Environmental factors and multiple sclerosis

Studies in Canada have provided strong evidence that environmental factors act at a population level to influence the unusual geographical distribution of multiple sclerosis (MS). However, the available data accommodate more than one type of environmental effect. Migration studies show that changes to early environment can greatly affect risk, and there are recent indications that risk can be altered in situ. The rising incidence rates of MS in Canada implied by longitudinal increases in sex ratio place this effect in temporal context and narrow the candidates for mediating the effect of environment. Similarly, geographical patterns in Australia imply that modifiable environmental factors hold the key to preventing some 80% of cases. Genetic epidemiology provides overwhelming evidence that genetic background has an important complementary role. If genetic factors are held constant, the environment sets the disease threshold. Although these could be independent additive risk factors, it seems more likely that susceptibility is mediated by direct interactions between the environment and genes.     

Genetic and environmental factors and the distribution of multiple sclerosis in Europe

Background: The observation that the incidence of multiple sclerosis (MS) increases further from the equator has prompted considerable interest in the factors that might underlie this latitude gradient. Potential candidates include population frequencies of disease‐associated Human Leukocyte Antigen (HLA) alleles which are the major genetic component of MS susceptibility. Ultraviolet (UV) exposure and smoking have also been implicated as key environmental risk factors. Methods: We used multiple sources of published data on MS prevalence, HLA allele frequencies, UV index and cigarette smoking to assess the contributions of both nature and nurture to the distribution of MS within Europe. Results: We observed that HLA alleles unequivocally interact with a population‐wide level to determine disease risk. The UV index and smoking behaviour was also shown to correlate with disease distribution in Europe. For countries with HLA, UV and smoking data, these three factors were shown to account for 75% of the variance in MS prevalence. Conclusions: Genetic (HLA) and environmental (UV and smoking) risk factors thus interact in a complex manner with each other to determine a large proportion of MS susceptibility within Europe.     

Epidemiology and natural history of multiple sclerosis: new insights

PURPOSE OF REVIEW: The cause of multiple sclerosis remains elusive. We review recent epidemiological studies of genetic and environmental factors that influence susceptibility to the disease and its clinical course. RECENT FINDINGS: Genetic advances strengthen the association of multiple sclerosis with the human leukocyte antigen (HLA)-DRB1 allele and interferon-gamma polymorphisms and suggest that apolipoprotein E alleles play an important role. In the environmental realm, nested case-control studies show that prior Epstein-Barr virus exposure is overrepresented in multiple sclerosis. Smoking has been associated with both risk of multiple sclerosis and progressive disease. Vitamin D deficiency might tie together environmental clues with higher multiple sclerosis prevalence rates; dietary vitamin supplementation is also associated with reduced multiple sclerosis risk. Natural history studies demonstrated dissociation between relapses and disease progression, facilitated the ability to distinguish neuromyelitis optica and related syndromes from typical multiple sclerosis, and spawned the exploration of large datasets to model long-term disease activity. SUMMARY: Our understanding of the contributions of specific genetic and environmental factors that contribute to multiple sclerosis has improved. Further refinements will eventually allow powerful longitudinal studies to assess genetic and environmental interactions with implications for prediction of individual disease susceptibility, clinical course, and response to therapy.     

Progress in deciphering the genetics of multiple sclerosis

PURPOSE OF REVIEW: Multiple sclerosis is the most common neurological disease affecting young adults. The aetiology is unknown, although many clues point to an autoimmune inflammatory nature. Family studies of multiple sclerosis have shown familial aggregation, and therefore suggest that the disease entails a genetic component that has been widely studied. Some of the studies from the extensive literature in the field of multiple sclerosis genetics published in the past year are discussed here. RECENT FINDINGS: A number of the recent publications considered in this review have reconfirmed the well-known association with the major histocompatibility complex as well as identifying that there are at least two important loci within this region. These findings add further complexity to the role of the major histocompatibility complex in multiple sclerosis. Links to other diseases have been few for multiple sclerosis, but the association with diabetes in the Sardinian population and, perhaps, a 'protective' effect of Down's syndrome can now be added. Numerous candidate genes for susceptibility and disease-modifying effect have also been studied in the literature, but with few replications. Associations with components of the endocrine and the neuro-endocrine system have also been considered in this review along with the potential value of microarray analysis. SUMMARY: Multiple sclerosis is a complex trait that is associated with the major histocompatibility complex, although the form of this association may not be as straightforward as previously thought. Recent findings raise the possibility of an association with haplotype blocks rather than with single alleles. The finding of allelic heterogeneity within the major histocompatibility complex, as with the Sardinians, adds an additional layer of complexity. Genome scans for this and other autoimmune diseases have often been notably disappointing despite many claims for linkages. The reasons for the difficulty may encompass locus heterogeneity, small effects and phenocopies, among others. A variety of attempts to study more restricted populations are in progress, including rare individual pedigrees with high recurrence risk.     

Genetic epidemiology: the use of old and new tools for multiple sclerosis

We review the practical application of the tools for studying the genetic epidemiology of complex disease. Whole-genome association studies highlight the need to understand the genetic epidemiology. Elucidating the genetic basis of disease anticipated from these studies has been incomplete, and the importance of the environment and its potential interaction with genes cannot be overlooked. Multiple sclerosis yields several key lessons including how epistatic effects might overshadow the small effects of genes identified from whole-genome association studies. We reinterpret twin studies and demonstrate the use and advantages of adoptee, half-sibling and avuncular-pair studies. These show that the environment acts at a population level, strongly indicating epigenetic modifications to germline susceptibility. There is good reason to think that such interactions will be within the major histocompatibility complex, in which strong epistatic effects have already been demonstrated. Family-based data in multiple sclerosis are applicable to other neurological traits.     

Racial predilection in multiple sclerosis

Summary Comparisons between the geographic distribution of multiple sclerosis and the habitats of various racial groups showed that racial factors alone could not explain the increase in prevalence of the disease with latitude. Racially similar groups living in different areas had different frequencies of multiple sclerosis. Conversely, racially different groups, living in the same area, had similar prevalence rates of multiple sclerosis. Moreover, migrants moving from one environment to another at a young age (before adolescence) appeared to acquire the risk of multiple sclerosis of the new environment. These observations suggest that an environmental factor independent of race influenced the risk of acquiring multiple sclerosis. Nonetheless, some genetic factors associated with race may also be implicated, for example, HL-A tissue antigens (perhaps by virtue of a common association with the immune response (Ir) gene), the Gm and Inv immunoglobulin characteristics and skin pigmentary characteristics (perhaps through interactions between pigmentation and calcium metabolism). The specific environmental factors determining risk of multiple sclerosis and the mechanism whereby the racial (genetic) factors may influence risk remain to be elucidated.Supported in part by the National Multiple Sclerosis Society, Grant No. 683B4, the Minnesota Medical Foundation, and the Minneapolis Veterans Administration Hospital.     

Non-familial Alzheimer's disease is mainly due to genetic factors

This team takes the position that what is commonly referred to as non-familial Alzheimer's disease (AD) is predominantly due to genetic factors. Population-based studies suggest that genetic factors cause the majority of cases that begin after age 60. There are several lines of evidence supporting this position: Data from the Nun Study suggest that the risk for AD is largely established by early adulthood, implying that later adult exposures likely play only a small role in causation. Family studies show that first-degree blood relatives of persons with non-familial AD have a substantially increased risk of AD relative to controls. Twin studies suggest that the heritability of AD exceeds 60%. Environmental factors, such as socioeconomic status, education, and head injury, are strong risk factors for AD only in individuals with a genetic predisposition. The APOE genotype is a powerful risk factor for AD and accounts for as much as 50%. There are numerous other candidate genes with strong associations with AD that presumably explain the remaining population risk. This paper further reviews the mechanisms associated with AD causation for APOE and other candidate genes and implications for the development of prevention strategies.     

APOE and risk of cognitive impairment in multiple sclerosis

OBJECTIVES: The APOE gene polymorphism and the -491 A/T polymorphism in its regulatory region have been associated with an increased risk for developing Alzheimer's disease. We examined these polymorphisms in multiple sclerosis (MS) patients, to determine if a genetic predisposition may explain the risk for developing cognitive decline in MS. MATERIAL AND METHODS: Eighty-nine relapsing-remitting and secondary progressive MS patients underwent to a full neuropsychological battery as well as to determination of APOE and -491 A/T polymorphisms. Genetic analysis was also performed in 107 population controls. RESULTS: The APOE polymorphism was not associated with the risk of cognitive impairment in MS patients. The AA genotype of the -491 A/T polymorphism in the APOE regulatory region was more frequent in cognitively impaired than in cognitively preserved MS subjects. CONCLUSION: The AA homozygous state of the -491 A/T polymorphism of the APOE regulatory region is associated with cognitive impairment in patients with MS.     

Multiple sclerosis in Australia: socioeconomic factors.

The data from an epidemiological study on multiple sclerosis in Australia have been analysed to determine the relation between the prevalence of the disease and educational level, and the association between level of disability and employment status. There was a significantly higher frequency of multiple sclerosis in those who left school at an older age and achieved a higher educational level. The explanation of this finding remains speculative and may be related to genetic or environmental factors. The study confirmed the recognised association between moderate-severe disability and divorce-separation and lower rates of employment.     

High incidence and prevalence of multiple sclerosis in south east Scotland: evidence of a genetic predisposition

OBJECTIVE—To determine the incidence andprevalence of multiple sclerosis in the Lothian and Border Health BoardRegions of south east Scotland.
METHODS—Incidence study: all patients wereidentified in whom a diagnosis of Poser category probable or definitemultiple sclerosis was made by a neurologist between 1992 and 1995. Prevalence study: all patients known to have multiple sclerosis whowere alive and resident in the study area on 15 March 1995 were recorded.
RESULTS—The crude annual incidence rates ofprobable or definite multiple sclerosis per 100 000 population were thehighest ever reported: 12.2 (95% confidence interval (95% CI)10.8-13.7) in the Lothian Region and 10.1 (95% CI 6.6-13.6) in theBorder Region. A total of 1613 patients with multiple sclerosis wereresident in the study area, giving standardised prevalence rates per100 000 population of 203 (95% CI 192-214) in the Lothian Region and219 (95% CI 191-251) in the Border Region. Prevalent cases were morelikely than expected to have a Scottish surname (risk ratio 1.24, 95% CI 1.14-1.34).
CONCLUSIONS—Orkney and Shetland were previouslythought to have by far the highest prevalence of multiple sclerosis inthe world: about double that found in England and Wales. However, theprevalence in south east Scotland is equally high, suggesting that theScottish population as a whole has a genetic susceptibility to thedisease, and undermining the hypothesis that patterns of infectionspecific to small sparsely populated island communities are importantin the causation of multiple sclerosis.

     

Genetic analysis of multiple sclerosis

The increased recurrence risk within families indicates a role for genetic factors in the etiology of multiple sclerosis. Genes may influence susceptibility to the development of multiple sclerosis and the subsequent course of the disease. To date, associations have only been demonstrated consistently with class II major histocompatibility complex (MHC) alleles. The relatively low yield from additional candidate gene studies is only modestly advanced by several whole-genome linkage analyses, and by the first in a series of planned whole-genome linkage disequilibrium screens for allelic associations. The aims of linkage and association are to narrow the search for chromosomal regions encoding genes for multiple sclerosis and, with information from the human gene project, suggest new positional candidates. In time, it is expected that these genes will include some that confer susceptibility to the general process of autoimmunity, others that are specific for multiple sclerosis in all populations, some that act only in defined ethic groups, and those that determine particular phenotypes or shape the clinical course. These genetic analyses are predicated on the assumption that multiple sclerosis is one disease; a major part of future studies will be to resolve the question of disease heterogeneity in multiple sclerosis. When eventually in place, the potential of this genetic knowledge for improved understanding of the pathogenesis of multiple sclerosis and designing novel treatments is considerable.     

Observational analytic studies in multiple sclerosis: controlling bias through study design and conduct. The Australian Multicentre Study of Environment and Immune Function

Rising multiple sclerosis incidence over the last 50 years and geographic patterns of occurrence suggest an environmental role in the causation of this multifactorial disease. Design options for epidemiological studies of environmental causes of multiple sclerosis are limited by the low incidence of the disease, possible diagnostic delay and budgetary constraints. We describe scientific and methodological issues considered in the development of the Australian Multicentre Study of Environment and Immune Function (the Ausimmune Study), which seeks, in particular, to better understand the causes of the well-known MS positive latitudinal gradient. A multicentre, case-control design down the eastern seaboard of Australia allows the recruitment of sufficient cases for adequate study power and provides data on environmental exposures that vary by latitude. Cases are persons with an incident first demyelinating event (rather than prevalent multiple sclerosis), sourced from a population base using a two tier notification system. Controls, matched on sex, age (within two years) and region of residence, are recruited from the general population. Biases common in case-control studies, eg, prevalence-incidence bias, admission-rate bias, non-respondent bias, observer bias and recall bias, as well as confounding have been carefully considered in the study design and conduct of the Ausimmune Study.     

The genetic aspects of multiple sclerosis

The epidemiology of multiple sclerosis has been extensively investigated and two features have consistently emerged: marked geographical variation in prevalence and substantial familial clustering. At first sight, geographic variation would seem to imply an environmental cause for the disease, while familial clustering would seem to suggest that genetic factors have the predominant etiological effect. However, given that geographic variation in prevalence could result from variation in the frequency of genetic risk alleles and that familial clustering might result from shared environmental exposure rather than shared genetic risk alleles, it is clear that these crude inferences are unreliable. Epidemiologists have been resourceful in their attempts to resolve this apparent conflict between “nurture and nature” and have employed a whole variety of sophisticated methods to try and untangle the etiology of multiple sclerosis. The body of evidence that has emerged from these efforts has formed the foundation for decades of research seeking to identify relevant genes and this is the obvious place to start any consideration of the genetics of multiple sclerosis.     

Risk factors in relation to an emergence of bipolar disorder: a systematic review

Objective:  There is a consensus that genetic factors are important in the causation of bipolar disorder (BPD); however, little is known about other risk factors in the aetiology of BPD. Our aim was to review the literature on such risk factors – risk factors other than family history of affective disorders – as predictors for the initial onset of BPD.
Methods:  We conducted a literature search using the MEDLINE, PsycINFO and EMBASE databases. We selected factors of interest including demographic factors, factors related to birth, personal, social and family backgrounds, and history of medical conditions. The relevant studies were extracted systematically according to a search protocol.
Results:  We identified approximately 100 studies that addressed the associations between antecedent environmental factors and a later risk for BPD. Suggestive findings have been provided regarding pregnancy and obstetric complications, winter–spring birth, stressful life events, traumatic brain injuries and multiple sclerosis. However, evidence is still inconclusive. Childbirth is likely to be a risk factor. The inconsistency across studies and methodological issues inherent in the study designs are also discussed.
Conclusion:  Owing to a paucity of studies and methodological issues, risk factors of BPD other than family history of affective disorders have generally been neither confirmed nor excluded. We call for further research.     

Multiple sclerosis in stepsiblings: recurrence risk and ascertainment

Reports implicating specific transmissible agents in multiple sclerosis (MS) susceptibility continue to appear. We therefore re-evaluated MS risk in 687 step-siblings of 19 746 MS index cases. We found the risk of MS to be indistinguishable from that of the general population after diagnostic verification. These results are coherent with studies of adopted children, half siblings and conjugals, showing no risk attributable to the familial microenvironment. This family based genetic epidemiological approach found no trace of transmissibility other than genetic from one affected individual to another in the high prevalence area of Canada. This adds to existing data showing that the action of environment in influencing MS risk is operative at a population level.     

Demyelinating optic neuritis in children

Acute demyelinating optic neuritis in children can occur in isolation or be associated with acute disseminated encephalomyelitis, multiple sclerosis, or neuromyelitis optica. Clinical features, neuroimaging, cerebrospinal fluid findings, and long-term prognosis were reviewed in 26 children diagnosed with optic neuritis at the first presentation of demyelinating disease. The risk factors for the subsequent diagnosis of multiple sclerosis were analyzed. The mean duration of follow-up was 6.2 years. To date, 6 children have been diagnosed with multiple sclerosis (23%). An abnormal brain magnetic resonance imaging, older age, oligoclonal bands in cerebrospinal fluid, and elevated immunoglobulin G index were associated with multiple sclerosis outcome. Children with monosymptomatic optic neuritis and an abnormal brain magnetic resonance imaging had a higher risk for multiple sclerosis. These children should be monitored closely for the subsequent diagnosis of multiple sclerosis and can be considered for early preventive therapy.     

Argentine Patagonia: prevalence and clinical features of multiple sclerosis

There are few studies reporting multiple sclerosis prevalence rates in the Buenos Aires region, Argentina (latitude 34 degrees S) (between 12-18.5/100 000 inhabitants), and no studies have been performed in the larger region between parallels 36 degrees and 55 degrees S. The aim of this study is to determine the prevalence rates and clinical features of multiple sclerosis in residents of the Argentine Patagonia. Four cities from the region were selected for this study, giving a sample population of 417 666 inhabitants (approximately 24% of the total Patagonia population). 1(st) March 2002 was determined as prevalence day. Patients were ascertained using multiple case-finding methods. The point prevalence rate was 17.2/100 000 (17.2 age-adjusted to the world population). Prevalence rates were higher for women than for men, 22.1 versus 12.2/100 000 inhabitants (21.4 versus 12.7 sex-adjusted to the world population). The study population was mainly of European descent and mestizoes. Clinical features were similar to those reported in other countries. This study shows that Argentine Patagonia is a medium-risk area with no south-north gradient between parallels 55 degrees and 36 degrees S. The Patagonia population shows recent internal migration that makes it difficult to determine whether the exposure to potential risk factors has been long enough to modify the disease incidence.     

Vaccinations and risk of central nervous system demyelinating diseases in adults

BACKGROUND: Several case reports of the onset or exacerbation of multiple sclerosis or other demyelinating conditions shortly after vaccination have suggested that vaccines may increase the risk of demyelinating diseases. OBJECTIVE: To evaluate the association between vaccination and onset of multiple sclerosis or optic neuritis. DESIGN: Case-control study involving cases of multiple sclerosis or optic neuritis among adults 18 to 49 years of age. Data on vaccinations and other risk factors were obtained from computerized and paper medical records and from telephone interviews. SETTING: Three health maintenance organizations. PARTICIPANTS: Four hundred forty case subjects and 950 control subjects matched on health maintenance organization, sex, and date of birth. INTERVENTIONS: None. MAIN OUTCOME MEASURES: Onset of first symptoms of demyelinating disease at any time after vaccination and during specified intervals after vaccination (<1 year, 1-5 years, and >5 years). RESULTS: Cases and controls had similar vaccination histories. The odds ratios (95% confidence intervals), adjusted for potential confounding variables, of the associations between ever having been vaccinated and risk of demyelinating disease (multiple sclerosis and optic neuritis combined) were 0.9 (0.6-1.5) for hepatitis B vaccine; 0.6 (0.4-0.8) for tetanus vaccination; 0.8 (0.6-1.2) for influenza vaccine; 0.8 (0.5-1.5) for measles, mumps, rubella vaccine; 0.9 (0.5-1.4) for measles vaccine; and 0.7 (0.4-1.0) for rubella vaccine. The results were similar when multiple sclerosis and optic neuritis were analyzed separately. There was no increased risk according to timing of vaccination. CONCLUSION: Vaccination against hepatitis B, influenza, tetanus, measles, or rubella is not associated with an increased risk of multiple sclerosis or optic neuritis.     

Immunoablation and autologous hematopoietic stem cell transplantation (AHSCT) in multiple sclerosis

Numerous pathophysiological arguments supporting immunosuppression for multiple sclerosis have been collected during recent years. The relevance of intense immunosuppression, in terms of clinical benefit and early or late risk, remains a matter of discussion. Immunoablation followed by autologous hematopoietic stem cell transplantation (AHSCT) in multiple sclerosis uses intense immunosuppression, followed by reinjection of AHSC, a rescue procedure for the induced aplasia. This method targets disappearance of the immune disorder, and thus, in theory, the interruption of the disease course. Use of AHSCT to treat several types of autoimmune diseases has been performed with contrasted results. In multiple sclerosis, the experience has been gained over the past 10 years through short series of patients treated at a late stage of their disease. This article highlights the recent data of this particular treatment option in multiple sclerosis as well as the therapeutic aims that should be investigated in further trials.     

Genetic studies in Alzheimer's disease

Alzheimer's disease (AD), the most common cause of dementia in aged populations, is believed to be caused by both environmental factors and genetic variations. Extensive linkage and association studies have established that a broad range of loci are associated with AD, including both causative and susceptibility (risk factor) genes. So far, at least three genes, APP, PS1, and PS2, have been identified as causative genes. Mutations in these genes have been found to cause mainly early-onset AD. On the other hand, APOE has been identified to be the most common high genetic risk factor for late-onset AD. Polymorphisms in the coding region, intron, and promoter region of certain genes constitute another kind of genetic variation associated with AD. A number of other genes or loci have been reported to have linkage with AD, but many show only a weak linkage or the results are not well reproduced. Currently, the measurable genetic associations account for about 50% of the population risk for AD. It is believed that more new loci will be found to associate with AD, either as causative genes or genetic risk factors, and that eventually the understanding of genetic factors in the pathogenesis of AD will be important for our efforts to cure this illness.