Faculty Bibliography

For most patients with end-stage heart failure, heart transplantation is the treatment of choice. Allograft rejection is one of the major post-transplantation complications affecting graft outcome and survival. Recent advancements in science and technology offer an opportunity to integrate genomic and other omics-based biomarkers into clinical practice, facilitating noninvasive evaluation of allograft for diagnostic and prognostic purposes. Omics, including gene expression profiling (GEP) of blood immune cell components and donor-derived cell-free DNA (dd-cfDNA) are of special interest to researchers. Several studies have investigated levels of dd-cfDNA and miroRNAs in blood as potential markers for early detection of allograft rejection. One of the achievements in the field of transcriptomics is AlloMap, GEP of peripheral blood mononuclear cells (PBMC), which can identify 11 differentially expressed genes and help with detection of moderate and severe acute cellular rejection in stable heart transplant recipients. In recent years, the utilization of GEP of PBMC for identifying differentially expressed genes to diagnose acute antibody-mediated rejection and cardiac allograft vasculopathy has yielded promising results. Advancements in the field of metabolomics and proteomics as well as their potential implications have been further discussed in this paper.

UNLABELLED:Lack of noninvasive diagnostic and prognostic biomarkers to reliably detect early allograft injury poses a major hindrance to long-term allograft survival in pediatric kidney transplant recipients. METHODS:mRNA levels in urinary cells are diagnostic of BKVN and prognostic for allograft failure. RESULTS:To date, 204 subjects are enrolled, with 1405 urine samples, including 144 biopsy-associated samples. Among 424 urine samples processed for mRNA, the median A260:280 ratio (RNA purity) was 1.91, comparable with Clinical Trials in Organ Transplantation-4 (median 1.82). The quality control failure rate was 10%. Preliminary results from urine supernatant showed that our metabolomics platform successfully captured a broad array of metabolites. Clustering of pool samples and overlay of samples from various batches demonstrated platform robustness. No study site effect was noted. CONCLUSIONS:Multicenter efforts to ascertain urinary biomarkers in pediatric kidney transplant recipients are feasible with high-quality control. Further study will inform whether these signatures are discriminatory and predictive for rejection and infection.

AIMS:Our objective was to better understand the genetic bases of dilated cardiomyopathy (DCM), a leading cause of systolic heart failure. METHODS AND RESULTS:We conducted the largest genome-wide association study performed so far in DCM, with 2719 cases and 4440 controls in the discovery population. We identified and replicated two new DCM-associated loci on chromosome 3p25.1 [lead single-nucleotide polymorphism (SNP) rs62232870, P = 8.7 × 10-11 and 7.7 × 10-4 in the discovery and replication steps, respectively] and chromosome 22q11.23 (lead SNP rs7284877, P = 3.3 × 10-8 and 1.4 × 10-3 in the discovery and replication steps, respectively), while confirming two previously identified DCM loci on chromosomes 10 and 1, BAG3 and HSPB7. A genetic risk score constructed from the number of risk alleles at these four DCM loci revealed a 3-fold increased risk of DCM for individuals with 8 risk alleles compared to individuals with 5 risk alleles (median of the referral population). In silico annotation and functional 4C-sequencing analyses on iPSC-derived cardiomyocytes identify SLC6A6 as the most likely DCM gene at the 3p25.1 locus. This gene encodes a taurine transporter whose involvement in myocardial dysfunction and DCM is supported by numerous observations in humans and animals. At the 22q11.23 locus, in silico and data mining annotations, and to a lesser extent functional analysis, strongly suggest SMARCB1 as the candidate culprit gene. CONCLUSION:This study provides a better understanding of the genetic architecture of DCM and sheds light on novel biological pathways underlying heart failure.

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.

OBJECTIVE:To assess whether women with a genetic predisposition to medical conditions known to increase preeclampsia risk have an increased risk of preeclampsia in pregnancy. DESIGN/METHODS:Case-control study. SETTING AND POPULATION/METHODS:Preeclampsia cases (n=498) and controls (n=1864) of European ancestry from 5 US sites genotyped on a cardiovascular gene-centric array. METHODS:Significant single nucleotide polymorphisms (SNPs) from 21 traits in 7 disease categories (cardiovascular, inflammatory/autoimmune, insulin resistance, liver, obesity, renal, thrombophilia) with published genome-wide association studies (GWAS) were used to create a genetic instrument for each trait. Multivariable logistic regression was used to test the association of each continuous, scaled genetic instrument with preeclampsia. Odds of preeclampsia were compared across quartiles of the genetic instrument and evaluated for significance. MAIN OUTCOME MEASURES/METHODS:Genetic predisposition to medical conditions and their relationship with preeclampsia. RESULTS:An increasing burden of risk alleles for elevated diastolic blood pressure (DBP) and increased body mass index (BMI) were associated with an increased risk of preeclampsia (DBP: overall OR 1.11 (95% CI: 1.01-1.21), p=0.025; BMI: OR 1.10 (1.00-1.20), p=0.042), while alleles associated with elevated alkaline phosphatase (ALP) were protective (OR 0.89 (0.82-0.97), p=0.008), driven primarily by pleiotropic effects of variants in the FADS gene region. The effect of DBP genetic loci was even greater in early-onset (<34 weeks) preeclampsia cases (OR 1.30 (1.08-1.56), p=0.005). For other traits, there was no evidence of an association. CONCLUSIONS:These results suggest that the underlying genetic architecture of preeclampsia may be shared with other disorders, specifically hypertension and obesity.

Bipolar disorder is often comorbid with anxiety, which is itself associated with poorer clinical outcomes, including suicide. A better etiologic understanding of this comorbidity could inform diagnosis and treatment. The present study aims to test whether comorbid anxiety in bipolar disorder reflects shared genetic risk factors. We also sought to assess the contribution of genetic risk for anxiety to suicide attempts in bipolar disorder. Polygenic risk scores (PRS) were calculated from published genome-wide association studies of samples of controls and cases with anxiety (n = 83,566) or bipolar disorder (n = 51,710), then scored in independent target samples (total n = 3369) of individuals with bipolar disorder who reported or denied lifetime anxiety disorders or suicidal attempts in research interviews. Participants were recruited from clinical and nonclinical settings and genotyped for common genetic variants. The results show that polygenic risk for anxiety was associated with comorbid anxiety disorders and suicide attempts in bipolar disorder, while polygenic risk for bipolar disorder was not associated with any of these variables. Our findings point out that comorbid anxiety disorders in bipolar disorder reflect a dual burden of bipolar and anxiety-related genes; the latter may also contribute to suicide attempts. Clinical care that recognizes and addresses this dual burden may help improve outcomes in people living with comorbid bipolar and anxiety disorders.

WHAT IS KNOWN AND OBJECTIVE/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/CONCLUSIONS:Pharmacogenomic variants are common in transplant recipients, and transplant recipients receive medications that have actionable variants. CLINICAL TRIAL/BACKGROUND:Genomics of Transplantation, clinicaltrials.gov (NCT01714440).

Genetic matching between transplant donor and recipient pairs has traditionally focused on the human leukocyte antigen (HLA) regions of the genome, but recent studies suggest that matching for non-HLA regions may be important as well. We assess four genetic matching scores for use in association analyses of transplant outcomes. These scores describe genetic ancestry distance using identity-by-state, or genetic incompatibility or mismatch of the two genomes and therefore may reflect different underlying biological mechanisms for donor and recipient genes to influence transplant outcomes. Our simulation studies show that jointly testing these scores with the recipient genotype is a powerful method for preliminary screening and discovery of transplant outcome related single nucleotide polymorphisms (SNPs) and gene regions. Following these joint tests with marginal testing of the recipient genotype and matching score separately can lead to further understanding of the biological mechanisms behind transplant outcomes. In addition, we present results of a liver transplant data analysis that shows joint testing can detect SNPs significantly associated with acute rejection in liver transplant.