Project description:Thyroid stimulating hormone (TSH) hormone levels are normally tightly regulated within an individual; thus, relatively small variations may indicate thyroid disease. Genome-wide association studies (GWAS) have identified variants in PDE8B and FOXE1 that are associated with TSH levels. However, prior studies lacked racial/ethnic diversity, limiting the generalization of these findings to individuals of non-European ethnicities. The Electronic Medical Records and Genomics (eMERGE) Network is a collaboration across institutions with biobanks linked to electronic medical records (EMRs). The eMERGE Network uses EMR-derived phenotypes to perform GWAS in diverse populations for a variety of phenotypes. In this report, we identified serum TSH levels from 4,501 European American and 351 African American euthyroid individuals in the eMERGE Network with existing GWAS data. Tests of association were performed using linear regression and adjusted for age, sex, body mass index (BMI), and principal components, assuming an additive genetic model. Our results replicate the known association of PDE8B with serum TSH levels in European Americans (rs2046045 p = 1.85×10-17, β = 0.09). FOXE1 variants, associated with hypothyroidism, were not genome-wide significant (rs10759944: p = 1.08×10-6, β = -0.05). No SNPs reached genome-wide significance in African Americans. However, multiple known associations with TSH levels in European ancestry were nominally significant in African Americans, including PDE8B (rs2046045 p = 0.03, β = -0.09), VEGFA (rs11755845 p = 0.01, β = -0.13), and NFIA (rs334699 p = 1.50×10-3, β = -0.17). We found little evidence that SNPs previously associated with other thyroid-related disorders were associated with serum TSH levels in this study. These results support the previously reported association between PDE8B and serum TSH levels in European Americans and emphasize the need for additional genetic studies in more diverse populations.

Project description:Translational Relevance Historically, African Americans have been underrepresented in clinical cancer research. Diversity helps to ensure equal access to new cancer therapies and better treatment for everyone. Cancer research is increasingly focused on classifying patients according to molecular profiles for particular groups. We provide a detailed molecular analysis from paired NSCLC tissues that identified differential coding and noncoding RNA expression in NSCLC from African Americans (AA) and European Americans (EA). Similar to other tumor types, we determined that race-enriched gene and microRNA expression signatures suggest a more aggressive disease in African Americans. Based on predicted drug resistance to adjuvant chemotherapies, AA may not equally benefit from the same range of clinical drugs as EA. Our findings provide a rationale for integrating coding and noncoding transcriptome profiles, along with clinical, demographic, and genomic data, when determining treatment options. Abstract Purpose: To determine if racial differences in gene and microRNA expression translates to differences in lung tumor biology with clinical relevance in African Americans (AA) and European Americans (EA). Experimental Design: The NCI-Maryland Case Control Study includes seven Baltimore City hospitals and is overrepresented with AA patients (~40%). Patients that underwent curative NSCLC surgery between 1998 and 2014 were enrolled. Comparative molecular profiling used mRNA (n = 22 AAs and n = 19 EAs) and microRNA (n = 42 AAs and n = 55 EAs) expression arrays to track differences in paired fresh frozen normal tissues and lung tumor specimens from AA and EA. Pathway enrichment, predicted drug response, tumor microenvironment infiltration, cancer immunotherapy antigen profiling, and microRNA target enrichment were assessed. Results: AA-enriched differential gene expression was characterized by stem-cell and invasion pathways. Differential gene expression in lung tumors from EA were primarily characterized by cell proliferation pathways. Population-specific gene expression was partly driven by population-specific miRNA expression profiles. Drug susceptibility predictions revealed a strong inverse correlation between AA resistance and EA sensitivity to the same panel of drugs. Statistically significant differences in M1 and M2 macrophage infiltration was observed in AA (P <0.05), however, PD-L1, PD-L2 expression was similar between both. Conclusions: Comparative transcriptomic profiling revealed clear differences in lung tumor biology between AA and EA. Increased participation by AA in lung cancer clinical trials are needed to integrate, and leverage, transcriptomic differences with other clinical information to maximize therapeutic benefit in both AA and EA. GSEA, Connectivity Map, CIBERSORT, cancer immunotherapy antigen profiling, and hypergeometric testing for overlapping miRNA targets were performed.

Project description:Translational Relevance Historically, African Americans have been underrepresented in clinical cancer research. Diversity helps to ensure equal access to new cancer therapies and better treatment for everyone. Cancer research is increasingly focused on classifying patients according to molecular profiles for particular groups. We provide a detailed molecular analysis from paired NSCLC tissues that identified differential coding and noncoding RNA expression in NSCLC from African Americans (AA) and European Americans (EA). Similar to other tumor types, we determined that race-enriched gene and microRNA expression signatures suggest a more aggressive disease in African Americans. Based on predicted drug resistance to adjuvant chemotherapies, AA may not equally benefit from the same range of clinical drugs as EA. Our findings provide a rationale for integrating coding and noncoding transcriptome profiles, along with clinical, demographic, and genomic data, when determining treatment options. Abstract Purpose: To determine if racial differences in gene and microRNA expression translates to differences in lung tumor biology with clinical relevance in African Americans (AA) and European Americans (EA). Experimental Design: The NCI-Maryland Case Control Study includes seven Baltimore City hospitals and is overrepresented with AA patients (~40%). Patients that underwent curative NSCLC surgery between 1998 and 2014 were enrolled. Comparative molecular profiling used mRNA (n = 22 AAs and n = 19 EAs) and microRNA (n = 42 AAs and n = 55 EAs) expression arrays to track differences in paired fresh frozen normal tissues and lung tumor specimens from AA and EA. Pathway enrichment, predicted drug response, tumor microenvironment infiltration, cancer immunotherapy antigen profiling, and microRNA target enrichment were assessed. Results: AA-enriched differential gene expression was characterized by stem-cell and invasion pathways. Differential gene expression in lung tumors from EA were primarily characterized by cell proliferation pathways. Population-specific gene expression was partly driven by population-specific miRNA expression profiles. Drug susceptibility predictions revealed a strong inverse correlation between AA resistance and EA sensitivity to the same panel of drugs. Statistically significant differences in M1 and M2 macrophage infiltration was observed in AA (P <0.05), however, PD-L1, PD-L2 expression was similar between both. Conclusions: Comparative transcriptomic profiling revealed clear differences in lung tumor biology between AA and EA. Increased participation by AA in lung cancer clinical trials are needed to integrate, and leverage, transcriptomic differences with other clinical information to maximize therapeutic benefit in both AA and EA.

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Serum Metabolites Associated with Healthy Diets in African Americans and European Americans.

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