Nephronophthisis (NPH) is the most prevalent genetic cause for ESRD in children. However, little is known about the prevalence of NPH in adult-onset ESRD. Homozygous full gene deletions of the
gene ...encoding nephrocystin-1 are a prominent cause of NPH. We determined the prevalence of NPH in adults by assessing homozygous
full gene deletions in adult-onset ESRD.
Adult renal transplant recipients from five cohorts of the International Genetics and Translational Research in Transplantation Network (iGeneTRAiN) underwent single-nucleotide polymorphism genotyping. After quality control, we determined autosomal copy number variants (such as deletions) on the basis of median log2 ratios and B-allele frequency patterns. The findings were independently validated in one cohort. Patients were included in the analysis if they had adult-onset ESRD, defined as start of RRT at ≥18 years old.
We included 5606 patients with adult-onset ESRD; 26 (0.5%) showed homozygous
deletions. No donor controls showed homozygosity for this deletion. Median age at ESRD onset was 30 (range, 18-61) years old for patients with NPH, with 54% of patients age ≥30 years old. Notably, only three (12%) patients were phenotypically classified as having NPH, whereas most patients were defined as having CKD with unknown etiology (
=11; 42%).
Considering that other mutation types in
or mutations in other NPH-causing genes were not analyzed, NPH is a relatively frequent monogenic cause of adult-onset ESRD. Because 88% of patients had not been clinically diagnosed with NPH, wider application of genetic testing in adult-onset ESRD may be warranted.
Immunoglobulin A nephropathy (IgAN) is a heterogeneous disorder with a strong genetic component. The advent of whole exome sequencing (WES) has accelerated the discovery of genetic risk factors ...underlying familial disorders.
We set out to test whether damaging variants in known kidney disease genes explain a proportion of IgAN cases recruited in Ireland.
We performed WES in 10 Irish families with multiple affected members having kidney disease where at least one member had biopsy confirmed IgAN. Candidate variants were identified based on being shared between affected family members, minor allele frequency, function and predicted pathogenicity. Pathogenicity of variants was determined according to American College of Medical Genetics and Genomics guidelines.
We detected candidate variants in 3 of 10 families. We identified a likely pathogenic variant in COL4A5 in one family and a variant of unknown significance (VUS) in COL4A3 in another. Variants in COL4A5 and COL4A3 are known to cause Alport syndrome. In the third family, we identified a VUS in LMX1B, a gene associated with Nail-patella syndrome.
We identified a number of cases of familial IgAN where the families harbored variants in known kidney disease-related genes indicating that potentially a number of cases of familial IgAN are mistaken for other familial kidney disorders. However, the majority of families studied did not carry a candidate variant in a known kidney disease causing gene indicating that there may be >1 underlying genetic mechanism present in these families.
Summary
The importance of genetic and biochemical variation in renal transplant outcomes has been clear since the discovery of the HLA in the 1950s. Since that time, there have been huge advancements ...in both transplantation and omics. In recent years, there has seen an increased number of genome‐, proteome‐ and transcriptome‐wide studies in the field of transplantation moving away from the earlier candidate gene/protein approaches. These areas have the potential to lead to the development of personalized treatment depending on individual molecular risk profiles. Here, we discuss recent progress and the current literature surrounding omics and renal transplant complications.
Utility of Genomic Testing after Renal Biopsy Murray, Susan L; Dorman, Anthony; Benson, Katherine A ...
American journal of nephrology,
01/2020, Volume:
51, Issue:
1
Journal Article
Peer reviewed
Open access
Renal biopsy is the mainstay of renal pathological diagnosis. Despite sophisticated diagnostic techniques, it is not always possible to make a precise pathological diagnosis. Our aim was to identify ...a genetic cause of disease in patients who had undergone renal biopsy and determine if genetic testing altered diagnosis or treatment.
Patients with suspected familial kidney disease underwent a variety of next-generation sequencing (NGS) strategies. The subset of these patients who had also undergone native kidney biopsy was identified. Histological specimens were reviewed by a consultant pathologist, and genetic and pathological diagnoses were compared.
Seventy-five patients in 47 families underwent genetic sequencing and renal biopsy. Patients were grouped into 5 diagnostic categories based on pathological diagnosis: tubulointerstitial kidney disease (TIKD; n = 18); glomerulonephritis (GN; n = 15); focal segmental glomerulosclerosis and Alport Syndrome (n = 11); thrombotic microangiopathy (TMA; n = 17); and nonspecific pathological changes (n = 14). Thirty-nine patients (52%) in 21 families (45%) received a genetic diagnosis; 13 cases (72%) with TIKD, 4 (27%) with GN, 6 (55%) with focal segmental glomerulosclerosis/Alport syndrome, and 10 (59%) with TMA and 6 cases (43%) with nonspecific features. Genetic testing resulted in changes in understanding of disease mechanism in 21 individuals (54%) in 12 families (57%). Treatment would have been altered in at least 26% of cases (10/39).
An accurate genetic diagnosis can result in changes in clinical diagnosis, understanding of pathological mechanism, and treatment. NGS should be considered as a complementary diagnostic technique to kidney biopsy in the evaluation of patients with kidney disease.
Renal transplant recipients have an increased risk of non‐melanoma skin cancer (NMSC) compared to in the general population. Here, we show polygenic risk scores (PRS) calculated from genome‐wide ...association studies (GWAS) of NMSC in a general, nontransplant setting, can predict risk of, and time to posttransplant skin cancer. Genetic variants, reaching predefined P‐value thresholds were chosen from published squamous cell carcinoma (SCC) and basal cell carcinoma (BCC) nontransplant GWAS. Using these GWAS, BCC and SCC PRS were calculated for each sample across three European ancestry renal transplant cohorts (n = 889) and tested as predictors of case:control status and time to NMSC posttransplant. BCC PRS calculated at P‐value threshold 1 × 10−5 was the most significant predictor of case:control status of NMSC posttransplant (OR = 1.61; adjusted P = .0022; AUC full model adjusted for clinical predictors and PRS = 0.81). SCC PRS at P‐value threshold 1 × 10−5 was the most significant predictor of time to posttransplant NMSC (adjusted P = 9.39 × 10−7; HR = 1.41, concordance full model = 0.74). PRS of nontransplant NMSC is predictive of case:control status and time to NMSC posttransplant. These results are relevant to how genomics can risk stratify patients to help develop personalized treatment regimens.
Polygenic risk score of nontransplant non‐melanoma skin cancer is predictive of case:control status and time to non‐melanoma posttransplant, demonstrating the use of genomics to stratify patients at risk for transplant complications.
Full text
Available for:
BFBNIB, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Polygenic risk scores (PRSs) calculated from genome‐wide association studies (GWASs) of non‐melanoma skin cancer (NMSC) in a general, non‐transplant setting have recently been shown to predict risk ...of and time to post‐renal transplant skin cancer. In this study, we set out to test these findings in a cohort of heart, lung, and liver transplant patients to see whether these scores could be applied across different organ transplant types. Using the PRS from Stapleton et al (2018), PRS was calculated for each sample across a European ancestry heart, lung, and liver transplant cohorts (n = 523) and tested as predictor of time to NMSC post‐transplant. The top PRS, squamous cell carcinoma (SCC) pT1 x 10−5, (n SNPs = 1953), SCC pT1 x 10−6, and SCC pT1 x 10−6 (n SNPs = 1061) were significantly predictive in the time to NMSC, SCC, and basal cell carcinoma (BCC) analysis across organ (P = .006, .02, and .02, respectively). We observed here a similar direction of effect and effect size NMSC HR = 1.31(1.08‐1.59) to that in the original discovery study with increased polygenic burden leading to a faster time to developing NMSC. In summary, we found that PRS of NMSC calculated from GWAS of NMSC in non‐transplant populations independently replicated in this cohort of heart, lung, and liver transplant.
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DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, UILJ, UKNU, UL, UM, UPUK
7.
The genetic determinants of renal allograft rejection Hernandez‐Fuentes, Maria; Stapleton, Caragh P.; Cavalleri, Gianpiero L. ...
American journal of transplantation,
August 2018, Volume:
18, Issue:
8
Journal Article
Peer reviewed
Open access
Full text
Available for:
BFBNIB, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Resistance to anti-seizure medications (ASMs) presents a significant hurdle in the treatment of people with epilepsy. Genetic markers for resistance to individual ASMs could support clinicians to ...make better-informed choices for their patients. In this study, we aimed to elucidate whether the response to individual ASMs was associated with common genetic variation.
A cohort of 3,649 individuals of European descent with epilepsy was deeply phenotyped and underwent single nucleotide polymorphism (SNP)-genotyping. We conducted genome-wide association analyses (GWASs) on responders to specific ASMs or groups of functionally related ASMs, using non-responders as controls. We performed a polygenic risk score (PRS) analyses based on risk variants for epilepsy and neuropsychiatric disorders and ASM resistance itself to delineate the polygenic burden of ASM-specific drug resistance.
We identified several potential regions of interest but did not detect genome-wide significant loci for ASM-specific response. We did not find polygenic risk for epilepsy, neuropsychiatric disorders, and drug-resistance associated with drug response to specific ASMs or mechanistically related groups of ASMs.
This study could not ascertain the predictive value of common genetic variants for ASM responder status. The identified suggestive loci will need replication in future studies of a larger scale.
BACKGROUNDEvidence is limited regarding acute rejection (AR) beyond human leukocyte antigens and studies investigating genetic background of AR are limited in size. This study combined genome-wide ...association studies (GWAS) following kidney transplantation to increase power and further understand mechanisms of AR. The cohorts in this meta-analysis are from the International Genetics and Translational Research in Transplantation Network (iGeneTRAiN).
METHODSWe performed a GWAS meta-analysis of AR anytime post-transplant in Caucasian recipients and donors after kidney transplantation using the “Tx Array” containing ~782,000 single-nucleotide polymorphisms (SNPs). AR was defined by treating physician. Genotype imputation was based on the 1000 Genomes project and Genomes of The Netherlands reference datasets. The analysis was adjusted for age, sex, living/deceased donors, and population stratification using principal components. We ran a fixed effect, inverse variance, meta-analysis to combine results from 7 cohorts. SNPs that were deemed to reach GWAS significance had p < 1x10-6, population frequency between 0.01 and 0.99 and R2 for imputation quality > 0.8.
RESULTSThe meta-analysis of 7 GWAS cohorts in iGeneTRAiN included 5,291 kidney transplant recipients with 1265 (24%) AR events (Table 1). Thirty recipient SNPs reached GWAS significance for their association with AR. The recipient SNP with strongest AR association was rs294768 (p = 1.24 x10-8) located 7.9 kb 5’ of UGT2B10. 14 of the 30 top recipient SNPs were located in or near UGT2B10, including rs2942857, which is an mRNA splice acceptor (p = 2.59x10-7). 3 significant recipient SNPs were located in or near each of UNC5D, CA10, and NLGN1. 39 donor SNPs reached GWAS significance for their association with AR. The top donor SNPs werers137878631, 33kb 3’ of DMP1 (p = 2.61x10-8); rs78140122, intron of MARCH1 (p = 4.16x10-8); rs140005264, intron of ALDH16A1 (p = 7.34x10-8); and rs62220573,19kb 3’ of KRTAP21-3 (p = 9.52x10-8). The remaining significant donor SNPs were located in or near the following genesEVX2, ATF7IP, MIR2054, TAS2R16, GPATCH1, RAB3GAP2, KIAA1328, FAM107B, ALDH16A1, TPP2, TXNDC5, ADAMTS19, HERPUD2 and 7 SNPs 3’ of FGFR2.(Table is included in full-text article.)
CONCLUSIONSWe identified several novel susceptibility loci associated with AR. UGT2B10 had the most variants associated with AR in this meta-analysis with p < 1x10-6. These SNPs need to be validated by independent cohorts and functionally assessed.
We set out to quantify shared genetic ancestry between unrelated kidney donor-recipient pairs and test it as a predictor of time to graft failure.
In a homogenous, unrelated, European cohort of ...deceased-donor kidney transplant pairs (n pairs = 1,808), we calculated, using common genetic variation, shared ancestry at the genic (n loci=40,053) and genomic level. We conducted a sub-analysis focused on transmembrane protein coding genes (n transcripts=8,637) and attempted replication of a previously published nonsynonymous transmembrane mismatch score. Measures of shared genetic ancestry were tested in a survival model against time to death-censored graft failure.
Shared ancestry calculated across the human leukocyte antigen (HLA) significantly associated with graft survival in individuals who had a high serological mismatch (n pairs = 186) with those who did not have any HLA mismatches indicating that shared ancestry calculated specific loci can capture known associations with genes impacting graft outcome. None of the other measures of shared ancestry at a genic level, genome-wide scale, transmembrane subset or nonsynonymous transmembrane mismatch score analysis were significant predictors of time to graft failure.
In a large unrelated, deceased-donor European ancestry renal transplant cohort, shared donor-recipient genetic ancestry, calculated using common genetic variation, has limited value in predicting transplant outcome both on a genomic scale and at a genic level (other than at the HLA loci).
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