Differentiating Types of Self-Reported Alcohol Abstinence.

We contrast three types of abstinence: quit after alcohol associated problems (Q-AP), quit for other reasons (Q-OR), and lifetime abstainer (LTA). We summarized the characteristics of people living with HIV (PLWH), and matched uninfected individuals, by levels of alcohol use and types of abstinence. We then identified factors that differentiate abstinence and determined whether the association with an alcohol biomarker or a genetic polymorphism is improved by differentiating abstinence. Among abstainers, 34% of PLWH and 38% of uninfected were Q-AP; 53% and 53% were Q-OR; and 12% and 10% were LTA. Logistic regression models found smoking, alcohol, cocaine, and hepatitis C increased odds of Q-AP, whereas smoking and marijuana decreased odds of LTA. Differentiating types of abstinence improved association. Q-APs and LTAs can be readily differentiated by an alcohol biomarker and genetic polymorphism. Differentiating type of abstinence may enhance understanding of alcohol health effects

Association of FADS1/2 Locus Variants and Polyunsaturated Fatty Acids With Aortic Stenosis.

IMPORTANCE: Aortic stenosis (AS) has no approved medical treatment. Identifying etiological pathways for AS could identify pharmacological targets. OBJECTIVE: To identify novel genetic loci and pathways associated with AS. DESIGN, SETTING, AND PARTICIPANTS: This genome-wide association study used a case-control design to evaluate 44 703 participants (3469 cases of AS) of self-reported European ancestry from the Genetic Epidemiology Research on Adult Health and Aging (GERA) cohort (from January 1, 1996, to December 31, 2015). Replication was performed in 7 other cohorts totaling 256 926 participants (5926 cases of AS), with additional analyses performed in 6942 participants from the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium. Follow-up biomarker analyses with aortic valve calcium (AVC) were also performed. Data were analyzed from May 1, 2017, to December 5, 2019. EXPOSURES: Genetic variants (615 643 variants) and polyunsaturated fatty acids (ω-6 and ω-3) measured in blood samples. MAIN OUTCOMES AND MEASURES: Aortic stenosis and aortic valve replacement defined by electronic health records, surgical records, or echocardiography and the presence of AVC measured by computed tomography. RESULTS: The mean (SD) age of the 44 703 GERA participants was 69.7 (8.4) years, and 22 019 (49.3%) were men. The rs174547 variant at the FADS1/2 locus was associated with AS (odds ratio [OR] per C allele, 0.88; 95% CI, 0.83-0.93; P = 3.0 × 10-6), with genome-wide significance after meta-analysis with 7 replication cohorts totaling 312 118 individuals (9395 cases of AS) (OR, 0.91; 95% CI, 0.88-0.94; P = 2.5 × 10-8). A consistent association with AVC was also observed (OR, 0.91; 95% CI, 0.83-0.99; P = .03). A higher ratio of arachidonic acid to linoleic acid was associated with AVC (OR per SD of the natural logarithm, 1.19; 95% CI, 1.09-1.30; P = 6.6 × 10-5). In mendelian randomization, increased FADS1 liver expression and arachidonic acid were associated with AS (OR per unit of normalized expression, 1.31 [95% CI, 1.17-1.48; P = 7.4 × 10-6]; OR per 5-percentage point increase in arachidonic acid for AVC, 1.23 [95% CI, 1.01-1.49; P = .04]; OR per 5-percentage point increase in arachidonic acid for AS, 1.08 [95% CI, 1.04-1.13; P = 4.1 × 10-4]). CONCLUSIONS AND RELEVANCE: Variation at the FADS1/2 locus was associated with AS and AVC. Findings from biomarker measurements and mendelian randomization appear to link ω-6 fatty acid biosynthesis to AS, which may represent a therapeutic target

Gene Expression Profiling of Archival Tumors from the Collaborative Ocular Melanoma Study: Association with Clinical Outcomes

From the Washington University Senior Honors Thesis Abstracts (WUSHTA), Volume 3, Spring 2011. Published by the Office of Undergraduate Research. Henry Biggs, Director, Office of Undergraduate Research / Associate Dean, College of Arts & Sciences; Joy Zalis Kiefer, Office of Undergraduate Research / Assistant Dean in the College of Arts & Sciences; E. Holly Tasker, Editor; Kristin Sobotka, Undergraduate Research Coordinator. Mentor: William Harbou

Gene Expression Profiling of Archival Tumors from the Collaborative Ocular Melanoma Study: Association with Clinical Outcomes

Uveal melanoma is the most common primary cancer of the eye. While there exist multiple treatment options to remove or destroy the primary ocular tumor, about half of patients develop metastatic disease, often in the liver, which is almost always fatal. We have previously developed a 15-gene PCR assay that can accurately assess the risk of metastasis for primary tumors. While this test has been positively evaluated on fine needle aspirate biopsy (FNAB) samples, there are no data to confirm whether our test can accurately classify formalin fixed, paraffin embedded (FFPE) archival samples. Such an analysis is of particular importance for uveal melanoma patients who had the affected eye removed, but fresh tissue could not be obtained. Here, in collaboration with the Collaborative Ocular Melanoma Study (COMS), we evaluate the accuracy of our 15- gene PCR assay on 117 archival COMS FFPE samples along with an additional 46 more recent FFPE samples collected at Barnes Jewish Hospital over the past ten years. Our results indicate a reduced accuracy of classification observed in FFPE samples compared to the original larger study of FNAB tumor samples. This reduction was tied to the misclassification of a handful of Class 2 tumors. We explore the possibilities that tumor heterogeneity and RNA degradation by FFPE might be the underlying factors obscuring the accuracy of our test and conclude that the RNA degradation is likely the dominant force responsible for the misclassifications observed

PCSK9 loss of function is protective against extra-coronary atherosclerotic cardiovascular disease in a large multi-ethnic cohort.

BackgroundTherapeutic inhibition of PCSK9 protects against coronary artery disease (CAD) and ischemic stroke (IS). The impact on other diseases remains less well characterized.MethodsWe created a genetic risk score (GRS) for PCSK9 using four single nucleotide polymorphisms (SNPs) at or near the PCSK9 locus known to impact lower LDL-Cholesterol (LDL-C): rs11583680, rs11591147, rs2479409, and rs11206510. We then used our GRS to calculate weighted odds ratios reflecting the impact of a genetically determined 10 mg/dL decrease in LDL-C on several pre-specified phenotypes including CAD, IS, peripheral artery disease (PAD), abdominal aortic aneurysm (AAA), type 2 diabetes, dementia, chronic obstructive pulmonary disease, and cancer. Finally, we used our weighted GRS to perform a phenome-wide association study.ResultsGenetic and electronic health record data that passed quality control was available in 312,097 individuals, (227,490 White participants, 58,907 Black participants, and 25,700 Hispanic participants). PCSK9 mediated reduction in LDL-C was associated with a reduced risk of CAD and AAA in trans-ethnic meta-analysis (CAD OR 0.83 [95% CI 0.80-0.87], p = 6.0 x 10-21; AAA OR 0.76 [95% CI 0.68-0.86], p = 2.9 x 10-06). Significant protective effects were noted for PAD in White individuals (OR 0.83 [95% CI 0.71-0.97], p = 2.3 x 10-04) but not in other genetic ancestries. Genetically reduced PCSK9 function associated with a reduced risk of dementia in trans-ethnic meta-analysis (OR 0.86 [95% CI 0.78-0.93], p = 5.0 x 10-04).ConclusionsGenetically reduced PCSK9 function results in a reduction in risk of several important extra-coronary atherosclerotic phenotypes in addition to known effects on CAD and IS, including PAD and AAA. We also highlight a novel reduction in risk of dementia, supporting a well-recognized vascular component to cognitive impairment and an opportunity for therapeutic repositioning

Association of FADS1/2 Locus Variants and Polyunsaturated Fatty Acids With Aortic Stenosis.

Importance: Aortic stenosis (AS) has no approved medical treatment. Identifying etiological pathways for AS could identify pharmacological targets. Objective: To identify novel genetic loci and pathways associated with AS. Design, Setting, and Participants: This genome-wide association study used a case-control design to evaluate 44 703 participants (3469 cases of AS) of self-reported European ancestry from the Genetic Epidemiology Research on Adult Health and Aging (GERA) cohort (from January 1, 1996, to December 31, 2015). Replication was performed in 7 other cohorts totaling 256 926 participants (5926 cases of AS), with additional analyses performed in 6942 participants from the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium. Follow-up biomarker analyses with aortic valve calcium (AVC) were also performed. Data were analyzed from May 1, 2017, to December 5, 2019. Exposures: Genetic variants (615 643 variants) and polyunsaturated fatty acids (ω-6 and ω-3) measured in blood samples. Main Outcomes and Measures: Aortic stenosis and aortic valve replacement defined by electronic health records, surgical records, or echocardiography and the presence of AVC measured by computed tomography. Results: The mean (SD) age of the 44 703 GERA participants was 69.7 (8.4) years, and 22 019 (49.3%) were men. The rs174547 variant at the FADS1/2 locus was associated with AS (odds ratio [OR] per C allele, 0.88; 95% CI, 0.83-0.93; P = 3.0 × 10-6), with genome-wide significance after meta-analysis with 7 replication cohorts totaling 312 118 individuals (9395 cases of AS) (OR, 0.91; 95% CI, 0.88-0.94; P = 2.5 × 10-8). A consistent association with AVC was also observed (OR, 0.91; 95% CI, 0.83-0.99; P = .03). A higher ratio of arachidonic acid to linoleic acid was associated with AVC (OR per SD of the natural logarithm, 1.19; 95% CI, 1.09-1.30; P = 6.6 × 10-5). In mendelian randomization, increased FADS1 liver expression and arachidonic acid were associated with AS (OR per unit of normalized expression, 1.31 [95% CI, 1.17-1.48; P = 7.4 × 10-6]; OR per 5-percentage point increase in arachidonic acid for AVC, 1.23 [95% CI, 1.01-1.49; P = .04]; OR per 5-percentage point increase in arachidonic acid for AS, 1.08 [95% CI, 1.04-1.13; P = 4.1 × 10-4]). Conclusions and Relevance: Variation at the FADS1/2 locus was associated with AS and AVC. Findings from biomarker measurements and mendelian randomization appear to link ω-6 fatty acid biosynthesis to AS, which may represent a therapeutic target

Genetic inactivation of ANGPTL4 improves glucose homeostasis and is associated with reduced risk of diabetes

Angiopoietin-like 4 (ANGPTL4) is an endogenous inhibitor of lipoprotein lipase that modulates lipid levels, coronary atherosclerosis risk, and nutrient partitioning. We hypothesize that loss of ANGPTL4 function might improve glucose homeostasis and decrease risk of type 2 diabetes (T2D). We investigate protein-altering variants in ANGPTL4 among 58,124 participants in the DiscovEHR human genetics study, with follow-up studies in 82,766 T2D cases and 498,761 controls. Carriers of p.E40K, a variant that abolishes ANGPTL4 ability to inhibit lipoprotein lipase, have lower odds of T2D (odds ratio 0.89, 95% confidence interval 0.85-0.92, p = 6.3 x 10(-10)), lower fasting glucose, and greater insulin sensitivity. Predicted loss-of-function variants are associated with lower odds of T2D among 32,015 cases and 84,006 controls (odds ratio 0.71, 95% confidence interval 0.49-0.99, p = 0.041). Functional studies in Angptl4-deficient mice confirm improved insulin sensitivity and glucose homeostasis. In conclusion, genetic inactivation of ANGPTL4 is associated with improved glucose homeostasis and reduced risk of T2D.Peer reviewe