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Background and purpose: In a longitudinal population-based dataset of patients with multiple sclerosis (MS), we have previously observed a substantial increase in the female to male sex ratio in Canada over the last 50 years. Here, we aimed to determine whether this change in sex ratio is related to the clinical course of MS. Methods: We calculated sex ratios by birth year in 11 868 patients with relapsing–remitting (RR) MS and 2825 patients with primary progressive (PP) MS identified as part of the Canadian Collaborative Project on the Genetic Susceptibility to MS. Results: Year of birth was a significant predictor for sex ratio in RR MS ( P < 0.0001, χ2 = 21.2; Spearman’s rank correlation r = 0.67), but not for PP MS ( P = 0.44, χ2 = 0.6; Spearman’s rank correlation r = 0.11). Conclusions: An increase in the number of female RR MS patients over time accounts for the increasing sex ratio of MS. This has implications for pathogenesis, for assessment of clinical trial results and for disease prevention. The factors underlying the selective increase in MS in females need to be uncovered. [ABSTRACT FROM AUTHOR]

Background: The ratio of female to male (F:M) multiple sclerosis (MS) cases varies geographically, generally being greater in areas of high prevalence. In many regions, including Canada, rising MS incidence in women has been implied by the marked increase in F:M ratio., Methods: We examined the F:M ratio over time in MS patients in the Canadian Collaborative Study born outside Canada, with onset postmigration (n = 2531). We compared the trends to native-born Canadians, by region of origin and age at migration., Results: Regression analysis showed that year of birth (YOB) was a significant predictor of sex ratio in immigrants (chi(2) = 21.4, p<0.001 correlation r = 0.61). The rate of change in sex ratio was increasing in all migrant subgroups (by a factor of 1.16 per 10-year period, p<0.001), with the steepest increase observed in those from Southern Europe (1.27/10 years, p<0.001). The overall immigrant F:M ratio was 2.17, but varied by country of origin. It was significantly lower in migrants from Southern Europe compared with Northern Europe or USA (1.89 vs 2.14 and 2.86, p = 0.023 and p = 0.0003, respectively). Increasing age at immigration was associated with decreasing sex ratio (p = 0.041). The sex ratio of individuals migrating <21 was significantly higher than those migrating > or =21 (2.79 vs 1.96, p = 0.004)., Conclusions: MS sex ratio in immigrants to Canada is increasing but variable by region of origin and influenced by age at migration. The findings highlight the importance of environmental effect(s) in MS risk, which are likely gender-specific.

Background: Multiple sclerosis (MS) is a complex neurologic disease with a striking geographical distribution. In Canada, prevalence is high in Caucasians of Northern European ancestry and uncommon in North American Aboriginals, many of whom now have Caucasian admixture., Methods: The population-based Canadian Collaborative Project on the Genetic Susceptibility to MS provided the characteristics of 58 individuals with 1 Caucasian and 1 North American Aboriginal parent from a database of 30,000 MS index cases., Results: We found that MS index cases with a Caucasian mother and a North American Aboriginal father had a higher sib recurrence risk and greater F:M sex ratio (p = 0.043) than patients with a North American Aboriginal mother and Caucasian father., Conclusions: Maternal parent-of-origin effects in multiple sclerosis disease etiology previously seen in studies of half-siblings and avuncular pairs are also seen in Caucasian-North American Aboriginal admixture matings and warrant further investigation. A differential influence of maternal risk transmission on the sex ratio of affected offspring is implied. The method of analysis used may have broader implications for detection of parent-of-origin effects in admixture cohorts.

HLA-DRB1 is the major locus associated with risk for multiple sclerosis (MS). A recent genome-wide study showed three additional single-nucleotide polymorphisms (SNPs), within the IL2RA and IL7RA genes respectively, also to be associated with MS. Consistent association but lower significance was found for 13 other SNPs. In this study, we aimed to verify association of these SNPs with MS in 46 MS patients and 194 controls from a Dutch genetically isolated population. Apart from the human leukocyte antigen locus, the EVI5 gene on chromosome 1 was confirmed as a novel risk gene, with odds ratios (ORs) even higher than those from the MS Consortium (ORs 2.01 and 1.9; P=0.01). The risk effect of EVI5 was further validated for the general MS population in an independent set of 1318 MS patients from the Canadian Collaborative Project on the Genetic Susceptibility to MS. On the basis of the transmission disequilibrium testing, a weak but significant risk effect was observed (OR 1.15; P=0.03 and OR 1.15; P=0.04). This study confirms EVI5 as another risk locus for MS; however, much of the genetic basis of MS remains unidentified.

Objective: Genetic and environmental factors have important roles in multiple sclerosis (MS) susceptibility. The precise nature of these factors and mode of inheritance remains unknown. A female predominance is universally found. Recently, offspring of affected fathers were reported to be more likely to have MS than those of affected mothers. This was attributed to the Carter effect, which is seen in polygenic disorders. The Carter effect predicts that affected parents of the sex lesser affected by a disease/trait are more genetically loaded for risk alleles and thus transmit these more often to their offspring. This hypothesis was tested in a population-based Canadian MS cohort., Methods: Using the longitudinal Canadian database, we identified 3,088 nuclear families with one affected parent and a total of 8,401 offspring, of which 798 had MS. Transmission to daughters and sons from affected mothers and fathers was compared., Results: There was equal transmission of MS from affected fathers vs affected mothers (9.41% vs 9.76%). Stratifying by gender of affected parent there were no differences in the female:male sex ratio of affected (2.46% vs 2.41%, p = 0.88) or unaffected offspring (0.91% vs 0.95%, p = 0.46)., Conclusions: We observed equal disease transmission to offspring from affected mothers and affected fathers, no difference in the female:male sex ratio of affected offspring, and previously no difference in sibling recurrence risk by gender of parent affected. These findings show no evidence for the Carter effect and do not support the hypothesis of polygenic inheritance of multiple sclerosis susceptibility by parent.