I’m currently attending the ISN-Nature Genetics Forefronts Symposium on Nephrogenetics in Danvers MA.

If the Human Variome Project were to produce a comprehensive synopsis of all the variants of a single gene important for kidney function, together with all the available evidence for their involvement in human disease, which gene would you choose for them to highlight? The synopsis would cover all the mendelian mutations, association studies with common variants and resequencing for rare variants. Please consider:

1) the prevalence and seriousness of the clinical condition(s)

2) the value added by combining all three types of genetic study listed above

3) the availability of all three kinds of evidence

Please send your recommendations with brief reasons to variome.pub(at)gmail.com which is an email address I have set up to collate responses to this question. If you are not a nephrogeneticist (or even if you are) please don’t restrict your answers to kidney genes, this is an important question for the future of the Human Variome Project. I will attempt to post all answers to the blog and would prefer to publish your name with your contribution. Please let me know if you would prefer the comment to be anonymous.

The gene-based view of human variation is fine for molecular biologists and will help clinical geneticists decide whether a variant is likely to cause disease, but I suspect most physicians will be more interested in a disease-based view. In other words, “how many genes can be mutated to produce this phenotype, and what tests are available to help me distinguish between them?”

At this meeting, the difficulty of producing such a view is obvious since the correspondence between genes and kidney diseases is often many-to-many rather than one-to-one. Mutations in the renin-angiotensin system result in tubular dysgenesis. Mutations affecting cilia and centrosomes mostly produce polycystic kidney disease, Bardet-Biedl syndrome and nephronophthisis. However, mutations affecting glomerular filtration by the podocytes and slit diaphragm rather unpredictably produce different clinical conditions: familial glomerulosclerosis and steroid resistant nephrotic syndrome.

Keynote speaker Richard Lifton (Yale) emphasized that studies of human heredity have shown that the ten mutations that raise blood pressure and nine that lower it all influence salt homeostasis in the kidney. There is every indication that variants in these same genes will be important at the population level.

It is certainly difficult to lower blood pressure simply by restricting salt intake. Some find that regular exercise or losing excess weight is also needed. Many also are prescribed diuretics and beta-blockers or ACE inhibitors on the advice of their physician. But to what extent is salt imposed on us by a food industry that exploits our evolutionary adaptation to crave salt? My co-convenor, Qais Al-Awqati (Columbia) said that it is the practice of the Salt Institute to highlight conflicting publications in order to represent the science of blood pressure regulation as “controversial”. Great argument, “the scientists can’t agree, so salt can’t be that bad, can it?”. Now where did I hear that one before, climate change?

To be fair, the Salt Institute response to Qais’s editorial of May last year can be found here.