Monday, August 1, 2011

Study : Lack of association between autism and four heavy metal regulatory genes

This study revisits the older idea that children with autism have an altered mercury (Hg) metabolism that makes them susceptible to even "safe" levels of Hg.  It did this by looking for an association between autism and mutations in four genes involved in Hg metabolism.

Not surprisingly, the study found no association.  I wouldn't make too much out of this result though, as interesting as it is.

For one thing, other larger genetic studies have taught us that most mutations and copy number variations that have a relation to autism only appear in a very small number of cases, typically less than one percent.  If that were the case here then the current study might not have included enough participants to find the association.

Another potential problem is that there is a difference between a genetic susceptibility and what the actual biological pathway is doing.  If you wanted to test the altered metabolism theory then the best way of doing so would be to devise some direct test of the metabolism.  Although I suspect that might be easier said than done.

In general, I think these sorts of genetic association studies are going to be useless until we come up with a way to separate out the different forms of autism.  Right now we are taking everyone with a label of "autism" and looking at them as a group and finding nothing.

That would be like taking anyone with any form of cancer and looking at them as a single group.  You wouldn't get any useful relationships that way either.  It is only when you separate out the different types and look at then individually that you get very useful results.

Lack of association between autism and four heavy metal regulatory genes.
Neurotoxicology. 2011 Jul 20.
Owens SE, Summar ML, Ryckman KK, Haines JL, Reiss S, Summar SR, Aschner M.
Department of Pediatric Toxicology, Vanderbilt University School of Medicine, Nashville, TN, USA.

Autism is a common neurodevelopmental disorder with genetic and environmental components. Though unproven, genetic susceptibility to high mercury (Hg) body burden has been suggested as an autism risk factor in a subset of children. We hypothesized that exposure to "safe" Hg levels could be implicated in the etiology of autism if genetic susceptibility altered Hg's metabolism or intracellular compartmentalization. Genetic sequences of four genes implicated in the transport and response to Hg were screened for variation and association with autism. LAT1 and DMT1 function in Hg transport, and Hg exposure induces MTF1 and MT1a. We identified and characterized 74 variants in MT1a, DMT1, LAT1 and MTF1. Polymorphisms identified through screening 48 unrelated individuals from the general and autistic populations were evaluated for differences in allele frequencies using Fisher's exact test. Three variants with suggestive p-values <0.1 and four variants with significant p-values <0.05 were followed-up with TaqMan genotyping in a larger cohort of 204 patients and 323 control samples. The pedigree disequilibrium test was used to examine linkage and association. Analysis failed to show association with autism for any variant evaluated in both the initial screening set and the expanded cohort, suggesting that variations in the ability of the four genes studied to process and transport Hg may not play a significant role in the etiology of autism.

PMID: 21798283

5 comments:

  1. "Not surprisingly, the study found no association. I wouldn't make too much out of this result though, as interesting as it is."

    I agree. The whole study concept seems as though they are studying the issues from afar. How solid are the assertions that the genes in question in fact regulate heavy metal. How was that ever determined?

    The type of autism in question is also very important with the distinctions between HFA and LFA with Intellectual Disability of particular significance.

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  2. The genetic susceptibility for transport of Hg as such is part of the situation , but not all. Even more, the genes tested in the OP are not the most important for inorganic mercury excretion- the main result of thimerosal injection and inorganic mercury impact.
    For example the manuscript cited LAT1 and DMT1 function in Hg transport, and MTF1 and MT1a. They identified and characterized 74 variants in MT1a, DMT1, LAT1 and MTF1, but they did not study for GSH genotypes.


    Arch Environ Occup Health. 2005 Jan-Feb;60(1):17-23.Genetic influences on the retention of inorganic mercury.Custodio HM, Harari R, Gerhardsson L, Skerfving S, Broberg K.
    . These results indicate that genotypes with decreased GSH availability for mercury conjugation affect the metabolism of inorganic mercury
    Even more the individual genetics is being studied today in terms of Heavy metal impact,and the study did not tested for crucial genes in Hg metabolism and oxidative stress

    Mutat Res. 2010 Oct;705(2):130-40.
    The relevance of the individual genetic background for the toxicokinetics of two significant neurodevelopmental toxicants: mercury and lead.
    Gundacker C, Gencik M, Hengstschläger M.
    The heavy metals mercury and lead are well-known and significant developmental neurotoxicants. This review summarizes the genetic factors that modify their toxicokinetics. Understanding toxicokinetics (uptake, biotransformation, distribution, and elimination processes) is a key precondition to understanding the individual health risks associated with exposure. We selected candidate susceptibility genes when evidence was available for (1) genes/proteins playing a significant role in mercury and lead toxicokinetics, (2) gene expression/protein activity being induced by these metals, and (3) mercury and lead toxicokinetics being affected by gene knockout/knockdown or (4) by functional gene polymorphisms. The genetic background is far better known for mercury than for lead toxicokinetics. Involved are genes encoding L-type amino acid transporters, organic anion transporters, glutathione (GSH)-related enzymes, metallothioneins, and transporters of the ABC family. Certain gene variants can influence mercury toxicokinetics, potentially explaining part of the variable susceptibility to mercury toxicity. Delta-aminolevulinic acid dehydratase (ALAD), vitamin D receptor (VDR) and hemochromatosis (HFE) gene variants are the only well-established susceptibility markers of lead toxicity in humans. Many gaps remain in our knowledge about the functional genomics of this issue. This calls for studies to detect functional gene polymorphisms related to mercury- and lead-associated disease phenotypes, to demonstrate the impact of functional polymorphisms and gene knockout/knockdown in relation to toxicity, to confirm the in vivo relevance of genetic variation, and to examine gene-gene interactions on the respective toxicokinetics. Another crucial aspect is knowledge on the maternal-fetal genetic background, which modulates fetal exposure to these neurotoxicants. To completely define the genetically susceptible risk groups, research is also needed on the genes/proteins involved in the toxicodynamics, i.e., in the mechanisms causing adverse effects in the brain. Studies relating the toxicogenetics to neurodevelopmental disorders are lacking (mercury) or very scarce (lead). Thus, the extent of variability in susceptibility to heavy metal-associated neurological outcomes is poorly characterized.

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  3. And other recent manuscript

    Biol Trace Elem Res. 2011 Jul 14. Altered Heavy Metals and Transketolase Found in Autistic Spectrum Disorder.
    Obrenovich ME, Shamberger RJ, Lonsdale D.
    Autism and autism spectrum disorder (ASD) are developmental brain disorders with complex, obscure, and multifactorial etiology. Our recent clinical survey of patient records from ASD children under the age of 6 years and their age-matched controls revealed evidence of abnormal markers of thiol metabolism, as well as a significant alteration in deposition of several heavy metal species, particularly arsenic, mercury, copper, and iron in hair samples between the groups. Altered thiol metabolism from heavy metal toxicity may be responsible for the biochemical alterations in transketolase, and are mechanisms for oxidative stress production, dysautonomia, and abnormal thiamine homeostasis. It is unknown why the particular metals accumulate, but we suspect that children with ASD may have particular trouble excreting thiol-toxic heavy metal species, many of which exist as divalent cations. Accumulation or altered mercury clearance, as well as concomitant oxidative stress, arising from redox-active metal and arsenic toxicity, offers an intriguing component or possible mechanism for oxidative stress-mediated neurodegeneration in ASD patients. Taken together, these factors may be more important to the etiology of this symptomatically diverse disease spectrum and may offer insights into new treatment approaches and avenues of exploration for this devastating and growing disease.

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  4. and this is very interesting
    Toxicol Environ Health A. 2011 Sep 15;74(18):1185-94.
    Ancestry of pink disease (infantile acrodynia) identified as a risk factor for autism spectrum disorders.
    Shandley K, Austin DW.
    Pink disease (infantile acrodynia) was especially prevalent in the first half of the 20th century. Primarily attributed to exposure to mercury (Hg) commonly found in teething powders, the condition was developed by approximately 1 in 500 exposed children. The differential risk factor was identified as an idiosyncratic sensitivity to Hg. Autism spectrum disorders (ASD) have also been postulated to be produced by Hg. Analogous to the pink disease experience, Hg exposure is widespread yet only a fraction of exposed children develop an ASD, suggesting sensitivity to Hg may also be present in children with an ASD. The objective of this study was to test the hypothesis that individuals with a known hypersensitivity to Hg (pink disease survivors) may be more likely to have descendants with an ASD. Five hundred and twenty-two participants who had previously been diagnosed with pink disease completed a survey on the health outcomes of their descendants. The prevalence rates of ASD and a variety of other clinical conditions diagnosed in childhood (attention deficit hyperactivity disorder, epilepsy, Fragile X syndrome, and Down syndrome) were compared to well-established general population prevalence rates. The results showed the prevalence rate of ASD among the grandchildren of pink disease survivors (1 in 22) to be significantly higher than the comparable general population prevalence rate (1 in 160). The results support the hypothesis that Hg sensitivity may be a heritable/genetic risk factor for ASD.

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  5. Thanks for the links Maria.

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