Ancestral Diversity in Lipoprotein(a) Studies Helps Address Evidence Gaps

INTRODUCTION: The independent and causal cardiovascular disease risk factor lipoprotein(a) (Lp(a)) is elevated in \u3e1.5 billion individuals worldwide, but studies have prioritised European populations. METHODS: Here, we examined how ancestrally diverse studies could clarify Lp(a)\u27s genetic architecture, inform efforts examining application of Lp(a) polygenic risk scores (PRS), enable causal inference and identify unexpected Lp(a) phenotypic effects using data from African (n=25 208), East Asian (n=2895), European (n=362 558), South Asian (n=8192) and Hispanic/Latino (n=8946) populations. RESULTS: Fourteen genome-wide significant loci with numerous population specific signals of large effect were identified that enabled construction of Lp(a) PRS of moderate (R CONCLUSIONS: Our results emphasise the merits of prioritising ancestral diversity when addressing Lp(a) evidence gaps

Abstract PO-257: Disparities in unawareness of hepatitis C virus among U.S. adults: An analysis of the 2019 Health Information National Trends Survey

Abstract Purpose Infection with Hepatitis C virus (HCV) is often asymptomatic and chronic infection may lead to liver cancer. In light of the 2020 USPSTF update to HCV screening guidelines to include all adults between 18-79 years old, our objective was to investigate demographic disparities in HCV unawareness with a specific interest in age and race/ethnicity. We estimated (1) HCV unawareness by demographic groups, (2) determinants of HCV unawareness, and (3) sources of health information among those with high HCV unawareness. Methods We used weighted nationally- representative data from the 2019 Health Information National Trends Survey(N=5438) to estimate frequencies of socio-demographic characteristics by HCV unawareness and determinants of HCV unawareness through multivariable logistic regression. We further estimated risk differences (RD) with 95% confidence intervals(CIs) of HCV unawareness by age and race/ethnicity compared to older non- Hispanic(NH)-Whites. Results Overall, 17.3% of adults were unaware of HCV. Younger adults <55 years (20.7%) were more likely to be unaware of HCV compared to older adults ≥55 years (11.6%, χ2 p<0.001). Multivariable analyses showed that younger age, low English fluency, and Hispanic or NH-Asian ethnicity were associated with HCV unawareness. When compared to NH-Whites ≥55 years, the largest differences in HCV unawareness was observed among NH-Asians (RD:25.6%,95%CI:8.2-43.1) and Hispanics (RD:17.1,95%CI:6.3-27.9) adults <55 years. Younger adults unaware of HCV reported primarily obtaining their health information from the internet (75.5%). Conclusions Younger adults, Hispanics, and NH-Asians are more likely to be unaware of HCV. Public health messaging should be targeted to these demographic groups to improve HCV screening coverage. Social media campaigns may increase reach as most young adults unaware of HCV obtain their health information on the internet. Citation Format: Jessica Y. Islam, Lisa Spees, Marlene Camacho-Rivera, Denise C. Vidot, Rina Yarosh, Christopher W. Wheldon. Disparities in unawareness of hepatitis C virus among U.S. adults: An analysis of the 2019 Health Information National Trends Survey [abstract]. In: Proceedings of the AACR Virtual Conference: Thirteenth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2020 Oct 2-4. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(12 Suppl):Abstract nr PO-257

HER2 Testing Characteristics Can Predict Residual Cancer Burden following Neoadjuvant Chemotherapy in HER2-Positive Breast Cancer

Objectives. The response to HER2-targeted neoadjuvant chemotherapy (NAC) in HER2-positive (+) breast cancer can be quantified using residual cancer burden (RCB) pathologic evaluation to predict relapse free/overall survival. However, more information is needed to characterize the relationship between patterns of HER2 testing results and response to NAC. We evaluated clinicopathologic characteristics associated with RCB categories in HER2+ patients who underwent HER2-directed NAC. Methods. A retrospective chart review was conducted with Stage I–III HER2+ breast cancer cases following NAC and surgical resection. HER2 immunohistochemistry (IHC) staining and fluorescence in situ hybridization (FISH), histologic/clinical characteristics, hormone receptor status, and RCB scores (RCB-0, RCB-I, RCB-II, and RCB-III) were evaluated. Results. 64/151 (42.4%) patients with HER2+ disease had pathologic complete response (pCR). Tumors with suboptimal response (RCB-II and RCB-III) were more likely to demonstrate less than 100% HER2 IHC 3+ staining (p<0.0001), lower HER2 FISH copies (p<0.0001), and lower HER2/CEP17 ratios (p=0.0015) compared to RCB-I and RCB-II responses. Estrogen receptor classification using ≥10% versus ≥1% staining showed greater association with higher RCB categories. Conclusions. HER2+ characteristics show differing response to therapy despite all being categorized as positive; tumors with less than 100% IHC 3+ staining, lower HER2 FISH copies, and lower HER2/CEP17 ratios resulted in higher RCB scores

Branched chain amino acids harbor distinct and often opposing effects on health and disease

Abstract Background The branched chain amino acids (BCAA) leucine, isoleucine, and valine are essential nutrients that have been associated with diabetes, cancers, and cardiovascular diseases. Observational studies suggest that BCAAs exert homogeneous phenotypic effects, but these findings are inconsistent with results from experimental human and animal studies. Methods Hypothesizing that inconsistencies between observational and experimental BCAA studies reflect bias from shared lifestyle and genetic factors in observational studies, we used data from the UK Biobank and applied multivariable Mendelian randomization causal inference methods designed to address these biases. Results In n = 97,469 participants of European ancestry (mean age = 56.7 years; 54.1% female), we estimate distinct and often opposing total causal effects for each BCAA. For example, of the 117 phenotypes with evidence of a statistically significant total causal effect for at least one BCAA, almost half (44%, n = 52) are associated with only one BCAA. These 52 associations include total causal effects of valine on diabetic eye disease [odds ratio = 1.51, 95% confidence interval (CI) = 1.31, 1.76], valine on albuminuria (odds ratio = 1.14, 95% CI = 1.08, 1.20), and isoleucine on angina (odds ratio = 1.17, 95% CI = 1.31, 1.76). Conclusions Our results suggest that the observational literature provides a flawed picture of BCAA phenotypic effects that is inconsistent with experimental studies and could mislead efforts developing novel therapeutics. More broadly, these findings motivate the development and application of causal inference approaches that enable ‘omics studies conducted in observational settings to account for the biasing effects of shared genetic and lifestyle factors

Ancestral diversity in lipoprotein(a) studies helps address evidence gaps

Introduction The independent and causal cardiovascular disease risk factor lipoprotein(a) (Lp(a)) is elevated in &gt;1.5 billion individuals worldwide, but studies have prioritised European populations.Methods Here, we examined how ancestrally diverse studies could clarify Lp(a)’s genetic architecture, inform efforts examining application of Lp(a) polygenic risk scores (PRS), enable causal inference and identify unexpected Lp(a) phenotypic effects using data from African (n=25 208), East Asian (n=2895), European (n=362 558), South Asian (n=8192) and Hispanic/Latino (n=8946) populations.Results Fourteen genome-wide significant loci with numerous population specific signals of large effect were identified that enabled construction of Lp(a) PRS of moderate (R2=15% in East Asians) to high (R2=50% in Europeans) accuracy. For all populations, PRS showed promise as a ‘rule out’ for elevated Lp(a) because certainty of assignment to the low-risk threshold was high (88.0%–99.9%) across PRS thresholds (80th–99th percentile). Causal effects of increased Lp(a) with increased glycated haemoglobin were estimated for Europeans (p value =1.4×10−6), although inverse effects in Africans and East Asians suggested the potential for heterogeneous causal effects. Finally, Hispanic/Latinos were the only population in which known associations with coronary atherosclerosis and ischaemic heart disease were identified in external testing of Lp(a) PRS phenotypic effects.Conclusions Our results emphasise the merits of prioritising ancestral diversity when addressing Lp(a) evidence gaps