Double CHEK2 Pathogenic and Low-Risk Variants and Associated Cancer Phenotypes.

Importance: CHEK2 pathogenic and likely pathogenic variants (PVs) are common, and low-risk (LR) variants, p.I157T, p.S428F, and p.

Cancer burden in individuals with single versus double pathogenic variants in cancer susceptibility genes.

Purpose: As panel testing expands, more individuals with double pathogenic variants (DPVs) in cancer susceptibility genes are likely to be identified. Little is known about the effects of DPVs on cancer phenotype, although this information is crucial for genetic counseling and risk management. We sought to describe the cancer phenotype among individuals with DPVs in cancer susceptibility genes.

Hereditary Transthyretin Amyloidosis in Patients Referred to a Genetic Testing Program.

Background: Diagnosis of hereditary amyloid transthyretin (hATTR) amyloidosis with cardiomyopathy is frequently delayed, in large part because of symptom overlap with other cardiovascular diseases and limited provider knowledge of this disease. The sponsored and provider referred hATTR Compass Genetic Testing Program (Ionis, Carlsbad, CA; Ambry Genetics, Aliso Viejo, CA) provided no-cost genetic testing to adults with a family history or clinical suspicion of hATTR amyloidosis. This study aims to characterize patients with hATTR amyloidosis and increase awareness of genetic testing for hATTR.

Characterization of POT1 tumor predisposition syndrome: Tumor prevalence in a clinically diverse hereditary cancer cohort.

Purpose: Germline variants in POT1 have been implicated in predisposition to melanoma, sarcoma, and glioma in limited studies. Here, we determine the prevalence of cancer types in individuals with POT1 pathogenic variants (PVs) undergoing multigene panel testing (MGPT) for a broad variety of cancer indications.

Methods: We performed a retrospective review of data provided on clinical documents from individuals with POT1 PVs identified via MGPT over a 5-year period.

Multi-ethnic GWAS and fine-mapping of glycaemic traits identify novel loci in the PAGE Study.

Aims/hypothesis: Type 2 diabetes is a growing global public health challenge. Investigating quantitative traits, including fasting glucose, fasting insulin and HbA, that serve as early markers of type 2 diabetes progression may lead to a deeper understanding of the genetic aetiology of type 2 diabetes development. Previous genome-wide association studies (GWAS) have identified over 500 loci associated with type 2 diabetes, glycaemic traits and insulin-related traits.

Genetic discovery and risk characterization in type 2 diabetes across diverse populations.

Genomic discovery and characterization of risk loci for type 2 diabetes (T2D) have been conducted primarily in individuals of European ancestry. We conducted a multiethnic genome-wide association study of T2D among 53,102 cases and 193,679 control subjects from African, Hispanic, Asian, Native Hawaiian, and European population groups in the Population Architecture Genomics and Epidemiology (PAGE) and Diabetes Genetics Replication and Meta-analysis (DIAGRAM) Consortia. In individuals of African ancestry, we discovered a risk variant in the gene (rs11466334, risk allele frequency (RAF) = 6.

Risk of breast cancer and prediagnostic urinary excretion of bisphenol A, triclosan and parabens: The Multiethnic Cohort Study.

Exposure to bisphenol A (BPA), triclosan and parabens is widespread but their impact on breast cancer risk remains unclear. This nested case-control study investigated endocrine-disrupting chemicals (EDCs) and breast cancer risk within the Multiethnic Cohort (MEC). We measured prediagnostic urinary BPA, triclosan and parabens in 1032 postmenopausal women with breast cancer (48 African American, 77 Latino, 155 Native Hawaiian, 478 Japanese American and 274 White) and 1030 individually matched controls, using a sensitive and validated liquid chromatography mass spectrometry assay.

Urinary phthalate exposures and risk of breast cancer: the Multiethnic Cohort study.

Background: The epidemiologic evidence from observational studies on breast cancer risk and phthalates, endocrine disrupting chemicals, has been inconsistent. In the only previous study based on pre-diagnostic urinary phthalates and risk of breast cancer, results were null in mostly white women.

Methods: We examined the association between pre-diagnostic urinary phthalates and breast cancer in a nested case-control study within the Multiethnic Cohort (MEC) study, presenting the first data from five major racial/ethnic groups in the USA.

Allelic Heterogeneity at the CRP Locus Identified by Whole-Genome Sequencing in Multi-ancestry Cohorts.

Whole-genome sequencing (WGS) can improve assessment of low-frequency and rare variants, particularly in non-European populations that have been underrepresented in existing genomic studies. The genetic determinants of C-reactive protein (CRP), a biomarker of chronic inflammation, have been extensively studied, with existing genome-wide association studies (GWASs) conducted in >200,000 individuals of European ancestry. In order to discover novel loci associated with CRP levels, we examined a multi-ancestry population (n = 23,279) with WGS (∼38× coverage) from the Trans-Omics for Precision Medicine (TOPMed) program.

Whole genome sequence association with E-selectin levels reveals loss-of-function variant in African Americans.

E-selectin mediates the rolling of circulating leukocytes during inflammatory processes. Previous genome-wide association studies in European and Asian individuals have identified the ABO locus associated with E-selectin levels. Using Trans-Omics for Precision Medicine whole genome sequencing data in 2249 African Americans (AAs) from the Jackson Heart Study, we examined genome-wide associations with soluble E-selectin levels.

Lipoprotein-associated phospholipase A and risk of incident peripheral arterial disease: Findings from The Atherosclerosis Risk in Communities study (ARIC).

Background And Aims: Results from prospective studies evaluating the relationship between elevated lipoprotein-associated phospholipase A (Lp-PLA) activity and incident peripheral arterial disease (PAD) have been mixed. We investigated whether higher Lp-PLA levels are associated with increased risk of incident PAD and whether PLA2G7 gene variants, which result in lower Lp-PLA levels, are associated with reduced risk of incident PAD.

Methods: Our analysis included 9922 participants (56% female; 21% African-American; mean age 63 years) without baseline PAD at ARIC Visit 4 (1996-1998), who had Lp-PLA activity measured and were subsequently followed for the development of PAD, defined by occurrence of a PAD-related hospitalization, through 2012.

Genetic invalidation of Lp-PLA as a therapeutic target: Large-scale study of five functional Lp-PLA-lowering alleles.

Aims Darapladib, a potent inhibitor of lipoprotein-associated phospholipase A (Lp-PLA), has not reduced risk of cardiovascular disease outcomes in recent randomized trials. We aimed to test whether Lp-PLA enzyme activity is causally relevant to coronary heart disease. Methods In 72,657 patients with coronary heart disease and 110,218 controls in 23 epidemiological studies, we genotyped five functional variants: four rare loss-of-function mutations (c.

Whole-exome sequencing reveals an inherited R566X mutation of the epithelial sodium channel β-subunit in a case of early-onset phenotype of Liddle syndrome.

To comprehensively evaluate a European-American child with severe hypertension, whole-exome sequencing (WES) was performed on the child and parents, which identified causal variation of the proband's early-onset disease. The proband's hypertension was resistant to treatment, requiring a multiple drug regimen including amiloride, spironolactone, and hydrochlorothiazide. We suspected a monogenic form of hypertension because of the persistent hypokalemia with low plasma levels of renin and aldosterone.

Whole-Exome Sequencing Identifies Loci Associated with Blood Cell Traits and Reveals a Role for Alternative GFI1B Splice Variants in Human Hematopoiesis.

Circulating blood cell counts and indices are important indicators of hematopoietic function and a number of clinical parameters, such as blood oxygen-carrying capacity, inflammation, and hemostasis. By performing whole-exome sequence association analyses of hematologic quantitative traits in 15,459 community-dwelling individuals, followed by in silico replication in up to 52,024 independent samples, we identified two previously undescribed coding variants associated with lower platelet count: a common missense variant in CPS1 (rs1047891, MAF = 0.33, discovery + replication p = 6.

Association of Exome Sequences With Cardiovascular Traits Among Blacks in the Jackson Heart Study.

Background: The correlation of null alleles with human phenotypes can provide insight into gene function in humans. In individuals of African ancestry, we set out to identify null and damaging missense variants, and test these variants for association with a range of cardiovascular phenotypes.

Methods And Results: We performed whole-exome sequencing in 3223 black individuals from the Jackson Heart Study and found a total of 729 666 variant sites with minor allele frequency <5%, including 17 263 null variants and 49 929 missense variants predicted to be damaging by in silico algorithms.

Large-Scale Exome-wide Association Analysis Identifies Loci for White Blood Cell Traits and Pleiotropy with Immune-Mediated Diseases.

White blood cells play diverse roles in innate and adaptive immunity. Genetic association analyses of phenotypic variation in circulating white blood cell (WBC) counts from large samples of otherwise healthy individuals can provide insights into genes and biologic pathways involved in production, differentiation, or clearance of particular WBC lineages (myeloid, lymphoid) and also potentially inform the genetic basis of autoimmune, allergic, and blood diseases. We performed an exome array-based meta-analysis of total WBC and subtype counts (neutrophils, monocytes, lymphocytes, basophils, and eosinophils) in a multi-ancestry discovery and replication sample of ∼157,622 individuals from 25 studies.

Platelet-Related Variants Identified by Exomechip Meta-analysis in 157,293 Individuals.

Platelet production, maintenance, and clearance are tightly controlled processes indicative of platelets' important roles in hemostasis and thrombosis. Platelets are common targets for primary and secondary prevention of several conditions. They are monitored clinically by complete blood counts, specifically with measurements of platelet count (PLT) and mean platelet volume (MPV).

Exome Genotyping Identifies Pleiotropic Variants Associated with Red Blood Cell Traits.

Red blood cell (RBC) traits are important heritable clinical biomarkers and modifiers of disease severity. To identify coding genetic variants associated with these traits, we conducted meta-analyses of seven RBC phenotypes in 130,273 multi-ethnic individuals from studies genotyped on an exome array. After conditional analyses and replication in 27,480 independent individuals, we identified 16 new RBC variants.

Association Between Absolute Neutrophil Count and Variation at TCIRG1: The NHLBI Exome Sequencing Project.

Neutrophils are a key component of innate immunity. Individuals with low neutrophil count are susceptible to frequent infections. Linkage and association between congenital neutropenia and a single rare missense variant in TCIRG1 have been reported in a single family.