An investigation of susceptibility loci in benign, aggressive and primary progressive multiple sclerosis in Northern Irish population

Abstract

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] ≤ 3.0 at 10 years), aggressive (Kurtzke EDSS ≥ 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)-α (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-α in the disease outcome in MS. Larger replication studies need to be performed to assess the role of markers D4S432, D2S347, and D19S903.

Identity-by-descent mapping in a Scandinavian multiple sclerosis cohort

“…Already in 2005, a linkage peak for MS was reported in 19p13 that acted independently from the HLA locus; 24 however, it is not specified as to where on 19p13 this effect was seen. In a paper in 2009, a microsatellite marker on 19p13 was associated to disease outcome, 25 but upon our inspection in a later build of the genome reference, it appears that this marker is more likely to reside at 19q13, an area with several published associations from both linkage and association analysis. 26 , 27 , 28 , 29 Thus, there is weak prior evidence for an importance of this locus in MS.…”

Gene variants of adhesion molecules act as modifiers of disease severity in MS

“…1–3 The majority of genetic studies have focused on susceptibility variants, and this effort has yielded more than 110 genetic risk factors of MS. 4 In addition, there is evidence that genetic factors may influence disease phenotype such as age at onset, disease severity, and the clinical course. 5–7 However, 3 genome-wide association studies (GWASs) investigating MS severity have failed to reach a genome-wide significance threshold. 8–10 A recent meta-analysis of 10 cohorts in 7,125 patients with MS also failed to detect any significant signal.…”

Original article Charcot-Marie-Tooth type 1C disease coexisting with progressive multiple sclerosis: a study of an overlapping syndrome

“…The published results are conflicting. Grey et al suggested a role of TNF-α in the outcome of multiple sclerosis [5]. The results of the association of MS with DRB1*15(2) and TNF-α in the Russian population, reported by Favorova et al indicate the interplay of three loci in susceptibility to multiple sclerosis [3].…”