ERA-EDTA 2015: Genetics & Kidney Disease

The 52nd ERA-EDTA Congress is taking place from May 28-31, 2015, in London, United Kingdom, and is being held jointly with the ERA-EDTA (European Renal Association – European Dialysis and Transplant Association) and The Renal Association. Dr. Paul Phelan from the AJKD Blog will be providing some highlights from the conference.

 

This symposium was an introduction to genetics for the nephrologist and comprised 4 talks. I would also suggest background reading from the NephMadness 2015 Genetics region.

Epigenetics (by Gerjan Navis)

Epigenetics refers to alterations of gene expression without changes to gene sequence.

These processes are cell-specific, modifiable by the environment and potentially inheritable. The processes include DNA methylation, histone (nuclear folding proteins in the chromatin) modifications, and gene regulatory changes induced by microRNAs (miRNAs). Interesting points from the talk included:

  1. Legacy effect: This explains the influence that early life exposures may have in later life (examples included early Na exposure and low birth weight with hypertension; hyperglycemia with subsequent cardiovascular risk as well as citing the classic Dutch 1944 famine example which may have influenced birth weight 2 generations later).
  2. Potential for these mechanisms to be influenced. Examples included exercise which can alter skeletal muscle methylation and drugs such as RAAS blockers decreasing acetylation of histones which may have consequences for renal development.
  3. Epigenetics influences on AKI/CKD & transplantation were only hinted at but here is one great example of the translational potential in renal fibrosis using demethylation to silence pro-fibrotic genes.
Importance of miRNAs (by Ariela Benigni)

These are a subset of small non-coding mRNAs (remember >95% of DNA is not coded) which alter post-transcriptional gene expression. A specific example in a model of renal
fibrosis was given where a in-silico methods were employed to find miRNAs likely to be involved in the pathway. The most likely RNA was miR-324-p which was found to be
over-expressed in rats with with the fibrotic phenotype. Prep was identified as a serine endopeptidase which breaks down Angiotensin I & II to less pathogenic proteins (less pressor and fibrotic ability). Rats with higher miR-324-p had less Prep which was reversed by addition of an ACE inhibitor.

GWAS & Kidney Disease (by Carsten Boger)

The methodologies and challenges of GWAS were discussed (see NephMadness 2015 Genetics Region) which I won’t go into but some nice examples of their benefits were
illustrated. When studying complex disease, the importance of precise phenotype was reiterated, potentially explaining why GWAS studies in CKD have not been as clinically useful as the following examples which are defined using histology:

  1. IgA Nephropathy: This fascinating study explained novel variants associated with the disease as well as linking it to geography (explaining predisposition in Asia) and specifically with mucosal pathogen diversity, especially helminths. It also showed shared risk loci with other autoimmune and inflammatory conditions in pathway analysis.
  1. Membranous Nephropathy: variants in PLA2R were uncovered in a GWAS of idiopathic membranous nephropathy which has helped understand pathogeneisis, prognosis, and hopefully soon therapeutics.
  2. UMOD: Then UMOD story is fascinating, with variants being associated with lower risk of UTIs and salt sensitive hypertension (beneficial throughout human history so not bred out) and CKD in modern times. In that respect it mirrors the APOL1 story, better known as the current NephMadness champion!
Next Generation Sequencing (by Nine Knoers)

Using massively parallel sequencing is an efficient way of sequencing multiple nucleotides (or the whole genome). It is quick and the cost is dropping all the time. It was explained that this can be customized for disease specific genes as well as performing more broad (but still targeted) exome sequencing as well as whole genome sequencing (WGS). The filtering mechanisms are crucial to find the 1 pathogenic mutation out of 20-50,000 uncovered by whole exome or the 2-5 million revealed by whole genome sequencing. Filtering is becoming easier with ever increasing databases of variants available to help exclude benign variants. It was also mentioned that we all carry about 100 highly penetrant mutations as well as 20 complete gene deletions without apparent clinical effect highlighting the issues with data interpretation.

Another interesting point made was the ability to identify unexplained phenotypes thereby providing precise molecular diagnoses. An example of a family with FSGS without deafness who was found to have COL4A mutations when WGS was performed. This is nicely illustrated in this paper using whole exome sequencing.

Overall, great introduction to modern genetic techniques but it could have filled a whole day!

Post written by Dr. Paul Phelan, AJKD Blog Contributor.

Check out more AJKD Blog coverage of the 2015 ERA-EDTA Congress.

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