AUTHOR=Geng Xin , Irvin Marguerite R. , Hidalgo Bertha , Aslibekyan Stella , Srinivasasainagendra Vinodh , An Ping , Frazier-Wood Alexis C. , Tiwari Hemant K. , Dave Tushar , Ryan Kathleen , Ordovas Jose M. , Straka Robert J. , Feitosa Mary F. , Hopkins Paul N. , Borecki Ingrid , Province Michael A. , Mitchell Braxton D. , Arnett Donna K. , Zhi Degui 

TITLE=An Exome-Wide Sequencing Study of the GOLDN Cohort Reveals Novel Associations of Coding Variants and Fasting Plasma Lipids

JOURNAL=Frontiers in Genetics

VOLUME=10

YEAR=2019

URL=https://www.frontiersin.org/journals/genetics/articles/10.3389/fgene.2019.00158

DOI=10.3389/fgene.2019.00158

ISSN=1664-8021

ABSTRACT=<p><bold>Background:</bold> Associations of both common and rare genetic variants with fasting blood lipids have been extensively studied. However, most of the rare coding variants associated with lipids are population-specific, and exploration of genetic data from diverse population samples may enhance the identification of novel associations with rare variants.</p><p><bold>Results:</bold> We searched for novel coding genetic variants associated with fasting lipid levels in 894 samples from the Genetics of Lipid Lowering Drugs and Diet Network (GOLDN) with exome-wide sequencing-based genotype data. In single variant tests, one variant (rs11171663 in <italic>ITGA7</italic>) was associated with fasting triglyceride levels (<italic>P</italic> = 7.66E-08), explaining approximately 3.2% of the total trait variance. In gene-based tests, we found statistically significant associations between <italic>ITGA7</italic> (<italic>P</italic> = 1.77E-07) and <italic>SLCO2A1</italic> (<italic>P</italic> = 7.18E-07) and triglycerides, as well as between <italic>POT1</italic> (<italic>P</italic> = 3.00E-07) and low-density lipoprotein cholesterol. In another independent replication cohort consisting of 3,183 African American samples from Hypertension Genetic Epidemiology Network (HyperGEN) and the Genetic Epidemiology Network of Arteriopathy (GENOA), the top genes achieved <italic>P</italic>-values of 0.04 (<italic>ITGA7</italic>), 0.08 (<italic>SLCO2A1</italic>), and 0.02 (<italic>POT1</italic>). In GOLDN, gene transcript levels of <italic>ITGA7</italic> and <italic>SLCO2A1</italic> were associated with fasting triglycerides (<italic>P</italic> = 0.07 and <italic>P</italic> = 0.02), highlighting functional relevance of our findings.</p><p><bold>Conclusion:</bold> In this study, we present preliminary evidence of novel rare variant determinants of fasting lipids, and reveal potential underlying molecular mechanisms. Moreover, these results were replicated in an independent cohort. Our findings may inform novel biomarkers of disease risk and treatment targets.</p>