5.1. DNA Polymorphism in Age-related Genes

 pp. 49-50 in Bioethics and the Impact of Human Genome Research in the 21st Century

Author: Tetsuro Miki (Geriatrics, Ehime University Medical School)

Editors: Norio Fujiki, Masakatu Sudo, and Darryl R. J. Macer
Eubios Ethics Institute

Copyright 2001, Eubios Ethics Institute All commercial rights reserved. This publication may be reproduced for limited educational or academic use, however please enquire with the author.
The causes of human diseases may depend on the ratio between the genetic factors and that environmental factors. For instance, myotonic dystrophy, familial Alzheimer's disease and Werner's syndrome are single Mendelian trait diseases whose symptoms resulted from the mutation of responsible single genes. Common diseases, so-called multifactorial diseases, are influenced by both genetic factors and environmental factors. Age related diseases are more influenced by environmental factors and the aging process.

It is thought that the human genome sequencer will be completely finished by the year 2003. After then, we will be able to find the new genes which contribute to human longevity and age related diseases.

Our final goal is to find the genes responsible for longevity. One of the strategies is to find the age of related genes by analyzing an unusual phenotype. For instance, lacuna syndrome is a rare autosomal recessive hereditary disorder. A patient manifests a reduced life span with presenile clinical symptoms. Werner syndrome is a typical progeroid syndrome. myotonic dystrophy is one of the triplet to repeat diseases. Alzheimer's disease and hypertension are complex diseases whose causes are multifactorial. I want to consider the gene and its single nucleotide polymorphism (SNP) for Werner's syndrome.

About 1000 cases of Werner syndrome patients have been reported all over the world, the incidence is about 1 or 2 in every 100,000 people, these symptoms include diffuse arteriosclerosis , glucose intolerance with a hyperinsulinia, high instance of neoplasms, hypogonadism, osteoporosis, bilateral cataracts, loss or graying of hair, muscles, skin ulcers and sclerosis. The mean age at death is about 50 years, and death usually is caused by complications of arteriosclerosis and malignant neoplasia .

The WRN gene contains helicase domains. It could function to unwind DNA during replication, repair, transcription, recombination or chromosome segregation. We found the DAN polymorphism on the 3' region of the WRN gene. This DNA polymorphism makes two alleles, cysteine and arginine, at amino acid codon 1367. We expected that this polymorphic variant would associate with age related diseases. The genotype was determined by the presence or absence of the PmaC1 site in the PCR product amplified from the genomic sequences.

The PmaC1 site is present in an allele coding for arginine, but not in one coding for cysteine. So, the allele with cysteine yielded a single 193 base pair (bp) fragment while the alleles with arginine yielded 101 bp and 92 bp fragments.

We analyzed five age related diseases, OPLL, MI, nonagenarian, NIDDM and LOAD. The minor allele coding arginine in the MI group is almost three times higher then of that in the control group. The odds of observing the CC genotype in MI cases was 2.78 times that of the controls. This result suggested that variable expression of the WRN helicase would contribute to the pathogenesis of arteriosclerosis and then the development of myocardial infarction. Myocardial infarction is a multifactorial disease. Both environmental factors and genetic factors influence the pathogenesis. The WRN helicase may be one of the genetic factors.

My second topic is stroke. In Japan the lacunar stroke is the most common typical clinical feature of ischemic stroke. It has been shown that lacunar stroke accounts for more than 40 percent of the ischemic stroke cases. Although, neurological symptoms of the lacunar stroke are known as lacunar syndromes, they are often silent. Introduction of magnetic resonance images (MRI) has made it possible to identify asymptomatic infarction.

The prevalence of asymptomatic cerebral lacuna has been shown to increase with hypertension and aging. However, the exact mechanisms to separate lacunar infarction to be symptomatic or asymptomatic are yet to be determined. We have tried to elucidate the possibility of genetic involvement in the manifestation of symptoms in lacunar infarction.

The Association studies were performed between symptomatic and asymptomatic lacunar patients in addition to the asymptomatic lacunar group, 289 community age matched dwelling healthy residents free from any neurological symptoms, were analyzed. Lacunar was evaluated by MRI. The genotype of the components of the renin-angiotensin system, ACE, aangiotensinogen, and angiotensin type 1 receptor was determined for each subject.

The prevalence of hypertension, dyslipidemia, as well as diabetes mellitus was not different between symptomatic and asymptomatic lacunar groups. The most common neurological symptoms was hemiparesis followed by sensory deficits, and gait disturbance. The frequency of DD, ID, and II genotype in the symptomatic lacunar group was not significantly different with that in the asymptomatic group, as well as in healthy residents.

The Association of ACE genotype with lacunar infarction was further evaluated according to the number of lacunae. Lacunar infarction was divided into three groups according to the number of lacunae , 1, 2-3, and 4 or more. In the symptomatic group, there was no difference in the frequency of ACE of I/D genotype among the three lacunar groups, while in the asymptomatic group the distribution of the ACE I/D genotype was significantly different among three groups categorized by the number of lacunae. The frequency of II genotype was significantly higher with multiple lacunar infarctions.

There was a significant difference in the genotype distribution between symptomatic and asymptomatic subjects with one lacunar as well as multiple lacunar infarctions. In subjects with one lacunar the odds ratio for the DD genotype for symptomatic lacunar was 4.8. In subjects with multiple lacunar infarctions (more than 4 lacunae) the odds ratio for the II genotype for symptomatic lacunar infarction was 0.24 which is statistically significant. These findings indicate that subjects with ACE DD genotype would be more likely to be symptomatic in the first ever lacunar stroke. It is also suggested that subjects with ACE II genotype would be resistant to be symptomatic even after multiple lacunar infarctions.

In conclusion, the present study showed that polymorphisms of the ACE gene are related to the development of symptomatic lacunar infarction. In other studies it has been found that the prenisilin 1 (PSEN1 gene, a major causative gene of familial early-onset Alzheimer's disease, also contributes to the etiology of sporadic Alzheimer's disease. One of the major goals of human genetics is to understand the role of common genetic variants in susceptibility to aging-related diseases.

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