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    • #14498

      For anyone studying research against neurodegenerative diseases, it is striking to note the large number of studies which each claim to have identified a key element different from the others, and which would be a causative factor of the disease. In addition, many studies are contradictory.

      In epidemiology, Mendelian randomization is a method of using measured gene variation, known to express the causal effect of exposure to a disease in observational studies, without the need for a traditional randomized clinical trial. Better still, it allows us to escape traditional biases in epidemiological studies, such as reverse causation and confusion.

      Among the various genetic and environmental factors that have been identified as being associated with ALS, the association between blood lipid metabolites and ALS has recently received considerable attention. The associations between lipids and ALS are strong and comparable in strength to many risk factors for ALS previously identified.

      Scientists have studied the causal effects of four blood lipid traits on the risk of ALS:
      * high density lipoprotein,
      * low density lipoprotein (LDL),
      * total cholesterol,
      * and triglycerides.

      Taking advantage of the instrument variables from several large-scale association studies on the genome in European and Asian populations, the authors performed one of the most important and comprehensive Mendelian randomization analyzes to date on the causal relationship between lipids and ALS. Among the four lipids, they found that * only LDL is causally associated with ALS * and that a higher level of LDL increases the risk of ALS in European and East Asian populations.

    • #14512
      Dagmar Munn

      Did the researchers look at if the high LDL levels were present prior to diagnosis? Perhaps the process of early ALS in the body causes LDL levels to rise once the disease is established?

      Most athletes (fit persons) diagnosed with ALS have low LDL levels due to their diet and activity.

    • #14514

      Hi Dagmar,

      Did the researchers look at if the high LDL levels were present prior to diagnosis?”

      To try to answer this question, the scientists did not check people with ALS directly. What the scientists did in this study was comparing large sets of genomes expression (GWAS), one obtained from healthy people and the other from people being diagnosed with ALS. They did that for European and Asian people.

      The rough idea is that if a gene is expressed in the disease but not in the healthy genome, then there is some relation between the gene (or protein) and the disease. But this technique is not enough powerful to isolate only a few causal relations.

      In addition they did what is called Mendelian randomization. Mendelian randomization helps to find only a few factors that really causative and not some random coincidence.

      Perhaps the process of early ALS in the body causes LDL levels to rise once the disease is established?

      LDL rises when the liver has processed increasing amounts of glycerol and fatty acids. Glycerol and fatty acids are processed by our body when it needs more energy, the energy in excess is stored as fat.

      I have the impression that nobody can answer your question at the moment. What seems to me is that more and more things hint at ALS as a metabolic disease. What I mean by that is that cells and particularly motoneurons, need a lot of energy. I suppose (but some scientists already told that) that when there is some event that impair the capacity of the body to deliver this energy, then the cells fail. Some of those event has been hinted by some scientists as maybe defective genes such as mutation in SOD1 or C9orf72, which makes the cell having to use other mechanisms to repair the proteins, hence using more energy that usually. My personal guess is that also happens with infection or when the body is harmed. But at the moment nobody knows the etiology of ALS.

      In conclusion, I would say that Mendelian randomization is a great investigative tool, that is as powerful as clinical research to assert if there is some causal relation between a protein and a disease. And it is about humans not mice, so it can be translated more easily in drugs.


    • #14523
      Dagmar Munn

      Thank you for that helpful explanation.

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