Extreme phenotype sampling and next generation sequencing to identify genetic variants associated with tacrolimus in African American kidney transplant recipients.

African American (AA) kidney transplant recipients (KTRs) have poor outcomes, which may in-part be due to tacrolimus (TAC) sub-optimal immunosuppression. We previously determined the common genetic regulators of TAC pharmacokinetics in AAs which were CYP3A5 *3, *6, and *7. To identify low-frequency variants that impact TAC pharmacokinetics, we used extreme phenotype sampling and compared individuals with extreme high (n = 58) and low (n = 60) TAC troughs (N = 515 AA KTRs).

Opportunities and challenges for immunosuppression in the context of pig-to-human xenotransplantation.

The transplantation of organ(s) across species may alleviate the shortage of available donor kidneys for an ever-growing number of patients on transplant waiting lists. However, this potential remains limited by uncharacterized physiologic and immune effects of xenotransplants in recipients, which Pan et al. investigated in the current study.

Limited Sampling Strategies Fail to Accurately Predict Mycophenolic Acid Area Under the Curve in Kidney Transplant Recipients and the Impact of Enterohepatic Recirculation.

Background: Therapeutic drug monitoring for mycophenolic acid (MPA) is challenging due to difficulties in measuring the area under the curve (AUC). Limited sampling strategies (LSSs) have been developed for MPA therapeutic drug monitoring but come with risk of unacceptable performance. The authors hypothesized that the poor predictive performance of LSSs were due to the variability in MPA enterohepatic recirculation (EHR).

Steroid-tacrolimus drug-drug interaction and the effect of CYP3A genotypes.

Aims: Tacrolimus, metabolized by CYP3A4 and CYP3A5 enzymes, is susceptible to drug-drug interactions (DDI). Steroids induce CYP3A genes to increase tacrolimus clearance, but the effect is variable. We hypothesized that the extent of the steroid-tacrolimus DDI differs by CYP3A4/5 genotypes.

Extreme Phenotype Sampling and Next Generation Sequencing to Identify Genetic Variants Associated with Tacrolimus in African American Kidney Transplant Recipients.

African American (AA) kidney transplant recipients (KTRs) have poor outcomes, which may in-part be due to tacrolimus (TAC) sub-optimal immunosuppression. We previously determined the common genetic regulators of TAC pharmacokinetics in AAs which were CYP3A5 *3, *6, and *7. To identify low-frequency variants that impact TAC pharmacokinetics, we used extreme phenotype sampling and compared individuals with extreme high (n=58) and low (n=60) TAC troughs (N=515 AA KTRs).

Pharmacomicrobiomics: Immunosuppressive Drugs and Microbiome Interactions in Transplantation.

The human microbiome is associated with human health and disease. Exogenous compounds, including pharmaceutical products, are also known to be affected by the microbiome, and this discovery has led to the field of pharmacomicobiomics. The microbiome can also alter drug pharmacokinetics and pharmacodynamics, possibly resulting in side effects, toxicities, and unanticipated disease response.

Effect of ginger supplementation on the fecal microbiome in subjects with prior colorectal adenoma.

Ginger has been associated with a decreased incidence of colorectal cancer (CRC) through reduction in inflammatory pathways and inhibition of tumor growth. Recent pre-clinical models have implicated changes in the gut microbiome as a possible mediator of the ginger effect on CRC. We hypothesized that, in adults previously diagnosed with a colorectal adenoma, ginger supplementation would alter the fecal microbiome in the direction consistent with its CRC-inhibitory effect.

Associations between MICA and MICB Genetic Variants, Protein Levels, and Colorectal Cancer: Atherosclerosis Risk in Communities (ARIC).

Background: The MHC class I chain-related protein A (MICA) and protein B (MICB) participate in tumor immunosurveillance and may be important in colorectal cancer, but have not been examined in colorectal cancer development.

Methods: sMICA and sMICB blood levels were measured by SomaScan in Visit 2 (1990-92, baseline) and Visit 3 (1993-95) samples in cancer-free participants in the Atherosclerosis Risk in Communities Study. We selected rs1051792, rs1063635, rs2516448, rs3763288, rs1131896, rs2596542, and rs2395029 that were located in or in the vicinity of MICA or MICB and were associated with cancer or autoimmune diseases in published studies.

Lower Expression of Is Associated with Higher Mortality in a Meta-Analysis of Individuals with Colorectal Cancer.

Individuals with cystic fibrosis (CF), caused by biallelic germline mutations in the cystic fibrosis transmembrane conductance regulator (, have higher risk and earlier onset of colorectal cancer (CRC). A subset of CRC patients in the non-CF population expresses low levels of tumoral mRNA which may also cause decreased CFTR activity. To determine the consequences of reduced expression in this population, we investigated association of tumoral expression with overall and disease-specific mortality in CRC patients.

Higher number of tacrolimus dose adjustments in kidney transplant recipients who are extensive and intermediate CYP3A5 metabolizers.

Kidney transplant recipients carrying the CYP3A5*1 allele have lower tacrolimus troughs, and higher dose requirements compared to those with the CYP3A5*3/*3 genotype. However, data on the effect of CYP3A5 alleles on post-transplant tacrolimus management are lacking. The effect of CYP3A5 metabolism phenotypes on the number of tacrolimus dose adjustments and troughs in the first 6 months post-transplant was evaluated in 78 recipients (64% Caucasians).

Fecal β-glucuronidase activity differs between hematopoietic cell and kidney transplantation and a possible mechanism for disparate dose requirements.

The intestinal microbiota produces β-glucuronidase that plays an essential role in the metabolism of the immunosuppressant mycophenolate mofetil (MMF). This drug is commonly used in organ and hematopoietic cell transplantation (HCT), with variations in dosing across transplant types. We hypothesized that β-glucuronidase activity differs between transplant types, which may account for differences in dosing requirements.

Randomised clinical study: oral aspirin 325 mg daily vs placebo alters gut microbial composition and bacterial taxa associated with colorectal cancer risk.

Background: Aspirin is associated with decreased risk of colorectal cancer (CRC), potentially by modulating the gut microbiome.

Aims: To evaluate the effect of aspirin on the gut microbiome in a double-blinded, randomised placebo-controlled pilot trial.

Methods: Healthy volunteers aged 50-75 received a standard dose of aspirin (325 mg, N = 30) or placebo (N = 20) once daily for 6 weeks and provided stool samples every 3 weeks for 12 weeks.

Adherence to the World Cancer Research Fund/American Institute for Cancer Research cancer prevention guidelines and colorectal cancer incidence among African Americans and whites: The Atherosclerosis Risk in Communities study.

Background: Adherence to the World Cancer Research Fund (WCRF)/American Institute for Cancer Research (AICR) cancer prevention recommendations is associated with colorectal cancer (CRC) risk in whites, but only 1 previous study has reported on this link in African Americans. This study assessed the association between the 2018 WCRF/AICR guidelines and CRC incidence in African Americans (26.5%) and whites (73.

Prospective Association of Serum and Dietary Magnesium with Colorectal Cancer Incidence.

Background: Laboratory and epidemiologic research suggests a protective role of magnesium in colorectal cancer development. We estimated the associations of serum and dietary magnesium with colorectal cancer incidence in the Atherosclerosis Risk in Communities (ARIC) study.

Methods: Serum magnesium concentration was measured in blood collected twice (1987-1989 and 1990-1992) and averaged.

Association between MICA polymorphisms, s-MICA levels, and pancreatic cancer risk in a population-based case-control study.

Background: Pancreatic tumor cells may avoid immune surveillance by releasing the transmembrane major histocompatibility complex class I chain-related A (MICA) protein in soluble form (s-MICA). We hypothesized that the presence of the A5.1 polymorphism in the MICA gene, which encodes a truncated MICA protein, is associated with higher s-MICA levels and increased pancreatic cancer risk.

Association between greater leg length and increased incidence of colorectal cancer: the atherosclerosis risk in communities (ARIC) study.

Purpose: Previous studies have reported that taller people have an increased risk of colorectal cancer (CRC). We examined the association of two height components-leg length and sitting height-with CRC risk in 14,532 individuals aged 45-64 years in the Atherosclerosis Risk in Communities study.

Methods: Anthropometrics were measured at baseline (1987-1989).

Soluble MICA is elevated in pancreatic cancer: Results from a population based case-control study.

Pancreatic cancer is diagnosed at a late stage and has one of the highest cancer mortality rates in the United States, creating an urgent need for novel early detection tools. A candidate biomarker for use in early detection is the soluble MHC class I-related chain A (s-MICA) ligand, which pancreatic tumors shed to escape immune detection. The objective of this study was to define the association between s-MICA levels and pancreatic cancer, in a population-based case-control study.