Download genetic epidemiology

GENETIC EPIDEMIOLOGY
Norio Fujuki, (Japan/Japon)
Vice-President of the IBC/
Vice-Président du CIB
Emeritus Professor Fukui Medical School
I.
Introduction
There are particularly interesting possibilities for genetic epidemiological research in
countries such as Japan and India, where consanguineous marriage holds a long-standing
tradition. This paper summarizes our research project on methodology using Koseki
records (family register book), inbreeding effect using anthropometric and medical surveys
and genetic susceptibility using polymorphic markers in different communities. It
contributes to a basis for prevention of genetic and common diseases.
II. Methodology in Isolated Communities
Isolated communities, composed of 200 -1,000 inhabitants in 50 to 250 households,
with relative high consanguinity (15 to 20%), were chosen. They can be divided into several
sub-communities within geographically isolated inland or island populations. It is assumed
that these communities have hardly migrated. This is supported by the evidence of the state
of excellent preservation of old documents, such as Juminhyo, Koseki as well as Josekibo,
Harakoseki, established at 1898 and possibly Jinshin Koseki, established at 1871. These
documents also shed light on geographic and historical factors and disease pattern. Of
course, before the field survey, the team requested the village-master, the school-teachers,
doctors and public health nurses their co-operation and collected information, through
personal interviews, concerning matrimonial migration habits and disease patterns, as well as
socio-economic patterns and biological data.
The information on Koseki of each household has been transcribed on blank sheet
drawing indicating parents, siblings and children, with their name, age, sex of household
head, just like a family tree, mentioning as many relatives as possible. Usually three or four
Koseki files are gathered in one pedigree sheet, including the persons who moved out or are
dead. Hence, tracing back from Koseki to Josekibo and Harakoseki, approximately 190
pedigree sheets have been drawn on entire villages of a single isolated community, where 243
persons live, organized in 97 households, representing a population of 1,432 names in these
genealogies, including the deceased and the individuals who have migrated.
These pedigree sheets are organized according to the surname, connected with each
other vertically and then horizontally, uniting both family sides of parents and compiling an
overall pedigree. These pedigrees provide useful information on migration trends and rates
of endogamous marriages. However, in large populations, the compilation of such pedigrees
are quite laborious and time-consuming. The marriages involving individuals related in more
than one way are not commonly encountered in the general population. Nevertheless, such
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marriages are often met in isolated communities, where a common ancestor, traced four or
five generations back, can be easily missed. Therefore, careful verifications are needed across
diagrams, in order to counter check information emanating from different records, for
instance, the Koseki church record and temple record, as well as through family interviews.
In the Yanase's method of retrospective dismembered pedigree, common ancestors are traced
back, starting from each sib-ship in Juminhyo. A pedigree sheet over five to seven generations
can be restored through the method described below. Honseki, present address, name of
initiating couple, their paternal and maternal lignage with birth and death places and dates, as
well as migration patterns, then their siblings with name, age, sex, birth and death dates,
migration and marriage, and numbers of children, birth order, address of the spouse, cause of
migration and death. Then the pedigree is worked up retrospectively, as far as possible, in
order to trace back the present Koseki to remote generations. The generations are
distinguished according to twenty year slices.
At the next stage, the occurrence of a given individual registered as an ancestor to two
couples is checked. If a certain individual happens to be registered in two or more places on
the same sheet, leads to conclude that the couple is consanguineous. This procedure plays an
indispensable role in listing the numbers and the kinds of consanguineous marriages occurring
in the population. It offers precious information for various uses, for example, calculation of
the rates of endogamous marriage, classification of families into male-dependent or
female-dependent type, and the connection of families in sociobiological studies. In summary,
the method to make a pedigree sheet depends upon the objects of investigation, quality and
quantity of basic data, and their purposes.
The clinical studies are focused on the hereditary diseases of haematological and
neurological order, carried out by well-trained physicians interested in genetic epidemiology,
as well as in adult diseases of polygenic inheritance, such as hypertension, diabetes, coronary
heart diseases. The examinations include the observation of a number of genetic traits, as
well as genetic polymorphic traits mentioned below. Blood pressure, ECG, routine blood
counts, serum protein, cholesterol and lipid fractions as well as anthropometry are performed
in connection with the physical examinations. At the time of the field survey, following a
procedure of informed consent, 5 ml of blood sample by venipuncture were taken from
individuals. In the field, HB, Ht and serum protein concentrations are determined. After a
day's work in the field, red-cell layers with ACD for red-cell enzyme typing, leukocyte layers
for HLA typing and DNA study, as well as serum layer for serum protein typing, are
immediately separated. Each sample is kept in a deepfreeze and brought back to the home
laboratory or other laboratories where further determinations are conducted.
Based on the genetic and physical data obtained by Koseki record and medical survey,
comparative studies are carried out on differences in the mortality and fertility rates, as well
as on anthropometric data between consanguineous and non-consanguineous groups, after
transferring all data to computerized cards and analyzing this information through
a FORTRAN IV program. The regression equations for the standardized values on the
inbreeding coefficients are computed using multivariate analysis.
The items investigated are determined according to the recommendation, of WHO
Trs. # 387 (1968) and IBP Handbook # 6. (1969) as well as IUBS document, in order to
compare other data obtained in other countries. Information on physical examinations, clinical
diagnosis and preventive treatment is communicated to each of the concerned individual, in a
simple language, through local health authorities and the medical practitioner. The health
data thus generated is used towards the improvement of local health programmes in these
communities, especially in the case of remote areas with relatively poor health care systems.
The family data is integrated in the family pedigree of the entire village, using manual and
computerized methods, now carried out in the experimental joint-study with the Department
of Computer Sciences of the University of Utah. Socio-economic data is also obtained with
the co-operation of sociologists.
III. Inbreeding Effects and Genetic Polymorphism
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For over 35 years, the status of inbreeding with Koseki record and genetic
polymorphisms, such as blood types red-cell enzyme and serum protein types, has been
investigated in 11 isolated communities. Screening surveys have also been carried out for
hereditary diseases and congenital malformations as well as for cardiovascular diseases,
which might be thought of as multi-factorial genetic diseases.
Among these communities, the studies have revealed 58% and 0.0241 as the highest
inbreeding rate and inbreeding index. This tends to indicate that all the members of this
population have, on average, the same degree of genetic similarity as if they were the
off-spring of a common set of great grandparents. Although isolated breaking was abruptly
occurring, some communities revealed, inversely, increased inbreeding. No remarkable
differences in the sib-ship size of inbreeding and non-inbreeding couples were demonstrated.
In some communities, reproductive compensation and inbreeding depression was
demonstrated.
There were clusters of very rare major birth defects, such as
Laurence-Moon-Biedl syndrome, due to increased homozygosity associated with inbreeding
mating, but few inherited anomalies were found.
Each community revealed different gene frequency of polymorphic traits with that of
neighbouring communities owing to geographic isolation inbreeding as well as adaptability to
environmental agents. This might be the result of interaction between the gene and the
environment in isolated communities. In the future, such data will suggest genetic
susceptibility to environmental agents and multifactorial diseases might be possibly prevented
by carefully avoiding exposure to such environmental agents. Hence, there is indication that
such diseases have some threshold for the occurrence of phenotypic abnormalities where
susceptibility to genotypical combinations seem easier.
IV. Discussion
Ethical problems raised by these studies are of four basic types:
1)
2)
3)
4)
free and informed consent: we should have the informed consent of all
concerned individuals, through local authorities;
use of research results: it should in no way harm persons nor result in possible
discrimination against individuals and the population concerned;
return of research results: the results of this non-profit making survey should
be communicated to the population surveyed. If, however, medical use is
made of the research results, they should be returned in an appropriate form,
such as medical treatment and health care system to the individual and
populations concerned;
management of genetic data banks: data is already duplicated in one or two
secondary banks, and access to the bank, method of retrieval, and use, should
be rigorously defined.
Not only for such genetic study in the isolated communities, but also for mass
screening in the working places and infantile mass screening for genetic susceptibility and
inborn error, some carrier screening and pre-symptomatic testing for genetic diseases, has
now became vividly aware of the potential damage from third parties, such as insurance
companies and employers. Ethical problems include balancing the prevention of harmful
genetic diseases against the possibility of discrimination on the work-place through social
stigmatization of carrier, balancing the public health concerns against the right of individuals
and also balancing the right of third parties such as employer's insurance company or relatives
of the family with genetic risks, against the individual right for privacy.
V. Summary
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Future increased ability to identify people genetically at risk for genetic and common
diseases, is accompanied with measures to protect the individual from stigmatization and
misuse of information by a third party. The same applies to the process of genetic screening
on the population basis, as well as to genetic screening on individual levels. Therefore,
medical genetics should assist in public education prior to each new effort for large-scale
genetic screening. The ability to detect relatively unburden some traits and conditions
reopens the inquiry with our ability to distinguish diseases from normalcy and diagnosis of
late nest and contingent conditions necessarily challenges the concept of genetic identity and
determinism as well as biodiversity concept.
Finally we should actively encourage greater public acceptance of variation and
vulnerability.
Acknowledgements
The studies partly supported by research grants of the Ministry of Health and
Welfare (1973-1982), the Ministry of Education (1973-1976, 1982-1983), NIGMS of
USPHS (1962-1967), WHO (1975-1983) and recently the Ministry of Education Human
Genome Research Grant (1991-1993) and several private foundations.