Thursday, 11 January 2018

Guest post: Familial MS: do your genes seal your fate?

MS is not considered a hereditary disorder, as there is no specific gene transmitted from parent to child that causes the disease (not yet confirmed! We've covered the topic on the blog before). However, around 20% of people with MS report another family member with the condition and the risk differs depending on the degree of relatedness.




These pwMS have what we call “familial MS” (FMS). Therefore, it is really clear that the genetic component plays a crucial role in determining susceptibility to MS.

To give you an idea of how complex MS genetics can be, more than 200 genes have been shown to affect the risk of developing the disease. As previously posted on this blog, the strongest genetic association in MS is seen with a particular variant of the human leucocyte antigen (HLA-DRB1) gene, termed 1501. HLA is a group of genes in charge of regulating the immune system in humans (read more about that here). Accumulating evidence suggests that people from MS families are more genetically loaded with that variant than sporadic cases.  However, the exact genetic model of FMS is still in draft form. Having said that, a good start would be to estimate its worldwide prevalence, but is it even possible?

Harirchian et al. performed a systematic review and a meta-analysis to address this gap in the literature. The pooled prevalence of FMS was 12.6%, based on data collected from studies including a total of 14,619 pwMS from 1964 to 2014.  They found high heterogeneity between included studies and addressed such substantial heterogeneity using a random – effects model. These results, however, should be interpreted with caution. The heterogeneity across the included studies may have been affected by as many factors as is MS prevalence: study designs, sample sizes and environmental risk factors. Further studies are needed to more deeply explore the sources of such heterogeneity.

The increased risk of MS in relatives of affected individuals is undoubtedly related to genetic factors!  But let’s be clear: Having an MS gene does not mean you get MS and having MS does not strictly mean you pass it onto your children (read more about MS genes).

Harirchian MH, Fatehi F1, Sarraf P1, Honarvar NM2, Bitarafan S. Worldwide prevalence of familial multiple sclerosis: A systematic review and meta-analysis. Mult Scler Relat Disord 2017 Dec 24;20:43-47.

BACKGROUND: Several studies have suggested that the existence of a history of multiple sclerosis (MS) in family, is one of the predisposing factors for MS. Based on our knowledge, the review and estimation of the prevalence of familial multiple sclerosis (FMS) in the world has not been reported up to now. This study is a systematic review and a meta-analysis of FMS prevalence in the world.

METHODS: Two researchers searched "epidemiology" or "prevalence" or "incidence" and "familial multiple sclerosis" as relevant keywords in international databases such as PubMed, web of science and Scopus up to 2016. MedCalc Version 15.8 was used to estimate the pooled prevalence of FMS. (PROSPERO ID = CRD42016033016) RESULTS: From the 184 total articles found from 1954 to 2016, we pooled and analyzed the data of 17 final eligible studies, according to the inclusion criteria. The prevalence of FMS was estimated as 12.6% within a total sample size of 14,619 MS patients in the world as of 95% confidence interval (CI: 9.6-15.9).

CONCLUSION: We detected significant heterogeneity from Hungary to Saskatchewan for FMS prevalence that was not latitude and ethnicity dependent. This highlighted the accumulation effects of genetic and environment on FMS prevalence. Pooled prevalence of FMS in MS population was calculated 12.6% by random effect in the world.

Please let  me know any questions or comments you may have.

Saúl Reyes


20 comments:

  1. "Pooled prevalence of FMS in MS population was calculated 12.6% by random effect in the world"

    Does this translate to "12.6% of the MS population has a family member with MS?"

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    1. If this is even then it's a low percentage, ie, about 87,4% of pwMS has no family member with MS.

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    2. Thank you for your comments! Yes, 12.6% of MS patients reported at least one family member with MS. They pooled the results of studies from different countries. However, the prevalence of familial MS reported in the included studies varied widely from 2% in Hungary to 32.7% in Saskatchewan, Canada.

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  2. I'm having a hard time reading that bar graph -- what exactly does it show?

    What are "Index case", "proband", "relative of male proband", "relative of female proband", "recurrence rate", ....

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    1. Thank you for your question!

      The height of each bar represents the risk of MS in relatives of patients with MS.

      The graph shows that this risk differs depending on the degree of relatedness-i.e., It seems to be higher for first-degree relatives.

      It also shows that the risk of MS for certain categories of relatives may be influenced by the sex of the patient with MS: Blue bars for relatives of male patients with MS and red bars for relatives of female patients with MS.

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  3. My understanding (until reading this) is that one of the seminal studies in this field was at Melbourne Uni.

    I recall a conversation with someone (Daniel Donahue?) who was involved that hinged upon the *non genetic* associations. For example my wife, whose mother died of MS complications the very day I was diagnosed. Daniel observed that this kind of thing, in 20% (?) of pwMS, was beyond chance and would make "a whole new study"

    That observation was very much in my mind as I read your piece.

    With any luck I may be in a position to see that this work gets done.

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    1. Thank you, David. we definitely need more research on this topic!

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  4. Will it ever be possible to know the effect of genes on MS when some people go through life with only clinically silent damage, or undiagnosed symptoms? Perhaps all family members of people with MS would need to investigation, which is unlikely to be undertaken?

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    1. Thank you very much for your question. The effect of both genetic and environmental factors before MS becomes clinically evident is very important.
      Currently (and sadly) we cannot diagnose presymptomatic MS (not even with the latest revision of the McDonald Criteria). I can see your point and I think is very important because an earlier diagnosis leads to earlier treatment and better outcomes.
      We need to improve our ability to predict who will develop MS and our understanding of the prodromal stage of the disease. These at-risk individuals could be studied for genetic and environmental factors and perhaps become a potential target for early interventions to prevent the disease.

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  5. We know that families exist in very similar environments for a long period of time. How can we remove the impact of similar environments from the genetic numbers? I.e. One family might get more vitamin D from outside activities than a neighboring family.

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    1. Exactly Aidan.

      And about the genes found to cause problems in the absorption and synthesis of Vitamin D, they looked at it in the family groups, how many members, for example, carried the mutation?

      And how many would have been infected by EBV, asymptomatic and or developing mononucleosis?

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    2. That's a very interesting question...we know MS is a very complex disease and undoubtedly both genetic and environmental factors are important. Both types of risk factors have been widely studied and reported in the literature.

      From the genetic perspective and beside the HLA association already mentioned, during the last decade genome-wide association studies have enabled the discovery of more than 50 genetic variants (non-HLA-related) associated with MS.

      On the other hand, epidemiological studies have also reinforced the crucial role of environmental factors. The strongest associations have been found with Epstein-Barr virus, smoking and latitude/Vitamin D.

      You can actually try to remove the impact of environmental factors from the genetic numbers -e.g., by conducting genetic research with pwMS from different regions located at the same latitude. However, as Cinara has already pointed out, it would be more interesting to study the interplay between both types of risk factors -e.g., some studies have found that Vitamin D interacts with HLA-DRB1*1501 to influence its expression and hence the risk of MS.

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    3. Yes Dr. Saul, studies with these goals would perhaps be more accurate in answering various questions about MS, even about gender differences and the onset of MS, and MS in children and adolescents (which intrigues me as well).

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  6. So I have heard it is not a hereditary disease like diabetes for example. But there are apparently genes passed down. Nobody ever in my family was known to have MS. Then my daughter was diagnosed when she was 20. It was a shock to us! Three years later I came down with transverse myelitis ( One of my daughters first major symptoms,)
    And because my daughter had MS I was prescribed an MRI of the spine showing two lesions and then a brain scan which solidified diagnosis of MS. ( I was 57 at the time was no specific answer clue that anything was wrong with me.)Can’t help but think that some of this was a hereditary gene, but it also could be other factors environmental, son, virus perhaps . It’s nothing definite anyone can really prove. My other four children have other autoimmune type diseases except one actually, but none of them have MS except for me and my one daughter.

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    1. Ellen, I think you are right. MS is unlikely to result from a single causative factor. Not only genetic factors but also lifestyle and environmental factors are important in the onset and progression of the disease. Thanks for your comment!

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  7. I thought the results for twins fascinating. Especially the switching of prevalence for male/female between identical and non-identical twins.

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    1. Yes, it is fascinating! Many thanks for your comment!

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  8. I'm also interested in how studies differentiate between the genes and environmental factors. My personal example having a family with no MS, with my sister and I both diagnosed with MS within months of each other in our early 40s. My sister and I share no familial genes as she is adopted, but my twin brother is disease free.

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  9. I have run across two different cases of mother and daughter getting their diagnosis within the same year. One was two MS and the other was MS/NMO. Me and my mother got the same year diagnosis for MS/Hashimoto (this last can be just coincidence, I dont know if MS and Hashimoto can have same root). It seems that enviromental factors can really affect gene susceptibility.

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    1. Thank you for your comment! You may find these posts useful:

      http://multiple-sclerosis-research.blogspot.com/2014/08/thyroid-autoimmunity-or-lack-of-it-what.html

      http://multiple-sclerosis-research.blogspot.com/2017/05/a-reason-for-thyroid-problems.html

      http://multiple-sclerosis-research.blogspot.com/2014/02/clinic-speak-thyroid-disease-is-not.html

      http://multiple-sclerosis-research.blogspot.com/2013/04/autoimmune-thyroid-disease-in-ms.html

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