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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=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.

Objective: To investigate the psychometric properties of the Multiple Sclerosis Impact Scale (MSIS-29) and to assess the relationship between the Kurtzke Expanded Disability Status Scale and the physical and psychological parts of this score., Methods: A population-based study identified cases with definite multiple sclerosis (MS) in the north-east region of Ireland. They were examined and completed the MSIS-29. Cases were classified as mild (Expanded Disability Status Score (EDSS) 0-3.0), moderate (EDSS 3.5-5.5), or severe (6.0-9.5) MS., Results: The 248 participants (82 male, 166 female) had a mean age of 49.1 years (SD 12.4). EDSS ranged from 0 to 9.5 (median 6.0). Data quality was excellent (0.02% missing data), physical and psychological scores spanned the entire range with low floor and ceiling effects. Internal consistency was high (Cronbach's alpha 0.97 - physical score, 0.93 - psychological score). The convergent validity of the physical impact score of the MSIS-29 with the Kurtzke EDSS was confirmed with a high Spearman's rank coefficient correlation of 0.63 (P = 0.01). Physical impact scores for mild, moderate, and severe disability as were statistically different at 25.9%, 48.0%, and 63.9%, respectively. Mean psychological score was non-significantly higher in the moderately disabled group at 47.4% compared with the severely disabled at 44.3% (P = 0.58)., Conclusions: The MSIS-29 is an acceptable, reliable, and valid method of recording quality of life. A significant relationship between higher physical impact scores of the MSIS-29 and higher Kurtzke EDSS values suggests that is may be of use in clinical trials to monitor progression.