Original article
Epidemiological
Analysis of Common Polymorphisms in Angiotensin-converting Enzyme and Apolipoprotein E Genes and Human Longevity in Colombia

https://doi.org/10.1016/j.arcmed.2006.04.001Get rights and content

Background

Genetic analysis of human longevity may be useful for the understanding of molecular mechanisms implicated in age-related diseases. The molecular genetics of human longevity is largely unexplored in Latin American populations and other developing countries.

Methods

To explore the possibility of an association of common polymorphisms in two candidate genes and longevity in Colombia, we analyzed two polymorphisms in apolipoprotein E (APOE) and angiotensin-converting enzyme (ACE) genes in a sample of 538 Colombian subjects (18–106 years), using previoulsy validated PCR-based methodologies.

Results

We found a significant decrease in ACE DD genotype (24 vs. 16%) between young and old subject groups (mean age: 45 vs. 77 years) (p = 0.03). The ACE DD genotype and D allele decrease was significant only in women. There were no differences for APOE polymorphism between young and old subjects.

Conclusions

Our results are compatible with the expected age-related decrease of ACE DD genotype. Future studies examining functional single nucleotide polymorphisms (SNPs) in the ACE gene and its correlation with serum ACE activity in the older subjects and their younger relatives in this sample are warranted.

Introduction

Genetic explorations of human longevity may shed light on molecular factors associated with resistance to several common age-related diseases 1, 2. The heritability of human longevity is estimated at ∼20–30%, although it varies in different ethnic groups and levels of longevity (3). It has been postulated that the effects of specific candidate gene polymorphisms on different human phenotypes may depend on the genetic background and may interact with environmental features 4, 5; it is expected that for a complex phenotype such as human longevity, non-lineal effects of specific genetic variants can be found (2). Although life expectancy is also increasing in developing countries having profound effects on health and social dimensions (life expectancy in Colombia is ∼70 years, in comparison, in countries such as Mozambique, Africa and Japan, Asia, it is about 37 and 81 years, respectively) (6), the molecular genetics of human longevity is largely unexplored in Latin America and other developing regions.

Because cardiovascular disease is one of the main causes of death worldwide, polymorphisms in genes involved in vascular dysfunction such as apolipoprotein E (APOE) and angiotensin-converting enzyme (ACE) have been postulated as strong candidates for longevity in different studies searching for age-related differences in the frequency of alleles and genotypes related to cardiovascular risk in Caucasian and Asian populations 2, 7.

APOE gene is localized in chromosome 19q (4 kb), coding for a mature protein of 299 aminoacids, which has a key role in lipid transport and neural repair and plasticity (8). Two common SNPs lead to changes in positions 112 (nt 3937 T/C) and 158 (nt 4075 C/T) of the protein and produce the three classic APOE haplotypes: E2 (Cys112/Cys158), E3 (Cys112/Arg158) and E4 (Arg112/Arg158), which have clear functional and differential effects on cell function and risk for some neurodegenerative and cardiovascular diseases 8, 9. ACE gene is localized in chromosome 17q (20.5 kb), coding for a mature protein of 1306 aminoacids, which has a key role in bioactive peptides degradation and cardiovascular and neuronal homeostasis (7). A common insertion/deletion (I/D, an Alu insertion) polymorphism in intron 16 of the gene with varying population frequencies around the world (10) has been described. In addition, particular genotypes in the ACE gene have been correlated with serum levels of the enzyme and associated with vascular (DD for myocardial infarction) and neurological disorders (II for Alzheimer's disease) 7, 10.

In this study we have analyzed the two common polymorphisms in APOE and ACE genes in a large sample of Colombian subjects of different ages, to explore the possibility that they may be associated with human longevity in this population.

Section snippets

Subjects and Methods

Five hundred thirty eight unrelated subjects (372 women, 69.1%) of different ages (18–106 years) were recruited in Bogotá, the capital city of Colombia (for ACE polymorphism, a subsample of 406 subjects was analyzed, 18–90 years, 70% women). The differences in the number of samples analyzed for APOE and ACE polymorphisms were due to DNA storage problems of the first recruited samples, which were analyzed for APOE gene but could not be studied for ACE polymorphism (due to DNA degradation). Group

Results

Genotype frequencies for APOE and ACE polymorphisms in all samples were in Hardy-Weinberg equilibrium (p >0.05). When the 538 subjects genotyped for APOE were divided into two subgroups of older and younger subjects (mean age: 40 vs. 77 years), there were no significant differences in the distribution of allele or genotype frequencies for APOE polymorphism (Table 1) (p >0.05). Stratification by sex did not show any significant difference for APOE genotype or allele frequencies between older and

Discussion

Although the exploration of genetic factors involved in the mechanisms of human aging through association studies have received increasing support 2, 7, the majority of genetic association studies of human longevity have been performed in North America, Europe and Asia. It has been proposed that the expression of human phenotypes of medical interest may be dependent on genetic background and environmental features 4, 5. A study in New York analyzing subjects of European, African and Latin

Acknowledgments

This work was supported by a grant from DIB-UNAL (822002) and COLCIENCIAS (11010416404). The authors thank Dr. Jorge López and members of Beneficencia of Cundinamarca for their help in recruiting older subjects.

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