G C Ebers, D E Bulman, A D Sadovnick, D W Paty, S Warren, W Hader, T J Murray, T P Seland, P Duquette, T Grey
Results from studies of twin concordance in multiple sclerosis have not conclusively differentiated between environmental and genetic factors that determine susceptibility to the disease. Published studies that have been based on case finding by public appeal have been characterized by difficulties in ascertainment. The data reported here are from a large population-based study of multiple sclerosis in twins, in which ascertainment has been relatively unbiased and the cooperation of patients nearly complete. A total of 5463 patients attending 10 multiple sclerosis clinics across Canada were surveyed. Twenty-seven monozygotic and 43 dizygotic twin pairs were identified, and the diagnosis of multiple sclerosis was verified by examination and laboratory investigation. Seven of 27 monozygotic pairs (25.9 percent) and 1 of 43 dizygotic pairs (2.3 percent) were concordant for multiple sclerosis. The concordance rate for 4582 nontwin siblings of patients at two multiple sclerosis clinics was 1.9 percent, closely paralleling the concordance rate in dizygotic twins. To the extent that the difference in concordance rates between monozygotic and dizygotic twins indicates genetic susceptibility, the results of this study show a major genetic component in susceptibility to multiple sclerosis.
Autoimmune Dis. 2012 ;2012 :593720 22536485
Center for Autoimmune Diseases Research (CREA), School of Medicine and Health Sciences, Universidad del Rosario, Carrera 24 no. 63C-69 Bogotá, Colombia.
Epigenetics is defined as the study of all inheritable and potentially reversible changes in genome function that do not alter the nucleotide sequence within the DNA. Epigenetic mechanisms such as DNA methylation, histone modification, nucleosome positioning, and microRNAs (miRNAs) are essential to carry out key functions in the regulation of gene expression. Therefore, the epigenetic mechanisms are a window to understanding the possible mechanisms involved in the pathogenesis of complex diseases such as autoimmune diseases. It is noteworthy that autoimmune diseases do not have the same epidemiology, pathology, or symptoms but do have a common origin that can be explained by the sharing of immunogenetic mechanisms. Currently, epigenetic research is looking for disruption in one or more epigenetic mechanisms to provide new insights into autoimmune diseases. The identification of cell-specific targets of epigenetic deregulation will serve us as clinical markers for diagnosis, disease progression, and therapy approaches.
J Virol. 2012 Apr ;86 (7):3713-22 22278236
Expression of HERV-Fc1, a human endogenous retrovirus, is increased in patients with active multiple sclerosis.
Magdalena Janina Laska, Tomasz Brudek, Kari Konstantin Nissen, Tove Christensen, Anné Møller-Larsen, Thor Petersen, Bjørn Andersen Nexø
Department of Biomedicine, Aarhus University, Aarhus, Denmark. email@example.com
Multiple sclerosis (MS) is considered to be an autoimmune disease with an unknown cause and with immune system dysregulation. Among environmental factors, viruses are most often connected with the etiology of MS. Human endogenous retroviruses (HERVs) constitute 5 to 8% of human genomic DNA and have been detected as transcripts and proteins in the central nervous system (CNS) and peripheral blood, frequently in the context of neuroinflammation. HERV-Fc1, which belongs to the HERV-H/F family, has received our attention largely because of the genetic association with MS. We studied the expression of a capsid (Gag) protein of HERV-H/F origin by flow cytometry in peripheral blood mononuclear cells (PBMCs) from healthy controls and from MS patients with nonactive or active disease. There was a significant increase in HERV-H/F Gag expression in CD4(+)(P < 0.001) and CD8(+)(P < 0.001) T lymphocytes and in monocytes (P = 0.0356) in PBMCs from MS patients with active disease. Furthermore, we have undertaken the first rigorous SYBR green-based absolute quantitative PCR (Q-PCR) evaluation approach to quantify extracellular HERV-Fc1 RNA viral loads in plasma from MS patients and healthy controls. We found a 4-fold increase in extracellular HERV-Fc1 RNA titers in patients with active MS compared with healthy controls (P < 0.001). These findings strengthen the link between HERV-Fc1 and the pathology of MS. The cause and biological consequences of these differential expression levels will be the subject of further investigation. HERV-Fc1 biology could be a compelling area for understanding the pathology of MS and possibly other autoimmune disorders.
Department of Nutrition, Harvard School of Public Health, Boston, MA 02115, USA. firstname.lastname@example.org
Multiple sclerosis (MS) is a relatively common debilitating neurologic disease that affects people in early adulthood. While the characteristic pathology of MS has been well described, the etiology of the disease is not well understood, despite decades of research and the identification of strong genetic and environmental candidates for susceptibility. A question central to all diseases, but posed specifically for MS at the XVI European Charcot Foundation Lecture, was 'Can MS be prevented?' To address this question, we have evaluated the available data regarding nutritional and environmental factors that may be related to MS susceptibility and suggest the extent to which a potential intervention may reduce disease burden. It is our opinion that intervention, particularly supplementation with vitamin D, could have a dramatic impact on disease prevalence. Understanding that any intervention or behavioral modification will surely act in the context of genetic susceptibility and unidentified stochastic events, it is likely that not all MS is 'preventable'. Epidemiologic observation has provided key insights into environmental and nutritional factors that may alter one's susceptibility to MS, however, there are still many questions in unraveling the etiology of this complex disease.
N-acetylglucosamine inhibits T-helper 1 (Th1)/T-helper 17 (Th17) cell responses and treats experimental autoimmune encephalomyelitis.
Department of Neurology, University of California, Irvine, California 92697, USA.
Current treatments and emerging oral therapies for multiple sclerosis (MS) are limited by effectiveness, cost, and/or toxicity. Genetic and environmental factors that alter the branching of Asn (N)-linked glycans result in T cell hyperactivity, promote spontaneous inflammatory demyelination and neurodegeneration in mice, and converge to regulate the risk of MS. The sugar N-acetylglucosamine (GlcNAc) enhances N-glycan branching and inhibits T cell activity and adoptive transfer experimental autoimmune encephalomyelitis (EAE). Here, we report that oral GlcNAc inhibits T-helper 1 (Th1) and T-helper 17 (Th17) responses and attenuates the clinical severity of myelin oligodendrocyte glycoprotein (MOG)-induced EAE when administered after disease onset. Oral GlcNAc increased expression of branched N-glycans in T cells in vivo as shown by high pH anion exchange chromatography, MALDI-TOF mass spectroscopy and FACS analysis with the plant lectin l-phytohemagglutinin. Initiating oral GlcNAc treatment on the second day of clinical disease inhibited MOG-induced EAE as well as secretion of interferon-γ, tumor necrosis factor-α, interleukin-17, and interleukin-22. In the more severe 2D2 T cell receptor transgenic EAE model, oral GlcNAc initiated after disease onset also inhibits clinical disease, except for those with rapid lethal progression. These data suggest that oral GlcNAc may provide an inexpensive and nontoxic oral therapeutic agent for MS that directly targets an underlying molecular mechanism causal of disease.
Haik Mkhikian, Ani Grigorian, Carey F Li, Hung-Lin Chen, Barbara Newton, Raymond W Zhou, Christine Beeton, Sevan Torossian, Gevork Grikor Tatarian, Sung-Uk Lee, Ken Lau, Erin Walker, Katherine A Siminovitch, K George Chandy, Zhaoxia Yu, James W Dennis, Michael Demetriou
Department of Microbiology and Molecular Genetics, University of California, Irvine, California 92697-4025, USA.
How environmental factors combine with genetic risk at the molecular level to promote complex trait diseases such as multiple sclerosis (MS) is largely unknown. In mice, N-glycan branching by the Golgi enzymes Mgat1 and/or Mgat5 prevents T cell hyperactivity, cytotoxic T-lymphocyte antigen 4 (CTLA-4) endocytosis, spontaneous inflammatory demyelination and neurodegeneration, the latter pathologies characteristic of MS. Here we show that MS risk modulators converge to alter N-glycosylation and/or CTLA-4 surface retention conditional on metabolism and vitamin D(3), including genetic variants in interleukin-7 receptor-α (IL7RA*C), interleukin-2 receptor-α (IL2RA*T), MGAT1 (IV(A)V(T-T)) and CTLA-4 (Thr17Ala). Downregulation of Mgat1 by IL7RA*C and IL2RA*T is opposed by MGAT1 (IV(A)V(T-T)) and vitamin D(3), optimizing branching and mitigating MS risk when combined with enhanced CTLA-4 N-glycosylation by CTLA-4 Thr17. Our data suggest a molecular mechanism in MS whereby multiple environmental and genetic inputs lead to dysregulation of a final common pathway, namely N-glycosylation.
Mult Scler. 2011 Sep ;17 (9):1060-6 21561958
Anne Wellek, Catharina Korsukewitz, Jan P Bach, Sabine Schock, Christian Eienbröker, Florian Seitz, Anna Spengler, Bernhard Hemmer, Kerstin Schlegel, Wolfgang H Oertel, Norbert Sommer, Björn Tackenberg
Philipps-University, Department of Neurology, Clinical Neuroimmunology Group, Marburg, Germany.
BACKGROUND The objective of this study was to address the differences in onset and disease progression between familial and sporadic multiple sclerosis (MS) and the association within sibling pairs. METHODS Ninety-eight siblings and their controls were included from a database of 763 sporadic MS-patients, randomly pair-matched for age, gender, clinical course, disease duration and treatment. Sixty-eight available siblings completed a prospective six-year follow-up. Outcome parameters included baseline Expanded Disability Status Scale (EDSS), age at onset, mono- or multifocal onset, disease progression and conversion to secondary progression of initially relapsing-remitting MS. For statistical analyses Wilcoxon's signed-rank statistics for categorical differences, t-statistics for continuous variables, McNemar's test for relative frequencies of categories, intra-class correlations for within sibling-pair associations, or Kaplan-Meier analysis for survival analyses were used; all two-sided at the 5% level. RESULTS Disease onset was slightly earlier (29.01 vs. 29.44 years, p = 0.0492) and multifocal onset significantly more often (p = 0.0052) in familial than in sporadic MS. Notably, a substantial within sibling-pair correlation for disease progression (rho = 0.40; p = 0.0062) as well as a higher risk for siblings than for controls to convert into secondary progression (0.545 vs. 0.227; p = 0.018) could be observed. CONCLUSIONS Familial MS differs from sporadic cases with respect to age at onset, multifocal involvement as first clinical event, and conversion into secondary progression. The progression rate of one out of two affected siblings may act as a predictor for the other sib.
Autoimmune Dis. 2011 ;2011 :519450 21541245
Wellcome Trust Centre for Human Genetics, University of Oxford, OX3 7BN Oxford, UK.
We review here our current understanding of the genetic aetiology of the common complex neurological disease multiple sclerosis (MS). The strongest genetic risk factor for MS is the major histocompatibility complex which was identified in the 1970s. In 2011, after a number of genome-wide association studies have been completed and have identified approximately 20 new genes for MS, we ask the question-what is next for the genetics of MS?
Department of Neurology, Aarhus University Hospital in Aalborg, Aalborg, Denmark. email@example.com
The uneven distribution of multiple sclerosis (MS) across populations can be attributed to differences in genes and the environment and their interaction. Prevalence and incidence surveys could be affected by inaccuracy of diagnosis and ascertainment, and prevalence also depends on survival. These sources of error might play a part in the geographical and temporal variations. Our literature search and meta-regression analyses indicated an almost universal increase in prevalence and incidence of MS over time; they challenge the well accepted theory of a latitudinal gradient of incidence of MS in Europe and North America, while this gradient is still apparent for Australia and New Zealand; and suggest a general, although not ubiquitous, increase in incidence of MS in females. The latter observation should prompt epidemiological studies to focus on changes in lifestyle in females. New insights into gene-environment and gene-gene interactions complicate interpretations of demographic epidemiology and have made obsolete the idea of simple causative associations between genes or the environment and MS.
Bruce V Taylor, Robyn M Lucas, Keith Dear, Trevor J Kilpatrick, Michael P Pender, Ingrid Af van der Mei, Caron Chapman, Alan Coulthard, Terence Dwyer, Anthony J McMichael, Patricia C Valery, David Williams, Anne-Louise Ponsonby
Menzies Research Institute, University of Tasmania, Hobart, Australia.
Increasing prevalence and variable geographic patterns of occurrence of multiple sclerosis suggest an environmental role in causation. There are few descriptive, population-level, data on whether such variability applies to first demyelinating events (FDEs). We recruited 216 adults (18-59 years), with a FDE between 1 November 2003 and 31 December 2006 in a multi-center incident case-control study in four locations on the south-eastern and eastern seaboard of Australia, spanning latitudes 27 degrees south to 43 degrees south. Population denominators were obtained from the Australian Bureau of Statistics censuses of 2001 and 2006. Age and sex adjusted FDE incidence rates increased by 9.55%(95% confidence interval (CI) 7.37-11.78, p < 0.001) per higher degree of latitude. The incidence rate gradient per higher degree of latitude varied by gender (male: 14.69%(95% CI 9.68-19.94, p < 0.001); female 8.13%(95% CI 5.69-10.62, p < 0.001)); and also by the presenting FDE type: optic neuritis 11.39%(95% CI 7.15-15.80, p < 0.001); brainstem/cerebellar syndrome 9.47%(95% CI 5.18-13.93, p < 0.001); and spinal cord syndrome 5.36%(95% CI 1.78-9.06, p = 0.003). Differences in incidence rate gradients were statistically significant between males and females (p = 0.02) and between optic neuritis and spinal cord syndrome (p = 0.04). The male to female ratio varied from 1 : 6.7 at 27 degrees south to 1 : 2.5 at 43 degrees south. The study establishes a positive latitudinal gradient of FDE incidence in Australia. The latitude-related factor(s) influences FDE incidence variably according to subtype and gender, with the strongest influence on optic neuritis presentations and for males. These descriptive case analyses show intriguing patterns that could be important for understanding the etiology of multiple sclerosis.
Season of birth and not vitamin D receptor promoter polymorphisms is a risk factor for multiple sclerosis.
D A Fernandes de Abreu, M C Babron, M C I Babron, I Rebeix, C Rebeix, C Fontenille, J Fontenille, J Yaouanq, D Yaouanq, D Brassat, B Brassat, B Fontaine, F Fontaine, F Clerget-Darpoux, F Jehan, F Feron
Neurobiologie des Interactions Cellulaires et Neurophysiopathologie (NICN), CNRS UMR 6184, IFR Jean Roche, Faculté de Médecine Nord, Marseille, France.
Both genetic and environmental factors contribute to multiple sclerosis, the most common neurodegenerative disorder with onset in young adults. The objective of the current study is, based on the hypothesis that environmentally predisposed individuals are at risk for multiple sclerosis, to investigate whether they also carry genetic variants within the vitamin D machinery. Using medical files and DNA samples from 583 trios (a patient and both parents) of the French Multiple Sclerosis Genetics Group as well as data from the French Statistics Bureau, we aimed to assess whether:(1) a seasonality of birth was observed in French multiple sclerosis patients;(2) three single nucleotide polymorphisms within the promoter region of the vitamin D receptor were associated with multiple sclerosis susceptibility; and (3) the combination of a high risk month of birth and vitamin D receptor polymorphisms were correlated to multiple sclerosis incidence. We observed a significantly reduced number of individuals born in November who were later diagnosed as multiple sclerosis patients. However, we found no association between the three studied vitamin D receptor polymorphisms and multiple sclerosis. In conclusion, our data suggest that high levels of vitamin D during the third trimester of pregnancy could be a protective factor for multiple sclerosis.
Other papers by authors:
G C Ebers, K Kukay, D E Bulman, A D Sadovnick, G Rice, C Anderson, H Armstrong, K Cousin, R B Bell, W Hader, D W Paty, S Hashimoto, J Oger, P Duquette, S Warren, T Gray, P O'Connor, A Nath, A Auty, L Metz, G Francis, J E Paulseth, T J Murray, W Pryse-Phillips, N Risch
The aetiology of multiple sclerosis (MS) is uncertain. There is strong circumstantial evidence to indicate it is an autoimmune complex trait. Risks for first degree relatives are increased some 20 fold over the general population. Twin studies have shown monozygotic concordance rates of 25-30% compared to 4% for dizygotic twins and siblings. Studies of adoptees and half sibs show that familial risk is determined by genes, but environmental factors strongly influence observed geographic differences. Studies of candidate genes have been largely unrewarding. We report a genome search using 257 microsatellite markers with average spacing of 15.2 cM in 100 sibling pairs (Table 1, data set 1 - DS1). A locus of lambda>3 was excluded from 88% of the genome. Five loci with maximum lod scores (MLS) of >1 were identified on chromosomes 2, 3, 5, 11 and X. Two additional data sets containing 44 (Table 1, DS2) and 78 sib pairs (Table 1, DS3) respectively, were used to further evaluate the HLA region on 6p21 and a locus on chromosome 5 with an MLS of 4.24. Markers within 6p21 gave MLS of 0.65 (non-significant, NS). However, D6S461, just outside the HLA region, showed significant evidence for linkage disequilibrium by the transmission disequilibrium test (TDT), in all three data sets (for DS1 chi2 = 10.8, adjusted P < 0.01)(DS2 and DS3 chi2 = 10.9, P < 0.0005), suggesting a modest susceptibility locus in this region. On chromosome 5p results from all three data sets (222 sib pairs) yielded a multipoint MLS of 1.6. The results support genetic epidemiological evidence that several genes interact epistatically to determine heritable susceptibility.
D A Dyment, C J Willer, B Scott, H Armstrong, A Ligers, J Hillert, D W Paty, S Hashimoto, V Devonshire, J Hooge, L Kastrukoff, J Oger, L Metz, S Warren, W Hader, C Power, A Auty, A Nath, R Nelson, M Freedman, D Brunet, J E Paulseth, G Rice, P O'Connor, P Duquette, Y Lapierre, G Francis, J P Bouchard, T J Murray, V Bhan, C Maxner, W Pryse-Phillips, M Stefanelli, A D Sadovnick, N Risch, G C Ebers
The Wellcome Trust Center for Human Genetics, Oxford, UK.
Four published genome screens have identified a number of markers with increased sharing in multiple sclerosis (MS) families, although none has reached statistical significance. One hundred and five markers previously identified as showing increased sharing in Canadian, British, Finnish, and American genome screens were genotyped in 219 sibling pairs ascertained from the database of the Canadian Collaborative Project on Genetic Susceptibility to MS (CCPGSMS). No markers examined met criteria for significant linkage. Markers located at 5p14 and 17q22 were analyzed in a total of 333 sibling pairs and attained mlod scores of 2.27 and 1.14, respectively. The known HLA Class II DRB1 association with MS was confirmed (P<0.0001). Significant transmission disequilibrium was also observed for D17S789 at 17q22 (P=0.0015). This study highlights the difficulty of searching for genes with only mild-to-moderate effects on susceptibility, although large effects of specific loci may still be present in individual families. Future progress in the genetics of this complex trait may be helped by (1) focussing on more ethnically homogeneous samples,(2) using an increased number of MS families, and (3) using transmission disequilibrium analysis in candidate regions rather than the affected relative pair linkage analysis.
P Duquette, T J Murray, J Pleines, G C Ebers, D Sadovnick, P Weldon, S Warren, D W Paty, A Upton, W Hader
Multiple sclerosis (MS) has its usual onset in early adult life (average age of 30 years), but age at clinical onset varies considerably. The implications of the age of onset on the clinical presentation and course of MS are unclear. This population-based retrospective study presents data from a group of 125 patients with onset of MS before age 16 years and can thus be considered as representative of MS occurring in childhood. It demonstrates that childhood MS is more frequent in girls, that it very often has a relapsing-remitting course, that initial bouts usually involve afferent structures of the central nervous system, that recovery from these is often complete, and that the pace of the disease is slow.
A D Sadovnick, H Armstrong, G P Rice, D Bulman, L Hashimoto, D W Paty, S A Hashimoto, S Warren, W Hader, T J Murray
University of British Columbia, Vancouver, Canada.
This study is a 7.5-year follow-up of a population-based series of twins with multiple sclerosis (MS) whose mean age now exceeds 50 years. The twin pairs were identified through the Canadian nationwide system of MS clinics and were drawn from a population of 5,463 patients. After 7.5 years, the monozygotic concordance rate increased from 25.9 to 30.8% and the dizygotic-like sex concordance rate from 2.4 to 4.7%. These results are very similar to those of other population-based studies and to our own modified replication twin data reported here. We interpret the data to mean that MS susceptibility is genetically influenced, and a single dominant or even a single recessive gene is unlikely to account for this effect. The difference in concordance rates suggests that at least two or more genes are operative. These data also have important implications for the nature of the environmental effect(s) in MS susceptibility. Most monozygotic twins are discordant even after a correction for age and magnetic resonance imaging findings. This unambiguously demonstrates the powerful effect of nonheritable factors.
Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia, Canada. firstname.lastname@example.org
BACKGROUND A month-of-birth (MOB) effect has been shown in multiple sclerosis (MS). METHODS Our chi(2) analyses looked at whether this MOB effect differed by MS phenotype ("bout onset,""primary progressive"). RESULTS The MOB effect was derived from "bout onset" MS patients (May/November ratio = 1.43; chi(2)= 17.32, df = 1, p = 0.000032). CONCLUSIONS An unspecified environmental effect in early development can influence both multiple sclerosis susceptibility and phenotype.
Conjugal multiple sclerosis: population-based prevalence and recurrence risks in offspring. Canadian Collaborative Study Group.
Department of Clinical Neurology, University of Oxford, UK.
From a population-based sample of 15,504 patients attending Canadian multiple sclerosis (MS) clinics, we have determined the frequency of conjugal MS and have estimated the recurrence risk in offspring of such matings. Twenty-three MS cases were found among 13,550 spouses of study probands for a crude conjugal rate of 0.17%(95% CI of 0.10%-0.24%). Despite ascertainment bias that expectedly inflates this number, this is a frequency intermediate between the point prevalence (0.1%) and lifetime risk (0.2%) for the general population and close to an order of magnitude less than reported for half siblings reared apart (1.06%) from the same population. Six of the 49 offspring of conjugal pairs also had MS, and age conversion gives a rate similar to the concordance rate for Canadian monozygotic twins. However, this correction may not be appropriate in this special case. Despite an ascertainment bias in favor of recognizing affected spouses and a large population sample, the common environment in adulthood shared by spousal pairs could not be shown to increase the risk of conjugal MS. Although the high recurrence rate in offspring is similarly subject to an upward bias, the low risk for MS spouses and the high risk for offspring support other data indicating that familial risk is genetically determined. Furthermore, these results imply that susceptibility alleles are shared by unrelated individuals with the disease.
The natural history of multiple sclerosis: a geographically based study: 8: familial multiple sclerosis.
G C Ebers, W J Koopman, W Hader, A D Sadovnick, M Kremenchutzky, P Mandalfino, D M Wingerchuk, J Baskerville, G P Rice
Department of Clinical Neurological Sciences, University of Western Ontario, London, Ontario, Canada. email@example.com
We have examined the demographics and long-term outcome of 1044 patients with sporadic and familial multiple sclerosis in a population-based cohort from London, Ontario. The mean follow-up was 25 years in duration, and by this time most patients had reached the unambiguous endpoint scores of the Kurtzke disability status scale (DSS), DSS 6, 8 or 10. An affected family member was identified in 19.8% of the total population, and this subgroup was further divided arbitrarily into the following three groups by the type and number of relatives affected:(i) first degree only;(ii) first degree plus others;(iii) second or third degree. The outcome in these groups was compared with that for those patients who, at a mean 25 year follow-up, had no relatives known to be affected. Familial cases closely resembled those remaining sporadic in both demographics and outcome, although onset in the most heavily loaded families was earlier and male/female ratio was greater. The times to DSS 6, 8 and 10 did not differ significantly when sporadic, familial and familial subgroups were compared. These results provide no clinical support for viewing familial multiple sclerosis as distinct from the sporadic form. The observed recurrence rate for siblings in a strictly defined epidemiological sample was 3.5%, much as projected. These results validate the recurrence risks which have previously been derived from age-corrected data for these first-degree relatives.
Absence of antibody to HTLV I and III in sera of Canadian patients with multiple sclerosis and chronic myelopathy.
Recently, elevated titers of antibody to HTLV I have been demonstrated in patients with tropical spastic paraparesis and multiple sclerosis. We evaluated the possible role of human retroviruses HTLV I and III in Canadian patients with multiple sclerosis and chronic idiopathic myelopathy. Using sensitive enzyme immunoassays, we were unable to find antibody to either HTLV I or III in 201 patients with multiple sclerosis, 29 patients with chronic myelopathy, 51 patients with other neurological disorders, or 29 normal subjects. These data do not support a role for these viruses in the cause of sporadic multiple sclerosis and chronic myelopathy in a regionally based Canadian population, but do not exclude a role for other antigenically distinct retroviruses.
Multiple Sclerosis Clinic, University of Western Ontario, London, Canada.
We have evaluated genetic and environmental influences in multiple sclerosis (MS) by comparing age of onset in 99 sibling pairs concordant for the disease. We used three methods of analysis:(1) comparison of mean differences in age of onset and year of onset,(2) linear regression of differences in age or year of onset vs difference in ages, and (3) intraclass correlation of age of onset which is also used for monozygotic twins concordant for MS. Comparison of the mean differences in age of onset or year of onset is found to be inappropriate and potentially misleading. No significant results were found in linear regression of the age of onset or year of onset vs differences in ages, although a trend towards onset at the same age is present. However, nontwin siblings show a significant intraclass correlation for age of onset (P less than 0.01) as is seen in genetic disorders. A stronger intraclass correlation in age of onset in concordant monozygotic twins vs concordant sibling pairs further suggests that age of onset is partly under genetic control, assuming common exposure to an environmental agent. The results give little support for common exposure to an environmental trigger in concordant MS sibling pairs. They are consistent with a mixture of random independent exposures and common exposures leading to the development of the disease, with the former predominating.
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Eur J Pain. 2012 Oct ;16 (9):1224-31 22416025
Growing pains: Twin family study evidence for genetic susceptibility and a genetic relationship with restless legs syndrome.
Department of Anaesthesia and Pain Medicine, Sydney Children's Hospital, Randwick, Australia; Faculty of Medicine, University of New South Wales, Sydney, Australia.
BACKGROUND Growing pains (GP) is a prevalent familial childhood disorder of unknown aetiology. Familial occurrence of GP, and individual and familial association of GP with restless legs syndrome (RLS) has been reported. METHODS We applied a twin family design to search for evidence of genetic susceptibility to GP, and for a genetic relationship between GP and RLS. The parents of 1843 twin pairs aged 3-16 years were administered a questionnaire, which identified 88 pairs with at least one twin individual fulfilling criteria for GP. Standard questionnaires for history of GP and RLS were completed for these twin pairs, their siblings and parents. RESULTS Twenty-five of 34 monozygotic (MZ) pairs were concordant for GP, compared with 12 of the 54 dizygotic (DZ) pairs. The casewise concordance was 0.85 and 0.36 for MZ and DZ pairs, respectively (p < 0.001). The lifetime GP prevalence for relatives of twins with GP was 51% for non-twin siblings, 47% for parents. Twenty-three percent of twin individuals with GP met RLS criteria compared with 8% of twin individuals without GP (p = 0.03). Of the twins with GP concordance, 19% met RLS criteria compared with 2% of twins with GP discordance (p = 0.01). In two MZ pairs, one had GP and the other RLS. The lifetime prevalence of RLS was 40% for mothers, and 24% for fathers and 18% for non-twin siblings. CONCLUSION This first twin family study of GP provides evidence for a genetic aetiology and for a genetic relationship to RLS.
Epidemiol Infect. 2011 Dec 8;:1-7 22152594
Department of Preventive Medicine and Norris Comprehensive Cancer Centre, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
SUMMARYInfectious mononucleosis is a clinical manifestation of primary Epstein-Barr virus infection. It is unknown whether genetic factors contribute to risk. To assess heritability, we compared disease concordance in monozygotic to dizygotic twin pairs from the population-based California Twin Program and assessed the risk to initially unaffected co-twins. One member of 611 and both members of 58 twin pairs reported a history of infectious mononucleosis. Pairwise concordance in monozygotic and dizygotic pairs was respectively 12·1%[standard error (s.e.)=1·9%] and 6·1%(s.e.=1·2%). The relative risk (hazard ratio) of monozygotic compared to dizygotic unaffected co-twins of cases was 1·9 [95% confidence interval (CI) 1·1-3·4, P=0·03], over the follow-up period. When the analysis was restricted to same-sex twin pairs, that estimate was 2·5 (95% CI 1·2-5·3, P=0·02). The results are compatible with a heritable contribution to the risk of infectious mononucleosis.
Genetic and Environmental Influences on Risk of Death due to Infections Assessed in Danish Twins, 1943-2001.
Genetic differences have been proposed to play a strong role in risk of death from infectious diseases. The study base of 44,005 included all same-sex twin pairs born in 1870-2001, with both twins alive on January 1, 1943, or those born thereafter. Cause of death was obtained from the Danish Cause of Death Register and was available for 18,359 deaths. The authors classified death due to infections by 3 definitions (narrow, broader, and broadest) and calculated concordance rates for same-sex monozygotic and dizygotic twin pairs. Heritability was estimated by using structural equation models. When the 3 definitions were applied, 211 (1.1%), 1,089 (5.9%), and 2,907 (15.8%) deaths, respectively, were due to infections. The probandwise concordance rates for monozygotic twin pairs were consistently higher than for dizygotic twin pairs regardless of the definition (9% vs. 0%(P = 0.04), 10% vs. 3%(P < 0.01), and 19% vs. 15%(P = 0.07), respectively). For the broader and broadest definitions, heritability was 40%(95% confidence interval: 12, 50) and 19%(95% confidence interval: 3, 35), respectively. The concordance rates were generally low, and, although a genetic influence on the risk of death from infectious diseases could be demonstrated, the absolute effect of the genetic component on mortality was small.
Concordance and heritability of multiple sclerosis in Finland: study on a nationwide series of twins.
Department of Neurology and Rehabilitation, Tampere University Hospital, Tampere, Finland. firstname.lastname@example.org
OBJECTIVES To evaluate the changes in the multiple sclerosis (MS) concordance in twins, and the contribution of genetic and environmental factors to the aetiology of MS in Finland. BACKGROUND Both genes and the environment contribute to the development of MS. A well-conducted twin study is an excellent means to assess the relative contribution of heritability and environmental factors. METHODS Multiple sclerosis concordance was assessed for 10 Monozygotic and 14 dizygotic twin pairs using pairwise and probandwise concordance rates. The tetrachoric correlations in liability to disease for twin pairs were computed and a polygenic multifactorial model was used to estimate heritability. RESULTS The pairwise concordance for MZ twins was 30% and for the DZ twins 14.3%, compared with 30% for MZ and 0% for DZ 20 years ago. The corresponding probandwise concordance rates were 46.2% and 25%. The genetic variance (heritability) was 15.3%(95% Cl 0.0-77.6), the common environmental variance 73.7%(95% Cl 14.1-93.9) and the unique environmental variance 11.1%(95% Cl 2.3-30.0). CONCLUSIONS As the concordance of MS in DZ twins has increased during the past two decades and the heritability estimate is low, it seems that the reported increase in MS incidence in Finland is mainly caused by environmental factors.
Department of Respiratory Medicine, Bispebjerg Hospital, DK-2400 Copenhagen NV, Denmark. email@example.com
BACKGROUND Sarcoidosis is a multiorgan granulomatous inflammatory disease of unknown aetiology. Familial clustering of cases and ethnic variation in the epidemiology suggests a genetic influence on susceptibility to the disease. This paper reports twin concordance and heritability estimates of sarcoidosis in order to assess the overall contribution of genetic factors to the disease susceptibility. METHODS Monozygotic and dizygotic twins enrolled in the Danish and the Finnish population-based national twin cohorts (61,662 pairs in total) were linked to diagnostic information on sarcoidosis obtained from the Danish National Patient Registry or the Social Insurance Institution, Finland registry of reimbursed medication using the 8th and 10th editions of the International Classification of Diseases. The Fisher exact test was used to compare probandwise concordance rates in different zygosity groups. Heritability was estimated based on a multifactorial threshold liability model. RESULTS A total of 210 twin pairs with at least one proband with a diagnosis of sarcoidosis were identified. The probandwise concordance rate was higher in monozygotic than in dizygotic twins (0.148 vs 0.012). Compared with the general population there was an 80-fold increased risk of developing sarcoidosis in co-twins of affected monozygotic brothers or sisters. The increased risk in dizygotic twins was only 7-fold. Aetiological model fitting gave a heritability of sarcoidosis of 0.66 (95% CI 0.45 to 0.80). CONCLUSIONS This study suggests that genetic factors play an important role in the susceptibility to sarcoidosis. This result should encourage the search for molecular genetic markers of susceptibility to the disease.
Martina E Spehlmann, Alexander Z Begun, Jens Burghardt, Patricia Lepage, Andreas Raedler, Stefan Schreiber
Institute for Clinical Molecular Biology, University Schleswig-Holstein, Kiel, Germany. firstname.lastname@example.org
BACKGROUND Genetic predisposition as a cause of inflammatory bowel disease (IBD) has been proven by both family and twin studies and genetic variants associated with the disease have been identified. The aim of our study was to determine the concordance rates for IBD in German twin pairs and to evaluate clinical characteristics of concordant and discordant twin pairs. METHODS Patients with IBD were asked to participate and complete a questionnaire that contained questions about zygosity, demographic data, and medical history. RESULTS A total of 189 twin pairs in which at least 1 member had IBD were recruited (68 monozygotic and 121 dizygotic pairs). Within monozygotic pairs, 11 out of 31 (35%) were concordant for Crohn's disease (CD) and 6 out of 37 (16%) for ulcerative colitis (UC). Two of the 58 (3%) dizygotic pairs with CD and 1 out of 63 (2%) dizygotic pairs with UC were concordant for the disease. In 14 out of 20 (70%) discordant monozygotic CD pairs and 25 out of 31 (81%) discordant monozygotic pairs with UC, the first-born was affected by IBD. For discordant dizygotic twins, the first in birth order had IBD in 33 out of 56 (59%) pairs with CD and 40 out of 62 (64.5%) pairs with UC. CONCLUSIONS This study confirms a stronger genetic influence in CD than in UC. The high preponderance in being affected of the first-born twin and the fact that concordance was only 35% for CD and 16% for UC monozygotic twins highlight the important role of environmental trigger factors.
Department of Obstetrics and Gynecology, Odense University Hospital, Sdr Boulevard 29, 5000 Odense C, Denmark. email@example.com
OBJECTIVE To determine the relative environmental and genetic influence in the development of carcinoma in situ (CIS) cervicis uteri. METHODS Retrospective follow-up study with record linkage between The Danish Twin Register and The Danish Cancer Register. The study base comprises 27,004 female twins from 13,502 same-sex twin pairs. 5,258 were monozygotic and 8,244 dizygotic twin pairs. The statistic measurements are the coincidence ratio and the probandwise concordance rate in the two groups of twins with different zygosity. RESULTS 750 twins were diagnosed with CIS cervicis uteri. 291 monozygotic twins came from 275 pairs and 459 dizygotic twins came from 435 pairs. There were 16 concordant monozygotic twin pairs and 24 concordant dizygotic pairs. The probandwise concordance rate was 0.11 (0.06-0.16) in monozygotic twins and 0.10 (0.06-0.14) in dizygotic twins. CONCLUSION A family clustering of CIS was demonstrated in both groups of zygosity. The probandwise concordance rate was equal in the monozygotic and the dizygotic groups, which means that genetic factors are not important in the development of the disease. However, a shared environment among twins plays a role in the development of CIS cervicis uteri.
The occurrence of multiple sclerosis (MS) in twins has not previously been studied in complete nationwide data sets. The existence of almost complete MS and twin registries in Denmark ensures that essentially unbiased samples of MS cases among twins can be obtained. In this population-based study, virtually all Danish MS cases among twins born before 1983 with onset of MS after 1948 and diagnosis before I January 1997 were identified. Of 13 286 MS cases, 178 were twins and, of these 164 twin pairs were discordant and seven were concordant. We found significantly higher proband-wise concordance among monozygotic twins than dizygotic twins, with estimated proband-wise concordances of 24%(95% confidence interval (CI): 5-39%) for monozygotic and 3%(95% CI: 0-8%) for dizygotic twins. Thus, a monozygotic twin whose co-twin has MS has a 24% risk of developing the disease, while the corresponding risk for a dizygotic twin is only 3%. Our results largely confirm previously published concordance estimates and indicate that genetic factors are of importance in susceptibility to MS.
J Halfvarson, A Standaert-Vitse, G Järnerot, B Sendid, T Jouault, L Bodin, A Duhamel, J F Colombel, C Tysk, D Poulain
Division of Gastroenterology, Department of Internal Medicine, Orebro University Hospital, Orebro 70185, Sweden. firstname.lastname@example.org
BACKGROUND AND AIMS: An increased occurrence of anti-Saccharomyces cerevisiae antibodies (ASCA) is reported in unaffected members of families with Crohn's disease. Whether ASCA is a familial trait due to genetic factors or is caused by exposure to environmental factors is unknown. To assess the genetic influence of ASCA we studied its occurrence in a twin population. PATIENTS AND METHODS: ASCA were analysed in 98 twin pairs with inflammatory bowel disease and were related to clinical phenotype and CARD15/NOD2 genotype. RESULTS: ASCA were more common in Crohn's disease than in ulcerative colitis (40/70 (57%) twins v 5/43 (12%) twins). Associations with ileal Crohn's disease, stricturing/penetrating behaviour, and young age, but not CARD15/NOD2 were confirmed. ASCA were found in 1/20 (5%) healthy siblings in discordant monozygotic pairs with Crohn's disease compared with 7/27 (26%) in discordant dizygotic pairs. Using the intraclass correlation coefficient (ICC), no agreement in ASCA titres was observed in discordant twin pairs with Crohn's disease, in monozygotic (ICC =-0.02) or dizygotic (ICC =-0.26) pairs. In contrast, strong agreement was seen within concordant monozygotic twin pairs with Crohn's disease (ICC = 0.76). CONCLUSIONS: These findings question the concept of ASCA as a marker of genetic susceptibility for Crohn's disease. The agreement in ASCA titres within concordant monozygotic twin pairs with Crohn's disease, suggests that the level of increase is genetically determined. We propose that ASCA are a marker of a response to an environmental antigen and that a specific gene(s) other than CARD15/NOD2 determines the level of response and perhaps also specific phenotypic characteristics.
Primary biliary cirrhosis in monozygotic and dizygotic twins: genetics, epigenetics, and environment.
Carlo Selmi, Marlyn J Mayo, Nancy Bach, Hiromi Ishibashi, Pietro Invernizzi, Robert G Gish, Stuart C Gordon, Harlan I Wright, Bruce Zweiban, Mauro Podda, M Eric Gershwin
Division of Rheumatology, Allergy, and Clinical Immunology, University of California at Davis, 95616, USA.
BACKGROUND & AIMS There is growing evidence that the interplay of genetic susceptibility and environmental factors leads to primary biliary cirrhosis (PBC). In particular, family members of an infected individual have up to a 100-fold higher risk of developing PBC. Although concordant rates for identical twins in other autoimmune diseases range between 25% and 50%, there are no such data on PBC. Accordingly, we evaluated the concordance of PBC in a genetically defined population of twin sets and evaluated the clinical characteristics between concordant subjects. METHODS We identified 16 pairs of twins within a 1400-family cohort followed up by several centers worldwide, evaluated the diagnosis of PBC in all individuals, and determined the zygosity of sets reported as identical by the analysis of 2 highly variable HLA class II regions and 5 short tandem repeats. RESULTS Eight of 16 sets of twins were monozygotic. In 5 of 8 monozygotic twin sets, both individuals had PBC (pairwise concordance rate, 0.63). Among the dizygotic twins (n = 8), no set was found to be concordant for PBC. Interestingly, the age at onset of disease was similar in 4 of 5 concordant sets of monozygotic pairs; however, there were differences in natural history and disease severity. CONCLUSIONS The concordance rate of PBC in identical twins is among the highest reported in autoimmunity. However, discordant pairs were identified. The data show not only the role of genetics but also emphasize that either epigenetic factors and/or environment play a critical role.