Strategies for investigating the genetics of chronic kidney disease

This short review describes the strategies employed for investigating genetic variation in chronic kidney disease as well as highlighting potential shortfalls that should be overcome in future studies. Mini Review Strategies for investigating the genetics of chronic kidney disease Sourabh Chand* Renal Department, Shrewsbury and Telford NHS Trust, UK Received: 27 June, 2018 Accepted: 26 July, 2018 Published: 28 July, 2018 *Corresponding author: Sourabh Chand, Renal Department, Shrewsbury and Telford NHS Trust, UK, E-mail: https://www.peertechz.com


Introduction
Since the 1980s, there have been more than 3000 research papers published on the genetics of chronic kidney disease (CKD) [1]. Initially, these had concentrated on Mendelian patterns of inheritance to understand the pathophysiology of inherited diseases such as adult polycystic kidney disease. The mutations in genes PKD1 and PKD2 have led to more informed genetic counselling regarding the progression of their disease as well as the pathways leading to this disease [2], and other familial mutations have been identifi ed when investigating other inheritable congenital kidney diseases resulting from single gene disorders, especially in children.

Candidate gene associations in CKD
Over the last decade, single gene studies have focused on biological plausible candidate gene association with kidney disease. These studies were often underpowered with inclusion of multiple ethnicities in cohort studies, with little attempt at replication and correction for multiple confounders. However, as the 1000 genome project has recently confi rmed, there is a large genomic discrepancy depending on your ethnicity and ancestry [3]. One method of counter-acting these issues is genome-wide linkage studies that combine the above two strategies, by examining large genomic regions in familybased collections of DNA to associate transmission of genetic variants to the development of CKD. Conditions such as CKD are likely to be more complex with many potential pathways and environmental changes leading to its development and progression. The ability to fi nd enough numbers of related individuals with an underlying condition to track genetic change across multiple generations remains a barrier to success for this method.

Single Nucleotide Polymorphisms
The most common type of genomic variation is Single Nucleotide Polymorphism (SNP) that must occur in over 1% of the population to be called a SNP and has the possibility of two alleles at a given site (biallelic) [4]. part of the genome, 1-2% of the human genome, or whole genome sequencing [6]. This technique is utilised especially when examining tissue or a subgroup of cells from tissue.
The advantage of this technique is the allowance to fi nd novel mutations with phenotype association, however also proposes the challenge of interpreting large volumes of data.

Genome wide association studies in CKD
The phenotypes studied in GWASs in CKD have tended to focus on estimated glomerular fi ltration rate (eGFR), CKD progression, proteinuria and renal disease prevalence, rather than measures of cardiovascular disease or mortality.
Examples of success in GWAS association with renal disease, using the above strategies comes from the CKDGen study group who performed a meta-analysis of 20 GWASs. This included over 67000 patients studied of European ancestry who had biopsies of either their native or transplant kidney. The analysis was from population-based studies rather than casecontrol and examined the glomerular and tubulointerstitial gene expression in relation to declining eGFR. They had not only found 13 new loci related to kidney function and serum creatinine secretion but also found vascular endothelial growth factor A gene expression in both renal compartments with strong enrichment for the hypoxia signalling pathway [7]. GWASs have also been able to confi rm laboratory fi ndings even in small populations of disease such as in membranous nephropathy. In a French cohort of just 75 cases, the phospholipase A 2 receptor (PLA 2 R) 1 gene was found to signifi cantly associate with membranous nephropathy [8], after previous confi rmation of serological M-type PLA 2 R autoantibody could be found in 70% of cases to differentiate between primary and secondary membranous nephropathy which in turn, has marked therapeutic implications [9]. Subsequent investigation has revealed an odds-ratio (OR) of 2.00 with the presence of the at risk SNP genotype for PLA 2 R1 despite being located within the fi rst intron (non-coding) part of the gene [10]. GWASs have also been able to confi rm that the pathogenesis of disease states such as antineutrophil cytoplasmic antibody associated vasculitis has a genetic component and the subsets of this condition granulomatosis with polyangiitis and microscopic polyangiitis show genetic distinctions and thus are distinct autoimmune syndromes [11].

Epigenetics
As well as inherited genetic infl uence on outcomes and prevalence in CKD, epigenetics is a fi eld that is helping researchers to understand the infl uence that environmental factors have on the human genome and thus disease presentation and variance amongst individuals. This has been observed even in phenotypic discordant monozygotic twins (with identical DNA sequence) to explain their differences [12]. There are