Irene M. Yee

Sex ratio of multiple sclerosis in Canada: a longitudinal study

BACKGROUND Incidence of multiple sclerosis is thought to be increasing, but this notion has been difficult to substantiate. In a longitudinal population-based dataset of patients with multiple sclerosis obtained over more than three decades, we did not show a difference in time to diagnosis by sex. We reasoned that if a sex-specific change in incidence was occurring, the female to male sex ratio would serve as a surrogate of incidence change. METHODS Since environmental risk factors seem to act early in life, we calculated sex ratios by birth year in 27 074 Canadian patients with multiple sclerosis identified as part of a longitudinal population-based dataset. FINDINGS The female to male sex ratio by year of birth has been increasing for at least 50 years and now exceeds 3.2:1 in Canada. Year of birth was a significant predictor for sex ratio (p<0.0001, chi(2)=124.4; rank correlation r=0.84). INTERPRETATION The substantial increase in the female to male sex ratio in Canada seems to result from a disproportional increase in incidence of multiple sclerosis in women. This rapid change must have environmental origins even if it is associated with a gene-environment interaction, and implies that a large proportion of multiple sclerosis cases may be preventable in situ. Although the reasons why incidence of the disease is increasing are unknown, there are major implications for health-care provision because lifetime costs of multiple sclerosis exceed pound1 million per case in the UK.

Association of Infectious Mononucleosis with Multiple Sclerosis

Background: Genetic and environmental factors have important roles in multiple sclerosis (MS) susceptibility. Several studies have attempted to correlate exposure to viral illness with the subsequent development of MS. Here in a population-based Canadian cohort, we investigate the relationship between prior clinical infection or vaccination and the risk of MS. Methods: Using the longitudinal Canadian database, 14,362 MS index cases and 7,671 spouse controls were asked about history of measles, mumps, rubella, varicella and infectious mononucleosis as well as details about vaccination with measles, mumps, rubella, hepatitis B and influenza vaccines. Comparisons were made between cases and spouse controls. Results: Spouse controls and stratification by sex appear to correct for ascertainment bias because with a single exception we found no significant differences between cases and controls for all viral exposures and vaccinations. However, 699 cases and 165 controls reported a history of infectious mononucleosis (p < 0.001, corrected odds ratio 2.06, 95% confidence interval 1.71–2.48). Females were more aware of disease history than males (p < 0.001). Conclusions: The data further confirms a reporting distortion between males and females. Historically reported measles, mumps, rubella, varicella and vaccination for hepatitis B, influenza, measles, mumps and rubella are not associated with increased risk of MS later in life. A clinical history of infectious mononucleosis is conspicuously associated with increased MS susceptibility. These findings support studies implicating Epstein-Barr virus in MS disease susceptibility, but a co-association between MS susceptibility and clinically apparent infectious mononucleosis cannot be excluded.

Age at Onset of Multiple Sclerosis May Be Influenced by Place of Residence during Childhood Rather than Ancestry

Multiple sclerosis (MS) most commonly affects individuals of Northern European descent who live in countries at high latitude. The relative contributions of ancestry, country of birth and residence as determinants of MS risk have been studied in adult MS, but have not been explored in the pediatric MS population. In this study, we compare the demographics of pediatric- and adult-onset MS patients cared for in Toronto, Ontario, Canada, a multicultural region. The country of birth, residence during childhood, and ancestry were compared for 44 children and 573 adults. Our results demonstrate that although both the pediatric and adult cohorts were essentially born and raised in the same region of Ontario, Canada, children with MS were more likely to report Caribbean, Asian or Middle Eastern ancestry, and were less likely to have European heritage compared with individuals with adult-onset MS. The difference in ancestry between the pediatric and adult MS cohorts can be explained by two hypotheses: (1) individuals raised in a region of high MS prevalence, but whose ancestors originate from regions in which MS is rare, have an earlier age of MS onset, and (2) the place of residence during childhood, irrespective of ancestry, determines lifetime MS risk – a fact that will be reflected in a change in the demographics of the adult MS cohort in our region as Canadian-raised children of recent immigrants reach the typical age of adult-onset MS.

Age of puberty and the risk of multiple sclerosis: a population based study.

Background and purpose:  Genetic and environmental factors have important roles in multiple sclerosis (MS) susceptibility. Given a potential role for sex hormones in MS, we have investigated whether or not the age of puberty influences the risk of developing MS in a population‐based cohort.

Sex ratio of multiple sclerosis and clinical phenotype.

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.

Nuclear Receptor NR1H3 in Familial Multiple Sclerosis

Multiple sclerosis (MS) is an inflammatory disease characterized by myelin loss and neuronal dysfunction. Despite the aggregation observed in some families, pathogenic mutations have remained elusive. In this study, we describe the identification of NR1H3 p.Arg415Gln in seven MS patients from two multi-incident families presenting severe and progressive disease, with an average age at onset of 34 years. Additionally, association analysis of common variants in NR1H3 identified rs2279238 conferring a 1.35-fold increased risk of developing progressive MS. The p.Arg415Gln position is highly conserved in orthologs and paralogs, and disrupts NR1H3 heterodimerization and transcriptional activation of target genes. Protein expression analysis revealed that mutant NR1H3 (LXRA) alters gene expression profiles, suggesting a disruption in transcriptional regulation as one of the mechanisms underlying MS pathogenesis. Our study indicates that pharmacological activation of LXRA or its targets may lead to effective treatments for the highly debilitating and currently untreatable progressive phase of MS.

Age of Onset in Concordant Twins and Other Relative Pairs With Multiple Sclerosis

The ages of onset in multiple sclerosis cases span more than 7 decades. Data are presented for affected relative pairs from a Canadian population base of 30,000 multiple sclerosis index cases (1993–2008). The effects of genetic sharing, parent of origin, intergenerational versus collinear differences, and gender on the ages of onset were evaluated in the following concordant pairs: monozygotic twins (n = 29), dizygotic twins (n = 10), siblings (n = 614), first cousins (n = 405), half siblings (n = 29), parent/child (n = 285), and aunt/uncle/niece/nephew (avunculars) (n = 289). Fishers z test assessed intraclass correlation (r) for ages of onset. Correlations for monozygotic twins, dizygotic twins, full siblings, and first cousins were 0.60, 0.54, 0.20, and 0.10, respectively. Dizygotic twins resembled monozygotic twins more than siblings. The age-of-onset correlation for maternal half siblings (r = 0.37) was higher than that for paternal half siblings (r = 0.26), consistent with other observations suggesting an intrauterine environmental effect on multiple sclerosis risk. Intergenerational comparisons are complicated by substantial increases of multiple sclerosis incidence over time. Genetic loading (familial vs. sporadic cases) did not generally influence the age of onset, but correlation of age of onset in multiple sclerosis relative pairs was proportional to genetic sharing. A maternal parent-of-origin effect on the age of onset in collinear generations was suggested.

Multiple sclerosis in the Iranian immigrant population of BC, Canada: prevalence and risk factors

Background: There is a well-documented increase in the risk of multiple sclerosis (MS) when migrating from a region of low prevalence to one of high prevalence. Objective: We present here an investigation of MS prevalence and candidate environmental and genetic risk factors among Iranian immigrants to British Columbia (BC), Canada. Methods: MS cases of Iranian ancestry were ascertained from a population-based Canadian study. We collected blood samples for genetic and serological analyses, and administered a personal history questionnaire to the cases. Results: The crude prevalence of MS in this population of Iranian ancestry was 287/100,000 (95% CI: 229 – 356/100,000). MS cases were more likely to have a history of infectious mononucleosis (odds ratio (OR) = 7.5; p = 0.005) and smoking (OR = 17.0; p < 0.0001), as compared to healthy controls from previous studies in Iran. Cases were also more likely than controls to have been born between April and September (OR = 2.1; p = 0.019). Conclusion: The prevalence of MS among Iranian immigrants to Canada is greater than the overall prevalence of MS in Iran by a factor of at least four, and is similar to that recently observed among Iranian immigrants in other western nations. No major genetic susceptibility variants were identified, suggesting the environment in Canada may be what is increasing the risk of MS in this population.

Prevalence of MS in Iranian immigrants to British Columbia, Canada.

Multiple sclerosis (MS) is an inflammatory disease of the central nervous system (CNS) characterized by myelin loss, varying degrees of axonal pathology and progressive neurological dysfunction [6]. The cause of the disease is not yet conclusively understood. We thus read with interest the report of Smestad and colleagues showing that immigrants who relocated from the Middle East to Oslo, Norway had a markedly higher prevalence of MS compared to other migrant groups [10], highlighting the fact that both genetic and environmental factors are important in disease susceptibility [2]. As part of the Canadian Collaborative Project on the Genetic Susceptibility to Multiple Sclerosis (CCPGSMS), 2,673 patients with clinically definite MS residing in British Columbia (BC), Canada were interviewed between 1997 and 2008 [9]. Information on ethnicity and migration was collected to assess risks of those born in ‘‘low’’ to ‘‘moderate’’ risk countries and now residing in the ‘‘high’’ MS risk region of BC [1, 7]. Forty-two Iranian-born MS patients had migrated to BC between 1976 and 2008. The average age of MS onset was 29.5 years of age (range: 12–46 years) and the gender ratio was 2.8 females to 1 male (31 F:11 M). The 42 probands had 82 siblings (all born in Iran), of whom four were affected with clinically definite MS yielding a crude sibling risk of 4.9%. Information on onset age and year of migration to BC was available for thirty-four of the 42 probands (80%). Of these, 18 had onset of symptoms in Iran and 16 had onset in BC. A total of 20,150 Iranians reside in BC (BC Census 2006). The crude prevalence of MS in the group of Iranian migrants with onset in BC was therefore 79/100,000 (95% confidence interval = 41/100,000–118/100,000), similar to the figure of 85/100,000 obtained by Smestad and colleagues [10]. The MS prevalence in Iran is 43/100,000 [8] and thus prevalence in the BC and Oslo patient groups is approximately double. It is likely that Iranians carry MS susceptibility genes (notably HLA-DRB1*15) at a greater frequency than other migrant groups [10] and consanguinity between migrants may elevate risk. However, it is more likely that environmental factors endemic to temperate climes are primarily responsible for substantially increasing background risk to MS. A study of environmental MS risk factors (e.g. sun exposure, Vitamin D [5], Epstein–Barr Virus [4], smoking [3]) in Iranian migrants is C. Guimond M. Criscuoli I. M. Yee A. D. Sadovnick Department of Medical Genetics, University of British Columbia, Vancouver, Canada

No effect of birth weight on the risk of multiple sclerosis. A population-based study.

Background: Genetic and environmental factors have important roles in multiple sclerosis (MS) susceptibility. A clear maternal effect has been shown in several population-based studies. This parent-of-origin effect could result from factors operating during gestation. It has been shown that a low birth weight increases the risk of several adult-onset diseases. In a population-based Canadian cohort, we investigated whether there is any difference in birth weight for MS index cases compared to spousal controls. Methods: Using the longitudinal Canadian database, we identified 6,188 MS index cases and 1,640 spousal controls with birth weight information. Additionally, data were available on 164 discordant MS twins. The birth weight was compared between index cases and controls as well as for twin pairs. Results: When stratifying by sex, no significant difference in birth weight was found (average female index case birth weight = 7.23 pounds, average female control birth weight = 7.19 pounds, p = 0.48; average male index case birth weight = 7.56 pounds, average male control birth weight = 7.55 pounds, p = 0.92). Furthermore, there was no difference in birth weight between affected and unaffected twins (average affected twin weight = 5.46 pounds, average unaffected twin weight = 5.44 pounds, p =0.85). Conclusions: The maternal effect in MS aetiology does not appear to act through a route that has an influence on birth weight. As birth weight is a relatively poor marker of fetal development, other factors involved in fetal and early development need to be explored to elucidate the mechanism of the increased MS risk conferred maternally.