Saturday, 24 October 2015

More MS genes identified

Lill CM, Luessi F, Alcina A, Sokolova EA, Ugidos N, de la Hera B, Guillot-Noël L, Malhotra S, Reinthaler E, Schjeide BM, Mescheriakova JY, Mashychev A, Wohlers I, Akkad DA, Aktas O, Alloza I, Antigüedad A, Arroyo R, Astobiza I, Blaschke P, Boyko AN, Buttmann M, Chan A, Dörner T, Epplen JT, Favorova OO, Fedetz M, Fernández O, García-Martínez A, Gerdes LA, Graetz C, Hartung HP, Hoffjan S, Izquierdo G, Korobko DS, Kroner A, Kubisch C, Kümpfel T, Leyva L, Lohse P, Malkova NA, Montalban X, Popova EV, Rieckmann P, Rozhdestvenskii AS, Schmied C, Smagina IV, Tsareva EY, Winkelmann A, Zettl UK, Binder H, Cournu-Rebeix I, Hintzen R, Zimprich A, Comabella M, Fontaine B, Urcelay E, Vandenbroeck K, Filipenko M, Matesanz F, Zipp F, Bertram L.Genome-wide significant association with seven novel multiple sclerosis risk loci. J Med Genet. 2015 Oct 16. pii: jmedgenet-2015-103442. doi: 10.1136/jmedgenet-2015-103442. [Epub ahead of print]

OBJECTIVE:A recent large-scale study in multiple sclerosis (MS) using the ImmunoChip platform reported on 11 loci that showed suggestive genetic association with MS. Additional data in sufficiently sized and independent data sets are needed to assess whether these loci represent genuine MS risk factors.
METHODS:The lead SNPs of all 11 loci were genotyped in 10 796 MS cases and 10 793 controls from Germany, Spain, France, the Netherlands, Austria and Russia, that were independent from the previously reported cohorts. Association analyses were performed using logistic regression based on an additive model. Summary effect size estimates were calculated using fixed-effect meta-analysis.
RESULTS:Seven of the 11 tested SNPs showed significant association with MS susceptibility in the 21 589 individuals analysed here. Meta-analysis across our and previously published MS case-control data (total sample size n=101 683) revealed novel genome-wide significant association with MS susceptibility (p<5×10-8) for all seven variants. This included SNPs in or near LOC100506457 (rs1534422, p=4.03×10-12), CD28 (rs6435203, p=1.35×10-9 a protien involved in T cell activation), LPP (rs4686953, p=3.35×10-8. Lipoma-preferred partner is a protien that may be involved in cell-cell adhesion and cell motility), ETS1 (rs3809006, p=7.74×10-9. A gene involed in T and B cell differentiation), DLEU1 (rs806349, p=8.14×10-12. Deleted in lymphocytic leukemia 1 ), LPIN3 (rs6072343, p=7.16×10-12.Lipin complexes are also thought to regulate gene expression as transcriptional co-activators in the nucleus ) and IFNGR2 (rs9808753, p=4.40×10-10. Interferon gamma receptor 2).
CONCLUSIONS:This study adds seven loci to the list of genuine MS genetic risk factors and further extends the list of established loci shared across autoimmune diseases.

There are over 100 genes identified that cxonfer MS susceptibility. These are immune associated genes or genes that affect the production of the gene products. This study adds 7 more in a large study. There is no MS gene but gene variants comer together in such a way that puts you at risk of developing MS. 

It has been  suggested that there are about 400-450 to find.  These are variants  that are perfectly normal genes that probably influence your ability to deal with infections. The consquence is risk of developing MS

7 comments:

  1. 450 genes is a lot ... so really could be the both viral and bacterial infections, and it already citing the EBV, possible triggers for the development of MS? Almost as in Guillain Barret Syndrome, or not?

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    1. There are 30,000 genes and many of them will play a role. There is no MS gene and they have found about variants of 150 genes so far and this accounts for about 40% of the genetic variability and they estimate there will be 300 more tvariants to find each with very small effects. The major one has been known for 40 years and is the HLA locus

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    2. Ok, but can we expect something from these studies or are they only of academic interest?

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    3. Regarding HLA locus: MHC is expressed by neurons. Does it mean that HLA genes are not restricted to immune response, but would have an effect in the way CNS functions, or malfunctions, in a particular individual?

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    4. MHC class I may be expresson on neurons but in CNS there is down regulation of MHC however the genetic link is with HLA-D which is a class II and this is not expressed by neurons usually and is usually restricted to the cells of the immune system

      Mol Cell Neurosci. 2013 Jan;52:117-27. doi: 10.1016/j.mcn.2012.11.004.
      MHC class I protein is expressed by neurons and neural progenitors in mid-gestation mouse brain. Chacon MA, Boulanger LM.

      Proteins of the major histocompatibility complex class I (MHCI) are known for their role in the vertebrate adaptive immune response, and are required for normal postnatal brain development and plasticity. However, it remains unknown if MHCI proteins are present in the mammalian brain before birth. Here, we show that MHCI proteins are widely expressed in the developing mouse central nervous system at mid-gestation (E9.5-10.5). MHCI is strongly expressed in several regions of the prenatal brain, including the neuroepithelium and olfactory placode. MHCI is expressed by neural progenitors at these ages, as identified by co-expression in cells positive for neuron-specific class III β-tubulin (Tuj1) or for Pax6, a marker of neural progenitors in the dorsal neuroepithelium. MHCI is also co-expressed with nestin, a marker of neural stem/progenitor cells, in olfactory placode, but the co-localization is less extensive in other regions. MHCI is detected in the small population of post-mitotic neurons that are present at this early stage of brain development, as identified by co-expression in cells positive for neuronal microtubule-associated protein-2 (MAP2). Thus MHCI protein is expressed during the earliest stages of neuronal differentiation in the mammalian brain. MHCI expression in neurons and neural progenitors at mid-gestation, prior to the maturation of the adaptive immune system, is consistent with MHCI performing non-immune functions in prenatal brain development. These results raise the possibility that disruption of the levels and/or patterns of MHCI expression in the prenatal brain could contribute to the pathogenesis of neurodevelopmental disorders.

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    5. Thank you, your answer clarifies the issue for me.

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  2. My question may sound easy, but it is not easy to answer unless you have gone through the bioinformatic analysis by yourself:
    MS susceptibility genes seem to be those that are directly involved in immune response, which makes sense. Is this because they specifically looked at that region? I wonder if there are other susceptibility genes out of the HLA region, but nobody looked for that.
    My question is easy to understand if you look at the EAE. I have read dozens of research papers that say MS is an autoimmune disease because this can be shown looking at the EAE. This is so dumb since the EAE was constructed assuming that MS is an autoimmune disease, so of course one would find that result, even so MS had nothing to do with a faulty immune system.
    Now again, is the bioinformatic analysis really that clear? I kinda doubt it...

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