Genetics in MS
Identification of risk factors
in Multiple Sclerosis
By Annette Bang Oturai, MD, PhD
Worldwide, several genome screens in MS have been published without
identification of any major gene(s). From these studies it seems more
likely that about 20 genes with small to moderate genetic effects
are interacting. Large-scale patient materials are needed to identify
these genes.
Through more than 10 years we have collected DNA from 800 Danish MS
patients and 1200 controls and a formal “Danish MS Biobank”
is established in 2006. Material (DNA, mRNA and CSF) in this bank
include among others all patients treated with immune modulating drugs
from whole Denmark.
In order to increase sample size for genetic testing we have participated
in the “Nordic MS Genetic Group” since 1994 and today
the Nordic material consists of 4000 MS cases, 4000 controls, 1000
trio families (one MS patient and both parents), and 177-affected
sib pairs.
From this collaboration several papers have been published, emphasizing
the latest paper finding association to the IL7R published summer
2007 by the Swedish group (Variation in interleukin 7 receptor alpha
chain (IL7R) influences risk of multiple sclerosis. Lundmark F et
al., Nat Genet. 2007). Simultaneous two other large scaled papers
were published showing disease association to the same IL7R snp, as
well to a snp in the IL2R gene. Both receptors are important for the
T cell regulation. These investigations constitute the first replicated
association to MS apart from the HLA-DR2 association found back in
1973, and appears as a break-through.
Since 2000 we have participated in GAMES (Genetic Analysis
of Multiple Sclerosis in EuropeanS).
Through this collaboration we have performed several studies also
during 2006-7:
1) A genome-wide linkage disequilibrium screens in Scandinavian
multiple sclerosis patients using 6000 micro-satellite markers on
pooled DNA. Results revealed several markers associated to MS including
the well-established association of MS to the HLA region on chromosome
6 ( Harbo H et al. A Scandinavian genome-wide linkage disequilibrium
screen in multiple sclerosis indicates association in 13 different
regions, J Neuroimmunity, 2003).
2) A confirmatory study from the Scandinavian and Icelandic
genome-wide linkage disequilibrium screens was then performed, and
we found significant association in the following 5, non-HLA, regions:
2p24, 19q13 (APOE), 3q21, 17q11 (chemokines and myeloperoxidase) and
1p22 (A follow-up study of Nordic multiple sclerosis candidate gene
regions .
Datta P et al., Multiple Sclerosis 2007)
3) Results from the GAMES meta-analysis, which includes 20
European genome-wide linkage disequilibrium screens, implicates JAG1
and POU2AF1 as susceptibility genes in Europeans” (The GAMES
collaborative group, Linkage disequilibrium screening for multiple
sclerosis implicates JAG1 and POU2AF1 as susceptibility genes in Europeans.
J Neuroimmunol. 2006 )
4) Another large scaled GAMES study investigated the clinical
expression in MS families and includes clinical information from more
than 700 families. Results showed concordance for age at onset and
clinical course (the latter only between siblings) (Familial affects
on the clinical course of multiple sclerosis. Hensiek AE, et al. Neurology.
2007).
The GAMES collaboration has February 2008 received grants from
Wellcome Trust Foundation for further genetic analysis.
· Project group:
Annette Oturai, Helle Back Søndergaard, Finn Sellebjerg,
Per Soelberg Sørensen
· Collaborators:
Department of Epidemiological Research, Statens Serum Institut,
Copenhagen, Denmark:
Trine Rasmussen Nielsen, Henrik Hjalgrim
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