Maria Criscuoli

Autoimmune disease in families with multiple sclerosis: a population-based study

BACKGROUND Evidence of an association between multiple sclerosis (MS) and other autoimmune diseases would substantiate the hypothesis that MS is an autoimmune disease, and implicate a common mechanism. We aimed to investigate and compare the rate of autoimmune disease in MS patients, in their first-degree relatives, and in their unrelated spouses. METHODS We used data from a national, multicentre, population-based sample to investigate the rate of autoimmune disease in 5031 MS patients, 30 259 of their first-degree relatives, and 2707 spousal controls. We asked patients and controls whether they had any of ten autoimmune diseases: Crohns disease, ulcerative colitis, rheumatoid arthritis, type 1 diabetes, psoriasis, pernicious anaemia, systemic lupus erythematosus, autoimmune thyroid disease, vitiligo, and myasthenia gravis. MS probands were also asked whether their first-degree relatives had Crohns disease, ulcerative colitis, rheumatoid arthritis, or type 1 diabetes. FINDINGS After correction for age and sex, we did not identify any increased risk of autoimmune diseases in MS patients compared with their spousal controls (odds ratio [OR]=1.07, 95% CI 0.86-1.23, chi(2)=0.47, p=0.49), or in the first-degree relatives of MS probands compared with controls (OR=0.89, 0.63-1.17, chi(2)=1.11, p=0.29). However, the reported frequency of autoimmune diseases did differ according to the sex of the interviewee (female vs male patients chi(2)=92.2, p<0.0001; female vs male spousal controls chi(2)=87.1, p<0.0001). MS patients had slightly higher rates of thyroid disease and pernicious anaemia than did controls, which is consistent with MHC associations for these diseases, but this effect disappeared when results were adjusted for sex. For eight other diseases the rates were similar in MS patients and controls. Families with multiple cases of MS were no more likely to report autoimmune diseases than families with single MS cases. INTERPRETATION When data were adjusted for sex, no excess of common autoimmune diseases could be identified in MS patients or their families, including multicase pedigrees. Our results suggest that women are more aware of family medical histories than men, which emphasises the potential for ascertainment bias in unstratified data for a sex-limited disease. Family histories should thus be taken from male patients in the presence of a spouse.

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.

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.

No effect of preterm birth on the risk of multiple sclerosis: A population based study

BackgroundGenetic 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.MethodsWe 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.ResultsThere 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.ConclusionPreterm 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.

Purinergic receptors P2RX4 and P2RX7 in familial multiple sclerosis

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.

Genetic modifiers of multiple sclerosis progression, severity and onset

The genetic contribution to clinical outcomes for multiple sclerosis (MS) has yet to be defined. We performed exome sequencing analysis in 100 MS patients presenting opposite extremes of clinical phenotype (discovery cohort), and genotyped variants of interest in 2016 MS patients (replication cohort). Linear and logistic regression analyses were used to identify significant associations with disease course, severity and onset. Our analysis of the discovery cohort nominated 38 variants in 21 genes. Replication analysis identified PSMG4 p.W99R and NLRP5 p.M459I to be associated with disease severity (p=0.002 and 0.008). CACNA1H p.R1871Q was found associated with patients presenting relapsing remitting MS at clinical onset (p=0.028) whereas NLRP5 p.M459I and EIF2AK1 p.K558R were associated with primary progressive disease (p=0.031 and 0.023). In addition, PSMG4 p.W99R and NLRP5 p.R761L were found to correlate with an earlier age at MS clinical onset, and MC1R p.R160W with delayed onset of clinical symptoms (p=0.010-0.041).

Analysis of NOD-like receptor NLRP1 in multiple sclerosis families

The implementation of exome sequencing technologies has started to unravel the genetic etiology of familial multiple sclerosis (MS). A homozygote p.G587S mutation in NLRP1 has been suggested as potentially causative for the onset of MS in an affected sibling pair, who later developed malignant melanoma. To validate the proposed role of recessive NLRP1 mutations in the pathological mechanisms of MS, we examined exome sequencing data from 326 MS patients from Canada for the identification of NLRP1 missense and nonsense variants. This analysis did not identify the previously described p.G587S mutation; however, three patients with potential NLRP1 compound heterozygote mutations were observed. Haplotype and segregation analyses indicate that the variants observed in these patients were inherited in cis, and do not segregate with disease within families. Thus, the analysis of MS patients from Canada failed to identify potentially pathogenic mutations in NLRP1, including the previously described p.G587S mutation. Further studies are necessary to confirm a role of NLRP1 in the pathophysiology of MS.

Congenital abnormalities and multiple sclerosis.

BackgroundThere 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.MethodsWe 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).ResultsThe frequency of congential anomalies were compared between index cases and controls. No significant differences were found.ConclusionsCongenital 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.