NephMadness 2015: Genetic Nephrology Region

Conall O'Seaghdha, MB MRCPI; Paul Phelan, MD

Disclosures

March 02, 2015

Editorial Collaboration

Medscape &

In This Article

Epigenetics in Nephrology vs Vesicoureteral Reflux

This unlikely match-up sees 2 teams that have never met in the big dance face off in the first round. Both have had quiet pre-seasons but have certainly earned their right to this year's tournament with a number of standout performances. We continue to learn more on the genetics of Vesicoureteral Reflux, and Epigenetics in Nephrology is an exciting team for the future that has commentators buzzing.

Epigenetics in Nephrology

Epigenetics refers to alterations of gene expression at the level of gene transcription and translation without changes to gene sequence. These processes are modifiable by the cellular environment, potentially inheritable, and include DNA methylation, histone (major proteins in the chromatin) modifications, and regulatory changes induced by microRNAs (miRNAs). DNA methylation involves the addition of a methyl group to a cytosine base within CpG sites within promoter sequencing which influences gene expression, generally causing gene silencing. These mechanisms may, at least partly, explain how environmental factors interact with the genome to influence complex traits like kidney disease.

The epigenome may also be thought of as a genetic-environmental footprint, explaining why in utero and early-life environmental conditions may lead to persistent lifetime and subsequent generation phenotypes (see Dutch Famine of 1944-45).

Technologies to perform large-scale epigenetic analysis are evolving and have lagged behind traditional genomic techniques. However, the International Human Epigenome Consortium is creating a reference map of the human epigenome which will facilitate in-depth epigenome wide studies. The influences of miRNAs may be particularly exciting given their ability to be manipulated, either antagonized or over-expressed, it is methylation where much of the evidence currently exists.

With GWAS failing to explain much of the variability in blood pressure, epigenetics may uncover some of the missing heritability. A genome-wide animal study of salt-sensitive hypertension in rats has implicated hypermethylation of the renin promoter. A human epigenome-wide methylation study in young males with hypertension reported hypermethylation of the SULF1 gene which was confirmed in the validation sample for individuals ≤30 years old.

Transplantation is also an area where epigenetics play a large role. T regulatory cells (Tregs), so important in immune recognition and restricting self-reactive T cells, are regulated by their transcriptional factor FOXP3. The expression of FOXP3 is governed by methylation/demethylation of Tregs. This system may be crucial in achieving the holy grail of transplant medicine, operational tolerance.

The realm of epigenetic gene silencing in renal fibrosis is a standout topic in nephrology genetics research with huge translational potential. Fibrosis, a pathological wound repair process that persists even when the initial injury has been removed, is a final common pathway of many disease processes.

There is accumulating evidence that the underlying molecular mechanism of fibrosis includes epigenetic processes, particularly gene hypermethylation. Bechtel et al demonstrated that hypermethylation of RASAL1 (an inhibitor of the Ras oncoprotein pathway) results in less inhibition of the Ras pathway and led to sustained fibroblast activation and subsequent renal fibrosis.

The potential of using de-methylating agents to allow RASAL1 to inhibit the Ras pathway and thus lead to less fibrosis appears very attractive. As mentioned above, gene silencing of RASAL1 via methylation results in increased intrinsic Ras-GTPase activity in affected fibroblasts leading to fibrosis. Tampe et al showed successful inhibition of experimental renal fibrosis via reversal of aberrant RASAL1 hypermethylation. They achieved this using bone morphogenic protein 7, known to have anti-fibrotic activity.

This toss-up is difficult to call. With 2 relatively unknown teams facing off for the first time, it's anyone's guess who will progress to the Round of 32. Is 2015 a year too early for the rookies of Team Epigenetics? We'll have to wait and see.

Vesicoureteral Reflux

Vesicoureteral reflux (VUR) is another condition where modern genetic advances have revolutionized our understanding of pathogenesis and heritability. It is the most common type of congenital anomaly of the kidney and the urinary tract (CAKUT) with an estimated prevalence of 1–2%, but may well be even higher. It is characterized by retrograde flow of urine from the bladder back to the ureter and the kidney.

VUR will often resolve with few significant sequelae but may be complicated by recurrent UTIs, scarring, and progressive renal disease. It remains unclear if the scars are a consequence of urine reflux/infections or if they represent co-existent developmental or dysplastic abnormalities. VUR may co-exist with other genitourinary abnormalities (ie, CAKUT) or as a part of syndromes with extra-renal developmental defects.

Family studies have long supported the heritability of VUR. There is a 30–50% incidence in first-degree relatives, full concordance among monozygotic and 50% among dizygotic twins. The mode of inheritance is often AD but AR and X-linked pedigrees have been described. However, specific genetic causes of VUR remained elusive until recent technological advances.

Results of genome-wide linkage analysis in several families across various populations suggested linkage at multiple different loci. This is likely due to genetic heterogeneity of VUR in the families studied. GWAS data also demonstrate this heterogeneity with multiple SNPs across the genome giving significant or borderline significant association with VUR.

Whole-exome sequencing has brought the most productivity in discovering single-gene causes of VUR. Most of the genes reported have not been in families with syndromic VUR/CAKUT and required large kindreds with many affected individuals.

An example of this is a 97-member pedigree with 16 affected individuals over 5 generations. Sequential genome–wide linkage and whole-exome sequencing was performed on the family. The causative mutation was discovered in TNXB , a gene associated with the joint hypermobility variant of Ehlers-Danlos syndrome.

Other genes implicated using next-generation sequencing have included ROBO2 , which may have multiple associated congenital abnormalities and HNF1B which may have liver, pancreas, and genital phenotypes (see Team AD Tubulointerstitial Nephritis above). RET may cause Hirschprung disease and multiple endocrine neoplasia type 2 as well as VUR and CAKUT. BMP4 mutations may cause defects in the eye, brain, and digits as well as CAKUT. PAX2 mutations cause renal coloboma syndrome, and variants in this gene have also been described causing an FSGS phenotype (see Team Familial FSGS).

These genes do not appear to play a major role in isolated, non-syndromic VUR. This underlines the complexity of genotype-phenotype interaction. It is likely that modifier genes with second "hits" or epigenetic alterations determine some of the varying phenotypes associated with certain gene variants and mutations.

The big clinical story regarding VUR in the past year was the RIVUR study published in NEJM (and covered on #NephJC). It demonstrated that prophylactic co-trimoxazole reduced the incidence of UTIs in children with VUR and a symptomatic UTI. However, this did not translate into less renal scarring at 2 years, which again questions the etiology of the "scars."

Therefore, modern genetic techniques have helped us understand that VUR is a complex phenotype. It may be an isolated, non-syndromic finding or inherited as part of a myriad of non-renal developmental abnormalities. Some VUR can be considered a complex trait, influenced by multiple genes each having small effect sizes, as demonstrated using genome-wide linkage and association. It can also be inherited as a single-gene disorder in multiple different risk genes, as demonstrated using next-generation sequencing. This genetic complexity should not be surprising given multi-component nature of the lower urinary tract and its intricate development. A major challenge of clinical relevance that remains is to distinguish children who will have a benign course from those who will develop severe, complicated reflux nephropathy.

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