Publications by authors named "Christopher I Amos"

574 Publications

Clonal Hematopoiesis Mutations in Lung Cancer Patients are Associated with Lung Cancer Risk Factors.

Cancer Res 2021 Nov 23. Epub 2021 Nov 23.

Department of Medicine, Baylor College of Medicine

Clonal hematopoiesis (CH) is a phenomenon caused by expansion of white blood cells descended from a single hematopoietic stem cell. While CH can be associated with leukemia and some solid tumors, the relationship between CH and lung cancer remains largely unknown. To help clarify this relationship, we analyzed whole-exome sequencing (WES) data from 1,958 lung cancer cases and controls. Potential CH mutations were identified by a set of hierarchical filtering criteria in different exonic regions, and the associations between the number of CH mutations and clinical traits were investigated. Family history of lung cancer (FHLC) may exert diverse influences on the accumulation of CH mutations in different age groups. In younger subjects, FHLC was the strongest risk factor for CH mutations. Association analysis of genome-wide genetic variants identified dozens of genetic loci associated with CH mutations, including a candidate SNP rs2298110, which may promote CH by increasing expression of a potential leukemia promoter gene OTUD3. Hundreds of potentially novel CH mutations were identified, and smoking was found to potentially shape the CH mutational signature. Genetic variants and lung cancer risk factors, especially FHLC, correlated with CH. These analyses improve our understanding of the relationship between lung cancer and CH, and future experimental studies will be necessary to corroborate the uncovered correlations.
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http://dx.doi.org/10.1158/0008-5472.CAN-21-1903DOI Listing
November 2021

Association of PCSK9 Variants with the Risk of Atherosclerotic Cardiovascular Disease and Variable Responses to PCSK9 Inhibitor Therapy.

Curr Probl Cardiol 2021 Nov 12:101043. Epub 2021 Nov 12.

The Michael E. DeBakey VA Medical Center, Houston, TX,; Section of Cardiology, Baylor College of Medicine, Houston, TX.

Genetic polymorphisms or variations, randomly distributed in a population, may cause drug-gene response variations. Investigation into these polymorphisms may identify novel mechanisms contributing to a specific disease process. Such investigation necessitates the use of Mendelian randomization, an analytical method that uses genetic variants as instrumental variables for modifiable risk factors that affect population health. In the past decade, advances in our understanding of genetic polymorphisms have enabled the identification of genetic variants in candidate genes that impact low-density lipoprotein cholesterol (LDL-C) regulating pathways and cardiovascular disease (CVD) outcomes. A specific candidate gene of interest is that of the LDL receptor degrading protein, PCSK9. In fact, loss-of-function genetic variants for the PCSK9 gene are what first highlighted this pathway as a candidate for pharmacological inhibition. PCSK9 inhibitors (PCSK9i) are a class of cholesterol-lowering medications that provide significant reductions in LDL by inhibiting the degradation of LDL receptors (LDLR). These inhibitors have also been found to reduce production and enhance clearance of lipoprotein A [Lp(a)], an LDL-like particle currently under study as a separate risk factor for atherosclerotic CVD. Here, we discuss the promise of personalized medicine in developing a more efficacious and individualized pharmacogenomics-based approach for the use of PCSK9i that considers genetic variation and targets different patient populations. This review explores the pharmacogenomics of PCSK9i in the context of PCSK9 allele variants related to drug-metabolizing enzymes and responses since more studies are demonstrating that some patients are hyporesponsive or non-responsive to PCSK9i . In summary, the pharmacogenomics of PCSK9 are a promising therapeutic target and genetic information from prospective randomized clinical trials is warranted to gain a full understanding of the efficacy and cost-effectiveness of such allele/gene-guided PCSK9i therapy.
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http://dx.doi.org/10.1016/j.cpcardiol.2021.101043DOI Listing
November 2021

Overcoming COVID-19 Vaccine Hesitancy: Insights from an Online Population-Based Survey in the United States.

Vaccines (Basel) 2021 Sep 28;9(10). Epub 2021 Sep 28.

Department of Medicine, Section of Epidemiology and Population Science, Baylor College of Medicine, Houston, TX 77030, USA.

This study sought to identify individual-level determinants of COVID-19 vaccine hesitancy based on the Health Belief Model (HBM) and Theory of Planned Behavior (TPB). An online population-based survey was distributed in English and Spanish. Data were derived from 1208 U.S. adults (52% female; 38.7% minorities), 43.5% of whom reported vaccine hesitancy. Multivariable analysis revealed that unemployed individuals were more likely (OR = 1.78, 95% CI: 1.16-2.73, = 0.009) and married (OR = 0.57, 95% CI: 0.39-0.81, = 0.002) and higher income individuals (OR = 0.52, 95% CI 0.32-0.84, = 0.008) were less likely to be hesitant. Individuals with greater perceived susceptibility to COVID-19 (OR = 0.82, 95% CI: 0.71-0.94, = 0.006), who perceived vaccination as being convenient (OR = 0.86, 95% CI: 0.74-1.00, = 0.047), and who afforded greater importance to cues to action from government (OR = 0.84, 95% CI: 0.74-0.95, = 0.005), public health (OR = 0.70, 95% CI: 0.59-0.82, < 0.001), and healthcare experts (OR = 0.59, 95% CI: 0.50-0.69, < 0.001) were also less likely to be hesitant. Findings suggest that HBM and TPB constructs may be useful in informing strategies to improve COVID-19 vaccine uptake. Specifically, framing appeals based on perceptions of COVID-19 susceptibility, making vaccination convenient, and rebuilding trust through unified cues to action may help to overcome vaccine hesitancy.
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http://dx.doi.org/10.3390/vaccines9101100DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8539129PMC
September 2021

Smoking Status and Factors associated with COVID-19 In-hospital Mortality among U.S. Veterans.

Nicotine Tob Res 2021 Oct 25. Epub 2021 Oct 25.

Department of Medicine, Baylor College of Medicine, Houston, TX 77030, USA.

Introduction: The role of smoking in risk of death among patients with COVID-19 remains unclear. We examined the association between in-hospital mortality from COVID-19 and smoking status and other factors in the United States Veterans Health Administration (VHA).

Methods: This is an observational, retrospective cohort study using the VHA COVID-19 shared data resources for February 1 to September 11, 2020. Veterans admitted to the hospital who tested positive for SARS-CoV-2 and hospitalized by VHA were grouped into Never (as reference, NS), Former (FS), and Current smokers (CS). The main outcome was in-hospital mortality. Control factors were the most important variables (among all available) determined through a cascade of machine learning. We reported adjusted odds ratios (aOR) and 95% confidence intervals (95%CI) from logistic regression models, imputing missing smoking status in our primary analysis.

Results: Out of 8,667,996 VHA enrollees, 505,143 were tested for SARS-CoV-2 (NS=191,143; FS=240,336; CS=117,706; Unknown=45,533). The aOR of in-hospital mortality was 1.16 (95%CI 1.01, 1.32) for FS vs. NS and 0.97 (95%CI 0.78, 1.22; P > 0.05) for CS vs. NS with imputed smoking status. Among other factors, famotidine and non-steroidal anti-inflammatory drugs (NSAID) use before hospitalization were associated with lower risk while diabetes with complications, kidney disease, obesity, and advanced age were associated with higher risk of in-hospital mortality.

Conclusions: In patients admitted to the hospital with SARS-CoV-2 infection, our data demonstrate that FS are at higher risk of in-hospital mortality than NS. However, this pattern was not seen among CS highlighting the need for more granular analysis with high quality smoking status data to further clarify our understanding of smoking risk and COVID-19-related mortality. Presence of comorbidities and advanced age were also associated with increased risk of in-hospital mortality.

Implications: Veterans who were former smokers were at higher risk of in-hospital mortality compared to never smokers. Current smokers and never smokers were at similar risk of in-hospital mortality.The use of famotidine and non-steroidal anti-inflammatory drugs (NSAIDs) before hospitalization were associated with lower risk while uncontrolled diabetes mellitus, advanced age, kidney disease, and obesity were associated with higher risk of in-hospital mortality.
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http://dx.doi.org/10.1093/ntr/ntab223DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8586728PMC
October 2021

Germline determinants of humoral immune response to HPV-16 protect against oropharyngeal cancer.

Nat Commun 2021 10 12;12(1):5945. Epub 2021 Oct 12.

Section of Hygiene, University Department of Life Sciences and Public Health, Università Cattolica del Sacro Cuore, Roma, Italy.

Although several oropharyngeal cancer (OPC) susceptibility loci have been identified, most previous studies lacked detailed information on human papillomavirus (HPV) status. We conduct a genome-wide analysis by HPV16 serology status in 4,002 oral cancer cases (OPC and oral cavity cancer (OCC)) and 5,256 controls. We detect four susceptibility loci pointing to a distinct genetic predisposition by HPV status. Our most notable finding in the HLA region, that is now confirmed to be specific of HPV(+)OPC risk, reveal two independent loci with strong protective effects, one refining the previously reported HLA class II haplotype association. Antibody levels against HPV16 viral proteins strongly implicate the protective HLA variants as major determinants of humoral response against L1 capsid protein or E6 oncoprotein suggesting a natural immune response against HPV(+)OPC promoted by HLA variants. This indicates that therapeutic vaccines that target E6 and attenuate viral response after established HPV infections might protect against HPV(+)OPC.
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http://dx.doi.org/10.1038/s41467-021-26151-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8511029PMC
October 2021

Pan-cancer evaluation of gene expression and somatic alteration data for cancer prognosis prediction.

BMC Cancer 2021 Sep 25;21(1):1053. Epub 2021 Sep 25.

Department of Biomedical Data Science, Geisel School of Medicine, Dartmouth College, Hanover, NH, USA.

Background: Over the past decades, approaches for diagnosing and treating cancer have seen significant improvement. However, the variability of patient and tumor characteristics has limited progress on methods for prognosis prediction. The development of high-throughput omics technologies now provides multiple approaches for characterizing tumors. Although a large number of published studies have focused on integration of multi-omics data and use of pathway-level models for cancer prognosis prediction, there still exists a gap of knowledge regarding the prognostic landscape across multi-omics data for multiple cancer types using both gene-level and pathway-level predictors.

Methods: In this study, we systematically evaluated three often available types of omics data (gene expression, copy number variation and somatic point mutation) covering both DNA-level and RNA-level features. We evaluated the landscape of predictive performance of these three omics modalities for 33 cancer types in the TCGA using a Lasso or Group Lasso-penalized Cox model and either gene or pathway level predictors.

Results: We constructed the prognostic landscape using three types of omics data for 33 cancer types on both the gene and pathway levels. Based on this landscape, we found that predictive performance is cancer type dependent and we also highlighted the cancer types and omics modalities that support the most accurate prognostic models. In general, models estimated on gene expression data provide the best predictive performance on either gene or pathway level and adding copy number variation or somatic point mutation data to gene expression data does not improve predictive performance, with some exceptional cohorts including low grade glioma and thyroid cancer. In general, pathway-level models have better interpretative performance, higher stability and smaller model size across multiple cancer types and omics data types relative to gene-level models.

Conclusions: Based on this landscape and comprehensively comparison, models estimated on gene expression data provide the best predictive performance on either gene or pathway level. Pathway-level models have better interpretative performance, higher stability and smaller model size relative to gene-level models.
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http://dx.doi.org/10.1186/s12885-021-08796-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8467202PMC
September 2021

Population simulations of COVID-19 outbreaks provide tools for risk assessment and continuity planning.

JAMIA Open 2021 Jul 24;4(3):ooaa074. Epub 2021 Jan 24.

Department of Medicine, Baylor College of Medicine, Houston, Texas, USA.

Objectives: We developed COVID-19 Outbreak Simulator (https://ictr.github.io/covid19-outbreak-simulator/) to quantitatively estimate the effectiveness of preventative and interventive measures to prevent and battle COVID-19 outbreaks for specific populations.

Materials And Methods: Our simulator simulates the entire course of infection and transmission of the virus among individuals in heterogeneous populations, subject to operations and influences, such as quarantine, testing, social distancing, and community infection. It provides command-line and Jupyter notebook interfaces and a plugin system for user-defined operations.

Results: The simulator provides quantitative estimates for COVID-19 outbreaks in a variety of scenarios and assists the development of public health policies, risk-reduction operations, and emergency response plans.

Discussion: Our simulator is powerful, flexible, and customizable, although successful applications require realistic estimation and robustness analysis of population-specific parameters.

Conclusion: Risk assessment and continuity planning for COVID-19 outbreaks are crucial for the continued operation of many organizations. Our simulator will be continuously expanded to meet this need.
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http://dx.doi.org/10.1093/jamiaopen/ooaa074DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7928848PMC
July 2021

SARS-CoV-2 Impairs Dendritic Cells and Regulates DC-SIGN Gene Expression in Tissues.

Int J Mol Sci 2021 Aug 26;22(17). Epub 2021 Aug 26.

Department of Epidemiology and Biostatistics, Arnold School of Public Health, University of South Carolina, Columbia, SC 29208, USA.

The current spreading coronavirus SARS-CoV-2 is highly infectious and pathogenic. In this study, we screened the gene expression of three host receptors (ACE2, DC-SIGN and L-SIGN) of SARS coronaviruses and dendritic cells (DCs) status in bulk and single cell transcriptomic datasets of upper airway, lung or blood of COVID-19 patients and healthy controls. In COVID-19 patients, DC-SIGN gene expression was interestingly decreased in lung DCs but increased in blood DCs. Within DCs, conventional DCs (cDCs) were depleted while plasmacytoid DCs (pDCs) were augmented in the lungs of mild COVID-19. In severe cases, we identified augmented types of immature DCs (CD22 or ANXA1 DCs) with MHCII downregulation. In this study, our observation indicates that DCs in severe cases stimulate innate immune responses but fail to specifically present SARS-CoV-2. It provides insights into the profound modulation of DC function in severe COVID-19.
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http://dx.doi.org/10.3390/ijms22179228DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8431536PMC
August 2021

Air Pollution, Residential Greenness and Metabolic Dysfunction during Early Pregnancy in the INfancia y Medio Ambiente (INMA) Cohort.

Int J Environ Res Public Health 2021 09 4;18(17). Epub 2021 Sep 4.

Center for Precision Environmental Health, Baylor College of Medicine, Houston, TX 77030, USA.

Despite extensive study, the role of air pollution in gestational diabetes remains unclear, and there is limited evidence of the beneficial impact of residential greenness on metabolic dysfunction during pregnancy. We used data from mothers in the Spanish INfancia y Medio Ambiente (INMA) Project from 2003-2008. We obtained spatiotemporally resolved estimates of fine particulate matter (PM) and nitrogen dioxide (NO) exposures in early pregnancy and estimated residential greenness using satellite-based Normal Difference Vegetation Index (NDVI) within 100, 300 and 500 m buffers surrounding the mother's residence. We applied logistic regression models to evaluate associations between each of the three exposures of interest and (a) glucose intolerance and (b) abnormal lipid levels. We found limited evidence of associations between increases in PM and NO exposures and the metabolic outcomes. Though not statistically significant, high PM exposure (≥25 µg/m) was associated with increased odds of glucose intolerance (OR = 1.16, 95% CI: 0.82, 1.63) and high cholesterol (OR = 1.14, 95% CI: 0.90, 1.44). High NO exposure (≥39.8 µg/m) was inversely associated with odds of high triglycerides (OR = 0.70, 95% CI: 0.45, 1.08). Whereas NDVI was not associated with glucose intolerance, odds of high triglycerides were increased, although the results were highly imprecise. Results were unchanged when the air pollutant variables were included in the regression models. Given the equivocal findings in our study, additional investigations are needed to assess effects of air pollution and residential greenness on metabolic dysfunction during pregnancy.
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http://dx.doi.org/10.3390/ijerph18179354DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8430971PMC
September 2021

The shared genetic architecture between epidemiological and behavioral traits with lung cancer.

Sci Rep 2021 09 2;11(1):17559. Epub 2021 Sep 2.

Institute for Clinical and Translational Research, Baylor College of Medicine, One Baylor Plaza, Houston, TX, 77030, USA.

The complex polygenic nature of lung cancer is not fully characterized. Our study seeks to identify novel phenotypes associated with lung cancer using cross-trait linkage disequilibrium score regression (LDSR). We measured pairwise genetic correlation (r) and SNP heritability (h) between 347 traits and lung cancer risk using genome-wide association study summary statistics from the UKBB and OncoArray consortium. Further, we conducted analysis after removing genomic regions previously associated with smoking behaviors to mitigate potential confounding effects. We found significant negative genetic correlations between lung cancer risk and dietary behaviors, fitness metrics, educational attainment, and other psychosocial traits. Alcohol taken with meals (r = - 0.41, h = 0.10, p = 1.33 × 10), increased fluid intelligence scores (r = - 0.25, h = 0.22, p = 4.54 × 10), and the age at which full time education was completed (r = - 0.45, h = 0.11, p = 1.24 × 10) demonstrated negative genetic correlation with lung cancer susceptibility. The body mass index was positively correlated with lung cancer risk (r = 0.20, h = 0.25, p = 2.61 × 10). This analysis reveals shared genetic architecture between several traits and lung cancer predisposition. Future work should test for causal relationships and investigate common underlying genetic mechanisms across these genetically correlated traits.
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http://dx.doi.org/10.1038/s41598-021-96685-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8413319PMC
September 2021

Genetic variants of SDCCAG8 and MAGI2 in mitosis-related pathway genes are independent predictors of cutaneous melanoma-specific survival.

Cancer Sci 2021 Oct 27;112(10):4355-4364. Epub 2021 Aug 27.

Duke Cancer Institute, Duke University Medical Center, Durham, NC, USA.

Mitosis is a prognostic factor for cutaneous melanoma (CM), but accurate mitosis detection in CM tissues is difficult. Therefore, the 8th Edition of the American Joint Committee on Cancer staging system has removed the mitotic rate as a category criterion of the tumor T-category, based on the evidence that the mitotic rate was not an independent prognostic factor for melanoma survival. As single-nucleotide polymorphisms (SNPs) have been shown to be potential predictors for cutaneous melanoma-specific survival (CMSS), we investigated the potential prognostic value of SNPs in mitosis-related pathway genes in CMSS by analyzing their associations with outcomes of 850 CM patients from The University of Texas MD Anderson Cancer Center in a discovery dataset and validated the findings in another dataset of 409 CM patients from the Harvard University Nurses' Health Study and Health Professionals Follow-up Study. In both datasets, we identified two SNPs (SDCCAG8 rs10803138 G>A and MAGI2 rs3807694 C>T) as independent prognostic factors for CMSS, with adjusted allelic hazards ratios of 1.49 (95% confidence interval = 1.17-1.90, P = .001) and 1.45 (1.13-1.86, P = .003), respectively. Furthermore, their combined unfavorable alleles also predicted a poor survival in both discovery and validation datasets in a dose-response manner (P  = .0006 and .0001, respectively). Additional functional analysis revealed that both SDCCAG8 rs10803138 A and MAGI2 rs3807694 T alleles were associated with elevated mRNA expression levels in normal tissues. Therefore, these findings suggest that SDCCAG8 rs10803138 G>A and MAGI2 rs3807694 C>T are independent prognostic biomarkers for CMSS, possibly by regulating the mRNA expression of the corresponding genes involved in mitosis.
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http://dx.doi.org/10.1111/cas.15102DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8486203PMC
October 2021

False positive findings during genome-wide association studies with imputation: Influence of allele frequency and imputation accuracy.

Hum Mol Genet 2021 Aug 9. Epub 2021 Aug 9.

Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX 77030.

Genotype imputation is widely used in genetic studies to boost the power of GWAS, to combine multiple studies for meta-analysis and to perform fine mapping. With advances of imputation tools and large reference panels, genotype imputation has become mature and accurate. However, the uncertain nature of imputed genotypes can cause bias in the downstream analysis. Many studies have compared the performance of popular imputation approaches, but few investigated bias characteristics of downstream association analyses. Herein, we showed that the imputation accuracy is diminished if the real genotypes contain minor alleles. Although these genotypes are less common, which is particularly true for loci with low minor allele frequency, a large discordance between imputed and observed genotypes significantly inflated the association results, especially in data with a large portion of uncertain SNPs. The significant discordance of p-values happened as the p-value approached 0 or the imputation quality was poor. Although elimination of poorly imputed SNPs can remove false positive (FP) SNPs, it sacrificed, sometimes, more than 80% true positive (TP) SNPs. For top ranked SNPs, removing variants with moderate imputation quality cannot reduce the proportion of FP SNPs, and increasing sample size in reference panels did not greatly benefit the results as well. Additionally, samples with a balanced ratio between cases and controls can dramatically improve the number of TP SNPs observed in the imputation based GWAS. These results raise concerns about results from analysis of association studies when rare variants are studied, particularly when case-control studies are unbalanced.
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http://dx.doi.org/10.1093/hmg/ddab203DOI Listing
August 2021

Genetic testing in ambulatory cardiology clinics reveals high rate of findings with clinical management implications.

Genet Med 2021 Dec 6;23(12):2404-2414. Epub 2021 Aug 6.

Department of Medicine, Division of Diabetes, Endocrinology and Metabolism, Baylor College of Medicine, Houston, TX, USA.

Purpose: Cardiovascular disease (CVD) is the leading cause of death in adults in the United States, yet the benefits of genetic testing are not universally accepted.

Methods: We developed the "HeartCare" panel of genes associated with CVD, evaluating high-penetrance Mendelian conditions, coronary artery disease (CAD) polygenic risk, LPA gene polymorphisms, and specific pharmacogenetic (PGx) variants. We enrolled 709 individuals from cardiology clinics at Baylor College of Medicine, and samples were analyzed in a CAP/CLIA-certified laboratory. Results were returned to the ordering physician and uploaded to the electronic medical record.

Results: Notably, 32% of patients had a genetic finding with clinical management implications, even after excluding PGx results, including 9% who were molecularly diagnosed with a Mendelian condition. Among surveyed physicians, 84% reported medical management changes based on these results, including specialist referrals, cardiac tests, and medication changes. LPA polymorphisms and high polygenic risk of CAD were found in 20% and 9% of patients, respectively, leading to diet, lifestyle, and other changes. Warfarin and simvastatin pharmacogenetic variants were present in roughly half of the cohort.

Conclusion: Our results support the use of genetic information in routine cardiovascular health management and provide a roadmap for accompanying research.
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http://dx.doi.org/10.1038/s41436-021-01294-8DOI Listing
December 2021

Large-scale cross-cancer fine-mapping of the 5p15.33 region reveals multiple independent signals.

HGG Adv 2021 Jul 12;2(3). Epub 2021 Jun 12.

Department of Laboratory Medicine and Pathology, Mayo Clinic Comprehensive Cancer Center, Mayo Clinic, Rochester, MN, USA.

Genome-wide association studies (GWASs) have identified thousands of cancer risk loci revealing many risk regions shared across multiple cancers. Characterizing the cross-cancer shared genetic basis can increase our understanding of global mechanisms of cancer development. In this study, we collected GWAS summary statistics based on up to 375,468 cancer cases and 530,521 controls for fourteen types of cancer, including breast (overall, estrogen receptor [ER]-positive, and ER-negative), colorectal, endometrial, esophageal, glioma, head/neck, lung, melanoma, ovarian, pancreatic, prostate, and renal cancer, to characterize the shared genetic basis of cancer risk. We identified thirteen pairs of cancers with statistically significant local genetic correlations across eight distinct genomic regions. Specifically, the 5p15.33 region, harboring the and genes, showed statistically significant local genetic correlations for multiple cancer pairs. We conducted a cross-cancer fine-mapping of the 5p15.33 region based on eight cancers that showed genome-wide significant associations in this region (ER-negative breast, colorectal, glioma, lung, melanoma, ovarian, pancreatic, and prostate cancer). We used an iterative analysis pipeline implementing a subset-based meta-analysis approach based on cancer-specific conditional analyses and identified ten independent cross-cancer associations within this region. For each signal, we conducted cross-cancer fine-mapping to prioritize the most plausible causal variants. Our findings provide a more in-depth understanding of the shared inherited basis across human cancers and expand our knowledge of the 5p15.33 region in carcinogenesis.
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http://dx.doi.org/10.1016/j.xhgg.2021.100041DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8336922PMC
July 2021

Gene-Based Association Testing of Dichotomous Traits With Generalized Functional Linear Mixed Models Using Extended Pedigrees: Applications to Age-Related Macular Degeneration.

J Am Stat Assoc 2021 28;116(534):531-545. Epub 2020 Jul 28.

Computational and Statistical Genomics Branch, National Human Genome Research Institute, NIH, Baltimore, MD.

Genetics plays a role in age-related macular degeneration (AMD), a common cause of blindness in the elderly. There is a need for powerful methods for carrying out region-based association tests between a dichotomous trait like AMD and genetic variants on family data. Here, we apply our new generalized functional linear mixed models (GFLMM) developed to test for gene-based association in a set of AMD families. Using common and rare variants, we observe significant association with two known AMD genes: and . Using rare variants, we find suggestive signals in four genes: , , , and . Intriguingly, is down-regulated in AMD aqueous humor, and deficiency leads to retinal inflammation and increased vulnerability to oxidative stress. These findings were made possible by our GFLMM which model the effect of a major gene as a fixed mean, the polygenic contributions as a random variation, and the correlation of pedigree members by kinship coefficients. Simulations indicate that the GFLMM likelihood ratio tests (LRTs) accurately control the Type I error rates. The LRTs have similar or higher power than existing retrospective kernel and burden statistics. Our GFLMM-based statistics provide a new tool for conducting family-based genetic studies of complex diseases. Supplementary materials for this article, including a standardized description of the materials available for reproducing the work, are available as an online supplement.
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http://dx.doi.org/10.1080/01621459.2020.1799809DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8315575PMC
July 2020

Reducing COVID-19 quarantine with SARS-CoV-2 testing: a simulation study.

BMJ Open 2021 07 16;11(7):e050473. Epub 2021 Jul 16.

Institute for Clinical & Translational Research, Baylor College of Medicine, Houston, Texas, USA

Objective: To evaluate the effectiveness of SARS-CoV-2 testing on shortening the duration of quarantines for COVID-19 and to identify the most effective choices of testing schedules.

Design: We performed extensive simulations to evaluate the performance of quarantine strategies when one or more SARS-CoV-2 tests were administered during the quarantine. Simulations were based on statistical models for the transmissibility and viral loads of SARS-CoV-2 infections and the sensitivities of available testing methods. Sensitivity analyses were performed to evaluate the impact of perturbations in model assumptions on the outcomes of optimal strategies.

Results: We found that SARS-CoV-2 testing can effectively reduce the length of a quarantine without compromising safety. A single reverse transcription-PCR (RT-PCR) test performed before the end of quarantine can reduce quarantine duration to 10 days. Two tests can reduce the duration to 8 days, and three highly sensitive RT-PCR tests can justify a 6-day quarantine. More strategic testing schedules and longer quarantines are needed if tests are administered with less-sensitive RT-PCR tests or antigen tests. Shorter quarantines can be used for applications that tolerate a residual postquarantine transmission risk comparable to a 10-day quarantine.

Conclusions: Testing could substantially reduce the length of isolation, reducing the physical and mental stress caused by lengthy quarantines. With increasing capacity and lowered costs of SARS-CoV-2 tests, test-assisted quarantines could be safer and more cost-effective than 14-day quarantines and warrant more widespread use.
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http://dx.doi.org/10.1136/bmjopen-2021-050473DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8290949PMC
July 2021

Development and Validation of a Risk Prediction Tool for Second Primary Lung Cancer.

J Natl Cancer Inst 2021 Jul 13. Epub 2021 Jul 13.

Quantitative Sciences Unit, Stanford University School of Medicine, Stanford, CA, USA.

Background: With advancing therapeutics, lung cancer (LC) survivors are rapidly increasing in number. While mounting evidence suggests LC survivors have high risk of second primary lung cancer (SPLC), there is no validated prediction tool available for clinical use to identify high-risk LC survivors for SPLC.

Methods: Using data from 6,325 ever-smokers in the Multiethnic Cohort (MEC) diagnosed with initial primary lung cancer (IPLC) in 1993-2017, we developed a prediction model for 10-year SPLC risk after IPLC diagnosis using cause-specific Cox regression. We evaluated the model's clinical utility using decision curve analysis and externally validated it using two population-based data, PLCO and NLST, that included 2,963 and 2,844 IPLC (101 and 93 SPLC cases), respectively.

Results: Over 14,063 person-years, 145 (2.3%) developed SPLC in MEC. Our prediction model demonstrated a high predictive accuracy (Brier score = 2.9, 95% confidence interval [CI] = 2.4-3.3) and discrimination (AUC = 81.9%, 95% CI = 78.2%-85.5%) based on bootstrap validation in MEC. Stratification by the estimated risk quartiles showed that the observed SPLC incidence was statistically significantly higher in the 4th versus 1st quartile (9.5% versus 0.2%; P < .001). Decision curve analysis indicated that in a wide range of 10-year risk thresholds from 1% to 20%, the model yielded a larger net-benefit versus hypothetical all-screening or no-screening scenarios. External validation using PLCO and NLST showed an AUC of 78.8% (95% CI = 74.6%-82.9%) and 72.7% (95% CI = 67.7%-77.7%), respectively.

Conclusions: We developed and validated a SPLC prediction model based on large population-based cohorts. The proposed prediction tool can help identify high-risk LC patients for SPLC and can be incorporated into clinical decision-making for SPLC surveillance and screening.
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http://dx.doi.org/10.1093/jnci/djab138DOI Listing
July 2021

Genetic variants of and in myeloid cell-related pathway genes independently predict cutaneous melanoma-specific survival.

Am J Cancer Res 2021 15;11(6):3252-3262. Epub 2021 Jun 15.

Duke Cancer Institute, Duke University Medical Center Durham, NC 27710, USA.

Both and evidence has supported a key role of myeloid cells in immune suppression in melanoma and in promoting melanocytic metastases. Some single-nucleotide polymorphisms (SNPs) have been shown to predict cutaneous melanoma-specific survival (CMSS), but the association between genetic variation in myeloid cell-related genes and cutaneous melanoma (CM) patient survival remains unknown.

Methods: we investigated associations between SNPs in myeloid cell-related pathway genes and CMSS in a discovery dataset of 850 CM patients and replicated the findings in another dataset of 409 CM patients.

Results: we identified two SNPs ( rs10151787 A>G and rs2069018 T>C) as independent prognostic factors for CMSS, with adjusted allelic hazards ratios of 1.56 (95% confidence interval =1.19-2.05, =0.001) and 1.66 (1.22-2.26, =0.001), respectively; so were their combined unfavorable alleles in a dose-response manner in both discovery and replication datasets ( <0.001 and 0.002, respectively). Additional functional analysis revealed that both rs10151787 G and rs2069018 C alleles were associated with elevated mRNA expression levels in normal tissues.

Conclusions: Our findings suggest that rs10151787 A>G and rs2069018 T>C are independent prognostic biomarkers for CMSS.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8263692PMC
June 2021

Two-Sample Mendelian Randomization Analysis of Associations Between Periodontal Disease and Risk of Cancer.

JNCI Cancer Spectr 2021 Jun 19;5(3):pkab037. Epub 2021 Apr 19.

Department of Public Health and Community Medicine, Tufts University School of Medicine, Boston, MA, USA.

Background: Observational studies indicate that periodontal disease may increase the risk of colorectal, lung, and pancreatic cancers. Using a 2-sample Mendelian randomization (MR) analysis, we assessed whether a genetic predisposition index for periodontal disease was associated with colorectal, lung, or pancreatic cancer risks.

Methods: Our primary instrument included single nucleotide polymorphisms with strong genome-wide association study evidence for associations with chronic, aggressive, and/or severe periodontal disease (rs729876, rs1537415, rs2738058, rs12461706, rs16870060, rs2521634, rs3826782, and rs7762544). We used summary-level genetic data for colorectal cancer (n = 58 131 cases; Genetics and Epidemiology of Colorectal Cancer Consortium, Colon Cancer Family Registry, and Colorectal Transdisciplinary Study), lung cancer (n = 18 082 cases; International Lung Cancer Consortium), and pancreatic cancer (n = 9254 cases; Pancreatic Cancer Consortia). Four MR approaches were employed for this analysis: random-effects inverse-variance weighted (primary analyses), Mendelian Randomization-Pleiotropy RESidual Sum and Outlier, simple median, and weighted median. We conducted secondary analyses to determine if associations varied by cancer subtype (colorectal cancer location, lung cancer histology), sex (colorectal and pancreatic cancers), or smoking history (lung and pancreatic cancer). All statistical tests were 2-sided.

Results: The genetic predisposition index for chronic or aggressive periodontitis was statistically significantly associated with a 3% increased risk of colorectal cancer (per unit increase in genetic index of periodontal disease;  = .03), 3% increased risk of colon cancer ( = .02), 4% increased risk of proximal colon cancer ( = .01), and 3% increased risk of colorectal cancer among females ( = .04); however, it was not statistically significantly associated with the risk of lung cancer or pancreatic cancer, overall or within most subgroups.

Conclusions: Genetic predisposition to periodontitis may be associated with colorectal cancer risk. Further research should determine whether increased periodontitis prevention and increased cancer surveillance of patients with periodontitis is warranted.
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http://dx.doi.org/10.1093/jncics/pkab037DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8242136PMC
June 2021

Thrombotic Microangiopathy Increases the Risk of Chronic Kidney Disease but Not Overall Mortality in Long-term Transplant Survivors.

Transplant Cell Ther 2021 10 1;27(10):864.e1-864.e5. Epub 2021 Jul 1.

Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington; Division of Nephrology, Seattle Children's Hospital, Seattle, Washington; Department of Pediatrics, University of Washington School of Medicine, Seattle, Washington.

Thrombotic microangiopathy (TMA) after allogeneic hematopoietic cell transplant (HCT) is associated with acute kidney injury (AKI) and increased mortality. The impact of TMA on chronic kidney disease (CKD) and long-term mortality among HCT survivors has not been fully examined. To assess the risk of CKD and mortality in HCT survivors with and without history of TMA, we conducted a retrospective cohort study among adult allogeneic HCT recipients who survived to at least 1 year post-transplantation. We examined the association between the history of TMA within 1 year and the onset of CKD longitudinally for 5 years with generalized estimating equation (GEE) while adjusting for other key confounders. CKD was defined as an estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m using the CKD-EPI formula with outpatient creatinine values collected during the annual long-term follow-up unit follow-up visits. Kaplan Meier curves landmarked at 1 year were used for survival analyses. Among 2091 adult patients who underwent allogeneic HCT, we identified 1151 patients who survived at least 1 year and had available long-term follow-up data. Among them, 57 patients developed TMA within 1 year and 1094 did not have TMA. There was no pretransplantation baseline difference in eGFR between groups. After adjusting for confounders, history of TMA was associated with an odds ratio of 2.83 (95% confidence interval 1.33-6.03) for CKD development over 5 years after transplantation. The conditional 5-year survival was 78% in the TMA survivors and 80% in the non-TMA survivors (log rank P = .122). HCT survivors with a history of TMA had increased risk of CKD development. Although TMA was associated with high risk of mortality within 1 year after transplantation, long-term survival was comparable with non-TMA survivors. Future therapeutic interventions should focus on not only short-term mortality outcomes, but also short- and long-term kidney outcomes for HCT patients with TMA.
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http://dx.doi.org/10.1016/j.jtct.2021.06.027DOI Listing
October 2021

Impact of anticoagulation on recurrent thrombosis and bleeding after hematopoietic cell transplantation.

Am J Hematol 2021 09 24;96(9):1137-1146. Epub 2021 Jun 24.

Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.

History of venous thromboembolism (VTE) is prevalent among patients undergoing hematopoietic cell transplantation (HCT). Management of anticoagulation is particularly challenging as most patients will have chemotherapy-induced thrombocytopenia while awaiting engraftment post-HCT. We conducted a retrospective study of autologous and allogeneic HCT recipients with prior VTE from 2006-2015 to 1) compare anticoagulant strategies on short-term VTE recurrence and bleeding and 2) assess predictors for VTE recurrence beyond 30 days. Patients with VTE were allocated to two cohorts based on anticoagulant strategy at thrombocytopenia onset and underwent inverse probability weighting to assess primary outcomes of VTE recurrence and bleeding within 30 days post-HCT. Subsequently, multivariable logistic regression model was used to assess the association of 100-day VTE recurrence by the HIGH-2-LOW VTE risk assessment score and whether patients resumed anticoagulation at platelet recovery. Thirteen percent of recipients had VTE prior to HCT; of those meeting inclusion criteria, 227 continued anticoagulation and 113 temporarily discontinued it. Anticoagulant strategy was not significantly associated with decreased risk of VTE recurrence within 30 days (3% vs 4%, p = 0.61); however, risk of overall bleeding was non-significantly higher in those who continued vs discontinued anticoagulation (41% vs 31%, p = 0.08). In a subgroup of 250 allogeneic HCT patients, every one-point increase of HIGH-2-LOW score was significantly associated with VTE recurrence at 100 days (OR 1.57 [95% CI 1.10-2.23]), while anticoagulation resumption upon platelet engraftment was associated with lower recurrent risk (OR 0.48 [0.20-1.14]). Temporarily withholding anticoagulation during thrombocytopenia may optimize risk-benefit tradeoffs, though additional strategies are essential to prevent VTE recurrence after hematopoietic recovery.
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http://dx.doi.org/10.1002/ajh.26268DOI Listing
September 2021

Analysis of alternative polyadenylation from single-cell RNA-seq using scDaPars reveals cell subpopulations invisible to gene expression.

Genome Res 2021 Oct 25;31(10):1856-1866. Epub 2021 May 25.

Division of Computational Biomedicine, Department of Biological Chemistry, School of Medicine, University of California at Irvine, Irvine, California 92697, USA.

Alternative polyadenylation (APA) is a major mechanism of post-transcriptional regulation in various cellular processes including cell proliferation and differentiation, but the APA heterogeneity among single cells remains largely unknown. Single-cell RNA sequencing (scRNA-seq) has been extensively used to define cell subpopulations at the transcription level. Yet, most scRNA-seq data have not been analyzed in an "APA-aware" manner. Here, we introduce dynamic analysis of APA from single-cell RNA-seq (scDaPars), a bioinformatics algorithm to accurately quantify APA events at both single-cell and single-gene resolution using either 3'-end (10x Chromium) or full-length (Smart-seq2) scRNA-seq data. Validations in both real and simulated data indicate that scDaPars can robustly recover missing APA events caused by the low amounts of mRNA sequenced in single cells. When applied to cancer and human endoderm differentiation data, scDaPars not only revealed cell-type-specific APA regulation but also identified cell subpopulations that are otherwise invisible to conventional gene expression analysis. Thus, scDaPars will enable us to understand cellular heterogeneity at the post-transcriptional APA level.
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http://dx.doi.org/10.1101/gr.271346.120DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8494218PMC
October 2021

An international genome-wide meta-analysis of primary biliary cholangitis: Novel risk loci and candidate drugs.

J Hepatol 2021 09 23;75(3):572-581. Epub 2021 May 23.

Academic Department of Medical Genetics, University of Cambridge, Cambridge, United Kingdom.

Backgrounds & Aims: Primary biliary cholangitis (PBC) is a chronic liver disease in which autoimmune destruction of the small intrahepatic bile ducts eventually leads to cirrhosis. Many patients have inadequate response to licensed medications, motivating the search for novel therapies. Previous genome-wide association studies (GWAS) and meta-analyses (GWMA) of PBC have identified numerous risk loci for this condition, providing insight into its aetiology. We undertook the largest GWMA of PBC to date, aiming to identify additional risk loci and prioritise candidate genes for in silico drug efficacy screening.

Methods: We combined new and existing genotype data for 10,516 cases and 20,772 controls from 5 European and 2 East Asian cohorts.

Results: We identified 56 genome-wide significant loci (20 novel) including 46 in European, 13 in Asian, and 41 in combined cohorts; and a 57 genome-wide significant locus (also novel) in conditional analysis of the European cohorts. Candidate genes at newly identified loci include FCRL3, INAVA, PRDM1, IRF7, CCR6, CD226, and IL12RB1, which each play key roles in immunity. Pathway analysis reiterated the likely importance of pattern recognition receptor and TNF signalling, JAK-STAT signalling, and differentiation of T helper (T)1 and T17 cells in the pathogenesis of this disease. Drug efficacy screening identified several medications predicted to be therapeutic in PBC, some of which are well-established in the treatment of other autoimmune disorders.

Conclusions: This study has identified additional risk loci for PBC, provided a hierarchy of agents that could be trialled in this condition, and emphasised the value of genetic and genomic approaches to drug discovery in complex disorders.

Lay Summary: Primary biliary cholangitis (PBC) is a chronic liver disease that eventually leads to cirrhosis. In this study, we analysed genetic information from 10,516 people with PBC and 20,772 healthy individuals recruited in Canada, China, Italy, Japan, the UK, or the USA. We identified several genetic regions associated with PBC. Each of these regions contains several genes. For each region, we used diverse sources of evidence to help us choose the gene most likely to be involved in causing PBC. We used these 'candidate genes' to help us identify medications that are currently used for treatment of other conditions, which might also be useful for treatment of PBC.
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http://dx.doi.org/10.1016/j.jhep.2021.04.055DOI Listing
September 2021

A multi-omics study links TNS3 and SEPT7 to long-term former smoking NSCLC survival.

NPJ Precis Oncol 2021 May 17;5(1):39. Epub 2021 May 17.

Department of Environmental Health, Harvard T.H. Chan School of Public Health, Harvard University, Boston, MA, 02115, USA.

The genetic architecture of non-small cell lung cancer (NSCLC) is relevant to smoking status. However, the genetic contribution of long-term smoking cessation to the prognosis of NSCLC patients remains largely unknown. We conducted a genome-wide association study primarily on the prognosis of 1299 NSCLC patients of long-term former smokers from independent discovery (n = 566) and validation (n = 733) sets, and used in-silico function prediction and multi-omics analysis to identify single nucleotide polymorphisms (SNPs) on prognostics with NSCLC. We further detected SNPs with at least moderate association strength on survival within each group of never, short-term former, long-term former, and current smokers, and compared their genetic similarity at the SNP, gene, expression quantitative trait loci (eQTL), enhancer, and pathway levels. We identified two SNPs, rs34211819 at 7p12.3 (P = 3.90 × 10) and rs1143149 at 7p14.2 (P = 9.75 × 10), were significantly associated with survival of NSCLC patients who were long-term former smokers. Both SNPs had significant interaction effects with years of smoking cessation (rs34211819: P = 8.0 × 10; rs1143149: P = 0.003). In addition, in silico function prediction and multi-omics analysis provided evidence that these QTLs were associated with survival. Moreover, comparison analysis found higher genetic similarity between long-term former smokers and never-smokers, compared to short-term former smokers or current smokers. Pathway enrichment analysis indicated a unique pattern among long-term former smokers that was related to immune pathways. This study provides important insights into the genetic architecture associated with long-term former smoking NSCLC.
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http://dx.doi.org/10.1038/s41698-021-00182-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8128887PMC
May 2021

Individual-Level Determinants of Lifestyle Behavioral Changes during COVID-19 Lockdown in the United States: Results of an Online Survey.

Int J Environ Res Public Health 2021 04 20;18(8). Epub 2021 Apr 20.

Department of Medicine, Section of Epidemiology and Population Science, Baylor College of Medicine, Houston, TX 77030, USA.

This study examined individual-level determinants of self-reported changes in healthy (diet and physical activity) and addictive (alcohol use, smoking, and vaping) lifestyle behaviors during the initial COVID-19 lockdown period in the USA. A national online survey was administered between May and June 2020 that targeted a representative U.S. sample and yielded data from 1276 respondents, including 58% male and 50% racial/ethnic minorities. We used univariate and multivariable linear regression models to examine the associations of sociodemographic, mental health, and behavioral determinants with self-reported changes in lifestyle behaviors. Some study participants reported increases in healthy lifestyle behaviors since the pandemic (i.e., 36% increased healthy eating behaviors, and 33% increased physical activity). However, they also reported increases in addictive lifestyle behaviors including alcohol use (40%), tobacco use (41%), and vaping (46%). With regard to individual-level determinants, individuals who reported adhering to social distancing guidelines were also more likely to report increases in healthy lifestyle behaviors (β = 0.12, 95% CI 0.04 to 0.21). Conversely, women (β = -0.37, 95% CI -0.62 to -0.12), and unemployed individuals (β = -0.33, 95% CI -0.64 to -0.02) were less likely to report increases in healthy lifestyle behaviors. In addition, individuals reporting anxiety were more likely to report increases in addictive behaviors (β = 0.26, 95% CI 0.09 to 0.43). Taken together, these findings suggest that women and unemployed individuals may benefit from interventions targeting diet and physical activity, and that individuals reporting anxiety may benefit from interventions targeting smoking and alcohol cessation to address lifestyle changes during the pandemic.
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http://dx.doi.org/10.3390/ijerph18084364DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8073729PMC
April 2021

Outcomes of Aortic Valve Replacement for Chronic Aortic Insufficiency: Analysis of the Society of Thoracic Surgeons Database.

Ann Thorac Surg 2021 Apr 25. Epub 2021 Apr 25.

Division of Cardiothoracic Surgery, Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Houston, Texas. Electronic address:

Background: This study evaluated outcomes and risk factors for surgical aortic valve replacement (SAVR) for aortic insufficiency (AI) in a national cohort. We analyzed the incidence, outcomes, and risk factors for SAVR for AI in the Society of Thoracic Surgeons Adult Cardiac Surgery Database.

Methods: The national database was queried for patients with moderate or greater AI undergoing isolated SAVR between July 2011 and December 2018. Patients with moderate or greater aortic stenosis, acute dissection, active endocarditis, concomitant procedures, or emergent operation were excluded. AI was staged using guideline criteria based on symptoms and ventricular remodeling. Operative mortality and morbidity were compared between stages, and risk factors for operative death were identified.

Results: A total of 12,564 patients underwent isolated SAVR for AI from 2011 to 2018. Patients were most frequently AI stage D (7019 [57.5%]), compared with B (1405 [11.2%]), C1 (1128 [9.0%]), or C2 (1325 [10.5%]). Operative mortality was 1.1% overall, and increased between stage C1, C2, and D (0.4% vs 0.7% vs 1.6%, respectively, P < .01), along with major morbidity (5.1% vs 7.5% vs 9.9%, respectively; P < .01). Mortality was higher in patients with severe ventricular dilation and an ejection fraction of less than 0.30 (2.7% vs 1.0%, P < .01). Risk factors for death were symptomatic AI, decreased ejection fraction, age, weight, body surface area, and dialysis.

Conclusions: Operative mortality and morbidity for isolated SAVR for AI is very low in a national cohort, providing a benchmark for future transcatheter approaches. Operative risk increases with advanced ventricular remodeling. SAVR before development of ventricular remodeling may be appropriate in patients with severe AI.
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http://dx.doi.org/10.1016/j.athoracsur.2021.04.027DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8542644PMC
April 2021

Genetic Variation and Recurrent Haplotypes on Chromosome 6q23-25 Risk Locus in Familial Lung Cancer.

Cancer Res 2021 06 14;81(12):3162-3173. Epub 2021 Apr 14.

Computational and Statistical Genomics Branch, National Human Genome Research Institute, National Institutes of Health, Baltimore, Maryland.

Although lung cancer is known to be caused by environmental factors, it has also been shown to have genetic components, and the genetic etiology of lung cancer remains understudied. We previously identified a lung cancer risk locus on 6q23-25 using microsatellite data in families with a history of lung cancer. To further elucidate that signal, we performed targeted sequencing on nine of our most strongly linked families. Two-point linkage analysis of the sequencing data revealed that the signal was heterogeneous and that different families likely had different risk variants. Three specific haplotypes were shared by some of the families: 6q25.3-26 in families 42 and 44, 6q25.2-25.3 in families 47 and 59, and 6q24.2-25.1 in families 30, 33, and 35. Region-based logarithm of the odds scores and expression data identified the likely candidate genes for each haplotype overlap: at 6q25.3, at 6q26, and (6q24.1) and (6q24.2). Further annotation was used to zero in on potential risk variants in those genes. All four genes are good candidate genes for lung cancer risk, having been linked to either lung cancer specifically or other cancers. However, this is the first time any of these genes has been implicated in germline risk. Functional analysis of these four genes is planned for future work. SIGNIFICANCE: This study identifies four genes associated with lung cancer risk, which could help guide future lung cancer prevention and treatment approaches.
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http://dx.doi.org/10.1158/0008-5472.CAN-20-3196DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8409178PMC
June 2021

Cannabis Use, Pulmonary Function, and Lung Cancer Susceptibility: A Mendelian Randomization Study.

J Thorac Oncol 2021 07 20;16(7):1127-1135. Epub 2021 Apr 20.

Lunenfeld-Tanenbaum Research Institute, Sinai Health System, Toronto, Ontario, Canada; Division of Epidemiology, Dalla Lana School of Public Health, University of Toronto, Toronto, Ontario, Canada.

Introduction: Because of widespread use, understanding the pulmonary effects of cannabis use is important; but its role independent from tobacco smoking is yet to be elucidated. We used Mendelian randomization (MR) to assess the effect of genetic liability to lifetime cannabis use and cannabis use disorder on pulmonary function and lung cancer.

Methods: We used four single nucleotide polymorphisms associated with lifetime cannabis use (p value <5 × 10) from a genome-wide association study (GWAS) of 184,765 individuals of European descent from the International Cannabis Consortium, 23andme, and U.K. Biobank as instrumental variables. Seven single nucleotide polymorphisms (p value <5 × 10) were selected as instruments for cannabis use disorder from a GWAS meta-analysis of 17,068 European ancestry cases and 357,219 controls of European descent from Psychiatric Genomics Consortium Substance Use Disorders working group, Lundbeck Foundation Initiative for Integrative PsychiatricResearch, and deCode. To assess lung function, GWAS included 79,055 study participants of the SpiroMeta Consortium, and for lung cancer GWAS from the International Lung Cancer Consortium contained 29,266 cases and 56,450 controls.

Results: MR revealed that genetic liability to lifetime cannabis use was associated with increased risk of squamous cell carcinoma (OR = 1.22, 95%, confidence interval = 1.07-1.39, p value = 0.003, q value = 0.025). Pleiotropy-robust methods and positive and negative control analyses did not indicate bias in the primary analysis.

Conclusions: The findings of this MR analysis suggest evidence for a potential causal association between genetic liability for cannabis use and the risk of squamous cell carcinoma. Triangulating MR and observational studies and addressing orthogonal sources of bias are necessary to confirm this finding.
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http://dx.doi.org/10.1016/j.jtho.2021.03.025DOI Listing
July 2021
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