

Discussion:
Centenarians, who have survived various age-associated diseases and attained the extreme limit of human life, are the best subjects for the genetic study of longevity. Although twin studies have suggested that the heritability of life span would be no more than 30%, genetic factors seem to play an important role in exceptional longevity. When the survival of siblings of centenarians was compared with that of a control group who were from a similar birth cohort, the relative risk of survival to older age steadily increased with age for siblings of the centenarians.

The e4 allele of the APOE gene is known to be associated with a greater risk of Alzheimer's disease and coronary artery disease through lipoprotein metabolism and atherogenesis. Previous studies demonstrated a decrease in e4 allele frequency and an increase in e2 allele frequency in centenarians. However, most studies on genetic polymorphisms and longevity have been conducted in Caucasian populations. It is not known whether APOE polymorphisms influence longevity differently in Koreans compared with Caucasians. Compared with Caucasian populations, Asians are reported to carry lower frequencies of the APOE e4 allele. Given the differential environmental exposures experienced by Korean centenarians, potential gene-environmental interactions would also be expected to differ from Western Caucasians.

Recently, significant genetic associations with human longevity have been found at the HLA [human leukocyte antigen], ACE, APOE, and APOB loci. Among them, the association between ACE gene polymorphism and longevity is rather controversial. Schachter and colleagues first reported that the frequency of the D allele of the ACE gene was higher in French centenarians than in the control group. However, this finding was not confirmed in a later, larger, French centenarian cohort study. In Asian populations, the association was only found in a certain ethnic group in China. Meanwhile, the D allele has been associated with an increased risk for cardiovascular diseases such as myocardial infarction, left ventricular hypertrophy, and coronary heart disease in diabetes mellitus. In addition, the D allele was reported to be more frequent among Alzheimer's disease subjects than in controls. It seems paradoxical that such an allele with adverse effects on major diseases is also related to survival to extreme old age.

Materials and MethodsStatistical analysis was carried out using SAS (Statistical Application System, Version 6.10; SAS, Inc., Cary, NC).

RESULTS

The frequencies of the genotypes and alleles of the ACE and APOE genes in Korean centenarians and control groups are compared in Tables 1 and 2. The genotype distributions of the samples were in Hardy-Weinberg equilibrium. There was no significant difference between the two groups in the overall distribution of the genotypes and alleles for the ACE gene. The frequencies of the e2 allele of the APOE gene in the centenarians and the control group were 6.3% and 6.4%, respectively. The frequencies of the e4 allele were 6.8% and 9.2%, respectively, which were not significantly different. Figure 1 presents the distribution of three alleles of the APOE gene according to the decade of subject age from the combined population of the control group and centenarians. Although it was not statistically significant, the frequency of the e4 allele slightly decreased after the eighth decade and tended to be lower in the centenarians. The e2 allele apparently did not indicate any age-dependent change in their proportion.