Genetics of Autoimmune Diseases

There is no organ in the body or there is an autoimmunity against it. These
diseases have in common that in the blood autoantibodies are present. There are
hundreds of different autoimmune disease, and some examples are:
Graves-Basedow en Hashimoto, Addison, Rheumatoid Arthritis, Myasthenia,
Lambert-Eaton , Systemic Lupus Erythematosus, Type 1 Diabetes, and Celiac
disease. Every disease is specified by specific reaction to anitgens. For
example, in Type 1Diabetes the defense system is directed against the insulin
producing beta-cells of the Islets of Langerhans in the pancreas. This
autoreactivity eventually leads to distruction of these cells and impaired
functionality.
Despite lots of research it is unknown what the exact cause of AID is. In
general it is assumed that it is an interplay between genetic and environmental
factors.

From families and twin research it has become clear that the contribution of
the hereditary component is between 15 and 70%, depending on the specific
sickness, and that the inheritance is complex, i.e. the risk for AID is
confered by an interplay between environmental and genetic factors. Indeed in
the previous years some important genetic factors for AID have been identified.
For nearly all AID, the major histocompatibility complex (MHC) on chromosome
6p21.3 has been shown the area in genome which consistently shows the highest
association. The contribution of the MHC to the total genetic impact varies by
AID, but explains for example for T1D and Celiac about 40% of heredity. It are
mainly allelische variaties of DQB1 and DRB1 the haplotype, which are
responsible for genetic risk. Sometimes the same DQB1-DRB1 haplotype has been
associated in several AID, for example DQB1*02-DRB1*03 the haplotype have been
associated with an increased risk for type of 1 diabetes, Celiac and Rheumatoid
Arthritis. By large-scale association studies a number of other gene variants
have been identified. A characteristic of these risk factors is that they give
a relatively moderately raised risk for sickness. Because of the low risk
expected for these risk factors it is to detect them. This is illustrated by
the large number of studies for which an association between AID is reported,
but that cannot be confirmed consistent by other studies. Such low risk factors
require a relatively large cohort of patients and controls to be able to
successful detect the relative low marginal effect.

The genen which are so far found explain only one part of heredity/complex
genetic context of AIZ. Since AIZ are a complex genetic sickness, can be
adopted that genen still more will show an association with this sickness. Such
as said detection of new genen is difficult by the lack of sufficient patients
and controls association of certain candidate or genomische order show genen.

The research strives for a large group of homogeneous AID patients, so that a
powerful association study can be performed to detect genetic risk factors.
These factors can be shared by several AIZ, or be specific is for a single AID.
The aim of this study is the identification of those genetic variants that
confer susceptibility of AID.

Despite years of research, a lot of candidate genes have not been sufficiently
examined. Large genome-wide association studies are undertaken at this moment
by other study groups in United Kingdom and America. These studies will report
according to the expectations several associations which must be tested for
their validity in the Dutch population. For this reason, we will collect a
large group of minimally 500 Dutch AID patients, which can be used with
controls already availlable for Case-Control study. The group size is
determined by power-calculation; with these numbers it is possible with more
than 80% probability that genetic factors are found which have a relative risk
of 1.5 or more.

Single venapunture with neglactable risk.