GENE-LEVEL GERMLINE INVESTIGATION OF BREAST CANCER SUBTYPES AND MORTALITY AMONG WOMEN OF EUROPEAN AND AFRICAN ANCESTRY

Genome-wide investigations to date have uncovered over 210 germline variants associated with BC incidence, and only a handful of mostly non-replicable variants associated with BC mortality. There remain a few key gaps in knowledge across genetic investigations of BC incidence and mortality. First, BC is a heterogeneous disease, with subtype-specific outcomes. Understanding of the germline genetic underpinnings of BC subtypes is sparse among individuals of European and even sparser for individuals of African ancestry. It is also thought that integration of BC subtype (i.e., stratification by) into germline investigations of BC mortality may a key step towards bettering understanding on this front. In this dissertation work, we address these gaps in knowledge by leveraging a statistically efficient and highly interpretable framework for genetic association testing in Transcriptome-Wide Association Study (TWAS). In Aim 1 (Chapter 4) multi-tissue (normal breast, breast tumor), multi-ancestry TWAS-based germline-regulated gene expression (GReX) analysis of 396 BC-related genes in relation to BC subtype, we find 40 GReX-prioritized genes for BC subtype, including ten shared, and 34 and six unique to Luminal-like (LL) and Basal-like (BL) subtype, respectively (after Bayesian correction for potential test statistic inflation and at global False Discovery Rate (FDR) <0.05). Among individuals of African ancestry, we see suggestion of association (global FDR = 0.06 to 0.18) for five genes. By comparison, the largest genome-wide study to date among African ancestry individuals has reported no loci at or near genome-wide significance. In Aim 2 (Chapter 5) ancestry and subtype specific GReX analysis of BC mortality, we find no associations at global FDR <0.05. However, we uncover potential differential germline-regulation of tumor expression across LL and BL subtypes, within each group of European and African ancestry individuals (321 loci across 37 genes for European ancestry, 23 loci across 4 genes for African ancestry). That, along with our methodological work on correction of collider stratification bias represents a valuable platform for future work. The spectrum of findings across the two studies are important towards more targeted risk and prognosis stratification and potentially therapeutic efforts to reduce burden of BC outcomes.Doctor of Philosoph

Aggregation tests identify new gene associations with breast cancer in populations with diverse ancestry

Low-frequency variants play an important role in breast cancer (BC) susceptibility. Gene-based methods can increase power by combining multiple variants in the same gene and help identify target genes. We evaluated the potential of gene-based aggregation in the Breast Cancer Association Consortium cohorts including 83,471 cases and 59,199 controls. Low-frequency variants were aggregated for individual genes' coding and regulatory regions. Association results in European ancestry samples were compared to single-marker association results in the same cohort. Gene-based associations were also combined in meta-analysis across individuals with European, Asian, African, and Latin American and Hispanic ancestry. In European ancestry samples, 14 genes were significantly associated (q < 0.05) with BC. Of those, two genes, FMNL3 (P = 6.11 × 10 ) and AC058822.1 (P = 1.47 × 10 ), represent new associations. High FMNL3 expression has previously been linked to poor prognosis in several other cancers. Meta-analysis of samples with diverse ancestry discovered further associations including established candidate genes ESR1 and CBLB. Furthermore, literature review and database query found further support for a biologically plausible link with cancer for genes CBLB, FMNL3, FGFR2, LSP1, MAP3K1, and SRGAP2C. Using extended gene-based aggregation tests including coding and regulatory variation, we report identification of plausible target genes for previously identified single-marker associations with BC as well as the discovery of novel genes implicated in BC development. Including multi ancestral cohorts in this study enabled the identification of otherwise missed disease associations as ESR1 (P = 1.31 × 10 ), demonstrating the importance of diversifying study cohorts. [Abstract copyright: © 2023. The Author(s).

Associations Between Environmental Quality and Infant Mortality in the United States, 2000–2005

Background: The United States (U.S.) suffers from high infant mortality (IM) rates and there are significant racial/ethnic differences in these rates. Prior studies on the environment and infant mortality are generally limited to singular exposures. We utilize the Environmental Quality Index (EQI), a measure of cumulative environmental exposure (across air, water, land, sociodemographic, and land domains) for U.S. counties from 2000 to 2005, to investigate associations between ambient environment and IM across maternal race/ethnicity. Methods: We linked 2000–2005 infant data from the U.S. Centers for Disease Control and Prevention to the EQI (n = 22,702,529; 144,741 deaths). We utilized multi-level regression to estimate associations between quartiles of county-level EQI and IM. We also considered associations between quartiles of county level domain specific indices with IM. We controlled for rural-urban status (RUCC1: urban, metropolitan; RUCC2: urban, non-metropolitan; RUCC3: less urbanized; RUCC4: thinly populated), maternal age, maternal education, marital status, infant sex, and stratified on race/ ethnicity. Additionally, we estimated associations for linear combinations of environmental quality and rural-urban status. Results: We found a mix of positive, negative, and null associations and our findings varied across domain and race/ethnicity. Poorer overall environmental quality was associated with decreased odds among Non-Hispanic whites (OR and 95% CI: EQIQ4 (ref. EQIQ1): 0.84[0.80,0.89]). For Non-Hispanic blacks and Hispanics, some increased odds were observed. Poorer air quality was monotonically associated with increased odds among Non-Hispanic whites (airQ4 (ref. airQ1): 1.05[0.99,1.11]) and blacks (airQ4 (ref. airQ1): 1.09 [0.9,1.31]). Rural status was associated with increased IM odds among Hispanics (RUCC4-Q4:1.36[1.04,1.78]; RUCC1-Q4: 1.04[0.92,1.16], ref. for both RUCC1-Q1). Conclusions: This study is the first to report on associations between ambient environmental quality and IM across the United States. It corroborates prior research suggesting an association between air pollution and IM and identifies residence in thinly populated (rural) areas as a potential risk factor towards IM amongst Hispanics. Some of the counterintuitive findings highlight the need for additional research into potentially differential drivers of environmental quality across the rural-urban continuum, especially with regards to the sociodemographic environment

Inspiratory capacity in chronic obstructive pulmonary disease: A measure of hyperinflation and relation with other parameters – A cross-sectional study

Introduction: Chronic obstructive pulmonary disease (COPD) is a leading cause of morbidity and mortality worldwide. Lung hyperinflation or air trapping is the hallmark of COPD and the primary cause of dyspnea, poor quality of life, and advertent disease prognosis associated with the disease. Debates continue to rise against the use of forced expiratory volume 1 as the single-main evaluative parameter for patients with COPD. Inspiratory capacity (IC) together with spirometry on the other hand has been shown to be a dependable parameter that can indicate the presence and management of lung hyperinflation. Patients and Methods: This cross-sectional study included fifty patients of COPD presenting to the department of respiratory medicine. All patients underwent spirometry and 6-min walk test (6MWT). They were grouped according to the GOLD guidelines for airflow limitation, body mass index (BMI), 6MWT, BODE index, number of exacerbations (NoEs), COPD “ABCD” assessment tool, and IC. t-test and one-way analysis of variance were applied. Results: There were 37 males and 13 females. A positive correlation was found between IC and 6MWT and BMI (coefficient of 0.678 and 0.149, respectively). There was a negative correlation between IC and NoEs and BODE index (coefficient of − 0.257 and − 0.631, respectively). IC correlated strongly with the GOLD classification for airflow limitation and combined assessment of COPD. A statistically significant difference between pre- and post-IC values showed IC as the predictor of lung hyperinflation. Conclusion: IC can be used along with 6MWT, BMI, BODE index and NoE for the prognostication and management of COPD

Structure and reorientational dynamics of angiotensin I and II: a microscopic physical insight

<div><p>We present a study of structural analysis and reorientational dynamics of Angiotensin I (AngI) and Angiotensin II (AngII) in aqueous solution. AngI is a decapeptide that acts as a precursor to the octapeptide AngII in the Renin–Angiotensin–Aldosterone system for blood pressure regulation. Experimental structural characterization of these peptides, carried out with circular dichroism and infrared spectroscopy, showed that the angiotensins are mostly disordered but exhibit a measurable population of ordered structures at room temperature. Interestingly, these change from the unordered polyproline-like conformation for AngI to a more compact and ordered conformation for AngII as the length of the peptide is decreased. Anisotropy decay measurements with picosecond time resolution indicate slower overall tumbling and a greater amplitude of internal motion in AngI compared to AngII, consistent with more compact and less flexible structure of the active form of the peptide. To model the microscopic behavior of the peptides, 2-μs molecular dynamics simulation trajectories were generated for AngI and AngII, at 300 K using the OPLS-AA potential and SPC water. The structures sampled in the simulations mostly agree with the experimental results, showing the prevalence of disordered structures, turns, and polyproline helices. Additionally, the computational results predict fewer sampled conformations, tighter side-chain packing and marked increase of Phe8 solvent accessibility upon AngI truncation to AngII. Our combined approach of experiment and extensive computer simulation thus yields new information on the conformational dynamics of the angiotensins, helping provide insight into the structural basis for the potency of AngI relative to AngII.</p> </div

Gene-Level Germline Contributions to Clinical Risk of Recurrence Scores in Black and White Patients with Breast Cancer

Continuous risk of recurrence scores (CRS) based on tumor gene expression are vital prognostic tools for breast cancer. Studies have shown that Black women (BW) have higher CRS than White women (WW). Although systemic injustices contribute substantially to breast cancer disparities, evidence of biological and germline contributions is emerging. In this study, we investigated germline genetic associations with CRS and CRS disparity using approaches modeled after transcriptome-wide association studies (TWAS). In the Carolina Breast Cancer Study, using race-specific predictive models of tumor expression from germline genetics, we performed race-stratified (N = 1,043 WW, 1,083 BW) linear regressions of three CRS (ROR-S: PAM50 subtype score; proliferation score; ROR-P: ROR-S plus proliferation score) on imputed tumor genetically regulated tumor expression (GReX). Bayesian multivariate regression and adaptive shrinkage tested GReX-prioritized genes for associations with tumor PAM50 expression and subtype to elucidate patterns of germline regulation underlying GReX-CRS associations. At FDR-adjusted P &lt; 0.10, 7 and 1 GReX prioritized genes among WW and BW, respectively. Among WW, CRS were positively associated with MCM10, FAM64A, CCNB2, and MMP1 GReX and negatively associated with VAV3, PCSK6, and GNG11 GReX. Among BW, higher MMP1 GReX predicted lower proliferation score and ROR-P. GReX-prioritized gene and PAM50 tumor expression associations highlighted potential mechanisms for GReX-prioritized gene to CRS associations. Among patients with breast cancer, differential germline associations with CRS were found by race, underscoring the need for larger, diverse datasets in molecular studies of breast cancer. These findings also suggest possible germline trans-regulation of PAM50 tumor expression, with potential implications for CRS interpretation in clinical settings. SIGNIFICANCE: This study identifies race-specific genetic associations with breast cancer risk of recurrence scores and suggests mediation of these associations by PAM50 subtype and expression, with implications for clinical interpretation of these scores

Associations Between Environmental Quality and Adult Asthma Prevalence in Medical Claims Data

As of 2014, approximately 7.4% of U.S. adults had current asthma. The etiology of asthma is complex, involving genetics, behavior, and environmental factors. To explore the association between cumulative environmental quality and asthma prevalence in U.S. adults, we linked the U.S. Environmental Protection Agency\u27s Environmental Quality Index (EQI) to the MarketScan® Commercial Claims and Encounters Database. The EQI is a summary measure of five environmental domains (air, water, land, built, sociodemographic). We defined asthma as having at least 2 claims during the study period, 2003–2013. We used a Bayesian approach with non-informative priors, implementing mixed-effects regression modeling with a Poisson link function. Fixed effects variables were EQI, sex, race, and age. Random effects were counties. We modeled quintiles of the EQI comparing higher quintiles (worse quality) to lowest quintile (best quality) to estimate prevalence ratios (PR) and credible intervals (CIs). We estimated associations using the cumulative EQI and domain-specific EQIs; we assessed U.S. overall (non-stratified) as well as stratified by rural-urban continuum codes (RUCC) to assess rural/urban heterogeneity. Among the 71,577,118 U.S. adults with medical claims who could be geocoded to county of residence, 1,147,564 (1.6%) met the asthma definition. Worse environmental quality was associated with increased asthma prevalence using the non-RUCC-stratified cumulative EQI, comparing the worst to best EQI quintile (PR:1.27; 95% CI: 1.21, 1.34). Patterns varied among different EQI domains, as well as by rural/urban status. Poor environmental quality may increase asthma prevalence, but domain-specific drivers may operate differently depending on rural/urban status