Genomic ascertainment to quantify prevalence and cancer risk in adults with pathogenic and likely pathogenic germline variants in RASopathy genes.

Purpose: Genomic ascertainment of electronic health record-linked exome data in two large biobanks was used to quantify germline pathogenic/likely pathogenic (P/LP) variant prevalence, cancer prevalence, and survival in adults with non- RAS/mitogen-activated protein kinase genes (RASopathies).

Patients And Methods: Germline RASopathy variants were examined from adult participants in UK Biobank (UKBB; n=469,802), Geisinger MyCode (n=167,050) and Mount Sinai Bio (n=30,470). Variants were classified as per American College of Medical Genetics/Association for Molecular Pathology criteria and reviewed by a RASopathy variant expert.

Genomic ascertainment of -related cancer predisposition.

Purpose: There is clear evidence that deleterious germline variants in increases risk for breast and prostate cancers; there is limited or conflicting evidence for other cancers. Genomic ascertainment was used to quantify cancer risk in germline pathogenic variant heterozygotes.

Patients And Methods: Germline variants were extracted from two exome-sequenced biobanks linked to the electronic health record: UK Biobank (n= 469,765) and Geisinger MyCode (n=170,503).

A genome-first approach to characterize DICER1 pathogenic variant prevalence, penetrance and cancer, thyroid, and other phenotypes in 2 population-scale cohorts.

Purpose: Population-scale, exome-sequenced cohorts with linked electronic health records (EHR) permit genome-first exploration of phenotype. Phenotype and cancer risk are well-characterized in children with a pathogenic (HGNC ID:17098) variant. Here, the prevalence, penetrance and phenotype of pathogenic germline variants in adults was investigated in two population-scale cohorts.

Applying a genetic risk score model to enhance prediction of future multiple sclerosis diagnosis at first presentation with optic neuritis.

Optic neuritis (ON) is associated with numerous immune-mediated inflammatory diseases, but 50% patients are ultimately diagnosed with multiple sclerosis (MS). Differentiating MS-ON from non-MS-ON acutely is challenging but important; non-MS ON often requires urgent immunosuppression to preserve vision. Using data from the United Kingdom Biobank we showed that combining an MS-genetic risk score (GRS) with demographic risk factors (age, sex) significantly improved MS prediction in undifferentiated ON; one standard deviation of MS-GRS increased the Hazard of MS 1.

Development of a Polygenic Risk Score to Predict Diverticulitis.

Background: Despite its prevalence and associated morbidity, we remain limited in our ability to predict the course of a patient with diverticular disease. Although several clinical and genetic risk factors have been identified, we do not know how these factors relate to one another.

Objective: Our aim was to determine whether a polygenic risk score could improve risk prediction for diverticulitis and recurrent diverticulitis compared with a model using only clinical factors.

A Genome-First Approach to Estimate Prevalence of Germline Pathogenic Variants and Risk of Pancreatic Cancer in Select Cancer Susceptibility Genes.

Patients with germline pathogenic variants (GPV) in cancer predisposition genes are at increased risk of pancreatic ductal adenocarcinoma (PDAC), the most common type of pancreatic cancer. The genes most frequently found to harbor GPV in unselected PDAC cases are , , , , and . However, GPV prevalence and gene-specific associations have not been extensively studied in the general population.

The role of resting myocardial blood flow and myocardial blood flow reserve as a predictor of major adverse cardiovascular outcomes.

Cardiac perfusion PET is increasingly used to assess ischemia and cardiovascular risk and can also provide quantitative myocardial blood flow (MBF) and flow reserve (MBFR) values. These have been shown to be prognostic biomarkers of adverse outcomes, yet MBF and MBFR quantification remains underutilized in clinical settings. We compare MBFR to traditional cardiovascular risk factors in a large and diverse clinical population (60% African-American, 35.

Genomic profiling of human vascular cells identifies TWIST1 as a causal gene for common vascular diseases.

Genome-wide association studies have identified multiple novel genomic loci associated with vascular diseases. Many of these loci are common non-coding variants that affect the expression of disease-relevant genes within coronary vascular cells. To identify such genes on a genome-wide level, we performed deep transcriptomic analysis of genotyped primary human coronary artery smooth muscle cells (HCASMCs) and coronary endothelial cells (HCAECs) from the same subjects, including splicing Quantitative Trait Loci (sQTL), allele-specific expression (ASE), and colocalization analyses.

Genetic and Epigenetic Fine Mapping of Complex Trait Associated Loci in the Human Liver.

Deciphering the impact of genetic variation on gene regulation is fundamental to understanding common, complex human diseases. Although histone modifications are important markers of gene regulatory elements of the genome, any specific histone modification has not been assayed in more than a few individuals in the human liver. As a result, the effects of genetic variation on histone modification states in the liver are poorly understood.

Cell-specific post-transcriptional regulation of γ-synuclein gene by micro-RNAs.

γ-Synuclein is a member of the synucleins family of small proteins, which consists of three members:α, β- and γ-synuclein. γ-Synuclein is abnormally expressed in a high percentage of advanced and metastatic tumors, but not in normal or benign tissues. Furthermore, γ-synuclein expression is strongly correlated with disease progression, and can stimulate proliferation, induce invasion and metastasis of cancer cells.

Beneficial effect of copper supplementation on deposition of fluoride in bone in fluoride- and molybdenum-fed rabbits.

Fluorosis is a major public health problem in the world, including India. The present study was undertaken to investigate the role of molybdenum (Mo) in the deposition of fluoride (F) in bone and whether copper (Cu) supplementation has any alleviating role when F and Mo are ingested together. For this purpose, four groups of rabbits were used [control (C), fluoride (F), fluoride + molybdenum (F + Mo), and fluoride + molybdenum + copper (F + Mo + Cu)] to find out the effect of these treatments on various bone-related parameters like intact parathyroid hormone (iPTH), alkaline phosphatase and Cu in serum, hydroxyproline and calcium (Ca) in urine, and minerals (F, Cu, manganese, and zinc) in femur bone ash.

Additional beneficial effect of tamarind ingestion over defluoridated water supply to adolescent boys in a fluorotic area.

Objective: We evaluated the effect of tamarind (Tamarindus indicus) on ingestion and whether it provides additional beneficial effects on mobilization of fluoride from the bone after children are provided defluoridated water.

Methods: A randomized, diet control study was conducted in 30 subjects from a fluoride endemic area after significantly decreasing urinary fluoride excretion by supplying defluoridated water for 2 wk. Subjects were then assigned to one of two groups, with 15 in each group.