HLA alleles and specific language impairment

I've talked about the [almighty] major histocompatibility complex (MHC) before on this blog (see here). The important duties that this biological system performs in relation to identification and communication insofar as antigen presentation and importantly, the process of differentiation between 'self' and 'non-self' from an immunological perspective, are not to be sniffed at.

Harold? @ Wikipedia

I've found myself quite interested in all things MHC (also referring to the human leukocyte antigen, HLA, genes) from quite a few different perspectives. Be it with reference to the genetics of coeliac (celiac) disease (see here) or the very preliminary work being discussed on HERVs [human endogenous retroviruses], or rather HERV proteins, as being possible superantigens in relation to a condition such as myalgic encephalomyelitis (ME) (see here), there's lots to think about when it comes to the MHC.

So when I stumbled across the paper by Ron Nudel and colleagues [1] (open-access here) talking about "a possible role for HLA loci in language disorders" my attention was piqued. Before progressing into some of the details behind the Nudel paper, it's important to note the authorship team involved in this research paper. Alongside some quite well-known names attached to autism research (see here and see here for example), I was also interested to see Gillie Baird as one of the research team. Prof. Baird has impressed me in recent times; not only with her research involvement looking into the whole functional bowel issues in autism research (see here) but also with that recent 'leaky gut' paper with autism in mind (see here) which despite some methodological 'issues' gave me cause to smile that this area was at last starting to be taken seriously in more orthodox circles. Who knows, one day even the NICE guidance might recognise it as a potentially important comorbidity?

No mind, a few details from the Nudel paper are noteworthy, accepting that the paper is open-access:

• This was a multi-centre study looking at "the possible involvement of HLA loci in SLI [specific language impairment]". Loci by the way, is the plural of locus, and with genes in mind, refers to specific locations on a gene, DNA sequence or chromosome; a sort of area or postcode if you will. Participants were mostly derived from the SLIC (SLI consortium) groups with additional families included. All were assessed as having a SLI; all did not have autism, but some had comorbid features of ADHD and/or dyslexia. A control group was also included for some of the analyses.
• OK here's where is starts to get a little bit complicated. I found quite a nice website talking about the ways and means that HLA genes are indexed in terms of nomenclature. The complexity of the HLA genes and their molecules derives from the fact that HLA genes are highly polymorphic (see here). Regular readers might have heard me talk about SNPs (Single Nucleotide Polymorphisms) before reflecting single changes to the genetic alphabet. In the case of HLA genes it gets a little more complex (see here) and, as such, specific terminology has been introduced. I'll also draw your attention the description of an allele too (see here). 
• So, first researchers went looking for SNPs "across the HLA [genetic] region". Further, they then imputed HLA type from the SNP data to see if there was any connection between HLA type(s) and SLI or the specific parts of SLI from a psychometric point of view.
• Results: The HLA-A locus seemed to show a possible connection for "susceptibility to SLI". The A1 allele (HLA-A A1) in particular came out as the "most highly positively correlated allele". When it came to looking at SLI cases vs. controls, the "DR10 allele of HLA-DRB1 was more frequent in individuals with SLI than population controls". There are some other findings reported in terms of parental inheritance patterns but I'm going to leave those for now.
• The authors conclude that their preliminary data requires further study but: "provide an intriguing link to those described by previous studies of other neurodevelopmental disorders suggesting a possible role for HLA loci in language disorders".

I'm sure you can see why I was so interested in this paper. The bigger picture of the HLA (MHC if you prefer) being potentially implicated in something other than just immune function and all those 'self' and 'non-self' duties, opens up a whole new world of research. Given also my increasing interest in all things autoimmunity with an autism research slant, I'm minded to suggest that this may go some much further than anyone ever suspected [2]. That being said I would direct readers to the graphs showing the frequencies of alleles across the different HLA genes to see how aside from the HLA-DRB1 DR10 allele, this is more of a 'shades of grey' over and above 'there or not' pattern of findings when comparing SLI and non-SLI groups.

Looking back at some of the quite limited autism research in this area, I did find some clues that HLA involvement in SLI should perhaps not be totally unexpected as a function of the potential overlap between autism and SLI [3]. I say this acknowledging the debates are still on-going about the links or not between the two conditions and also that Nudel and colleagues ruled out autism as a diagnosis in their particular cohort. As an aside, readers might also find a recent post by Dorothy Bishop of interest, and in particular her model C for language development.

HLA alleles and autism? Well, you might say this is an emerging area in light of results like those from Mostafa and colleagues [4]. I dare say there may be other HLA overlap with other findings from autism research (see the open-access review from Torres and colleagues [5] for further reading). More recently I also stumbled across the paper by Al-Hakbany and colleagues [6] (open-access) which continued discussions about overlapping alleles (I'll probably formulate a separate post on that research soon).

The late Reed Warren also talked about the null allele of C4B [7] (see here for some more explanation on this) quite a few years back now, and as intimated in a past blog entry on his later work, reading disorders and ADHD actually turned up as being more relevant to the null allele than autism did (67%, 56% and 48% respectively). OK SLI is not necessarily reading disorder or ADHD, but as Nudel and colleagues noted there is a "high degree of co-occurrence for SLI and ADHD or dyslexia".

I think it's also important to recognise that those HLA types talked about in the Nudel study aren't just limited to behavioural or psychiatric conditions. I'm not going to go through the myriad of conditions and clinical findings related to the HLA alleles identified, but suffice to say that we perhaps need to look at a bigger picture when interpreting this data. This includes whether there may be other comorbidity present in those SLI cases - including somatic comorbidity - which might link into HLA genotype as per previous work looking at coeliac disease and ADHD for example (see here). SLI like autism like every other behavioural, developmental or psychiatric condition does not just exist in a diagnostic vacuum.

Still, I'll say again that this is a potentially very important paper which potentially opens up a whole new world of research...

Music. The life and times of Nelson Mandela will always remain in the public consciousness. I always fondly remember the Special AKA tribute to the great man.

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[1] Nudel R. et al. Associations of HLA alleles with specific language impairment. J Neurodev Disord. 2014 Jan 17;6(1):1.

[2] Choudhury N. & Benasich AA. A family aggregation study: the influence of family history and other risk factors on language development. J Speech Lang Hear Res. 2003 Apr;46(2):261-72.

[3] Bishop DV. Autism and specific language impairment: categorical distinction or continuum? Novartis Found Symp. 2003;251:213-26

[4] Mostafa GA. et al. The link between some alleles on human leukocyte antigen system and autism in children. J Neuroimmunol. 2013 Feb 15;255(1-2):70-4.

[5] Torres AR. et al. HLA Immune Function Genes in Autism. Autism Res Treat. 2012;2012:959073.

[6] Al-Hakbany M. et al. The Relationship of HLA Class I and II Alleles and Haplotypes with Autism: A Case Control Study. Autism Res Treat. 2014; 2014: 242048

[7] Warren RP. et al. Increased frequency of the null allele at the complement C4b locus in autism. Clin Exp Immunol. 1991 Mar;83(3):438-40.

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Nudel R, Simpson NH, Baird G, O Hare A, Conti-Ramsden G, Bolton PF, Hennessy ER, Monaco AP, Knight JC, Winney B, Fisher SE, & Newbury DF (2014). Associations of HLA alleles with specific language impairment. Journal of neurodevelopmental disorders, 6 (1) PMID: 24433325