One man’s (or child’s or woman’s) meat is another’s poison… so what exactly is a rare disease haplotype?

Anil Mehta

University of Dundee

In our rare disease focus month, Anil Mehta explores the importance of understanding rare diseases.

Why are Verdi’s operas so tragic? Could it be that he never recovered from the premature death of his beloved wife and children at so young an age? Why did he alone survive to give us the glory of his music and, would it have been so magnificent without his devastation? We will never know but writing in the Hammersmith historical record in October 1959, P.D. Whiting pointed out that in 1858, of all children born in the London Borough of Hammersmith, ‘nearly half should die without attaining one fourteenth part of the three scores and 10 allotted to mankind’. This article will relate this miserable outlook for families to the underbelly of rare disease and the related genetic idea of a haplotype.

A haplotype is a variable set of inherited genetic material from each parent whose elements combine in the fertilised egg to generate an adaptive bio-niche for the forthcoming baby that alters its susceptibility to one or more attacks that were (historically) largely infective (cholera, typhus, malaria, typhoid etc). A good example can be found in the era before Whiting’s chosen period. Until about 200 years ago, 7 out of 10 babies born in the UK died before their 6th birthday. Because only the survivors passed on their genes, the sustained high childhood mortality created sustained selection pressure on the population of big cities. For example, the area of London near the Thames was both a densely populated and poor, being ‘blessed’ with 112, 12th century parishes, their attendant administrations and their choking, unregulated raw sewage outlets.

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“But we now pay a price for our escape from the Hobbsian nightmare of a brutish, short and nasty life – the emergence of rare diseases…”

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It required a local Board established by an Act of Parliament in 1855 (Metropolis Management Act) to mitigate the twin scourges of the Scylla and Charybdis of overcrowding and sewage outflow whose twinned and monstrous death toll decimated childhood life. No wonder children were fed beer to stop premature death from diarrhoea, no doubt creating its own selection pressure on alcohol dehydrogenease. So if you are reading this as a Londoner, or the resident of any big city, your forebears survived sustained filth and were able to procreate for reasons that relate to their regional haplotypes the mitigated against the repeated ravages of locally prevalent infectious diseases. But we now pay a price for our escape from the Hobbsian nightmare of a brutish, short and nasty life – the emergence of rare diseases when, by accident certain haplotypes, that would have been lethal as recently as 200 years ago, now combine to create disease.

So how does the context of home as an overcrowded slum, its associated drink and drugs such as opium, exactly link to rare diseases? Hammersmith is today a thriving middle class part of London but in 1856, 100 years before I was born (albeit with my non-European, different Indian haplotypes), mortality was so bad that that it was common for the dead to rot in the home for want of burial space.

Epidemics of typhus carried off many children with reports of dysentery leading a local medical officer to ask: ‘of a [fatal] sickness does there not prevail a large amount of [non-fatal] sickness? This survival issue was the topic of my last article on rare diseases being merely the clinically recognised symbolic tip of an iceberg of resistance to a range of much commoner diseases. I argued that the children who survived poverty, overcrowding and poor nutrition were not just plain lucky but were haplotype-driven super-survivors (sickle cell and G6PD deficiency and malaria resistance is a well understood example of childhood protection).

Even today, that minority of humans who are oblivious to winter vomiting Norovirus because of a different inheritance of a set of genes that alter the sweetness of selected sugars (fucoses) located on the outside of their intestinal cells, these sugars being covalently bound by transferase enzymes to proteins that face the contents of the gut. These sweet barrage balloons of sugared-proteins shield guts against incoming pathogens but have been used by Norovirus to attach to human guts!

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“…my plea is to stop thinking of rare diseases as rare meaning unimportant.”

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Haplotypically inheriting fully or partially defective fucosyltransferase enzymes could, on the one hand, give rise to a rare disease (fucosidosis), but inheriting one or more variant transferase genes could have been protective for generations against viral attack.

Surely understanding this process and the equivalent binding sites for related viruses attacking other organs such as the lung could save lives, particularly in the developing world?

Equivalent examples in resisting HIV infection despite high viral exposure are well documented. Thus inheriting certain combinations of genes from each parent equips some offspring with different sets of proteins – proteins that create differential interactive shapes lying at critical points on (pathogen-hijacked) cellular pathways. These haplotypic differences set pathway-traps for invading pathogens and it is these inheritance patterns that differ between siblings but are inherited as blocks of genes closely linked to one another (haplotypes and linkage are related ideas) .

This understanding will arise from the human gene sequencing projects. Thus my plea is to stop thinking of rare diseases as rare meaning unimportant. They are sentinel diseases, explanatory diseases and from a therapeutic perspective, biochemically tractable diseases for pharma in general to grasp.

Pathways hijacked by pathogens should be required reading for all those engaged in personalised medicine. We must understand how to use the data from the human genome project to compute haplotypes automatically so we can stratify our patients prior to clinical trials. The resultant data will be far more informative.

A brave new world is here, but can we read the runes? Rare disease points the way to molecular understanding.

References

1. Hansman GS, Shahzad-Ul-Hussan S, McLellan JS, Chuang GY et al. Structural basis for norovirus inhibition and fucose mimicry by citrate. J Virol. 2012 Jan,86(1):284-92. doi: 10.1128/JVI.05909-11. Epub 2011 Oct 26.

2. Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA.

3. Rydell GE, Kindberg E, Larson G, Svensson L. Susceptibility to winter vomiting disease: a sweet matter. Rev Med Virol. 2011 Nov,21(6):370-82. doi:10.1002/rmv.704. Epub 2011 Aug 25. Review. PMID: 22025362

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About the author:

Anil Mehta, a practicing Paediatrician, has been working in the rare disease field for over twenty years. His experience spans the disciplines of bioengineering, biochemistry and medicine/epidemiology. His undergraduate work was undertaken in Oxford and London and his postgraduate experience was supported by the UK Medical Research Council and, thereafter, by grants from the Wellcome Trust and other leading UK charities.

Anil is currently a Clinical Academic at the University of Dundee, an Institute of Higher Education in Scotland with extensive links to industry. He has published over seventy peer reviewed papers with publications in the rare disease field in leading Journals including two recent papers in the Lancet where a podcast of his research is available in an archive at www.lancet.com/lancet-audio-2010 (March 20th 2010).

How can we place more importance on the understanding of rare diseases?