Uncovering myocardial infarction genetic signatures using GWAS exploration in Saudi and European cohorts.

Genome-wide association studies (GWAS) have yielded significant insights into the genetic architecture of myocardial infarction (MI), although studies in non-European populations are still lacking. Saudi Arabian cohorts offer an opportunity to discover novel genetic variants impacting disease risk due to a high rate of consanguinity. Genome-wide genotyping (GWG), imputation and GWAS followed by meta-analysis were performed based on two independent Saudi Arabian studies comprising 3950 MI patients and 2324 non-MI controls. Meta-analyses were then performed with these two Saudi MI studies and the CardioGRAMplusC4D and UK BioBank GWAS as controls. Meta-analyses of the two Saudi MI studies resulted in 17 SNPs with genome-wide significance. Meta-analyses of all 4 studies revealed 66 loci with genome-wide significance levels of p < 5 × 10-8. All of these variants, except rs2764203, have previously been reported as MI-associated loci or to have high linkage disequilibrium with known loci. One SNP association in Shisa family member 5 (SHISA5) (rs11707229) was evident at a much higher frequency in the Saudi MI populations (> 12% MAF). In conclusion, our results replicated many MI associations, whereas in Saudi-only GWAS (meta-analyses), several new loci were implicated that require future validation and functional analyses.

Oral microbiota analyses of paediatric Saudi population reveals signatures of dental caries.

BACKGROUND: Oral microbiome sequencing has revealed key links between microbiome dysfunction and dental caries. However, these efforts have largely focused on Western populations, with few studies on the Middle Eastern communities. The current study aimed to identify the composition and abundance of the oral microbiota in saliva samples of children with different caries levels using machine learning approaches. METHODS: Oral microbiota composition and abundance were identified in 250 Saudi participants with high dental caries and 150 with low dental caries using 16 S rRNA sequencing on a NextSeq 2000 SP flow cell (Illumina, CA) using 250 bp paired-end reads, and attempted to build a classifier using random forest models to assist in the early detection of caries. RESULTS: The ADONIS test results indicate that there was no significant association between sex and Bray-Curtis dissimilarity (p ~ 0.93), but there was a significant association with dental caries status (p ~ 0.001). Using an alpha level of 0.05, five differentially abundant operational taxonomic units (OTUs) were identified between males and females as the main effect along with four differentially abundant OTUs between high and low dental caries. The mean metrics for the optimal hyperparameter combination using the model with only differentially abundant OTUs were: Accuracy (0.701); Matthew's correlation coefficient (0.0509); AUC (0.517) and F1 score (0.821) while the mean metrics for random forest model using all OTUs were:0.675; 0.054; 0.611 and 0.796 respectively. CONCLUSION: The assessment of oral microbiota samples in a representative Saudi Arabian population for high and low metrics of dental caries yields signatures of abundances and diversity.

Gut microbiota analyses of inflammatory bowel diseases from a representative Saudi population.

BACKGROUND: Crohn's diseases and ulcerative colitis, both of which are chronic immune-mediated disorders of the gastrointestinal tract are major contributors to the overarching Inflammatory bowel diseases. It has become increasingly evident that the pathological processes of IBDs results from interactions between genetic and environmental factors, which can skew immune responses against normal intestinal flora. METHODS: The aim of this study is to assess and analyze the taxa diversity and relative abundances in CD and UC in the Saudi population. We utilized a sequencing strategy that targets all variable regions in the 16 S rRNA gene using the Swift Amplicon 16 S rRNA Panel on Illumina NovaSeq 6000. RESULTS: The composition of stool 16 S rRNA was analyzed from 219 patients with inflammatory bowel disease and from 124 healthy controls. We quantified the abundance of microbial communities to examine any significant differences between subpopulations of samples. At the genus level, two genera in particular, Veillonella and Lachnoclostridium showed significant association with CD versus controls. There were significant differences between subjects with CD versus UC, with the top differential genera spanning Akkermansia, Harryflintia, Maegamonas and Phascolarctobacterium. Furthermore, statistically significant taxa diversity in microbiome composition was observed within the UC and CD groups. CONCLUSIONS: In conclusion we have shown that there are significant differences in gut microbiota between UC, CD and controls in a Saudi Arabian inflammatory bowel disease cohort. This reinforces the need for further studies in large populations that are ethnically and geographically diverse. In addition, our results show the potential to develop classifiers that may have add additional richness of context to clinical diagnosis of UC and CD with larger inflammatory bowel disease cohorts.

Family-base rare variant association analysis in Saudi Arabian hydrocephalus subjects using whole exome sequencing.

BACKGROUND: Hydrocephalus is a highly heterogeneous multifactorial disease that arises from genetic and environmental factors. Familial genetic studies of hydrocephalus have elucidated four robustly associated hydrocephalus associated loci. This study aims to identify potential genetic causation in cases of hydrocephalus, with or without spina bifida and Dandy Walker Syndrome (DWS), using family-based rare variant association analysis of whole exome sequencing. METHODS: We performed whole exome sequencing in 143 individuals across 48 families where at least one offspring was affected with hydrocephalus (N.=27), with hydrocephalus with spina bifida (N.=21) and with DWS (N.=3), using Illumina HiSeq 2500 instrument. RESULTS: No pathogenic or putative pathogenic single-nucleotide variants were evident in the four known hydrocephalus loci in our subjects. However, after examining 73 known hydrocephalus genes previously identified from literature, we identified three potentially impactful variants from the cohort. Using a gene panel comprising variants in known neural tube defects loci, we identified a total of 1024 potentially deleterious variants, of which 797 were missense variants and 191 were frameshift variants, 36 were stop gain/loss variants. A small portion of our family pedigree analyses yielded putative genetic signals which may be responsible for hydrocephaly elated phenotypes, however the low diagnostic yield may be due to lack of capture of genetic variants in the exonic regions i.e. structural variants may only be evident from whole genome sequencing. CONCLUSIONS: We identified three potentially impactful variants from our cohort in 73 known hydrocephalus genes previously identified in literature.

Genome-wide copy number variant screening of Saudi schizophrenia patients reveals larger deletions in cases versus controls.

Introduction: Genome-wide association studies have discovered common polymorphisms in regions associated with schizophrenia. No genome-wide analyses have been performed in Saudi schizophrenia subjects. Methods: Genome-wide genotyping data from 136 Saudi schizophrenia cases and 97 Saudi controls in addition to 4,625 American were examined for copy number variants (CNVs). A hidden Markov model approach was used to call CNVs. Results: CNVs in schizophrenia cases were twice as large on average than CNVs in controls (p = 0.04). The analyses focused on extremely large >250 kilobases CNVs or homozygous deletions of any size. One extremely large deletion was noted in a single case (16.5 megabases on chromosome 10). Two cases had an 814 kb duplication of chromosome 7 spanning a cluster of genes, including circadian-related loci, and two other cases had 277 kb deletions of chromosome 9 encompassing an olfactory receptors gene family. CNVs were also seen in loci previously associated with schizophrenia, namely a 16p11 proximal duplication and two 22q11.2 deletions. Discussion: Runs of homozygosity (ROHs) were analyzed across the genome to investigate correlation with schizophrenia risk. While rates and sizes of these ROHs were similar in cases and controls, we identified 10 regions where multiple cases had ROHs and controls did not.

LoFTK: a framework for fully automated calculation of predicted Loss-of-Function variants and genes.

BACKGROUND: Loss-of-Function (LoF) variants in human genes are important due to their impact on clinical phenotypes and frequent occurrence in the genomes of healthy individuals. The association of LoF variants with complex diseases and traits may lead to the discovery and validation of novel therapeutic targets. Current approaches predict high-confidence LoF variants without identifying the specific genes or the number of copies they affect. Moreover, there is a lack of methods for detecting knockout genes caused by compound heterozygous (CH) LoF variants. RESULTS: We have developed the Loss-of-Function ToolKit (LoFTK), which allows efficient and automated prediction of LoF variants from genotyped, imputed and sequenced genomes. LoFTK enables the identification of genes that are inactive in one or two copies and provides summary statistics for downstream analyses. LoFTK can identify CH LoF variants, which result in LoF genes with two copies lost. Using data from parents and offspring we show that 96% of CH LoF genes predicted by LoFTK in the offspring have the respective alleles donated by each parent. CONCLUSIONS: LoFTK is a command-line based tool that provides a reliable computational workflow for predicting LoF variants from genotyped and sequenced genomes, identifying genes that are inactive in 1 or 2 copies. LoFTK is an open software and is freely available to non-commercial users at https://github.com/CirculatoryHealth/LoFTK .

Whole-exome sequencing of a Saudi epilepsy cohort reveals association signals in known and potentially novel loci.

BACKGROUND: Epilepsy, a serious chronic neurological condition effecting up to 100 million people globally, has clear genetic underpinnings including common and rare variants. In Saudi Arabia, the prevalence of epilepsy is high and caused mainly by perinatal and genetic factors. No whole-exome sequencing (WES) studies have been performed to date in Saudi Arabian epilepsy cohorts. This offers a unique opportunity for the discovery of rare genetic variants impacting this disease as there is a high rate of consanguinity among large tribal pedigrees. RESULTS: We performed WES on 144 individuals diagnosed with epilepsy, to interrogate known epilepsy-related genes for known and functional novel variants. We also used an American College of Medical Genetics (ACMG) guideline-based variant prioritization approach in an attempt to discover putative causative variants. We identified 32 potentially causative pathogenic variants across 30 different genes in 44/144 (30%) of these Saudi epilepsy individuals. We also identified 232 variants of unknown significance (VUS) across 101 different genes in 133/144 (92%) subjects. Strong enrichment of variants of likely pathogenicity was observed in previously described epilepsy-associated loci, and a number of putative pathogenic variants in novel loci are also observed. CONCLUSION: Several putative pathogenic variants in known epilepsy-related loci were identified for the first time in our population, in addition to several potential new loci which may be prioritized for further investigation.

Gut microbiota analyses of Saudi populations for type 2 diabetes-related phenotypes reveals significant association.

BACKGROUND: Large-scale gut microbiome sequencing has revealed key links between microbiome dysfunction and metabolic diseases such as type 2 diabetes (T2D). To date, these efforts have largely focused on Western populations, with few studies assessing T2D microbiota associations in Middle Eastern communities where T2D prevalence is now over 20%. We analyzed the composition of stool 16S rRNA from 461 T2D and 119 non-T2D participants from the Eastern Province of Saudi Arabia. We quantified the abundance of microbial communities to examine any significant differences between subpopulations of samples based on diabetes status and glucose level. RESULTS: In this study we performed the largest microbiome study ever conducted in Saudi Arabia, as well as the first-ever characterization of gut microbiota T2D versus non-T2D in this population. We observed overall positive enrichment within diabetics compared to healthy individuals and amongst diabetic participants; those with high glucose levels exhibited slightly more positive enrichment compared to those at lower risk of fasting hyperglycemia. In particular, the genus Firmicutes was upregulated in diabetic individuals compared to non-diabetic individuals, and T2D was associated with an elevated Firmicutes/Bacteroidetes ratio, consistent with previous findings. CONCLUSION: Based on diabetes status and glucose levels of Saudi participants, relatively stable differences in stool composition were perceived by differential abundance and alpha diversity measures. However, community level differences are evident in the Saudi population between T2D and non-T2D individuals, and diversity patterns appear to vary from well-characterized microbiota from Western cohorts. Comparing overlapping and varying patterns in gut microbiota with other studies is critical to assessing novel treatment options in light of a rapidly growing T2D health epidemic in the region. As a rapidly emerging chronic condition in Saudi Arabia and the Middle East, T2D burdens have grown more quickly and affect larger proportions of the population than any other global region, making a regional reference T2D-microbiome dataset critical to understanding the nuances of disease development on a global scale.

Donor and recipient polygenic risk scores influence the risk of post-transplant diabetes.

Post-transplant diabetes mellitus (PTDM) reduces allograft and recipient life span. Polygenic risk scores (PRSs) show robust association with greater risk of developing type 2 diabetes (T2D). We examined the association of PTDM with T2D PRS in liver recipients (n = 1,581) and their donors (n = 1,555), and kidney recipients (n = 2,062) and their donors (n = 533). Recipient T2D PRS was associated with pre-transplant T2D and the development of PTDM. T2D PRS in liver donors, but not in kidney donors, was an independent risk factor for PTDM development. The inclusion of a combined liver donor and recipient T2D PRS significantly improved PTDM prediction compared with a model that included only clinical characteristics: the area under the curve (AUC) was 67.6% (95% confidence interval (CI) 64.1-71.1%) for the combined T2D PRS versus 62.3% (95% CI 58.8-65.8%) for the clinical characteristics model (P = 0.0001). Liver recipients in the highest quintile of combined donor and recipient T2D PRS had the greatest risk of PTDM, with an odds ratio of 3.22 (95% CI 2.07-5.00) (P = 1.92 × 10-7) compared with those in the lowest quintile. In conclusion, T2D PRS identifies transplant candidates with high risk of PTDM for which pre-emptive diabetes management and donor selection may be warranted.

Whole transcriptome profiling of prospective endomyocardial biopsies reveals prognostic and diagnostic signatures of cardiac allograft rejection.

BACKGROUND: Heart transplantation provides a significant improvement in survival and quality of life for patients with end-stage heart disease, however many recipients experience different levels of graft rejection that can be associated with significant morbidities and mortality. Current clinical standard-of-care for the evaluation of heart transplant acute rejection (AR) consists of routine endomyocardial biopsy (EMB) followed by visual assessment by histopathology for immune infiltration and cardiomyocyte damage. We assessed whether the sensitivity and/or specificity of this process could be improved upon by adding RNA sequencing (RNA-seq) of EMBs coupled with histopathological interpretation. METHODS: Up to 6 standard-of-care, or for-cause EMBs, were collected from 26 heart transplant recipients from the prospective observational Clinical Trials of Transplantation (CTOT)-03 study, during the first 12-months post-transplant and subjected to RNA-seq (n = 125 EMBs total). Differential expression and random-forest-based machine learning were applied to develop signatures for classification and prognostication. RESULTS: Leveraging the unique longitudinal nature of this study, we show that transcriptional hallmarks for significant rejection events occur months before the actual event and are not visible using traditional histopathology. Using this information, we identified a prognostic signature for 0R/1R biopsies that with 90% accuracy can predict whether the next biopsy will be 2R/3R. CONCLUSIONS: RNA-seq-based molecular characterization of EMBs shows significant promise for the early detection of cardiac allograft rejection.

The Impact of Donor and Recipient Genetic Variation on Outcomes After Solid Organ Transplantation: A Scoping Review and Future Perspectives.

At the outset of solid organ transplantation, genetic variation between donors and recipients was recognized as a major player in mechanisms such as allograft tolerance and rejection. Genome-wide association studies have been very successful in identifying novel variant-trait associations, but have been difficult to perform in the field of solid organ transplantation due to complex covariates, era effects, and poor statistical power for detecting donor-recipient interactions. To overcome a lack of statistical power, consortia such as the International Genetics and Translational Research in Transplantation Network have been established. Studies have focused on the consequences of genetic dissimilarities between donors and recipients and have reported associations between polymorphisms in candidate genes or their regulatory regions with transplantation outcomes. However, knowledge on the exact influence of genetic variation is limited due to a lack of comprehensive characterization and harmonization of recipients' or donors' phenotypes and validation using an experimental approach. Causal research in genetics has evolved from agnostic discovery in genome-wide association studies to functional annotation and clarification of underlying molecular mechanisms in translational studies. In this overview, we summarize how the recent advances and progresses in the field of genetics and genomics have improved the understanding of outcomes after solid organ transplantation.

Early detection of SARS-CoV-2 and other infections in solid organ transplant recipients and household members using wearable devices.

The increasing global prevalence of SARS-CoV-2 and the resulting COVID-19 disease pandemic pose significant concerns for clinical management of solid organ transplant recipients (SOTR). Wearable devices that can measure physiologic changes in biometrics including heart rate, heart rate variability, body temperature, respiratory, activity (such as steps taken per day) and sleep patterns, and blood oxygen saturation show utility for the early detection of infection before clinical presentation of symptoms. Recent algorithms developed using preliminary wearable datasets show that SARS-CoV-2 is detectable before clinical symptoms in >80% of adults. Early detection of SARS-CoV-2, influenza, and other pathogens in SOTR, and their household members, could facilitate early interventions such as self-isolation and early clinical management of relevant infection(s). Ongoing studies testing the utility of wearable devices such as smartwatches for early detection of SARS-CoV-2 and other infections in the general population are reviewed here, along with the practical challenges to implementing these processes at scale in pediatric and adult SOTR, and their household members. The resources and logistics, including transplant-specific analyses pipelines to account for confounders such as polypharmacy and comorbidities, required in studies of pediatric and adult SOTR for the robust early detection of SARS-CoV-2, and other infections are also reviewed.

Pharmacogenomics in kidney transplant recipients and potential for integration into practice.

WHAT IS KNOWN AND OBJECTIVE: Pharmacogenomic biomarkers are now used in many clinical care settings and represent one of the successes of precision medicine. Genetic variants are associated with pharmacokinetic and pharmacodynamic changes leading to medication adverse effects and changes in clinical response. Actionable pharmacogenomic variants are common in transplant recipients and have implications for medications used in transplant, but yet are not broadly incorporated into practice. METHODS: From the Clinical Pharmacogenetics Implementation Consortium and Dutch Pharmacogenetics Working Group guidelines, and PharmGKB databases, 12 pharmacogenomic genes with 30 variants were selected and used to create diplotypes and actionable pharmacogenomic phenotypes. A total of 853 kidney allograft recipients who had genomic information available from a genome-wide association study were included. RESULTS: Each recipient had at least one actionable pharmacogenomic diplotype/phenotype, whereas the majority (58%) had three or four actionable diplotypes/phenotypes and 17.4% had five or more among the 12 genes. The participants carried actionable diplotypes/phenotypes for multiple medications, including tacrolimus, azathioprine, clopidogrel, warfarin, simvastatin, voriconazole, antidepressants and proton-pump inhibitors. WHAT IS NEW AND CONCLUSION: Pharmacogenomic variants are common in transplant recipients, and transplant recipients receive medications that have actionable variants. CLINICAL TRIAL: Genomics of Transplantation, clinicaltrials.gov (NCT01714440).

Genomics and Liver Transplantation: Genomic Biomarkers for the Diagnosis of Acute Cellular Rejection.

Acute cellular rejection (ACR) is a common complication in liver transplantation recipients (LTRs), especially within the first 12 months, and it is associated with increased morbidity and mortality. Although abnormalities in standard liver biochemistries may raise the clinical suspicion for ACR, it lacks specificity, and invasive liver biopsies, which are associated with numerous risks, are required for definitive diagnoses. Biomarker discovery for minimally invasive tools for diagnosis and prognostication of ACR after liver transplantation (LT) has become a rapidly evolving field of research with a recent shift in focus to omics-based biomarker discovery. Although none are yet ready to replace the standard of care, there are several promising minimally invasive, blood-derived biomarkers that are under intensive research for the diagnosis of ACR in LTRs. These omics-based biomarkers, encompassing DNA, RNA, proteins, and metabolites, hold tremendous potential. Some are likely to become integrated into ACR diagnostic algorithms to assist clinical decision making with a high degree of accuracy that is cost-effective and reduces or even obviates the need for an invasive liver biopsy.

Polygenic risk score of non-melanoma skin cancer predicts post-transplant skin cancer across multiple organ types.

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.

Genome-wide non-HLA donor-recipient genetic differences influence renal allograft survival via early allograft fibrosis.

Donor-recipient (D-R) differences at human leukocyte antigen (HLA) loci are currently incorporated into organ sharing, allocation and immunosuppression decisions. However, while acute rejection episodes have substantially diminished, progressive histologic damage occurs in allografts and improved long-term survival remains an unrealized goal among kidney recipients. Here we tested the hypothesis that non-HLA dependent, genome-wide D-R genetic differences could contribute to unchecked alloimmunity with histologic and functional consequences, culminating in long-term allograft failure. Genome-wide single nucleotide polymorphism (SNP) array data, excluding the HLA region, was utilized from 385 transplants to study the role of D-R differences upon serial histology and allograft survival. ADMIXTURE analysis was performed to quantitatively estimate ancestry in each D-R pair and PLINK was used to estimate the proportion of genome-shared identity-by-descent (pIBD) between D-R pairs. Subsequently, quantitative measures of recipient ancestry based on non-HLA SNPs was associated with death-censored allograft survival in adjusted Cox models. In D-R pairs of similar ancestry, pIBD was significantly associated with allograft survival independent of HLA mismatches in 224 transplants. Surprisingly, pIBD and recipient ancestry were not associated with clinical or subclinical rejection at any time post-transplant. Significantly, in multivariable analysis, pIBD inversely correlated with vascular intimal fibrosis in 160 biopsies obtained less than one year which in turn was significantly associated with allograft survival. Thus, our novel data show that non-HLA D-R differences associate with early vascular intimal fibrosis and allograft survival.

Current and Future Approaches for Monitoring Responses to Anti-complement Therapeutics.

Aberrations in complement system functions have been identified as either direct or indirect pathophysiological mechanisms in many diseases and pathological conditions, such as infections, autoimmune diseases, inflammation, malignancies, and allogeneic transplantation. Currently available techniques to study complement include quantification of (a) individual complement components, (b) complement activation products, and (c) molecular mechanisms/function. An emerging area of major interest in translational studies aims to study and monitor patients on complement regulatory drugs for efficacy as well as adverse events. This area is progressing rapidly with several anti-complement therapeutics under development, in clinical trials, or already in clinical use. In this review, we summarized the appropriate indications, techniques, and interpretations of basic complement analyses, exemplified by a number of clinical disorders.

Genome-Wide Study Updates in the International Genetics and Translational Research in Transplantation Network (iGeneTRAiN).

The prevalence of end-stage renal disease (ESRD) and the number of kidney transplants performed continues to rise every year, straining the procurement of deceased and living kidney allografts and health systems. Genome-wide genotyping and sequencing of diseased populations have uncovered genetic contributors in substantial proportions of ESRD patients. A number of these discoveries are beginning to be utilized in risk stratification and clinical management of patients. Specifically, genetics can provide insight into the primary cause of chronic kidney disease (CKD), the risk of progression to ESRD, and post-transplant outcomes, including various forms of allograft rejection. The International Genetics & Translational Research in Transplantation Network (iGeneTRAiN), is a multi-site consortium that encompasses >45 genetic studies with genome-wide genotyping from over 51,000 transplant samples, including genome-wide data from >30 kidney transplant cohorts (n = 28,015). iGeneTRAiN is statistically powered to capture both rare and common genetic contributions to ESRD and post-transplant outcomes. The primary cause of ESRD is often difficult to ascertain, especially where formal biopsy diagnosis is not performed, and is unavailable in ∼2% to >20% of kidney transplant recipients in iGeneTRAiN studies. We overview our current copy number variant (CNV) screening approaches from genome-wide genotyping datasets in iGeneTRAiN, in attempts to discover and validate genetic contributors to CKD and ESRD. Greater aggregation and analyses of well phenotyped patients with genome-wide datasets will undoubtedly yield insights into the underlying pathophysiological mechanisms of CKD, leading the way to improved diagnostic precision in nephrology.

Tacrolimus troughs and genetic determinants of metabolism in kidney transplant recipients: A comparison of four ancestry groups.

Tacrolimus trough and dose requirements vary dramatically between individuals of European and African American ancestry. These differences are less well described in other populations. We conducted an observational, prospective, multicenter study from which 2595 kidney transplant recipients of European, African, Native American, and Asian ancestry were studied for tacrolimus trough, doses, and genetic determinants of metabolism. We studied the well-known variants and conducted a CYP3A4/5 gene-wide analysis to identify new variants. Daily doses, and dose-normalized troughs were significantly different between the four groups (P < .001). CYP3A5*3 (rs776746) was associated with higher dose-normalized tacrolimus troughs in all groups but occurred at different allele frequencies and had differing effect sizes. The CYP3A5*6 (rs10264272) and *7 (rs413003343) variants were only present in African Americans. CYP3A4*22 (rs35599367) was not found in any of the Asian ancestry samples. We identified seven suggestive variants in the CYP3A4/5 genes associated with dose-normalized troughs in Native Americans (P = 1.1 × 10-5 -8.8 × 10-6 ) and one suggestive variant in Asian Americans (P = 5.6 × 10-6 ). Tacrolimus daily doses and dose-normalized troughs vary significantly among different ancestry groups. We identified potential new variants important in Asians and Native Americans. Studies with larger populations should be conducted to assess the importance of the identified suggestive variants.

The impact of donor and recipient common clinical and genetic variation on estimated glomerular filtration rate in a European renal transplant population.

Genetic variation across the human leukocyte antigen loci is known to influence renal-transplant outcome. However, the impact of genetic variation beyond the human leukocyte antigen loci is less clear. We tested the association of common genetic variation and clinical characteristics, from both the donor and recipient, with posttransplant eGFR at different time-points, out to 5 years posttransplantation. We conducted GWAS meta-analyses across 10 844 donors and recipients from five European ancestry cohorts. We also analyzed the impact of polygenic risk scores (PRS), calculated using genetic variants associated with nontransplant eGFR, on posttransplant eGFR. PRS calculated using the recipient genotype alone, as well as combined donor and recipient genotypes were significantly associated with eGFR at 1-year posttransplant. Thirty-two percent of the variability in eGFR at 1-year posttransplant was explained by our model containing clinical covariates (including weights for death/graft-failure), principal components and combined donor-recipient PRS, with 0.3% contributed by the PRS. No individual genetic variant was significantly associated with eGFR posttransplant in the GWAS. This is the first study to examine PRS, composed of variants that impact kidney function in the general population, in a posttransplant context. Despite PRS being a significant predictor of eGFR posttransplant, the effect size of common genetic factors is limited compared to clinical variables.