Pacific Center for Genome Research

Research Projects

Pacific Center for Genome Research

Research Projects

Project 1

Project 1: Integrating genome, other layers of omics, and non-genetic data to improve understanding of the etiology of human diseases in multi-ethnic populations

A variety of diseases show disparities across different racial and ethnic groups, such as Africans, Hispanics/Latinos, Asians, Europeans, and Native Hawaiians. The etiology of many human diseases is not fully understood, despite substantial efforts to identify associated non-genetic and genetic factors, including common and rare genetic variants. More work focusing on different layers of omic markers including DNA methylation (DNAm), gene, protein, and metabolite markers is urgently needed. Basic research supports the important roles of certain CpG sites, genes, proteins, and metabolites in development of many diseases. Epidemiological studies also have identified multiple candidate DNAm, gene, protein, and metabolite biomarkers for diseases/traits. However, conventional epidemiologic studies were conducted primarily in individuals with European ancestry, and it is unclear which DNAm/gene/protein/metabolite biomarkers identified to date are European ancestry-specific or pan-ancestry. Also, findings with many of these biomarkers have been inconsistent, potentially due to major methodological limitations, such as selection bias and uncontrolled confounding. There are critical needs to apply a novel study design with reduced limitations of conventional biomarker studies for characterizing causally related biomarkers in blood for human diseases across populations to improve our understanding of disease etiology and reduce health disparities.

One strategy to potentially decrease limitations of selection bias and unmeasured confounding is to use genetic instruments for assessing the relationship between DNAm/gene/protein/metabolite markers and diseases. Our preliminary work applying conventional methods to develop genetic prediction models has revealed promising DNAm, gene, protein, and metabolite biomarkers in blood associated with risk of several diseases in Europeans.

The proposed project will apply a series of new studies to address these important knowledge gaps. Specifically, we will 1) develop ethnic-specific DNAm, gene, protein, and metabolite marker genetic prediction models in blood tissue across African Americans, Hispanics/Latinos, Asian Americans, European Americans, and Native Hawaiians by applying novel methods (Aim 1); 2) identify putative causal DNAm, gene, protein, and metabolite biomarkers in blood for risk of multiple diseases across multi-ethnic populations by leveraging large scale genetic and non-genetic data (Aim 2); and 3) evaluate potential interactions between known risk factors and predicted levels of established and newly identified markers on risks of diseases of interest (Aim 3).

Our study will generate important new knowledge for substantially improving our understanding of the etiology of multiple human diseases across Africans, Hispanics/Latinos, Asians, Europeans, and Native Hawaiians. The proposed new methods can also be applied to other omic markers.

Project 2

Project 2:

Lung cancer is the second most common cancer in the United States and the leading cause of cancer-related deaths. Significant disparities in incidence and outcome of lung cancer characterize the disease’s manifestation among ethnically and racially diverse populations. It has been found that Native Hawaiians (NH), Pacific Islanders (PI), and African Americans (AA) have the highest lung cancer risk and poorest survival outcomes compared to other populations. The influence of race and ethnicity is more evident at relatively low levels of smoking. After accounting for known lung cancer risk factors, NH and AAs remain at highest risk of lung cancer. The cause of these significant lung cancer health disparities is undoubtedly multifactorial. However, an unexplored factor is the molecular profiles of tumors arising in the NH/PI communities. In the past decade, large-scale lung cancer genomic studies have found clear racial disparity for lung cancer driver mutation genes. However, NHs have been strikingly underrepresented in The Cancer Genome Atlas Project (TCGA) and other cancer genome projects. There are almost no NH lung cancer patients included in the previous projects. There have also been no studies to compare DNA methylation changes between tumor and adjacent normal samples from NH/PI lung cancer patients, despite the importance of understanding how DNA methylation changes contribute to NH lung cancer development.

To address the critical gap in lung cancer genomics studies and to understand the key factors that contribute to the health disparity of NH/PI lung cancer patients, we propose the following specific aims: 1. Characterize genomic landscape of lung cancer in NH patients. 2. Perform epigenomic profiling of lung cancer tissues in NH patients. 3. Identify NH specific genomic and epigenomic risk factors of lung cancer by comparing the profiles from NH with the published genomic and epigenomic data from other racial/ethnic populations.

This project has the potential to be translated into improved lung cancer screening, precision prevention, and therapeutic intervention in NH and other populations.