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Objective: To evaluate the impact of temporal increase of female to male (F:M) sex ratio for persons with multiple sclerosis (MS) on the familial risk (empiric recurrence risks or RRs) for biological relatives of affected individuals. Methods: Detailed family histories were systematically obtained from people with MS attending the University of British Columbia Hospital MS Clinic. The study cohort was born in 1970 or more recently. Data were collected from 1 September 2015 to 31 January 2019. The study was designed to allow only one proband per family. Age-corrected RRs for biological relatives of probands were calculated based on a modification of the maximum-likelihood approach. Results: Data analyses were possible for 746 unique probands (531 females; 215 males) and 19,585 of their biological relatives. RRs were temporally impacted. Conclusion: Both genetic sharing and environmental factors are important in determining RRs. It appears that there is an increase in MS risk due to environmental factors in later life (i.e. not shared family environment). Environmental exposures in genetically predisposed individuals might be driving the MS risk. The increase in F:M ratio of RRs for sisters/brothers of female probands over time is likely due to environmental differences. [ABSTRACT FROM AUTHOR]

Abstract Background There is a strong maternal parent-of-origin effect in determining susceptibility to multiple sclerosis (MS). One hypothesis is that an abnormal intrauterine milieu leading to impaired fetal development could plausibly also result in increased susceptibility to MS. A possible marker for this intrauterine insult is the presence of a non-fatal congenital anomaly. Methods We investigated whether or not congenital anomalies are associated with MS in a population-based cohort. We identified 7063 MS index cases and 2655 spousal controls with congenital anomaly information from the Canadian Collaborative Project on Genetic Susceptibility to MS (CCPGSMS). Results The frequency of congential anomalies were compared between index cases and controls. No significant differences were found. Conclusions Congenital anomalies thus do not appear to be associated with MS. However, we did not have complete data on types and severity of congenital anomalies or on maternal birth history and thus this study should be regarded as preliminary.

Abstract Background Genetic and environmental factors have important roles in multiple sclerosis (MS) susceptibility. A clear parent of origin effect has been shown in several populations, perhaps resulting from factors operating during gestation. Preterm birth (birth at less than 37 weeks gestational age) has been shown to result in long-term health problems, including impaired neurological development. Here, in a population-based cohort, we investigate whether preterm birth increases the risk to subsequently develop MS. Methods We identified 6585 MS index cases and 2509 spousal controls with preterm birth information from the Canadian Collaborative Project on Genetic Susceptibility to MS. Rates of individuals born preterm were compared for index cases and controls. Results There were no significant differences between cases and controls with respect to preterm births. 370 (5.6%) MS index cases and 130 (5.2%) spousal controls were born preterm, p = 0.41. Conclusion Preterm birth does not appear to contribute to MS aetiology. Other factors involved in foetal and early development need to be explored to elucidate the mechanism of the increased risk conferred by the apparent maternal effect.

Genetic variants in the purinergic receptors P2RX4 and P2RX7 have been shown to affect susceptibility to multiple sclerosis (MS). In this study, we set out to evaluate whether rare coding variants of major effect could also be identified in these purinergic receptors. Sequencing analysis of P2RX4 and P2RX7 in 193 MS patients and 100 controls led to the identification of a rare three variant haplotype ( P2RX7 rs140915863:C>T [p.T205M], P2RX7 rs201921967:A>G [p.N361S], and P2RX4 rs765866317:G>A [p.G135S]) segregating with disease in a multi-incident family with six family members diagnosed with MS (logarithm of odds = 3.07). Functional analysis of this haplotype in HEK293 cells revealed impaired P2X7 surface expression ( P < 0.01), resulting in over 95% inhibition of adenosine triphosphate (ATP)-induced pore function ( P < 0.001) and a marked reduction in phagocytic ability ( P < 0.05). In addition, transfected cells showed 40% increased peak ATP-induced inward current ( P < 0.01), and a greater Ca2+ response to the P2X4 135S variant compared with wild type ( P < 0.0001). Our study nominates rare genetic variants in P2RX4 and P2RX7 as major genetic contributors to disease, further supporting a role for these purinergic receptors in MS and the disruption of transmembrane cation channels leading to impairment of phagocytosis as the pathological mechanisms of disease. [ABSTRACT FROM AUTHOR]

Background. A population-based prevalent cohort of 150 clinical definite multiple sclerosis (MS) cases (102 women; 48 men) ascertained on January 1,1977, Saskatoon, Saskatchewan, was found to have a familial rate of MS as 17.3%. Objectives. To determine the occurrence of familial MS cases and the frequency of MS among the biological relatives of the study cohort. Methods. The search for new familial cases MS affected relatives continued for 35 years until 2012. The natural history of the disease of sporadic cases is compared with that of the familial cases. SPSS V19 and Kaplan-Meier survival analysis were used for data analysis. Results. Of the 150 unrelated MS patients, 49 cases (32.7%) (36 women and 13 men) were reported of having at least one family member with MS. There were a total of 86 affected relatives, 26 (30.2%) first-degree relatives, 15 (17.4%) second-degree relatives, 20 (23.3%) third-degree relatives, and 25 (29.1%) distant relatives. The average age of MS onset for men with sporadic MS was 33.9 (SD = 10) years and 27.6 (SD = 8.4) years for familial cases and 29.3 (SD = 8.3) years and 26.8 (SD = 8.5) years for women. Conclusion. This 35-year longitudinal natural history study reveals a high frequency of cases with family members developing MS and supports a genetic influence in the etiology of MS. [ABSTRACT FROM AUTHOR]

Background: Genetic and environmental factors have important roles in multiple sclerosis (MS) susceptibility. A clear parent of origin effect has been shown in several populations, perhaps resulting from factors operating during gestation. Preterm birth (birth at less than 37 weeks gestational age) has been shown to result in long-term health problems, including impaired neurological development. Here, in a population-based cohort, we investigate whether preterm birth increases the risk to subsequently develop MS. Methods: We identified 6585 MS index cases and 2509 spousal controls with preterm birth information from the Canadian Collaborative Project on Genetic Susceptibility to MS. Rates of individuals born preterm were compared for index cases and controls. Results: There were no significant differences between cases and controls with respect to preterm births. 370 (5.6%) MS index cases and 130 (5.2%) spousal controls were born preterm, p = 0.41. Conclusion: Preterm birth does not appear to contribute to MS aetiology. Other factors involved in foetal and early development need to be explored to elucidate the mechanism of the increased risk conferred by the apparent maternal effect. [ABSTRACT FROM AUTHOR]

The etiopathogenesis of multiple sclerosis (MS) remains unclear. However, genetic factors are believed to be important in disease susceptibility. A methodological approach is presented for a population-based study aimed at investigating MS familial incidence and patterns of familial clustering in Northern Sardinia, Italy, with a reported MS prevalence of 150/100,000 population. Patients with MS since 1965 to the present and known to the MS Register for the province of Sassari will be asked to provide genealogical, comorbid and demographic information. Statistical analyses of the familial risk for MS will depend on the completeness of MS 'age at onset' data for affected individuals and age at the time family history is obtained (or age at death) for unaffected family members. [ABSTRACT FROM AUTHOR]

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., (© The Author(s) 2014.)

Objective: To determine the incidence of multiple sclerosis (MS) in a longitudinal surveillance over 35 years and to estimate the prevalence rate in Saskatoon, Saskatchewan, on January 1, 2005., Methods: A population-based registry was established in 1969, and identification of cases continued to 2005, from medical records, physicians, neurologists, community and provincial resources. A modified classification of Allison and Millar and the Schumacher diagnostic criteria were originally applied, and patients with definite and probable MS were included. The rates were age- and sex-adjusted to the US, European, and world 2000 populations., Results: From 1970 to 2004, there were 558 incidence cases identified, 402 women and 156 men, for a sex ratio of 2.6:1 The average annual incidence rate was 9.5 in 100,000 (95% CI 8.8 to 10.4) and was stable over the three decades. The innate risk or residence at onset rate was 197 in 100,000 (95% CI 170 to 226). The crude prevalence rate for the living 587 cases on January 1, 2005, was 298.3 in 100,000 (95% CI 274.7 to 323.6)., Conclusions: The incidence and prevalence rates adjusted to the standardized populations were statistically higher than the longitudinal European studies and similar to North American studies. Our incidence study confirms the high risk of multiple sclerosis (MS) in Saskatoon, and these rates seem to be stable over the past 35 years. The high crude prevalence rate results from an accumulation of incidence and nonresident cases over time. Long-term follow-up studies and comparison with standardized populations are recommended to estimate reliable incidence and the true risk of MS in the world.

Background: Genetic epidemiological studies suggest both genetic and environmental factors have a role in multiple sclerosis (MS). Environmental effects are strongly suggested from geographical gradients, migration data, and discordance rates in twins. In epidemiological studies, risk of MS in offspring of small families and in those with an early birth-order position has been reported and interpreted in the context of the hygiene hypothesis, which is that infections at an early age, introduced by older siblings, are protective. We aimed to study the effect of birth order on MS risk., Methods: A longitudinal, population-based sample of individuals with MS and their healthy siblings were identified from the Canadian Collaborative Project on Genetic Susceptibility to MS. Data were grouped according to single (simplex) or multiple (multiplex) siblings with MS in a sibship. Separate analyses were done for each sibship size., Findings: We studied 10 995 individuals with MS and 26 336 healthy siblings, and found no relation between MS risk and birth-order position. In simplex sibships of at least seven siblings, slightly more siblings who were born late in the birth order had MS; the same was found for the first-born sibling with MS in a multiplex sibship. Siblings with MS were slightly younger (p<0.0001) than those without MS, contrary to the expected age at onset bias., Interpretation: These findings do not support the hygiene hypothesis and could be due to a cohort effect resulting from increasing MS incidence. Birth order has no effect on MS risk in most families, and there is no support for the hypothesis that having older siblings protects against MS.