If you or someone in your family has Type 1 diabetes,
you may wonder if other family members are at risk.
It turns out that Type 1 diabetes does often run in
families. In fact, researchers have found nearly 20
that can affect your risk for developing diabetes.
of the best studied genes in Type 1 diabetes are the
HLA region and the insulin gene. Although many more
Type 1 diabetes genes exist, we will focus on these
two because of their central role in the disease. (For
recent news about the genetics of Type 1 diabetes, see
Related News below.)
The HLA (human leukocyte antigen) region is a section of a chromosome that contains several genes that are involved in how the immune system works. These genes make proteins that dot the surface of some cells
in the immune system. These proteins are important in order for the immune system to distinguish between its own cells and an infectious agent, such as a bacteria or virus. When this system fails, the immune cells attack other cells of the body (such as pancreas cells) in a process called an autoimmune reaction.
There are at least two genes in the HLA region that account for 40 to 50 percent of the diabetes risk that people inherit from their parents. Different versions (or alleles) of these genes can put a person at risk for or prevent them from developing Type 1 diabetes. One gene in the HLA region that plays an important role in diabetes is called DR. People can inherit one form of DR from their mother and one form of DR from their father. It's the combination of these two forms of the gene that determine a person's overall risk.
Two forms of DR, designated DR3 and DR4, are present in 95 percent of Type 1 diabetics, and 30 percent have inherited both DR3 and DR4. This is in contrast with the general population, where only 50 percent of people have DR3 or DR4 and 1 to 3 percent have both.
both DR3 and DR4 alleles put a person at risk for developing
diabetes, the two alleles cause slight differences in
gene in the HLA region, called DQ, also contributes to
the development of Type 1 diabetes. Like DR, certain versions
of the DQ gene put a person at higher risk for developing
the disease, while other forms seem to be protective.
To make matters worse, people who inherit DR3 or DR4 also
tend to inherit a form
of DQ that adds to their risk of developing diabetes.
protective forms of DQ and DR tend to be inherited together.
In fact, these DQ alleles may be responsible (in part)
for the risk or prevention reported for the different
who have inherited DR3 (but not DR4) develop diabetes
at an older age, and tend to have antibodies
against pancreatic beta cells but not against insulin.
These people are also more likely to develop thyroid
who have inherited DR4 (but not DR3) tend to develop
diabetes earlier in life and have an immune reaction
who inherit both DR3 and DR4 develop diabetes
at the youngest age and have the highest levels of
antibodies against insulin.
The insulin gene is the region of DNA that codes for the protein insulin. Changes in DNA
near the insulin gene seem to influence a person's susceptibility
to diabetes. This region, which is different lengths
in different people, determines how much insulin the
gene makes. It is composed of a repeated section of
DNA called the Variable Number of Tandem Repeats (VNTR).
Smaller VNTR regions contain only 26 to 63 DNA repeats,
while long regions contain 140 to 200 repeats. If a
person inherits two short VNTR regions, they are two
to five times more likely to develop Type 1 diabetes
than a person with at least one long VNTR.
(protective) VNTR region seems to decrease the amount
of insulin produced in the pancreas. This finding may
seem contradictory, because the longer VNTR also protects
a person from developing diabetes. However, researchers
have found that insulin is produced in the thymus during
development. (The thymus is also where many cells in
the immune system develop). During this time, the longer
VNTR causes more insulin to be produced. Researchers
think that when developing immune cells are exposed
to high levels of insulin, they learn to identify insulin
and are less likely to react against it and cause diabetes
later in life.
patterns of Type 1 diabetes are complicated, with many
different genes influencing a person's risk. Because
of this array of genes, Type 1 diabetes is not inherited
in a clearly dominant
manner. Instead, a person may have one gene that increases
their risk (a DR3 or DR4 allele, for example) and other
genes that decrease their risk (a long VNTR region).
Together, these 20 genes along with environmental factors
determine a person's overall risk for developing diabetes.
With so many
variables to consider, researchers are still a long
way from a genetic test for Type
1 diabetes. Two hurdles to developing a genetic test
have not yet identified all the gene mutations that
put a person at risk for Type 1 diabetes. Even
if they did know all of the mutations, researchers
find that people with low risk genes (DR2, DR5, or
long VNTR regions) can still develop diabetes, so
a genetic test might identify people as negative who
eventually go on to develop diabetes.
if a genetic test reveals that a person is at high
risk, doctors have no course of action for preventing
diabetes. Instead, the test may simply add stress
to the family and create health insurance problems,
while still not improving the person's health.
At this time,
knowing a child's genetic risk does not change how doctors
treat the disease. For this reason, the American Diabetes
Association recommends screening children for diabetes
risk (HLA type and the presence of antibodies) only
if the child satisfies the following criteria:
- The child
has a parent or sibling with Type 1 diabetes.
- The child
intends to enter a diabetes prevention study that
requires this information.
J. A., et al. (1996). The role of HLA class II genes
in insulin-dependent diabetes mellitus: molecular analysis
of 180 Caucasian, multiplex families. Am J Hum Genet,
Dorman, J., et al., (1999). Risk Factors for Insulin-Dependent
Diabetes. In (Ed. 2nd), Diabetes in America (pp. 165-178).
Bethesda, MD: National Diabetes Data Group, NIH.
Dubois-Laforgue, D., et al. (1997). Insulin-dependent
diabetes mellitus in non-DR3/non-DR4 subjects. Hum
Immunol, 57, 104-109.
Owerbach, D. and Gabbay, K. H. (1993). Localization
of a type I diabetes susceptibility locus to the variable
tandem repeat region flanking the insulin gene. Diabetes,
Bennett, S. T., et al. (1995). Susceptibility to human
type 1 diabetes at IDDM2 is determined by tandem repeat
variation at the insulin gene minisatellite locus [see
comments]. Nat Genet, 9, 284-292.