Vitamin D metabolic gene variants and risk for autism

I was really rather happy to see the "preliminary evidence" reported by Rebecca Schmidt and colleagues [1] when it came to examining whether selected vitamin D metabolic gene variants might show linkage to autism spectrum disorder (ASD) based on data derived from the CHARGE initiative.

For quite a while now I've discussed the various peer-reviewed science on the topic of vitamin D deficiency / insufficiency with autism in mind on this blog (see here and see here for example). Specifically, how a diagnosis of ASD seems to offer little protection against issues with vitamin D appearing and what that could mean for important issues such as bone health (see here) for example.

A key component that seemed to be missing from the growing volume of research looking at vitamin D and autism was some discussion about whether the genetics of vitamin production and usage might offer some further clues to how vitamin D might more directly be 'linked' to [some] autism. Schmidt et al have started to put some flesh on to the scientific bones in this area following their previous research discussions on vits and SNPs with autism in mind (see here) .

So: "Maternal, paternal, and child DNA samples for 384 (81%) families of children with ASD and 234 (83%) families of TD [typically developing] children were genotyped for: TaqI, BsmI, FokI, and Cdx2 in the vitamin D receptor (VDR) gene, and CYP27B1 rs4646536, GC rs4588, and CYP2R1 rs10741657." In effect, researchers looked for potential genetic 'issues' with the vitamin D receptor (VDR) gene that have previously been linked to various health issues. They found some potentially interesting information including: "Paternal VDR TaqI homozygous variant genotype was significantly associated with ASD in case-control analysis." Homozygous by the way, refers to the concept of zygosity and the fact we have pairs of chromosomes. Further: "A significant association between decreased ASD risk and child CYP2R1 AA-genotype was found in hybrid log-linear analysis."

This is early days research insofar as the genetics of vitamin D and autism only being mentioned once before in the research literature as per the report from Yan and colleagues [2]. I'm excited at the Schmidt data but am not going to go all out on this very preliminary inspection of vitamin D receptor gene functioning without further large-scale replication and validation studies being carried out including discussions on things like cognitive ability in light of other recent data [3]. Whilst we are however, on the topic of vitamin D and its potential extra-skeletal activities, I'm minded to also bring in the paper by Kaneko and colleagues [4] and their results implying that "vitamin D affects brain serotonin concentrations" with mention of autism among other labels. Reporting on a particularly interesting enzyme - tryptophan hydroxylase (TPH)2 - which has an important role in serotonin metabolism (see here) I'll be watching closely on how vitamin D research with autism in mind also develops in this area.

And then there are the Raftery results [5] to bring to your attention putting further scientific flesh on to the bones about the possibility of a relationship between vitamin D levels and intestinal permeability (see here). Given what has been mentioned about 'leaky gut' and autism in the peer-reviewed literature so far (see here) one might also add this to further investigations in this area...

Music: I am the Monarch of the Sea.

----------

[1] Schmidt RJ. et al. Selected vitamin D metabolic gene variants and risk for autism spectrum disorder in the CHARGE Study. Early Hum Dev. 2015 Jun 11;91(8):483-489.

[2] Yan J. et al. Vitamin D receptor variants in 192 patients with schizophrenia and other psychiatric diseases. Neurosci Lett. 2005 May 20-27;380(1-2):37-41.

[3] Jorde R. et al. Vitamin D and cognitive function: The Tromsø Study. J Neurol Sci. 2015 Jun 7. pii: S0022-510X(15)00350-0.

[4] Kaneko I. et al. 1,25-Dihydroxyvitamin D regulates expression of the tryptophan hydroxylase 2 and leptin genes: implication for behavioral influences of vitamin D. FASEB J. 2015 Jun 12. pii: fj.14-269811.

[5] Raftery T. et al. Effects of vitamin D supplementation on intestinal permeability, cathelicidin and disease markers in Crohn's disease: Results from a randomised double-blind placebo-controlled study. United European Gastroenterol J. 2015 Jun;3(3):294-302.

----------

Schmidt RJ, Hansen RL, Hartiala J, Allayee H, Sconberg JL, Schmidt LC, Volk HE, & Tassone F (2015). Selected vitamin D metabolic gene variants and risk for autism spectrum disorder in the CHARGE Study. Early human development, 91 (8), 483-489 PMID: 26073892

Maternal recall vs. medical records: implications for autism research

I don't want to dwell too much on the findings reported by Paula Krakowiak and colleagues [1] talking about the accuracy of "maternally-reported diabetes and hypertensive disorders, and reliability of BMI [body mass index] measurements during periconception and pregnancy compared with medical records when mothers are interviewed 2-5 years after delivery" but they are potentially important.

With authors such as Krakowiak and Irva Hertz-Picciotto on the paper in question, those who follow the autism research scene might have already made the connection back to the CHARGE (CHildhood Autism Risks from Genetics and the Environment) study (beincharge!) as the source of the current data. Indeed from CHARGE, findings such as a link between maternal obesity and offspring autism risk (see here) and maternal diabetes and autism (see here) have been previously discussed on this blog. For the most part, examination of such factors linked to subsequent offspring autism diagnosis has been through self-report and post-event questioning which potentially opens up such studies to various forms of bias.

The results from Krakowiak et al seemed to suggest when questioned about such issues: "self-reported diabetes and hypertensive disorders during periconception and pregnancy show high validity among mothers." Further: "Recall of pre-pregnancy BMI is reliable compared with self-reported values in medical records." In other words, still with some caution, families involved in initiatives such as CHARGE can and do quite accurately communicate their medical history. Of course this is not the first time that science has shown parentally-derived medical information to be pretty accurate when it comes to autism as per the Gorrindo findings [2]: "sensitive to the existence, although not necessarily the nature of" gastrointestinal issues related to autism (see here). That being said, developmental history recall is still subject to some forms of bias (see here).

There's little more for me to say about this topic aside from highlighting how: "Multiparity was associated with higher discrepancies in BMI and misreporting of hypertensive disorders" suggestive that 'the state of having borne a number of children' might interfere with recall in these areas. Still, when it comes to asking parents about their health and wellbeing before, during and after the birth of their children with autism research in mind and without over-generalising, one might be a little less critical of the value of the information received.

Music to close: The Flaming Lips and Race For The Prize. Scientists... don't race for the prize!

----------

[1] Krakowiak P. et al. Maternal Recall Versus Medical Records of Metabolic Conditions from the Prenatal Period: A Validation Study. Matern Child Health J. 2015 Feb 6.

[2] Gorrindo P. et al. Gastrointestinal dysfunction in autism: parental report, clinical evaluation, and associated factors. Autism Res. 2012 Apr;5(2):101-8.

----------

Krakowiak P, Walker CK, Tancredi DJ, & Hertz-Picciotto I (2015). Maternal Recall Versus Medical Records of Metabolic Conditions from the Prenatal Period: A Validation Study. Maternal and child health journal PMID: 25656730

Pesticides and autism: chapter II

I've labelled this entry a chapter II post reflecting some continued interest in how agricultural pesticide exposure might fit into autism research (see here for the chapter I post). In that previous post, I talked about various issues such as the old correlation-is-not-necessarily-causation mantra and indeed, how use of something like galantamine for cases of autism spectrum disorder (ASD) [1] might present something of a paradox for certain types of pesticides being involved in the condition, as a function of its similar acetylcholinesterase inhibitor activity (albeit reversible).

Altogether Now? @ Wikipedia 

Continuing the pesticide theme, I'm talking today about the paper by Janie Shelton and colleagues [2] (open-access) and their results strengthening "the evidence linking neurodevelopmental disorders with gestational pesticide exposures, and particularly, organophosphates". Some of the press on this study be seen here.

Based on data derived from the CHARGE study (beincharge!) authors reported that maternal residence during pregnancy close to locations undertaking "agricultural pesticide application" might elevate the risk of offspring autism; something previously discussed by some of the authors [3]. Results from CHARGE by the way, have already talked about other environmental associations with autism risk such as air pollution (see here). This initiative also recently confirmed what many people already knew in saying the gastrointestinal (GI) symptoms seem to be over-represented in cases of autism (see here).

The Shelton paper is open-access but here are a few pointers:

• With an authorship list of the great and the good associated with CHARGE, commercial pesticide use data was linked to the addresses of mothers when pregnant for groups diagnosed with autism (n=486) or developmental delay (DD) (n=168) compared with asymptomatic controls (n=316) living in California, USA. As alluded to in a post on that most undesirable of jobs - the commercial pesticide applicator - commercial pesticide use tends to be quite tightly regulated as a result of the potential for health effects when mis-used.
• Various models and algorithms built up a statistical picture of different classes of pesticides, their use and when and where they sprayed. The authors aimed to ascertain whether gestational exposure was linked to autism risk and whether there were "specific windows of vulnerability during gestation". 
• Results: bearing in mind there were quite a few estimates built into this study, a few points are worth mentioning. "Proximity to organophosphates at some time during gestation was associated with a 60% increased risk for ASD". Organophosphate (OP) pesticides were also "the most commonly applied agricultural pesticide near the home during pregnancy" and chlorpyrifos exposure in particular, during the 2nd trimester, seemed to show some association with offspring ASD risk.
• "Children of mothers residing near pyrethroid insecticide applications, just prior to conception or during 3rd trimester were at greater risk for both ASD and DD". Pyrethroids were the "second most commonly applied class of pesticides".
• A few additional points: males were slightly more likely than females to be exposed to pesticides during gestation, and the effects of multiple exposures (various different classes of pesticides) was generally "not found to be higher that the observations of the individual classes of pesticides".

Reiterating that this was a study based on estimation rather than looking at actual individual pesticide exposure during pregnancy or any biological testing for said exposure, this is an interesting study. I say that not to further condemn pesticides, which actually do quite a good job at helping to maintain our food supply and reduce our exposure to various pests. But rather that further study is indicated in this area as a result. The authors note the various strengths of their study based to a large extent on the fairly extensive data held on CHARGE participants. Likewise they note that their study did not for example, take into account "external non-agricultural sources" of pesticides such as those which many of us see sprayed around our homes, gardens and other areas of residence/work which could have affected their data. An 'underestimate' in actual exposure according to some external commentary on the study.

The question of pesticide exposure being potentially linked to autism risk carries quite a bit of the same baggage as the air pollution correlation. Yes, to some degree, we're all pretty unfit for consumption (see here) as a function of our 'chemical load' - bearing in mind the mis-representation of that word. Some people use this generality as a stick to beat such hypotheses on environment being potentially linked to conditions like autism (yes, we know the autisms are a complicated set of conditions). But as we've seen with the air pollution work, it may be the sum of the environmental risks combined with some genetic fragility which eventually provides the more important answers (see here); something which Shelton et al conclude: "Further research on gene-by-environment interactions may reveal vulnerable sub-populations". I might at this point also throw in a related post on Reelin and OPs as one area where we might begin searching.

In terms of the mechanism of effect, well if other autism research is anything to go by, it's gonna be complicated and probably not just confined to old the grey-pink matter. The obvious place to start looking would be the biological mechanisms which we rely on to metabolise things like OPs. PON1 is a good example, and as I've mentioned in other posts (see here) how PON1 has already seen some autism research action [4]. Indeed the paper by Gaita and colleagues [5] adds to the interest here and their findings of decreased serum arylesterase activity in case of autism. Paşca and colleagues [6] further suggested that a correlation (that word again) between high levels of homocysteine and low serum paraoxonase 1 arylesterase activity in cases of autism might be important. Certainly, when it comes to the 'big H' there is quite a bit of data with autism in mind (see here) but I'm not going to get ahead of myself here. I'll also direct your attention to other research talking about in-utero OP exposure being linked to shortened gestational duration [7] as an example of how effects may be peripheral as well as central. Oh and how PON1 enzyme levels might also tie into birth measurements [8].

If there is a take-home point to this post it is that the Shelton results suggestive of a link between gestational pesticide exposure and autism risk invite quite a bit more further scientific inspection of this area. I don't give clincial or medical advice on this blog but certainly the idea that pregnant women should perhaps "take special care to avoid contact with agricultural chemicals whenever possible" seems like a sensible statement to make (see here).

----------

[1] Ghaleiha A. et al. Galantamine efficacy and tolerability as an augmentative therapy in autistic children: A randomized, double-blind, placebo-controlled trial. J Psychopharmacol. 2013 Oct 15;28(7):677-685.

[2] Shelton JF. et al. Neurodevelopmental disorders and prenatal residential proximity to agricultural pesticides: The CHARGE study. Environ Health Perspect. 2014: June 23.

[3] Shelton JF. et al. Tipping the balance of autism risk: potential mechanisms linking pesticides and autism. Environ Health Perspect. 2012 Jul;120(7):944-51.

[4] D'Amelio M. et al. Paraoxonase gene variants are associated with autism in North America, but not in Italy: possible regional specificity in gene-environment interactions. Mol Psychiatry. 2005 Nov;10(11):1006-16.

[5] Gaita L. et al. Decreased serum arylesterase activity in autism spectrum disorders. Psychiatry Res. 2010 Dec 30;180(2-3):105-13.

[6] Paşca SP. et al. High levels of homocysteine and low serum paraoxonase 1 arylesterase activity in children with autism. Life Sci. 2006 Apr 4;78(19):2244-8.

[7] Eskenazi B. et al. Association of in Utero Organophosphate Pesticide Exposure and Fetal Growth and Length of Gestation in an Agricultural Population. Environ Health Perspect. 2004; 112(10): 1116–1124.

[8] Harley KG. et al. Association of organophosphate pesticide exposure and paraoxonase with birth outcome in Mexican-American women. PLoS One. 2011;6(8):e23923.

----------

Janie F. Shelton, Estella M. Geraghty, Daniel J. Tancredi, Lora D. Delwiche, Rebecca J. Schmidt, Beate Ritz, Robin L. Hansen, & Irva Hertz-Picciotto (2014). Neurodevelopmental disorders and prenatal residential proximity to agricultural pesticides: The CHARGE study Environmental Health Perspectives : 10.1289/ehp.1307044

Even more air pollution and autism risk findings

Air pollution.

I'm pretty sure most people are aware of all the talk about air pollution these days and how the human body is not particularly fond of air pollution in terms of potential adverse health outcomes (assuming that is, you leave things like selenium out of the equation). If you happen to live in China, I'm sure your mind was put at ease when reading about 'The Five Surprising Gains from the Smog'... or maybe not.

Most people generally find it easier to accept that air pollution might show a possible connection with something like respiratory diseases for example, given that the airways are generally a first point of entry for said pollution getting access to the body (although not the only route). Mention that something like autism risk for example, might also be linked to air pollution exposure and I'm sure that a significant degree of eye-rolling begins, alongside mutterings of the old 'correlation is not the same as causation' argument.

The Alchemist @ Wikipedia 

Personally I'm quite intrigued by the results emerging looking at something like childhood or maternal exposure to air pollution and proximity to sources of air pollution being linked to child or offspring autism risk. In these times of the autisms and various external forces implicated in autism risk (think valproate for example and the recent special reminder from the MHRA on this matter; even someone mentioning the word 'proven' [1] as if such a thing exists) I don't think we can rule most things out yet.

You have for example, the data from Heather Volk and colleagues [2] which was talked about in this post compounded by the data from Tracy Ann Becerra and colleagues [3] (see this post) both quite recently pinpointing something of a statistical association at least. That and other studies looking at a possible association.

Enter then another study by Volk and colleagues [4] which adds another layer of intrigue and complexity to the air pollution link by suggesting that a certain kind of genotype combined with air pollution exposure might elevate the risk of autism. There has been some media coverage of this paper (see here).

I suppose the first thing to take from the latest Volk paper is it's concentration on gene x environment interactions potentially modifying the risk of something like autism. I'm sure readers are used to hearing about [variable] gene-environment interactions quite loudly proclaimed these days as accounting for the presence of autism, but to see a study looking experimentally at the issue is very refreshing.

The next thing to note about the Volk paper is the specific focus on the MET receptor tyrosine kinase (MET) gene and a particular version of this gene potentially interacting with something like air pollution. In the post titled: 'I'm glad I MET you' (no prizes for the headline there) I talked about some other rather interesting findings when it came to MET and autism. Alongside all the chatter about things like synaptic development which MET has been tied to [5] was the suggestion that "the functional MET promoter variant rs1858830 C allele was strongly associated with the presence of an ASD-specific 37+73-kDa band pattern of maternal autoantibodies to fetal brain proteins (P=0.003)" as per the paper from Heuer and colleagues [6]. Maternal autoantibodies, as regular readers might know, are an upcoming area with autism risk in mind (see here).

It is then perhaps no surprise that the MET rs1858830 genotype, same as that one looked at with maternal autoantibodies in mind, was also the focus on the recent Volk paper and in particular the 'CC' genotype (see here for some information on zygosity). This genotype seems to be one which is more commonly noted in relation to cases of autism [7]. Indeed, based on an analysis of participants involved with the CHARGE initiative (beincharge!) the authors suggested: "Subjects with both MET rs1858830 CC genotype and high air pollutant exposures were at increased risk of autism spectrum disorder compared with subjects who had both the CG/GG genotypes and lower air pollutant exposures". Big words, I'm sure you'll agree.

These results are obviously crying out for replication for starters. The focus of this study was (a) on one gene, one specific variant of one gene, in our entire genome (b) looking at structural issues with said gene not necessarily gene function as per that rising star which is epigenetics for example might have on gene expression, and (c) based on air pollution exposure estimates from "local traffic-related sources and regional sources (particulate matter, nitrogen dioxide, and ozone)". With those factors in mind, caution still needs to be applied to these results before anyone goes and tries to for example, market any sort of genetic test for air pollution related autism or anything similar... Oh and 'steering clear of cities' is probably not a realistic option for most people either. Indeed, even residing in the countryside has been linked to autism risk (see here).

But still I'm interested in these results and indeed, the next question of biological processes from genes to environment to development and behaviour.

---------

[1] Harden CL. In Utero Valproate Exposure and Autism: Long Suspected, Finally Proven. Epilepsy Currents 2013; November/December 2013: 13; 282-284.

[2] Volk HE. et al. Traffic-related air pollution, particulate matter, and autism. JAMA Psychiatry. 2013 Jan;70(1):71-7.

[3] Becerra TA. et al. Ambient air pollution and autism in Los Angeles county, California. Environ Health Perspect. 2013 Mar;121(3):380-6.

[4] Volk HE. et al. Autism Spectrum Disorder: Interaction of Air Pollution with the MET Receptor Tyrosine Kinase Gene. Epidemiology. 2013 Nov 14.

[5] Judson MC. et al. A new synaptic player leading to autism risk: Met receptor tyrosine kinase. J Neurodev Disord. 2011 Sep;3(3):282-92.

[6] Heuer L. et al. Association of a MET genetic variant with autism-associated maternal autoantibodies to fetal brain proteins and cytokine expression. Transl Psychiatry. 2011 Oct 18;1:e48. doi: 10.1038/tp.2011.48.

[7] Jackson PB. et al. Further evidence that the rs1858830 C variant in the promoter region of the MET gene is associated with autistic disorder. Autism Res. 2009 Aug;2(4):232-6. doi: 10.1002/aur.87.

----------

Volk HE, Kerin T, Lurmann F, Hertz-Picciotto I, McConnell R, & Campbell DB (2013). Autism Spectrum Disorder: Interaction of Air Pollution with the MET Receptor Tyrosine Kinase Gene. Epidemiology (Cambridge, Mass.) PMID: 24240654

Functional GI issues and autism: not just an accumulation of case reports?

I've taken my time in posting this entry specifically dedicated to the paper by Virginia Chaidez and colleagues* which "puts to rest the idea that gastrointestinal problems among children with autism spectrum disorder are just an accumulation of case reports" according to one of the paper authors (see here). It's not that I don't see these findings to be absolutely fascinating, but rather that I wanted the research dust to settle a little before I added my [inflation adjusted] 10 pence worth of commentary.

Connecting the dots? @ Wikipedia  

Whilst receiving some media exposure at the time of publication, the Chaidez paper was slightly over-shadowed by another potentially interesting autism development published at a similar time by Warren and Klin (briefly discussed in a previous post) looking at eye gaze in young infants.

I suppose it's to be expected that chatter about [potential] novel early markers for autism will garner more headlines that the mundane task of scientific replication. Indeed, replication is once again the name of the game when it comes to the Chaidez paper, building on quite a bit of previous research suggesting that functional gastrointestinal (GI) issues can and do appear alongside quite a few cases of autism.

The details of the Chaidez paper are pretty straight-forward insofar as asking parents of children involved in the CHARGE study (beincharge!) to report on their children's behaviour and bowel activity via a couple of questionnaires (the Aberrant Behavior Checklist and the CHARGE Gastrointestinal History Questionnaire (GIH)). According to the study press release, the CHARGE GIH questionnaire "measures such disorders as abdominal pain, diarrhea, constipation and difficulty swallowing" but as yet I've not been able to find out too much about it's content validity and reliability within the peer-reviewed domain. Since I've mentioned CHARGE, I'll also draw your attention to some interesting research on air pollution and autism which I'll be posting about fairly soon.

Anyhow, based on responses from just shy of 1000 participants spread across categories of autism spectrum disorder (ASD) diagnosed, developmental delay (DD) diagnosed and typically-developing (TD), the results corroborate quite a lot of previous research undertaken in this area: "Compared to TD children, those with ASD [aOR 7.92 (4.89-12.85)] and DD [aOR 4.55 (2.51-8.24)] were more likely to have at least one frequent GI symptom". Functional bowel issues do seem to be more commonly reported in cases of ASD (and DD) compared with asymptomatic controls. A shocker, I know. Oh and just in case I have to say it again, parental reports of offspring GI complaints in relation to autism are actually quite sensitive as per the findings by Gorrindo and colleagues**.

There are some other very interesting details also discussed in the Chaidez paper and commentary which are worthy of comment. A long quote for you: "The researchers said that the study suggests that a chronic GI symptom, which can cause pain, discomfort and anxiety, could contribute to increased irritability and social withdrawal, particularly in children with deficits in social and communication skills. For children with autism, hyperactivity and repetitive behaviors may represent coping mechanisms for physical discomfort".

It's not rocket science to understand that having a functional bowel issue, or perhaps even something more pathological, which may impinge on a persons quality of life and may even cause some significant amount of physical and psychological distress, is probably going to [variably] show on a person's day-to-day behaviour. I think back to the paper by Kushak and colleagues*** (which was discussed in this post) on lactose intolerance in cases of autism and their quote: "Lactase deficiency not associated with intestinal inflammation or injury is common in autistic children and may contribute to abdominal discomfort, pain and observed aberrant behavior". I've used food as the example to highlight this issue but am not as yet, making any connection with those issues identified by Chaidez et al. Indeed, in a similar vein, I'm also brought back to the findings of Micah Mazurek and colleagues which talked about gut issues being potentially linked to anxiety and sensory issues in relation to autism as further evidence for that gut-brain or rather gut-behaviour relationship. The important mention that autism is rarely, in ESSENCE, a stand-alone condition is also worthwhile reiterating here.

You can probably tell that I'm pretty much sold on the idea that digestive issues can and do appear with greater frequency alongside cases of autism. This finding now being replicated quite a few times in the peer-reviewed arena and across different geographical boundaries. I hold off from saying this is a universal issue across all autism because the data don't point to that, and universals tend to be few and far between when it comes to the autisms. Perhaps GI issues form a part of one or more particular 'types' of autism?

As per yet another quote about the Chaidez paper: "The researchers did not address the reasons why the children with autism and developmental delay experienced more GI difficulties in this study. They noted that their findings suggest that the subject warrants additional inquiry". To me this then represents the important next step in this area of investigation. We know for example, that children with autism are more likely to experience problem issues in relation to food and feeding habits (see here and here). Research is also starting to appreciate that physical activity levels are also an important area of further investigation in relation to autism (see here) which might also impact on such GI issues.

After that it starts to get a little bit more 'interesting'. Are such issues a manifestation of problems with specific food groups? Gluten, casein or something more general like carbohydrates and their metabolism (see here)? Are there other factors which might be implicated in the presentation of such GI issues, bearing in mind this could be genetic factors and possibly even more environmentally-based factors? With all the quite detailed information available to the various research groups about cohorts such as those involved in CHARGE, the possible answers are already locked in the available data.

Without giving any medical or clinical advice, if readers need any further information about this topic, you are directed to your healthcare provider and the various evidence-based guidance on the subject**** (open-access). The commentary from Dr Tim Buie on the Chaidez study also contains some nuggets of information which readers might find useful (see here). And if readers are so inclined, another big name in GI issues and autism - Prof. Simon Murch - is talking at the NAS 2014 Professional Conference here in the UK (see here). One to see I'd say.

----------

* Chaidez V. et al. Gastrointestinal Problems in Children with Autism, Developmental Delays or Typical Development. J Autism Dev Disord. 2013 Nov 6. [Epub ahead of print]

** Gorrindo P. et al. Gastrointestinal dysfunction in autism: parental report, clinical evaluation, and associated factors. Autism Res. 2012 Apr;5(2):101-8.

*** Kushak RI. et al. Intestinal disaccharidase activity in patients with autism: effect of age, gender, and intestinal inflammation. Autism. 2011 May;15(3):285-94.

**** Buie T. et al. Evaluation, diagnosis, and treatment of gastrointestinal disorders in individuals with ASDs: a consensus report. Pediatrics. 2010 Jan;125 Suppl 1:S1-18.

----------

Chaidez V, Hansen RL, & Hertz-Picciotto I (2013). Gastrointestinal Problems in Children with Autism, Developmental Delays or Typical Development. Journal of autism and developmental disorders PMID: 24193577

Maternal diabetes and offspring autism risk

The systematic review and meta-analysis reported by Xu and colleagues* caught my eye recently. Concluding that: "maternal diabetes was significantly associated with a greater risk of ASD in the offspring" my interest was truly piqued.

Insulin @ Wikipedia  

Diabetes in relation to autism has cropped up a few times on this blog. I've talked about the possibility of a more general connection (see here) and also more specific as part of some of the CHARGE results (see here).

Indeed those CHARGE results, based on the study by Paula Krakowiak and colleagues** (open-access) I remember generated quite a bit of discussion at the time of their publication given the suggested link with various facets making up metabolic syndrome in mums.

I'm not really surprised by the Xu results when you think that the association between gestational diabetes and offspring autism risk has been talked about before based on some pretty strong association data. I note for example, that the study by Lyall and colleagues*** (open-access) flagged up this association - "gestational diabetes was associated with a significantly increased risk of ASD" - based on quite a nice sample size. That and the paper by Hannah Gardener and colleagues**** (open-access) who suggested that gestational diabetes was perhaps one of several factors which might elevate offspring risk as per the Krakowiak results.

The question of mechanism of effect is slightly less clear it has to be said. In my first post on autism and diabetes, quite a lot was made of the connection between type 1 diabetes and autism as per the familial autoimmune connection (have a look at my Money post for example). Granted this doesn't really add anything more specific than to say that autoimmune conditions can 'club together' (see here) which might take us down some other avenues particularly when talking about at least some autism comorbidity (see here). That and the implication that autism might also be an autoimmune condition***** as some have implied.

As to any mechanism of gestational diabetes being linked to the aetiology of autism, well I'm afraid I can't offer anything too concrete at this point. There is some speculation that gestational diabetes might be linked to other cognitive and developmental issues as per the research on ADHD (Attention-deficit hyperactivity disorder)****** and schizophrenia*******. Indeed, that paper by Van Lieshout & Voruganti (open-access) on gestational diabetes and risk of offspring schizophrenia suggests: "at least 3 prenatal mechanisms: hypoxia, oxidative stress and increased inflammation" of potential effect. Suffice to say that all of them have also been banded around as being involved with cases of autism at various times (particularly the roles of inflammation and oxidative stress). I might also draw reader's attention to the paper by Nousen and colleagues******** too.

The take-home message whilst still one of caution in singling out one particular factors as being linked to autism (or should that be the autisms?) is that maternal diabetes should be registering on the various investigations into pregnancy and birth factors linked to offspring autism risk to further explore mechanisms. Whether altering the presentation of maternal diabetes (lifestyle changes or even reviewing medication*********) might also impact on offspring outcome is another question which should be on the lips of autism research...

----------

* Xu G. et al. Maternal Diabetes and the Risk of Autism Spectrum Disorders in the Offspring: A Systematic Review and Meta-Analysis. J Autism Dev Disord. 2013 Sep 22.

** Krakowiak P. et al. Maternal metabolic conditions and risk for autism and other neurodevelopmental disorders. Pediatrics. 2012 May;129(5):e1121-8. doi: 10.1542/peds.2011-2583.

*** Lyall K. et al. Pregnancy complications and obstetric suboptimality in association with autism spectrum disorders in children of the Nurses' Health Study II. Autism Res. 2012 Feb;5(1):21-30. doi: 10.1002/aur.228.

**** Gardener H. et al. Prenatal risk factors for autism: comprehensive meta-analysis. Br J Psychiatry. 2009 Jul;195(1):7-14. doi: 10.1192/bjp.bp.108.051672.

***** Ashwood P. & Van de Water J. Is autism an autoimmune disease? Autoimmun Rev. 2004 Nov;3(7-8):557-62.

****** Nomura Y. et al. Exposure to gestational diabetes mellitus and low socioeconomic status: effects on neurocognitive development and risk of attention-deficit/hyperactivity disorder in offspring. Arch Pediatr Adolesc Med. 2012 Apr;166(4):337-43. doi: 10.1001/archpediatrics.2011.784.

******* Van Lieshout RJ. & Voruganti LP. Diabetes mellitus during pregnancy and increased risk of schizophrenia in offspring: a review of the evidence and putative mechanisms. J Psychiatry Neurosci. 2008 Sep;33(5):395-404.

******** Nousen EK. et al. Unraveling the Mechanisms Responsible for the Comorbidity between Metabolic Syndrome and Mental Health Disorders. Neuroendocrinology. 2013. Sept 21.

********* Barnard KB. et al. Antidepressant Medication as a Risk Factor for Type 2 Diabetes and Impaired Glucose Regulation. Systematic review. Diabetes Care. 2013; 36: 3337-3345.

----------

Xu G, Jing J, Bowers K, Liu B, & Bao W (2013). Maternal Diabetes and the Risk of Autism Spectrum Disorders in the Offspring: A Systematic Review and Meta-Analysis. Journal of autism and developmental disorders PMID: 24057131

Maternal C-reactive protein and autism

As per my previous blog entry on the possibility of some involvement of a skin-brain axis to cases of autism (no, seriously), one of the key themes seemingly increasing in importance in autism research is the possibility of some connection with inflammation and the inflammatory processes.

Whilst sounding completely at odds with how autism is commonly described - a developmental disorder variably manifesting specific behavioural and cognitive features - there is a surprisingly long and growing interest in how physiological processes like inflammation may overlap with cases of autism. I've covered a tiny, tiny portion of that research interest in a few posts on this blog previously (here and here for example) outside of the whole gastrointestinal inflammation side of things, which for some still remains a contentious area.

Karjalanpiirakka @ Wikipedia   

I wouldn't dream of trying to offer any consistent or reliable hypothesis for how inflammation might link into at least some cases of (the) autism(s) in either a correlative or causative way because it's way outside my area of competence. Instead I'll leave it to others looking at other, possibly related, conditions to speculate on one or two suspected mechanisms.

In this post however, I would like to talk some more about inflammation and autism following the publication of a study by Alan Brown and colleagues* reporting on the possibility that inflammation or rather one particular marker of inflammation - C-reactive protein (CRP) - in autism might have at least some of its roots and effects in the very earliest days of life. Prof. Brown by the way, seems to have some interest in how early life variables might link into later life psychiatry as per his name being on the recent Lehti paper on IVF covered in this post.

Before going further I will offer a caveat or two about the Brown paper and it's emphasis on looking at maternal CRP levels during early pregnancy. Although measuring maternal inflammation (via CRP) is the name of the game, this does not mean that autism or anything else is 'caused' by such inflammation based on the current bank of evidence. Everyone seems to be 'inflammed' to some degree and for lots of different reasons but not everyone has autism. Neither does it sound any return to the parental 'blame game' of times gone by in much the same way that de novo mutations and paternal age shouldn't either.

I could be wrong but Brown and colleagues seem to have based at least part of their collected data on a Finnish initiative detailed in this paper by Lampi and colleagues** that basically aimed to examine whether there were any interesting links between "prenatal serologic factors, mediating and moderating developmental antecedents, and risk of autism spectrum disorders (ASD)". In their recent paper they report a significant association between maternal CRP levels and risk of offspring autism; especially pronounced when comparing that fifth of the population where CRP levels were highest compared with the fifth where they were lowest.

With again all caveats in active play, this is not the first time that maternal inflammation related to risk of offspring autism has been discussed. My mind wanders back to my 'you give me fever' post based on some interesting observations from the CHARGE initiative on mum's [retrospectively] reporting fever during pregnancy and offspring autism risk. Also potentially important, and again CHARGE-related, is the whole air pollution exposure - inflammation link albeit slightly more speculative at this point. And of course there are the Paul Patterson mouse studies, which to regular readers probably require little introduction, but for everyone else implies some maternal immune activation to be potentially important to offspring autism, and in need of further investigation.

Outside of the autism risk bit, this is also not the first time that elevated maternal CRP levels have been reported in relation to autism and other developmental conditions. The possibility for example that CRP levels could be related to caring for a child with autism was discussed in this post and how the stress of raising a child with behavioural difficulties might take an inflammatory toll on parents. With all due respect to the Lovell findings***, the more recent Brown paper implies that the caring aspect might not necessarily be the root cause of elevated CRP given its measurement during pregnancy which, speaking from a bystander point of view, can be a stress in itself (also not ruling out caring duties enhancing any effect or being related to other physiological measures with a stress element).

I'm also drawn back to how the Brown findings might also relate to those studies which have actually looked at CRP in people with autism. I posted on the Khakzad study a while back and how they reported some very significant elevations in CRP in their cohort of participants with autism. On the basis of that study one might think that elevated CRP is a pretty consistent finding in autism. That being said there is still a relatively small body of CRP-autism research and in some studies, such elevations were not detected compared to controls (see this post). Such is the variable nature of the autism(s).

Brown and colleagues suggest that maternal CRP measures might potentially translate into "identifying preventive strategies and pathogenic mechanisms in autism". Personally I don't think we are quite there yet in terms of determining just how elevated CRP might translate into autism or anything else given that (a) we don't really know how far back CRP goes beyond mothers as per a family history of elevated CRP and whether any other comorbidity might be connected to it****, and (b) spot determinations of CRP levels (which I assume is what they did) don't necessarily translate into chronic elevations of CRP and says very little about other relationships such as those of the cytokines.

I am however sufficiently convinced from the cumulative data on inflammation (both maternal and first-person levels) and autism that this is an area worthy of much, much, much more investigation.

----------

* Brown AS. et al. Elevated maternal C-reactive protein and autism in a national birth cohort. Molecular Psychiatry. January 2013.

** Lampi KM. et al. Finnish Prenatal Study of Autism and Autism Spectrum Disorders (FIPS-A): overview and design. J Autism Dev Disord. 2011; 41: 1090-1096.

*** Lovell B. et al. The psychosocial, endocrine and immune consequences of caring for a child with autism or ADHD. Psychoneuroendocrinology. 2012; 37: 534-542.

**** Ridker PM. et al. C-reactive protein and other markers of inflammation in the prediction of cardiovascular disease in women. N Engl J Med. 2000; 342: 836-843.

---------

Brown, A., Sourander, A., Hinkka-Yli-Salomäki, S., McKeague, I., Sundvall, J., & Surcel, H. (2013). Elevated maternal C-reactive protein and autism in a national birth cohort Molecular Psychiatry DOI: 10.1038/mp.2012.197

More air pollution and autism risk findings

Happy New Year! Καλή Χρονιά (in Greek). Welcome back to Questioning Answers. We continue our journey across the autism research landscape.

So correlation... Yep I know correlation is not the same as causation. Cause-and-effect is a notoriously difficult relationship to map out when talking about conditions like autism with all their heterogeneity (autisms if you please) and that old genes vs. environment grudge match.

But that doesn't mean correlational studies are all bunk.

Mind the smog @ Wikipedia (Claude Monet)

Take for example the relationship between air pollution and risk of autism presented in a paper by Volk and colleagues*. I recently covered these findings from the CHARGE initiative and how, not for the first time, there was speculation on either in-utero or early years exposure to air pollution such as traffic fumes potentially having some modifying effect on a child's risk of receiving a diagnosis of an autism spectrum disorder (ASD). Some interesting research but correlational research nonetheless.

Then the study by Tracy Ann Becerra and colleagues** is published (a pre-print version available here open-access) and suddenly things start to get a little more interesting, as now more than one study based in a similar geographical area (California, USA) start to arrive at similar conclusions.

A few choice factoids from the Becerra paper:

• A large sample were included for analysis - over 7,500 children diagnosed with autism based on Department of Developmental Services (DDS) records - and an even larger control group (10 controls to each autism case) matched for gender and quite a few other variables.
• The paper was a very statistical affair looking at birth addresses and "measured and modeled exposures to prenatal air pollution and autism in children". I can't give you all the statistical details because they are a little complicated and somewhat beyond my very limited statistical capabilities. It basically boiled down to correlation and some statistical modeling based on various factors including something called a land use regression (LUR) model.
• Results: "We estimated an approximately 3 to 9% relative increase in the odds of Autistic Disorder per inter-quartile range increase in entire pregnancy exposure to NO (9.40 ppb) and NO2 (5.41 ppb) as estimated by our two-pollutant LUR models". In other words, a possible relationship was hinted at by the data and its analysis between risk of offspring autism and facets of traffic fume exposure.
• A few other points of note: maternal education (a marker for socio-economic status) was a strong modifier of this pollution-autism risk relationship and ozone (O3) (remember that hole in the ozone layer) also featured very strongly among the statistics, potentially increasing risk for autism by 12 - 15%. 

Reiterating the correlational nature of this study and all the problems associated with tracking participant records and examining individual specific environmental exposures as being 'the one', I'm sufficiently intrigued by this study adding as it does the growing literature in this area.

You could perhaps question that autism rates are rising (yes they are) yet generally our pollution levels are dropping (the removal of lead from petrol as one example) so why would this be a particularly strong relationship? Of course you'd be right, assuming that is, that such pollution acts solely and directly on the foetus and doesn't for example start to mess around with things like the germline or possess epigentic effects***. That and the fact that pollution levels tend to vary from area to area, city to city, country to country, so we can't necessarily assume any uniform exposure to be widely distributed across everyone and every place. Take a look at similar research on air pollution and things like cardiovascular disease mortality for example (see here****) and you'll perhaps see that dose might not necessarily be the overriding factor in any relationship.

I am of course open to other explanations for the growing literature looking at the air pollution - autism risk correlations being reported including factors such as the availability of neighbourhood-level diagnostic resources***** (covered here), but I must admit at the moment, I'm a little stumped by any environmental factor which could replace the air pollution variable seemingly so universally. Unless one starts to consider things like water sources, food sources or things like medication and their residues as potentially showing other correlations?

To finish, I'm all Christmas-movied out after watching quite a few classics with the brood. Mary Poppins is always a favourite, so how about a spoonful of sugar with that correlation?

----------

* Volk HE. et al. Traffic-related air pollution, particulate matter, and autism. Arch Gen Psychiatry. November 2012.

** Becerra TA. et al. Ambient air pollution and autism in Los Angeles County, California. Environ Health Perspect. December 2012.

*** Stoccoro A. et al. Epigenetic effects of nano-sized materials. Toxicology. December 2012.

**** Chen H. et al. Long-term exposure to traffic-related air pollution and cardiovascular mortality. Epidemiology. 2013; 24: 35-43.

***** Mazumdar S. et al. Spatial clusters of autism births and diagnoses point to contextual drivers of increased prevalence. Soc Sci Med. December 2012.

----------

Becerra TA, Wilhelm M, Olsen J, Cockburn M, & Ritz B (2012). Ambient Air Pollution and Autism in Los Angeles County, California. Environmental health perspectives PMID: 23249813

CHARGE, traffic pollution and autism

The headline reads "Traffic fumes linked to autism". The sub-heading describes how babies who were exposed to traffic air pollution during their first year of life "are more likely to become autistic". Welcome to the study by Heather Volk and colleagues* on traffic pollution, particulate matter and risk of autism.

Motorbiking... @ Wikipedia  

Before heading into the paper, the discerning autism research reader will no doubt remember that this is a topic which has already cropped up in autism research circles, and indeed by the same authorship group** (open-access).

The difference being that on the previous occasion, the focus was on in-utero proximity to traffic-related air pollution "as a surrogate for air pollution exposure", whereas the current study looked at both gestation and first-year estimates of exposure.

A few details of the most recent study:

• Another CHARGE-related investigation, which estimated air pollution and air quality based on mum's address for the various stages of pregnancy and first year of life for 279 children diagnosed with an autism spectrum disorder (ASD) compared with 245 typically-developing controls.
• The US Environmental Protection Agency (EPA) datasets on regional air pollution were cross-indexed with addresses, and some statistical wizardry applied.
• Results: compared with control participants, exposure to traffic-related air pollution by residence was highest for the autism group particularly during the first year of life (adjusted odds ratio = 3.1). Exposure to particulates (sub 10 and 2.5 micrometres) based on regional exposure measures were also associated with autism during the first year of life.
• The authors conclude: "Exposure to traffic-related air pollution, nitrogen dioxide, PM2.5, and PM10 during pregnancy and during the first year of life was associated with autism". The possible effect being one of inflammation (quite a regular visitor to autism shores it has to be said).

One obviously has to be quite careful with such studies of association and all that 'correlation does not equal causation' jazz. On that basis I'm not going to start any great fanfare about this research despite the intricate datasets which have been compared, and the previous body of research that it follows.

That being said, neither am I going to discard these results as being just coincidence. Air pollution is a serious environmental issue related to health; potentially acting in a multitude of ways depending on what type of pollution is present, the level of exposure*** and the age of the exposee. We've seen hints that air pollutants might play some role in cases of autism as per another study of association on meteorological factors and autism recently discussed on this blog. Definitive data is however somewhat lacking including more direct measurement of airborne pollutants and any residual traces that they may leave.

Autism is also not alone in its purported link to air pollution as exemplified by this paper by Siddique and colleagues looking at air pollution and ADHD****. Other research has attempted to link air pollution to issues with cognitive abilities*****. The primary question arising from such research is to ask whether the recent Volk data may reflect any of these comorbidities/issues above and beyond an exclusive link to autism?

Outside of just traffic-related air pollution, the air that we breathe is home to lots of other things too; some things which just don't even bear thinking about (dog poo bacteria, yep you heard me right). Questions are being asked about air quality in our cities on quite a grand scale nowadays and in conditions like autism, fast becoming a 'health priority' (and not before time), the research net should be cast as wide as possible to determine the contribution of environment (if any) to the astounding number of cases of autism estimated and being diagnosed.

----------

* Volk HE. et al. Traffic-related air pollution, particulate matter, and autism. Arch Gen Psychiatry. November 2012.

** Volk HE. et al. Residential proximity to freeways and autism in the CHARGE study. Environ Health Perspect. 2011; 119: 873–877.

*** Valavanidis A. et al. Airborne particulate matter and human health: toxicological assessment and importance of size and composition of particles for oxidative damage and carcinogenic mechanisms. J Environ Sci Health C Environ Carcinog Ecotoxicol Rev. 2008; 26: 339-362.

**** Siddique S. et al. Attention-deficit hyperactivity disorder in children chronically exposed to high level of vehicular pollution. Eur J Pediatr. 2011; 170: 923-929.

***** Suglia SF. et al. Association of black carbon with cognition among children in a prospective birth cohort study. Am J Epidemiol. 2008; 167: 280-286.

----------

Volk, H. (2012). Traffic-Related Air Pollution, Particulate Matter, and AutismAir Pollution, Particulate Matter, and Autism Archives of General Psychiatry DOI: 10.1001/jamapsychiatry.2013.266

CHARGE, you give me fever

The recent passing away of Robin Gibb is a sad loss to the music world. The falsetto tones of the Bee Gees made them one of the most instantly recognisable groups with their string of hits worldwide. Many of their best loved songs were part and parcel of the film 'Saturday Night Fever' in which John Travolta single-handedly shaped a disco generation mirroring millions of male preparations for that Saturday disco odyssey. Move over Disco Stu.

Fever of another sort has also been making news of late with specific reference to autism or more precisely to the offspring risk of autism spectrum conditions in mums-to-be reporting fever or the more scientific term pyrexia (I assume from the Greek to mean fire). The paper in question is this one by Zerbo and colleagues* reporting yet more results from the CHARGE initiative and their cleverly worded website 'beincharge'.

I'm not going to give this paper the mega-post treatment but a few details are noteworthy:

• Data for upwards of 500 children diagnosed with an autism spectrum condition were compared with that from children with a developmental delay (n=163) and asymptomatic controls (n=421). Such data for this paper included quite a bit of information around pregnancy in terms of mum's report of illness, fever and medications taken during the mum-to-be period.
• No significant link was found between either reports of maternal influenza or flu vaccination during pregnancy and subsequent offspring autism. When it came to asking about fever during pregnancy, this was a slightly different story as the odds ratios show (OR = 2.12 CI: 1.17-3.84) where offspring autism was over twice as likely to be present in mums reporting fever during pregnancy. Having said that the OR was even greater for those children diagnosed with developmental delays (OR = 2.5 CI: 1.2-5.2).
• Self-medicating for fever during pregnancy using antipyretics such as ibuprofen or paracetamol (acetaminophen) seemed to be associated with a reduction in the risk of offspring autism.

OK let's take a step back before we get too readily involved in these findings. CHARGE whilst being a good starting point for ascertaining any potential environmental links to autism is still very much a preliminary attempt to look at any associations. Asking about fevers retrospectively is a good idea but still open to some degree of bias. Nine months pregnancy, equivalent to about 280 days, is quite a long time period to look into retrospectively. This is aside from the fact that one person's fever might be another person's 'off-day' and as for medication practices over that time, particularly self-medication (presumably OTC not requiring a prescription) ... I'll leave you to decide on potential accuracy.

Having said all that there are some potential nuggets of information to be derived from this study. Inflammation and those dastardly proinflammatory cytokines are a pretty well recognised feature of at least some cases of autism. I'm not necessarily saying that they are causative or anything like that, but some clues seem to be attached to such findings. I seem to remember some findings from not so long ago in relation to MET and autism attached to the CHARGE study which may very well tie into this latest offering and in particular, lower levels of the anti-inflammatory cytokine IL-10 among other things.

CHARGE has also suggested quite a few other potential associations between pregnancy and risk of offspring autism including: obesity, vits and SNPs, and living next to a motorway (freeway). I would be very interested in seeing some grand analysis of all of these factors published by the CHARGE team just to see how all these various elements might tie together. Even based on each individual participants throughout the various studies, one gets the impression that there is some valuable data to be mined from the initiative pertinent to the formulation of more prospective trials.

To finish, some associated clips to relive those Halcyon days of Boogie.

* Zerbo O. et al. Is maternal influenza or fever during pregnancy associated with autism or developmental delays? Results from the CHARGE (CHildhood Autism Risks from Genetics and Environment) study. JADD. May 2012.