Cover Story: Family Genes & MS
Just One Piece of the Puzzle
Genetics and Environmental Risk Factors Associated with MS
Written by A. Dessa Sadovnick, PhD
Professor, Medical Genetics and Neurology, University of British Columbia
Director, MS Society of Canada endMS Western Pacific Regional Research
and Training Centre
Edited by Susan Wells Courtney
Reviewed by Jack Burks, MD
Multiple sclerosis (MS) is the most common cause of neurological disability in young adults, other than trauma. The etiology (cause) of MS remains unknown, but it is increasingly recognized that genes, environment, and interactions thereof are all important. Thus, while it is clear that genes have roles in MS susceptibility and probably disease progression, understanding and dissecting the relative roles of genes and environment remain topics of intensive research.
To assist with our understanding of genetics, we have included brief descriptions of a few basic terms.
DNA is deoxyribonucleic acid, which is a long, spiral-shaped molecule that carries our genetic information. Humans have approximately three billion base pairs of DNA. Just as letters of the alphabet are building blocks for words, DNA is the building block for genes (http://www.genetics.com.au).
Genes are the fundamental units of inheritance (or heredity) and are segments of a DNA molecule, containing all of the information required for the development of a living organism. Humans are estimated to have 30,000 to 40,000 genes.
Chromosomes are strands of DNA that contain genes. They determine the characteristics that are inherited from one generation to another. This structure is in the nucleus of each cell and carries all of the genetic information. Humans usually have 23 pairs of (or 46 total) chromosomes, including the XX and the XY pairs that determine a person’s gender. Simply put, a chromosome is similar to a book — a book is a collection of words, and a chromosome is a collection of genes (http://www.genetics.com.au/).
Karyotype is a group of symbols, using numbers, letters, and other images, to represent the chromosomal makeup of an individual.
Locus refers to a specific location on a chromosome. Each gene is located at a specific locus and the 30,000 to 40,000 human genes are carried on different chromosomes.
Genome is an organism’s full set of chromosomes, giving the entirety of genetic information.
Alleles are one of two or more alternative forms of a gene. These can occur at a certain locus (location) on a chromosome and can determine alternative, inherited characteristics (such as the color of one’s eyes or hair).
Linkage refers to the association of genes being located (“having loci”) close to one another on the same chromosome, which has a tendency to be associated with inherited characteristics.
Recombination is the process that creates new combinations of genes by shuffling the linear order of DNA.
Genotype is an individual’s genetic makeup.
Phenotype is the observable characteristics of an individual, which are determined by a combination of genotype and environmental factors.
EDITOR’S NOTE: This article contains many references, which are noted within the copy as a number in parentheses. Please refer to pages 30 and 31 for the articles associated with each reference. In addition, a website is sometimes included in parentheses within the copy; this specifies the source of a definition provided.
Each one of us inherits 50 percent of our genetic material (DNA) from our mothers and 50 percent from our fathers. Thus, within biological family members, there is more common DNA sharing than compared to the general, unrelated population. To illustrate, brothers and sisters (siblings) share 50 percent of their DNA, half-siblings (with only one parent in common) share 25 percent of their DNA, and first cousins share one eighth, or 12.5 percent, of their DNA. Sharing DNA increases the chance that family members will have similar genetic risks for disease.
Hermann Eichhorst was a German-Swiss internist and director of the medical clinic in Zurich. In the late 1800’s, he was the first to describe MS as “an inherited transmissible disease.”(1) By 1950, there were 85 reports of families with two or more members having “disseminated sclerosis”(2) (another name for multiple sclerosis that has not been used for decades). However, it is important to note that this report of 85 families with two or more members with MS was before standardized diagnostic criteria for MS were developed(3, 4) and before scientists had an understanding of the complexity of genes and chromosomes.
An allele is one member of a pair of genes, each inherited from one parent and is an “alternative” gene. An allele is located at a specific position on a specific chromosome (http://biology.about.com/od/geneticsglossary/g/alleles.htm). Until relatively recently, the standard approach for identifying “susceptibility alleles” (those genes which may increase one’s risk of disease) has been linkage and association studies.
Genetic linkage assesses the co-transmission of alleles (alternative genes) and disease within families. In the mid-19th century, an Austrian monk named Gregor Mendel was able to categorize patterns of genetic inheritance through gardening and observation of nature. Mendel’s laws are still used today to assist with our understanding of alleles, linkage, and the possible relationship between genes and disease.
GENETICS AND MS
In the absence of a solid understanding of the mechanisms that underlie MS, there are no compelling primary candidate genes for MS. Hence, the list of genes which have been investigated for MS susceptibility is long and continually expanding.
Linkage studies can detect a major susceptibility allele. These studies are less powerful when genetic effects are small, as suggested in MS. MS linkage screens highlight a locus (or location on a chromosome) with the strongest genetic effect in MS. This is the major histocompatibility complex (MHC), which is a cluster of genes on chromosome 6.
This cluster of genes (MHC) produces human lymphocyte antigens (HLA genes), which enable the immune system to respond appropriately to an antigen (determining if the antigen belongs to one’s own body or if it is foreign). Should anything go wrong with the unique order of the HLA alleles (alternate genes), self antigens could be misinterpreted as non-self (or foreign), triggering an inappropriate immune response and potentially leading to an autoimmune disorder.
Additionally, other genes must make considerably weaker contributions to MS disease risk. Learning about these other genes requires genetic association studies which are sensitive to differences in allele frequencies between individuals with MS and the general population.(6) This will also require a large number of genetic markers at different stages, as well as large sample sizes.(7) More recently, genome-wide association studies (GWAS) have become technically feasible. A consortium of more than 50 British groups, known collectively as the Wellcome Trust Case Control Consortium,(8) set the benchmark for genome-wide association studies in terms of sample size, quality control, and statistical analysis.
The first direct evidence for a relationship between genes and MS susceptibility came in 1972 when MS researcher C. Jersild and others(9) reported an association between MS and the major histocompatibility complex (MHC) on chromosome 6. A decade later, MS researcher G. C. Ebers and others provided insight into the familial nature of MS with a report of genotyping (identifying an individual’s genetic makeup) sibling pairs affected with MS for human lymphocyte antigens (HLA).(10)
The International Multiple Sclerosis Genetics Consortium published the first genome-wide association studies for MS in 2007.(11) The group screened 931 MS trios (two unaffected parents and one affected offspring). From this report, several genes appear to have a modest effect on suceptibility to MS(11) and these results have also been replicated in other studies. These genes include the interleukin 7 receptor alpha gene (IL7RA); interleukin 2 receptor alpha (IL2RA); C-type lectin domain family 16, member A (CLEC16A); and the CD58
genes. However, the strongest genetic effect in MS remains within the MHC,
although these findings are far from straightforward with complex gene-gene
interactions at play.(12, 13)
Despite ongoing research and advanced techniques, genotyping an unaffected individual cannot predict who, in the future, will develop MS. In addition, the complexity of gene-gene interactions, even within the MHC, makes understanding the roles of genes in MS even more complex.
What can be said at present is that genes have some role in susceptibility to MS but exact mechanisms remain unclear. Nevertheless, genetic epidemiological studies in MS have clearly shown that the increased frequency of MS seen within families is a result of relatives sharing DNA and not the common family environment.
FAMILY MEMBERS AND MS
The most widely accepted definition of genetic epidemiology is “a science which deals with the etiology, distribution, and control of disease in groups of relatives and with inherited causes of disease in populations”. In the 1980’s, it was recognized objectively for the first time that first-degree relatives (parents, children, and siblings) of MS patients had the disease more often than more distant relatives and those who did not have a relative with MS.(14) Nevertheless, “familial aggregation,” or the grouping of a specific disease (i.e., MS) within a family, is not necessarily related to genetic sharing. Hence, it is important to test the relative roles of genes and environment (nature versus nurture) within MS families.
A number of strategies has been used to separate the environmental components from the genetic components underlying MS susceptibility. To date, several genetic epidemiological studies have been conducted through the longitudinal, population-based Canadian Collaborative Project on Genetic Susceptibility to MS (CCPGSMS).
Based on earlier work on familial rates,(14) first-degree relatives were shown to have a recurrence risk (RR) for MS of 3 to 5 percent. Recurrence risk in medical genetics is defined as “the chance that a genetic (inherited) disease present in the family will recur in that family and affect another person (or persons)” (http://www.medterms.com/script/main/art.asp?articlekey=5257).
Adoptees and their adoptive relatives were studied with respect to MS risks.(15) The study focused on individuals who were adopted as infants by persons to whom they were not biologically related (e.g., no DNA sharing), and the adoptee subsequently developed MS.
When these non-biological relatives of adoptees with MS were studied, the occurrence of MS reflected the rate for the general population and in no way approached the estimated 3-to-5 percent recurrence risk reported for biological brothers and sisters. Thus, being raised in the same household as someone destined to develop MS does not increase your own risk to develop MS. The risk was no different than that for the general population if you did not share DNA.
Of importance is the fact that these findings were shown again with stepsiblings,(16) half-siblings,(17, 18) and spouses,(19, 20) according to the Canadian Collaborative Project’s population. While stepsiblings (as in “The Brady Bunch”) can be raised together, they do not share any genetic material. A study of the Canadian Collaborative Project’s population looked at 687 stepsiblings of individuals with MS and found that only one stepsibling had MS, which is the same rate as expected for the general population.(16)
Half-siblings(17, 18) share only one parent in common (a mother or a father) and thus only share 25 percent of their genetic material, compared to full siblings (with both parents in common) who share 50 percent of their DNA. Half-siblings share their childhood environment to various degrees if “raised together,” or “raised apart” in separate environments, depending on the family situation. Data from the Canadian Collaborative Project clearly show that the risk for half-siblings to develop MS is approximately 2 percent, regardless of whether they were raised apart or together. This reflects 25-percent DNA sharing, regardless of environmental sharing.
Studies of MS in couples(19, 20) have shown that “spouses” (longterm sexual partners) of MS patients develop MS no more often than the general population.
Thus, taken together, adoptee, stepsibling, half-sibling, and couple studies clearly show that it is the sharing of DNA and not the shared family environment that is responsible for the increased occurence of MS within families compared to the general population.
In very general terms, there are two kinds of “environments” which individuals can share. The first is the “common family environment” as discussed earlier in this article, and the second is the more wide-spread, population-based environment. While DNA sharing is key in families with more than one member with MS, this does not mean that MS is entirely a genetic disease. In fact, this is confirmed by twin studies(21) among other evidence.
Monozygotic (identical) twins share 100 percent of their genetic material and yet, if one female monozygotic (MZ) twin has MS, the risk for the co-twin is 340 in 1,000, or 34-percent recurrence risk.(21) The fact that only one-third of identical twins will both have MS if one twin has the disease, suggests that environmental factors also play a role. Some environmental risk factors for MS must act at a very early time period, as some factors at the beginning of life (e.g., in utero) are determinants of the future MS risk.
Incidence is the number of newly diagnosed cases during a specific time period (http://www.medterms.com/script/main/art.asp?articlekey=11516) and prevalence is the number of cases of a specific disease present in a given population at a certain time. In general, within regions of a temperate climate, the incidence and prevalence of MS increases with latitude (or distance from the equator).(22) The clearest example of this effect is seen in Australia.(23) The prevalence of MS in Hobart (southern Australia; temperate climate; farther from the equator) is 75.6 per 100,000 compared with a prevalence of 11 per 100,000 in northern Queensland (northern Australia; tropical climate; closer to the equator). Some of the geographical distribution of MS can be explained on the basis of ethnicity (or race) and genetic factors,(24) but latitude remains the strongest factor for risk after taking race into consideration.(25)
Place of Birth
The effects of migration between low- and high-risk geographic regions for MS (i.e., from Asia or Japan or theMediterranean, to Canada or the northern United States) have been examined in several populations. These studies consistently show that MS risk is influenced at least to some extent by a person’s country of origin.(26) This is highlighted by the observation that first-generation Afro-Caribbean and Asian citizens (individuals living in countries closer to the equator) relocating to Britain(27) and Canada (countries at higher latitudes, farther from the equator), have a much lower incidence of MS than the next generation who are born in the high-risk geographic regions. It is important to point out that immigrants, while changing their geographic place of residence, obviously do not change their genetic makeup.
An increase in the incidence of MS specifically in women has been documented.(25, 28, 29) A recent Canadian Collaborative Project study was able to show that this increase was real and not merely a reflection of improvements in case identification and diagnosis.(30) Year of birth was shown to be a significant predictor of the female-to-male (F:M) gender ratio of MS over the period of birth years from 1931 to 1980, with the ratio increasing from 1.9 (almost twice as many women as men) to 3.2 (more than three times as many women as men) during this time.(30) There was no evidence to suggest decreasing incidence in males,(30) but rather that the rate of MS in males is more constant over time. This observed increase of women with MS has since been confirmed in a number of other populations (in addition to that of the Canadian Collaborative Project).(31 to 33)
In developed countries, strong evidence of steady rises in the incidence of allergic and some autoimmune diseases parallels a decreasing incidence of childhood infections. Antibiotics, vaccinations, or improved hygiene and better socioeconomic conditions have been credited. The “hygiene hypothesis” proposes that early life infections help to reduce the risk of allergic and autoimmune disorders.(34) Simply put, the earlier in life you are exposed to infections, the sooner your autoimmune system becomes effective. Thus, it is consistent with this hypothesis that, for example, first-born children are less exposed to infection at an early age than later-born children, who are exposed through their older brothers and sisters. However, using data from the Canadian Collaborative Project, it was found that one’s position in birth order does not impact the risk to develop MS.(35)
Later-Acting Environmental Factors
Because the average age of onset of MS is approximately 30 years, there is a long time period from birth to MS diagnosis for the environment to influence one’s risk of MS. Migration data highlights adolescence as being important, further illustrated by additional associations, such as the age of menarche (beginning menstruation) and adolescent obesity with the onset of MS.(36, 37) Other epidemiological studies (e.g., occupational data) suggest influences of the environment extending into adult life.(38) The risk of developing MS is age-related and drops off dramatically after the age of 50,(39) so whatever risk factors that do play a role must be unable to stimulate the development of MS after a certain point of time.
Suspected Environmental Risk Factors in MS
Although the above data point to the time when environmental factors are likely to increase the risk of MS, we still do not have absolute evidence for the identity of environmental factors involved. To follow is a summary of the factors with the strongest evidence for involvement in MS etiology, namely Epstein-Barr virus (EBV), vitamin D, and smoking.
Epstein-Barr Virus (EBV): There have been many reports suggesting an association between one or more infectious diseases and MS.(40, 41) However, the epidemiological data associating EBV infection with MS has been supported through numerous studies.
Virtually all subjects with MS (more than 99 percent) are infected with EBV compared to approximately 94 percent of age-matched control subjects (individuals without MS).(42) The corollary to this is that MS is very rare in adult subjects who are not infected with EBV; the relative risk of getting MS if you are EBV negative is very low.(42, 43) Further supporting a role for EBV in MS is the finding that individuals with a history of infectious mononucleosis (IM) have an increased risk of developing MS. Infectious mononucleosis is an illness that is caused by EBV. A systematic review and meta-analysis of 14 case-control and cohort studies (those which observe a group of people over time) reported a relative risk of MS after infectious mononucleosis of 2.3,(44) which is more than twice the risk of MS in the general population.
Vitamin D: Sunlight exposure and associated vitamin D status are potential explanations for the link between geography (in terms of latitude) and the incidence of MS.(45) Levels of past sun exposure during childhood and adolescence are inversely related to MS susceptibility.(46) This means that as one’s level of sun exposure during childhood and adolescence increases, the risk of MS susceptibility decreases. Questionnaire-based studies are prone to bias or inaccuracies as individuals answer questions according to their own perceptions and what they are able to recall from the past. Nonetheless, an effect of sun exposure on MS could be confirmed when using the objective measure of long-term skin damage from the sun.
Experimental and epidemiological data suggest that vitamin D is the connection to the sunlight effect. It was noted many years ago that the consumption of fatty seafood and cod liver oil in Norway – both rich sources of vitamin D – provided protection against the risk of MS,(47) although this outcome may also arise from the biological effects of omega-3 fatty acids. A prospective cohort study (observing groups of people over time) found that taking vitamin supplementation which included vitamin D was associated with an approximate 40-percent reduction in the risk of developing MS.(48) However, the amounts of vitamin D taken via vitamin supplementation in this study are thought to be insufficient to make much change in circulating vitamin D levels,(49) and effects of multivitamin intake may be misinterpreted as other factors could contribute to the observed reduction of MS risk.
The strongest evidence of a role for vitamin D comes from a prospective, case-control study in military personnel in the United States who had bloodserum samples systematically stored. This study showed that a lower risk of MS was associated with high serum vitamin D levels (specifically, 25-hydroxyvitamin D).(50) In Caucasians, the risk of developing MS decreased significantly with increasing vitamin Dlevels in the blood.(50)
Smoking: A recent meta-analysis of several completed studies gave a combined risk estimate for developing MS of 1.51 for “ever smoking” versus “never smoking,”(51) which means that smoking may increase one’s risk of MS by 50 percent. Earlier studies showed a dose-dependent (i.e., number of cigarettes smoked) relationship to MS risk.(52) A Swedish study showed that the use of snuff (a form of tobacco that is inhaled through the nose) does not increase the risk of MS. This suggests that factors present in smoked tobacco, rather than just the route of administration, is important.(53)
In summary, the etiology of MS is still unclear, but it is now recognized that the degree of complexity is beyond what was previously believed – even as recently as 10 to 15 years ago. The complexity comes from the realization that one cannot predict a person’s risk of developing MS just by considering the individual effects of single factors alone. Genes, environment, post-genomic modifications, and chance all appear to be involved and to interact with one another.
The associated risk factors for MS appear to come together to form a “causal cascade,” where several things need to occur before developing MS. Factors largely defined from birth (i.e., gender, HLA status, place of birth) appear to need certain environmental factors (vitamin D deficiency, late EBV exposure) to provoke the development of the abnormalities required that subsequently can lead to MS. The effect of where someone lives in early life (in relation to the equator and latitude) and associations with infectious mononucleosis in adolescence would support the notion that vitamin D deficiency precedes EBV infection.(54) However, the Australian migration data and the evidence for vitamin-D related influences on risk during adult life (e.g., outdoor occupations decrease MS risk)(55) suggest that vitamin D has the potential to play a role over a wider time period.
It is not yet clear whether MS susceptibility is a result of a chain of adverse factors that need to occur in a specific order and are dependent on one another (e.g., a domino effect), or whether risk factors are independent of each other but each adds to the collection and strength of factors that push an individual closer to the threshold of developing MS. Since a single cause for the development of MS has not been found in all MS patients, this suggests that “causal pathways” (the events leading to MS) will likely differ in individuals. Should this be the case, this could support the hypothesis where independent risk factors add up, pushing someone closer to developing MS or the hypothesis that the interaction of risk factors is critical.
Although some progress has been made, our understanding of the stages involved in the development of MS is still limited. Further study is vital to identifying and understanding the causes of MS. Once we have these answers, we can work to prevent its occurrence, create more effective treatments, and hopefully one day cure this challenging disease.
Commonly Asked Questions and Answers
1. Can my family members also “inherit” MS if I have MS?
MS itself cannot be directly inherited as is the case for a single gene disorder (such as cystic fibrosis and Huntington’s disease). However, a genetic susceptibility (“risk”) to develop MS does exist. This is highlighted by the fact that the increased frequency of MS among family members only holds true for family members who share genetic material (DNA). Family members who grow up together in the same environment but do not share genetic material (e.g., adopted brothers and sisters, as well as stepsiblings) have no increased risk to develop MS compared to the general population.
Conversely, if you do share genetic material, your risk does not change whether you were “raised together” or “raised apart” from the family member who eventually develops MS. The risk of MS among family members can be influenced by several factors including gender, ethnicity, the country/location of where one grows up, age, and biological relationship (percentage of DNA sharing) to other family members with MS, etc.
If you are concerned about your risk to develop MS because you have other family members with MS, or you have MS and are worried about the risk of passing it on, please contact genetic counseling services in your area for more information (http://www.nsgc.org; ccmg-ccgm.org).
2. Can my child catch MS if he or she hugs, kisses or shares a cookie with someone who has MS?
MS is not a transmissible disease and cannot be caught by human contact either during childhood or adulthood. This is clearly shown by a variety of genetic epidemiological studies which have repeatedly shown this finding in separate groups (e.g., adoption studies, couples studies, and others as discussed earlier in this article).
3. If my relative also develops MS, will he or she have the same clinical course of the disease that I do?
The clinical course of MS does not appear to “run true” in families if more than one family member is affected. Thus, if you develop MS, you cannot assume that you will have the same disease course as your mother, sister, or other relative with MS.
4. Can you predict, in advance of any signs or symptoms, who is destined to develop MS in the future?
There are no definitive biomarkers for MS. A bio-marker can be “anatomic, physiologic, biochemical, or molecular parameters associated with the presence and severity of specific disease states” (http://www.biomarkers.org/NewFiles/faqs/ definition.html#Anchor-What-35882). This means that if you study two large groups – for example, 1,000 MS patients and 1,000 unaffected controls – you may find “risk factors” occurring more often in the affected group than in the controls, but these risk factors will still exist in both groups. Thus, you cannot test an unaffected person for a specific biomarker (such as HLA genotype or low levels of vitamin D) and then state with any certainty whether a person with or without this factor will end up being affected or unaffected by MS in the future. Hence we use the term “susceptibility” with respect to MS risk rather than “causal.”
5. Can MS be prevented?
There is no way to prevent MS. No fault can be assigned if someone develops MS. There are no clear protective preventive measures that can be taken.
6. If I have MS, should I have children?
Much is still to be known about reproduction and MS. If you have MS and are planning to get pregnant or to father a child, you may want to discuss various issues involved in the decision-making process with your healthcare professionals. There is no right or wrong answer. Each couple must make their own informed decision. Topics to consider include the risk of pregnancy on MS, the risk of MS on pregnancy, possible risks of MS therapy at the time of conception and/or gestation, psychosocial issues, and the long-term commitment to raising a child (see references 56 and 57). Please note that while several factors should be considered in advance, many individuals with MS have been able to successfully raise children and enjoy the countless benefits of a loving family. For more information on pregnancy and raising children with MS in the family, individuals may speak with one of MSAA’s Helpline consultants at (800) 532-7667.
7. If I am from a region where MS is rare (i.e., Shanghai, China) and am Chinese, do I change my risk to develop MS when I move to Canada? Do my genes change?
Although your genes do not change when you move, your environment does. Thus, by moving from Shanghai to Canada, you may have a higher risk to develop MS than if you stayed in Shanghai. This may be due to different environmental exposures as well as genetic and environmental interactions.
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Additional resources for definitions and information include:
Ben-Zacharia A, Morgante L, The Basics of Genetics in Multiple
Sclerosis, Consortium of MS Centers, March 28, 2005 (published
Dorland’s Illustrated Medical Dictionary, 31st edition, Saunders
Elsevier, Philadelphia, PA.