Association of Genetic Markers with CSF Oligoclonal Bands in Multiple Sclerosis Patients

OBJECTIVE: to explore the association between genetic markers and Oligoclonal Bands (OCB) in the Cerebro Spinal Fluid (CSF) of Italian Multiple Sclerosis patients. METHODS: We genotyped 1115 Italian patients for HLA-DRB1*15 and HLA-A*02. In a subset of 925 patients we tested association with 52 non-HLA SNPs associated with MS susceptibility and we calculated a weighted Genetic Risk Score. Finally, we performed a Genome Wide Association Study (GWAS) with OCB status on a subset of 562 patients. The best associated SNPs of the Italian GWAS were replicated in silico in Scandinavian and Belgian populations, and meta-analyzed. RESULTS: HLA-DRB1*15 is associated with OCB+: p\u200a=\u200a0.03, Odds Ratio (OR)\u200a=\u200a1.6, 95% Confidence Limits (CL)\u200a=\u200a1.1-2.4. None of the 52 non-HLA MS susceptibility loci was associated with OCB, except one SNP (rs2546890) near IL12B gene (OR: 1.45; 1.09-1.92). The weighted Genetic Risk Score mean was significantly (p\u200a=\u200a0.0008) higher in OCB+ (7.668) than in OCB- (7.412) patients. After meta-analysis on the three datasets (Italian, Scandinavian and Belgian) for the best associated signals resulted from the Italian GWAS, the strongest signal was a SNP (rs9320598) on chromosome 6q (p\u200a=\u200a9.4 710(-7)) outside the HLA region (65 Mb). DISCUSSION: genetic factors predispose to the development of OCB

The relationship between body size and the risk of multiple sclerosis. The EnvIMS study

Introduction: Two recent studies from Canada and Sweden have shown that a large body size around 18-20 years may increase the risk of Multiple Sclerosis (MS), suggestive of a possible effect of reduced circulating levels of vitamin D in overweight individuals. We assessed this association in a large multinational case-control study (EnvIMS). Methods: A population based sample of 959 cases (286 men, 673 women) and 1718 controls (462 men, 1256 women) in Norway and 732 cases (261 men, 471 women) and 1439 controls (471 men, 968 women) in Italy reported their body size using body silhouettes ranging from 1 to 9 where 9 represents the largest. Body sizes at age (in years) 5, 10, 15, 25, 30 and current age (after onset of disease for MS cases) were reported. Self-report of body size was validated against current body mass index. We analyzed men and women separately and compared the cases to controls with independent samples t-test and logistic regression, using body size 3 as a reference group and smoking and education as co-variates. Results: In Norway cases reported a larger average body size between age 5 and 30, being significant from age 15 to 25 among men and age 10 to 25 among women. In Italy cases reported a slightly larger, non-significant, average body size up to 20 years among men and 25 years among women. Interestingly, at current age cases in general had a lower average body size compared with controls in both countries. In Norway we found that a large body size (silhouettes 6-9) at age 25 was associated with an increased risk for MS [men: OR=2.20 (95% CI: 1.14-4.24, p-trend=0.003), women: OR=1.62 (95% CI 1.04-2.53, p-trend=0.0005)]. The corresponding results at age 20 were OR=1.55 (95% CI: 0.71-3.36, p-trend=0.001) for men and OR=1.16 (95% CI: 0.72-1.88, p-trend=0.01) for women. No significant trend was found in Italy. Adjustment for smoking and education did not materially change the results. In both countries we found a protective effect for the slimmest body sizes (1-2) compared with body size 3 in all age groups (5-30). Conclusions: Our analyses show that factors related to a large body size, particularly around 20-25 years, seem to be a risk factor for MS in Norway, but less so in Italy. These results are compatible with low circulating vitamin D or a chronic inflammatory state in overweight individuals. The difference between the countries might be related to protection through higher sun exposure in Italy

Familial effects on the clinical course of multiple sclerosis

BACKGROUND: Familial factors influence susceptibility to multiple sclerosis (MS) but it is unknown whether there are additional effects on the natural history of the disease. METHOD: We evaluated 1,083 families with > or = 2 first-degree relatives with MS for concordance of age at onset, clinical course, and disease severity and investigated transmission patterns of these clinical features in affected parent-child pairs. RESULTS: There is concordance for age at onset for all families (correlation coefficient 0.14; p < 0.001), as well as for affected siblings (correlation coefficient 0.15; p < 0.001), and affected parent-child pairs (correlation coefficient 0.12; p = 0.03) when each is evaluated separately. Concordance for year of onset is present among affected siblings (correlation coefficient 0.18; p < 0.001) but not the parent-child group (correlation coefficient 0.08; p = 0.15). The clinical course is similar between siblings (kappa 0.12; p < 0.001) but not affected parents and their children (kappa -0.04; p = 0.09). This influence on the natural history is present in all clinical subgroups of relapsing-remitting, and primary and secondary progressive MS, reflecting a familial effect on episodic and progressive phases of the disease. There is no concordance for disease severity within any of the considered family groups (correlation coefficients: all families analyzed together, 0.02, p = 0.53; affected sibling group, 0.02, p = 0.61; affected parent-child group, 0.02, p = 0.69). Furthermore, there are no apparent transmission patterns of any of the investigated clinical features in affected parent-child pairs and no evidence for anticipation or effects of genetic loading. CONCLUSION: Familial factors do not significantly affect eventual disease severity. However, they increase the probability of a progressive clinical course, either from onset or after a phase of relapsing remitting disease. The familial effect is more likely to reflect genetic than environmental conditions. The results are relevant for counseling patients and have implications for the design of studies seeking to identify factors that influence the natural history of the disease