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Re: "Genetics versus enviroment controversy in IDDM ..."

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INSÄNT AV Fortsättning ... DEN 18 :e JANUARI, 1997 vid 21 - tiden

SOM REPLIK PÅ: "Genetics versus enviroment controversy in IDDM ..." INSÄNT AV Red DiabetologNytt DEN 17 :e JANUARI, 1997 vid 22 - tiden

Genes versus environment in
insulin-dependent diabetes: the phoney
war

Insulin-dependent diabetes (IDDM) has been described in all racial
groups but its incidence varies almost 60 fold between countries.1
The extent to which the variation in incidence reflects differences in
genetic susceptibility or environmental influences has long been
controversial.

The Mediterranean island of Sardinia has the second highest
incidence of childhood-onset IDDM in the world (30·2 per 100 000
per year). This ranking is in striking contrast to the low incidence
(6·5) in Lazio, a region of neighbouring mainland Italy, and to the
general trend in Europe of a reducing incidence of IDDM as one
moves South from Scandinavia. In this issue Muntoni and
colleagues examine whether this difference in incidence reflects
differences in genetic predisposition or the environment in Sardinia.
They report that the incidence of IDDM in children born in Lazio to
parents of Sardinian origin was fourfold higher than the incidence in
children born to parents from mainland Italy. Children with one
parent of Sardinian origin had intermediate risk. The numbers are
small, so confidence limits are wide, but the findings support
genetic factors being more important than environmental factors in
determining the high incidence of diabetes in Sardinia.

The genetics of IDDM are the best delineated of all polygenic
conditions. The MHC HLA region is the major locus, contributing
about 35% to genetic susceptibility, but at least 12 other loci have
been identified.2,3 The variation in incidence of diabetes between
races can be explained, at least in part, by variation in the incidence
of high-risk genotypes.4 There is a high prevalence of predisposing
HLA haplotypes in Sardinia.5

Many of the epidemiological features in IDDM cannot be explained
by genetic variation, hence it is dangerous to assume a "dominance"
of genetics over the environment. Identical twins of patients with
IDDM have the same genetic predisposition as the patient, but,
despite usually being bought up in the same surroundings, only
30-50% will develop IDDM. The seasonal variation in incidence and
the recent rapid increase in the incidence of young-onset IDDM most
likely reflect environmental changes.6

In contrast to the progress in the understanding of the genetics of
IDDM, the critical environmental factors that trigger and maintain the
initial autoimmune attack against the ß-cell remain elusive. Although
viruses and cow's milk albumin have been accused on the basis of
epidemiological evidence, the Scottish legal verdict of "not proven"
is the only fair one at present.6 The study of environmental factors
involved in IDDM is difficult. In-depth study of the environment of
children at diagnosis is unlikely to be helpful: longitudinal studies of
first-degree relatives have shown that autoantibodies and ß-cell
dysfunction may be present at least 5 years before diagnosis. The
delineation of the crucial components in the environment that initiate
the autoimmune insulitis and result in continuing ß-cell destruction
will require careful longitudinal studies from birth of large cohorts
of at-risk individuals. The size of these studies will make them
logistically difficult and expensive. A further problem is that results
in one country or population may not be generally applicable.
However, if primary prevention is to become a reality in IDDM this
work is vital.

It is interesting to contrast IDDM with maturity-onset diabetes of the
young (MODY), an unusual subgroup of non-insulin dependent
diabetes usually diagnosed before age 25. MODY is an autosomal
dominant, single-gene disorder and is a rare example of diabetes
where environmental influences are relatively unimportant. In most
families diabetes results from mutations in the recently described
hepatic nuclear factor 1 (HNF1) gene.8,9 These mutations result
in diabetes in many racial groups from varied environments, and
protective environmental features have not been described. The high
penetrance of HNF1 means that prediction of diabetes by genetic
testing is over 90% accurate, but it also means that prevention of
diabetes by environmental manipulation is likely to have limited
success. By contrast, in IDDM prediction of diabetes by genetic
testing is unlikely to be more than 30% accurate, but there is greater
chance of reducing the incidence of the disease if the environmental
precipitants can be identified and avoided.

Ultimately the role of genes and environment in IDDM will be
judged by their clinical usefulness. Genetic analysis will need to
identify reliably individuals who are genetically at risk. Our
understanding of the environmental factors will need to allow
changes in the environment of these at-risk individuals to reduce
their likelihood of developing diabetes. The ultimate aim of work on
the aetiology of IDDM is not to establish a superiority of genes or
environment but to develop their dual role in disease prevention.
Andrew T Hattersley

Department of Vascular Medicine and Diabetes Research,
Postgraduate Medical School, Exeter EX2 5AX, UK

1 Karvonen M, Tuomilehto J, Libman I, LaPorte R. A review of the
recent epidemiological data on the worldwide incidence of type 1
(insulin-dependent) diabetes mellitus. Diabetologia 1993; 36:
883-92.

2 Davies JL, Kawaguchi Y, Bennett ST, et al. A genome-wide
search for human type 1 diabetes susceptibility genes. Nature 1994;
371: 130-36.

3 Todd JA. Genetic analysis of type 1 diabetes using whole genome
approaches. Proc Natl Acad Sci USA 1995; 92: 8560-65.

4 Dorman JS, LaPorte RE, Stone RA, Trucco M. Worldwide
differences in the incidence of type 1 diabetes are associated with
amino acid variation at position 57 of the HLA-DQ beta-chain. Proc
Natl Acad Sci USA 1990; 87: 7370-74.

5 Cucca F, Muntoni F, Lampis R, et al. Combinations of specific
DRB1, DQA1, DQB1 haplotypes are associated with
insulin-dependent diabetes mellitus in Sardinia. Hum Immunol
1993; 37: 85-94.

6 Lounamaa R. Epidemiology of childhood-onset IDDM. Bailliere's
Clin Paediatr 1996; 4: 609-26.

7 Yamagata K, Oda N, Kaisaki PJ et al. Mutations in the hepatic
nuclear factor 1 alpha gene in maturity-onset diabetes of the young
(MODY3). Nature 1996; 384: 455-58.

8 Frayling T, Bulman M, Ellard S, et al. Mutations in the hepatocyte
nuclear factor 1 alpha gene are a common cause of maturity-onset
diabetes of the young in the United Kingdom. Diabetes (in press).