Parent-of-origin effect in multiple sclerosis: observations in half-siblings

doi:10.1016/S0140-6736(04)16304-6

The Lancet

Volume 363, Issue 9423, 29 May 2004, Pages 1773-1774

https://doi.org/10.1016/S0140-6736(04)16304-6 Get rights and content

Summary

Multiple sclerosis is a complex trait in which occurrence rates in offspring are 20–50-fold greater than in the general population. Parent-of-origin effects have been difficult to screen for, since most cases are sporadic. We have compared recurrence risks in half-siblings with respect to their parent in common. Of the 1567 index cases with half-siblings in multiple sclerosis clinics across Canada, we recorded 3436 half-siblings and 2706 full-siblings. Age-adjusted full-sibling risk was 3·11%. By contrast, half-sibling risk in the same families was significantly lower at 1·89% χ² test, p=0·006), but higher than expected if familial risk was simply polygenic. For maternal half-siblings, the risk was 2·35% (34 affected siblings of 1859), and 1·31% for paternal half-siblings (15 of 1577), (p=0·048). The difference in risk suggests a maternal parent-of-origin effect in multiple sclerosis susceptibility.

References (5)

AD Sadovnick et al.
Evidence for the genetic basis of multiple sclerosis. The Canadian Collaborative Study Group
Lancet
(1996)
CJ Willer et al.
Twin concordance and sibling recurrence rates in multiple sclerosis
Proc Natl Acad Sci USA
(2003)

There are more references available in the full text version of this article.

Cited by (227)

Epidemiology, epigenetics, and etiological factors in multiple sclerosis
2024, Clinical Aspects of Multiple Sclerosis Essentials and Current Updates
The risk factors for the development of MS are complicated and incompletely understood. Genetic predisposition and environmental risk factors all contribute in different ways, with no single factor able to incite MS development on its own. The prevalence of MS increases with associated risk factors, like smoking and obesity. These trends, along with migration studies, point to a greater influence of environmental risk factors than genetic ones on the risk of MS overall. In this chapter, we explore these trends in epidemiology and associated risk factors for disease.
Vitamin D mechanisms of protection in multiple sclerosis
2023, Feldman and Pike's Vitamin D: Volume Two: Disease and Therapeutics
Vitamin D insufficiency is now believed to contribute causally to multiple sclerosis (MS) pathogenesis consistent with current paradigms for causal inference, and in light of new Mendelian randomization studies, which are akin to randomized interventions. We explore recent advances in understanding the transcriptional and epigenetic mechanisms through which 1,25-dihydroxyvitamin D₃ (1,25(OH)₂D₃) protects the CNS from autoimmune damage. Myeloid cells produce 1,25(OH)₂D₃, signaling to diverse cells within CNS and lymphoid tissues. CD4⁺ T lymphocytes respond by transdifferentiating to a protective phenotype, whereas oligodendrocyte precursor cells differentiate into myelin-producing oligodendrocytes (OLGs). The FOXP3 gene in CD4⁺ T cells may be the site of protective interactions between 1,25(OH)₂D₃ and sex hormones that underpin sex differences in MS. Genes that repress OLG differentiation and myelin synthesis may utilize epigenetic silencing mechanisms that benefit from 1,25(OH)₂D₃-mediated enhancement of the methionine cycle. We close with several research challenges to guide employment of the vitamin D system to reduce the impact of MS.
Biomarkers in multiple sclerosis
2023, Translational Neuroimmunology: Multiple Sclerosis: Volume 8
The search for biomarkers in multiple sclerosis (MS) is a wide area of interest, due to the complexity and unpredictability of the disease: from pathogenesis and disease course further down to treatment options. In the last few decades, the use of cerebrospinal fluid (CSF) biomarkers has become a staple in MS diagnosis, especially after the reintroduction of CSF study in the latest diagnostic criteria. On the other hand, evidence on serum biomarkers is rapidly growing, suggesting their potential future applications in clinical practice, as is the case with serum neurofilaments. In this chapter, we discuss the main biological markers, chosen by their utility in MS prediction, diagnosis, prognosis, disease activity, and treatment management.
Genetics and familial distribution of multiple sclerosis: A review
2022, Revue Neurologique
This article reviews the genetics of multiple sclerosis (MS), as well as intra-familial concordance and clinical correlations between different members of a family. Indeed, significant findings have been made on these topics in recent years.
The influence of specific genes on the clinical or radiological presentation of MS has been described as well as preliminary findings in the field of pharmacogenomics. Within familial forms of MS, correlations on specific aspects of the disease have been described, such as the age of onset or the clinical course between siblings.
The genetic contribution to the risk of developing MS is now estimated to be about 50%, with the genes involved mainly located within the major histocompatibility complex. Familial MS represents 12.6% of all MS cases, with the risk depending on the degree of genetic proximity to the index case. Furthermore, these familial cases seem to have a different clinical presentation from sporadic cases such as earlier worsening of disability and more severe long-term disability. Clinical correlations between different members of a family with MS have also been described, such as a similar age of onset between siblings, but deep clinical and radiological phenotyping is warranted to investigate MS disease severity concordance within familial cases of MS.
High birth weight and risk of multiple sclerosis: A multicentre study in Argentina
2021, Multiple Sclerosis and Related Disorders
Multiple sclerosis (MS) is now recognized as a multifactorial disease in which genetic and environmental factors intervene. Considerable efforts have been made to identify external risk factors present in childhood, adolescence and youth, though only a few perinatal risk factors have been positively associated with MS. Previously, we found an association between high birth weight and MS in male patients in a small study in Argentina. The present research was designed to further assess the association between high birth weight and MS in a larger sample of patients, using an extensive and validated general population database as control.
We present an analytical observational, multicentre, population-based, and case-control study. A total of 637 patients (cases) with confirmed MS diagnosis attending five MS specialized centres in Argentina were included. Birth weight (BW) data was recalled by the patient's mother, which is a validated approach. A two-way comparison was performed. First, we used the standard categories of high, adequate and low BW in grams. Then, we applied the weight percentile distribution to provide reproducible results for further research. For a proper assessment and comparison of variables, we adopted the guidelines of the American Academy of Pediatrics for neonate classification according to gestational weeks and to BW in grams. The neonate's BW distribution of the general population was used as control. For the purposes of the study, we adapted Urquía's et al. curves, which are based on an extensive database of all the live births registered in the country from 2003 to 2007. To measure the magnitude of the proportional differences between low, adequate and high BW, the odds ratio (OR) and their 95% confidence interval (CI) were estimated. The mean BW and percentile values for each sex were compared using a z-Normal test. The respective MS patients and general population BW distribution curves by sex were compared between each other.
Cases and controls were comparable in their demographic, geographic and environmental characteristics. Males showed higher BW than females both in the MS patients and the general population groups. When we applied the sex stratified analysis separately, we found that males in the MS group showed an almost seven times higher risk of high birth weight than males from the general population (OR 6.58 [95% CI 4.81–8.99]). Female patients showed an almost five times higher risk of high BW than their respective controls (OR 4.5 [95% CI 3.06–6.58]). The comparison based on the BW percentile distribution confirmed that MS patients showed higher BW than the general population. This result reached statistical significance from the 75^th percentile onwards for both sexes.
In summary, our findings suggested that high BW could be one of the earliest risk factors for MS in life. If this results were reproduced in other centres, high birth weight would emerge as a novel and very early risk factor, potentially modifiable in utero or immediately postpartum, representing a unique opportunity to prevent the disease in future generations.
Demographic and clinical characteristics of familial and sporadic multiple sclerosis: A single center exploratory study from Abu Dhabi
2020, Journal of Clinical Neuroscience
Citation Excerpt :
However, the differences between FMS and SMS seems to be strictly dependent on the genetic load of MS disease in the families [1,4–12] and thus, more relevant in younger generation of family members with MS and in MS patients with first degree relatives affected by MS. For instance, the anticipation of the age of disease onset and a greater male to female ratio have been observed especially in these types of FMS patients, while no differences were observed between older generations of FMS vs. SMS cases and in FMS with other than first degree relatives [1,4–12]. In our exploratory study, however, we were not able to stratify FMS patient’s selection according to family generational composition or degree of relatives as well as we were not able to investigate the family tree and the parental origin effect [1,4,5,31], and this may explain our lack of differences. On the other hand, our study has a smaller sample size compared to the majority of previous studies finding differences between FMS and SMS.
Demographic and clinical characteristics of Familial Multiple Sclerosis (FMS) have not been fully investigated yet in Abu Dhabi. The aim of this single center exploratory study was to investigate demographic and clinical characteristics of FMS compared to sporadic MS (SMS) in Abu Dhabi.
A chart review single center study was conducted in 98 patients with MS. Group comparisons were performed using Mann-Whitney and Chi-Square tests as appropriate. A p < 0.05 was considered statistically significant. 24.5% were patients with FMS and 83% were Emirates. No significant differences in demographic and clinical characteristics were found between patients with FMS and SMS in overall all MS patients and in the Emirati group analyzed alone.
Patients with FMS did not differ in demographic and clinical characteristics compared to patients with SMS. Further prospective studies are needed to elucidate environmental and genetic risk factors contributing to FMS in the Emirati population.

View all citing articles on Scopus

View full text

Research LettersParent-of-origin effect in multiple sclerosis: observations in half-siblings

Summary

Lancet

Twin concordance and sibling recurrence rates in multiple sclerosis

Proc Natl Acad Sci USA

Research Letters
Parent-of-origin effect in multiple sclerosis: observations in half-siblings