|Year : 2015 | Volume
| Issue : 2 | Page : 46-49
Genetic Factors for End-Stage Renal Disease
Renal Department and Institute of Nephrology, Sichuan Provincial People's Hospital; School of Medicine, University of Electronic Science and Technology of China, Chengdu 610072, China
|Date of Web Publication||24-Apr-2015|
Renal Department and Institute of Nephrology, Sichuan Provincial People's Hospital, Sichuan; School of Medicine, University of Electronic Science and Technology of China, Chengdu 610072
Source of Support: This study was supported by the Nation Basic Research
Program of China 973 Program, No. 2012CB517600, Confl ict of Interest:
None declared., Conflict of Interest: None
Genetic factor plays an important role in the progression of chronic kidney diseases and in the development of end-stage renal disease (ESRD). Present studies on ESRD, estimated glomerular filtration rate, and renal fibrosis have demonstrated a great number of genetic variants that are associated with the susceptibility to ESRD by different genetic study strategies. These results may provide novel insights about the development and prevention of ESRD.
Keywords: End-stage renal disease, estimated glomerular filtration rate, fibrosis, genetics
|How to cite this article:|
Li G. Genetic Factors for End-Stage Renal Disease. J Integr Nephrol Androl 2015;2:46-9
| Introduction|| |
Chronic kidney disease (CKD) has become a significant public health issue. Recent data have revealed a 10.8% incidence rate of CKD among Chinese adults, that is, an estimated number of over 119 million.  Once progressed to end-stage renal disease (ESRD), which is followed by renal replacement therapy (RRT), the risk of a series of complications would rise, accompanied by a markedly reduced life expectancy; meanwhile, more ESRD patients would die earlier without proper RRT.  Moreover, RRT and treatment for other complications occupy a tremendous amount of medical resources, causing severe socioeconomic burden. Thus, it has become a major subject on preventing or postponing CKD from advancing to ESRD. More and more researchers have focused on the role of genetic factors in the development of ESRD, which has been confirmed by massive published researches. 
The earliest researches on the genetic background of ESRD were likely to apply linkage analysis or were based on candidate gene association study. In recent years, rapid development of genetic research strategies and technologies have witnessed the application of genome-wide association study (GWAS), exome sequencing, whole genome sequencing, epigenetic study, and so forth, on the genetic background investigations of CKD and ESRD.
However, ESRD is the common pathway of various kidney diseases in their end-stages. Due to varied etiology of ESRD and complicated pathophysiological process of CKD progression, the genetic background investigation of ESRD occurrence is still very challenging. Recent studies have covered the following three aspects related to ESRD, which were, (1) direct inclusion of ESRD patients for genetic background investigations; (2) application of glomerular filtration rate (GFR) as a surrogate. GFR is known as the most important parameter to reflect renal function, and is influenced by genetic factors as well; with this aspect, the genetic risk factors were further explored regarding the advancement from CKD to ESRD; (3) some authors investigated the common pathway to ESRD, for instance, the relation between key factors of genetic mutation in renal interstitial fibrosis and its genetic susceptibility of ESRD.
| Genetic Susceptibility Studies of End-Stage Renal Disease|| |
Common research strategies concerning the genetic susceptibility to ESRD include linkage analysis, candidate gene association analysis, GWAS, exome sequencing, and so forth. Candidate gene association analysis and GWAS are two most widely applied methods.
Candidate gene association analysis
The major candidate gene association analysis related to ESRD is mainly focused on renin-angiotensin system-associated genes (including angiotensinogen (AGT) genes, angiotensin-converting enzyme (ACE) genes, angiotensin receptor genes, etc.), immune response genes (including human leukocyte antigen [HLA] and its receptors), cytokines or inflammation factors related genes, and so forth. A number of previous studies have revealed that the insertion or deletion of ACE genes (ACE I/D) is associated with the incidence of ESRD.  A recent meta-analysis that included 12 researches indicated that the D allele of ACE (odds ratio [OR] = 1.32, 95% confidence interval [CI]: 1.11-1.56, P = 0.002) and DD genotype (OR = 1.67, 95% CI: 1.25-2.21, P = 0.0004) were associated with diabetic nephropathy-induced ESRD.  These genetic polymorphisms may also increase the risk of developing CKD in Asian hypertensive patients.  Similarly, a recent meta-analysis that included 16 researches on the polymorphism of AGT gene indicated that the T allele (OR = 1.13, 95% CI: 1.02-1.25, P = 0.02) and TT genotype (OR = 1.22, 95% CI: 1.03-1.45, P = 0.02) of AGT M235T are associated with ESRD development in Caucasians. 
A number of other candidate genes were included as well. Prakash  discovered that killer-cell immunoglobulin (Ig)-like receptors and HLA-associated genetic polymorphism were associated with the susceptibility to ESRD. Kim  adopted interleukin-17 (IL-17) and its receptor gene as a candidate gene and discovered that IL-17E rs10137082*C and IL-17RA rs4819554*A allele genes were associated with nondiabetic nephropathy-associated ESRD in Korea. Reznichenko  discovered that the T allele of rs12917707 (G/T) in UMOD gene reduced the risk of developing ESRD. Bostrom  included 96 African American with nondiabetic nephropathy complicated with ESRD and 96 healthy subjects for direct sequencing in 19 exons of ACTN4, its promoter region and 3' untranslated region, and discovered that the single nucleotide polymorphisms (SNPs) (rs10404257) of ACTN4 was associated with the susceptibility of nondiabetic nephropathy in developing ESRD. 
Genome-wide association study
Compared with candidate gene association study, presumptions to determine certain specific genes or loci for GWAS is not necessary. This method, however, has not been widely applied in genetic susceptibility research until recent years, with limited application in ESRD patients. One typical example was the GWAS study performed among 1372 ESRD (703 diabetic ESRDs and 669 nondiabetic nephropathy ESRD) and 806 controlled subjects and discovered strong association in multiple SNPs of nonmuscle myosin heavy chain 9 (MYH9) in nondiabetic nephropathy-induced ESRD in African Americans,  but high-precision sequencing for MYH9 failed to identify mutation loci to induce genetic function alteration.  Further analysis on this gene and nearby regions discovered that the mutation of APOL1, a gene strongly linked to MYH9, was markedly relevant with ESRD, in other word, APOL1 might be the real susceptible gene to ESRD.  A further research among 3067 African Americans indicated that individuals carrying two mutated allele (G1 and G2) simultaneously had a markedly elevated risk of developing CKD and advancement to ESRD.  The interaction of environmental factors (e.g., HIV infection) and APOL1 risk alleles further increased the risk of developing CKD and ESRD.  Another research on a group of collapsing focal segmental glomerulosclerosis patients induced by interferon indicated that interferon and toll-like receptor antagonists markedly increased the expression level of APOL1, suggesting a possible underlying mechanism of APOL1 involved in the development of nephropathy. 
| End-Stage Renal Disease-Relevant Susceptibility Genes Aiming From The Angle of Estimated Glomerular Filtration Rate|| |
Glomerular filtration rate is a major criterion to evaluate kidney function. Researches published in recent years tend to focus on estimated glomerular filtration rate (eGFR) to look for susceptible genes related to ESRD. Köttgen  discovered that SNPs of UMOD, SHROOM3, and GATM/SPATA5L1 were related with eGFR level, and the T allele of rs12917707 (G/T) in UMOD reduced the risk of developing CKD.  Another GWAS study for Caucasians discovered 13 relevant SNPs in various genes that were related to CKD, and 7 SNPs related to eGFR.  A large sample GWAS study for European ancestors by Chambers  discovered that rs10206899 and rs4805834 were not only significantly relevant with their serum creatine level, but also with CKD incidence. However, for an SNP (rs17319721) discovered among European ancestors that was reported to be relevant with eGFR and CKD, our validations found no relevance among Chinese population,  indicating a possible underlying difference of ethnicity.
The studies above were performed as cross-section studies only. Böger  included 26,308 European ancestors without CKD and prospectively followed for 7.2 years. Total 2122 were documented with newly onset of CKD. Association study revealed 11 SNPs (including UMOD, PRKAG2, ANXA9, DAB2, SHROOM3) related with CKD, suggesting that these SNPs may be relevant with the susceptibility of ESRD. A recent study included 63,558 European ancestors who were determined consecutively for eGFR levels and investigated genetic variations that caused eGFR reduction. The first-phase GWAS meta-analysis aimed at 16 cohorts and a total of 45,530 patients in CKDGen Consortium and was repeated in 13 cohorts in phase-two study. The meta-analysis for the two phases indicated that the SNPs in UMOD (rs12917707), GALNT11 (rs1019173), and CDH23 (rs875860) were relevant with the rapid drop of eGFR. 
Another study was based on a large sample population GWAS and selected 24 million SNP insertion/deletion (INDEL). It revealed 19 loci relevant with kidney function, and 4 among the 5 newly discovered loci were rare variations (missense mutations and loss-of-function variations). The result indicated that rare variations had bigger influence on serum creatine compared to common variations reported previously.  This result suggested that regular GWAS study may not able to identify rare variations that are more important in CKD or ESRD.
| Genetic Susceptibility of End-Stage Renal Disease Aiming from Kidney Fibrosis|| |
Interstitial fibrosis is the most important common pathway leading to chronic renal failure. Hence, many researchers attempted to investigate the genetic background of chronic renal failure focusing on kidney fibrosis. Tubular interstitial fibrosis is a complicated pathophysiological process involving various cytokines, signaling pathways, as well as inflammatory cells and kidney inherent cells.  Cytokines that are commonly investigated include transforming growth-factor β1 (TGFβ1), bone morphogenetic protein, platelet-derived growth factor, hepatocyte growth factor, and so forth.  Theoretically, genetic variations of these cytokines or signaling molecules related to kidney fibrosis may influence its incidence and development.  Among these, TGFβ1 has attracted wide attention for its central part in fibrosis development. , A study of Caucasian ESRD patients discovered that variations on T869C and C509T in TGFβ1 were related to an increase of susceptibility of ESRD.  Research data in China also showed that T869C variation in TGFβ1 was responsible for the deterioration of kidney function in male hypertensive patients.  A study on immunoglobulin A nephropathy (IgAN) discovered that T869C variation in TGFβ1 was related to severe renal interstitial fibrosis in IgAN,  but because only a few patients would undergo kidney biopsy in early stages of ESRD or repeated biopsies, the severity and progress of interstitial fibrosis are unknown, thus limitations still exist focusing from the angle of renal fibrosis.
Although a number of studies on genetic susceptibility of ESRD have been published, they could only explain the genetic susceptibility of part of the patient population, and the risk of CKD patients in developing ESRD was not predicted. Different genetic variations may exist between ethnicities, and the mechanism of certain genetic variations in the development of ESRD (e.g., how APOL1 variation increases ESRD risk) is still unclear. Hence, we need to fully utilize novel genetic strategies and technologies to explore the relativity and the underlying mechanism of genetic variations and ESRD.
| Acknowledgments|| |
This study was supported by the Nation Basic Research Program of China 973 Program, No. 2012CB517600.
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