of ACE and APOE and Their Relations With Dementia Status in Korean Centenarians

1 2 2 3 1 Yoon-Ho Choi, Ji-Hae Kim, Doh Kwan Kim, Jong-Won Kim, Duk-Kyung Kim, 4 5 6 Mee Sook Lee, Cheol Ho Kim, and Sang Chul Park

3Department of Clinical Pathology, Sungkyunkwan University School of Medicine, Seoul, Korea. 4Department of Food and Nutrition, Hannam University, Daejeon, Korea.

6Department of Biochemistry, Aging and Apoptosis Research Center, Seoul National University College of Medicine, Seoul,

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

Methods. We investigated the distributions of the ACE and APOE genotypes and their relations with dementia status in Korean centenarians by cross-sectional study. A total of 103 centenarians (13 men and 90 women, mean age 102.4 6 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 6 9.6 years for the ACE genotyping, and 6435 adults (5008 men and 1427 women) of mean age 50.7 6 7.9 years for the APOE genotyping. The dementia status of the centenarians was assessed by 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 with dementia even at age 100 and older.

for cardiovascular diseases such as myocardial infarction (11,12), left ventricular hypertrophy (13), and coronary heart disease in diabetes mellitus (14). In addition, the D allele was reported to be more frequent among Alzheimer’s disease subjects than in controls (15). It seems paradoxical that such an allele with adverse effects on major diseases is also related to survival to extreme old 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% (1,2), genetic factors seem to play an important role in exceptional longevity (3). When the survival of siblings of centenarians was compared with the survival of siblings 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 (4).

The e4 allele of the APOE gene is known to be associated with a greater risk of Alzheimer’s disease (16). And it is also related with coronary artery disease through lipoprotein metabolism and atherogenesis (17,18). Previous studies demonstrated the decrease of the e4 allele frequency and the increase of the e2 allele frequency in centenarians (6,8). However, most of the studies in search of the association between genetic polymorphisms and longevity have been conducted in Caucasian populations. It is not known whether the APOE polymorphisms influence longevity differently in Korean compared with Caucasian populations (6,8,19,20). Compared with Caucasian populations, Asians are reported to carry lower frequencies of the APOE e4 allele (21,22). Given the differential environment exposures experienced by Korean centenarians, potential gene–envi- ronmental 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] (5), ACE [angiotensin-converting enzyme] (6,7), APOE [apolipoprotein E] (6,8), and APOB [apolipoprotein B] loci (9). Among them, the association between ACE gene polymorphism and longevity is rather controversial. Sha¨chter and colleagues (6) first reported that the frequency of the D allele of the ACE gene was higher in French cen- tenarians than in the control group. However, this finding was not confirmed in a later, larger, French centenarian cohort study (10). In Asian populations, the association was only found in a certain ethnic group in China (7). Mean- while, the D allele has been associated with increased risk

Table 1. Distribution of Angiotensin-converting Enzyme Genotypes and Alleles in Centenarian and Control Groups

Table 2. Distribution of Apolipoprotein E Genotypes and Alleles in Centenarian and Control Groups

Centenarians Controls (n 5 103) (n 5 6435) Number (frequency) Number (frequency) Genotype E2/2 0 (.0%) 27 (.4%) E2/3 11 (10.7%) 690 (10.7%) E3/3 78 (75.7%) 4585 (71.3%) E4/2 2 (1.9%) 78 (1.2%) E4/3 12 (11.7%) 1005 (15.6%) E4/4 0 (.0%) 50 (.8%) p value .702 Allele e2 13 (6.3%) 822 (6.4%) e3 179 (86.9%) 10865 (84.4%) e4 14 (6.8%) 1183 (9.2%) p value .492 (e21e3) 192 (93.2%) 11687 (90.8%) e4 14 (6.8%) 1183 (9.2%) p value .237

Centenarians Controls (n 5 102) (n 5 7232) Number (frequency) Number Genotype DD 15 (14.7%) 1041 (14.4%) ID 52 (51.0%) 3549 (49.1%) II 35 (34.3%) 2639 (36.5%) p value .899 Allele D 82 (40.2%) 5631 (39.0%) I 122 (59.8%) 8827 (61.0%) p value .716