An investigation of susceptibility loci in benign, aggressive and primary progressive multiple sclerosis in Northern Irish population.
OBJECTIVE
To investigate the possibility that susceptibility loci in multiple sclerosis (MS) have a role in determining the disease outcome in Northern Ireland population.


BACKGROUND
The Genetic Analysis of Multiple Sclerosis in Europeans (GAMES) initiative and follow-up refined analysis identified 15 candidate susceptibility loci within the Northern Irish population for MS. We aimed to investigate the 12 most significant markers for their role in disease outcome.


METHODS
Cases with probable or definite MS (Poser criteria) were classified as benign onset (Kurtzke Expanded Disability Status Scale [EDSS]<or=3.0 at 10 years), aggressive (Kurtzke EDSS>or=6.0 by 10 years), or primary progressive MS. All cases were Caucasian of Northern Irish origin. DNA was extracted from venous blood, microsatellite markers were amplified using polymerase chain reaction and typed using fluorescent fragment analysis. Allele frequencies were compared statistically using a chi-squared test with allowance for multiple comparisons (critical P<0.0042); significant markers were further analyzed by CLUMP (critical P<0.0014).


RESULTS
Two microsatellite markers were significant: D3S1278 (Chr 3q13, P<0.001) and tumor necrosis factor (TNF)-alpha (Chr 6p21, P<0.001). A further three markers were significant in our preliminary analysis suggesting a trend toward impact on disease outcome; D4S432 (Chr 4p16, P=0.001), D2S347 (Chr 2q14, P=0.003), and D19S903 (Chr 19p13, P=0.003).


CONCLUSIONS
This is the first study to suggest a role for TNF-alpha in the disease outcome in MS. Larger replication studies need to be performed to assess the role of markers D4S432, D2S347, and D19S903.
Gray
O M
OM
Department of Neurology, Royal Victoria Hospital, and Epidemiology Research Group, Queen's University, Grosvenor Road, Belfast, N. Ireland. BT12 6BA. orlagray@hotmail.com
Abdeen
H
H
McDonnell
G V
GV
Patterson
C C
CC
Graham
C A
CA
Hawkins
S A
SA
D000328:Adult; D000483:Alleles; D005260:Female; D005819:Genetic Markers; D020022:Genetic Predisposition to Disease / Q000453:epidemiology; D006801:Humans; D008297:Male; D018895:Microsatellite Repeats; D008875:Middle Aged; D020528:Multiple Sclerosis, Chronic Progressive / Q000453:epidemiology* / Q000235:genetics*; D020529:Multiple Sclerosis, Relapsing-Remitting / Q000453:epidemiology* / Q000235:genetics*; D009660:Northern Ireland / Q000453:epidemiology; D011237:Predictive Value of Tests; D012720:Severity of Illness Index
D005819:Genetic Markers