An exome-wide sequencing study of the GOLDN cohort reveals novel associations of coding variants and fasting plasma lipids

Authors: GENG, XIN - University Of Texas; IRVIN, MARGUERITE - University Of Alabama; HIDALGO, BERTHA - University Of Alabama; ASLIBEKYAN, STELLA - University Of Alabama; SRINIVASASAINAGENDRA, VINODH - University Of Alabama; AN, PING - Washington University; FRAZIER-WOOD, ALEXIS - Baylor University; TIWARI, HERMANT - University Of Alabama; DAVE, TUSHAR - University Of Maryland; RYAN, KATHLEEN - University Of Maryland; ORDOVAS, JOSE - Jean Mayer Human Nutrition Research Center On Aging At Tufts University; STRAKA, ROBERT - University Of Minnesota; FEITOSA, MARY - Washington University; HOPKINS, PAUL - University Of Utah; BORECKI, INGRID - University Of Washington; PROVINCE, MICHAEL - Washington University; MITCHELL, BRAXTON - University Of Maryland; ARNETT, DONNA - University Of Kentucky; ZHI, DEGUI - University Of Texas

Submitted to: Frontiers in Genetics
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 2/13/2019
Publication Date: 2/26/2019
Citation: Geng, X., Irvin, M.R., Hidalgo, B., Aslibekyan, S., Srinivasasainagendra, V., An, P., Frazier-Wood, A.C., Tiwari, H.K., Dave, T., Ryan, K., Ordovas, J.M., Straka, R.J., Feitosa, M.F., Hopkins, P.N., Borecki, I., Province, M.A., Mitchell, B.D., Arnett, D.K., Zhi, D. 2019. An exome-wide sequencing study of the GOLDN cohort reveals novel associations of coding variants and fasting plasma lipids. Frontiers in Genetics. 10:158. https://doi.org/10.3389/fgene.2019.00158.
DOI: https://doi.org/10.3389/fgene.2019.00158

Interpretive Summary: Genetic and environmental factors drive blood lipid concentrations. Many studies have been conducted to identify common genetic variants involved in dyslipidemia; however, most of the heritability remains to be determined. It has been proposed that that hidden heritability could be found in rare coding variants. Along these lines, 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. The results of this search identified one variant (named rs11171663 in the gene known as ITGA7) that was associated with fasting triglyceride levels, explaining approximately 3.2% of the triglyceride variance. When we searched by genes, we found statistically significant associations between the ITGA7 and SLCO2A1 genes and triglycerides, as well as between the POT1 gene and low-density lipoprotein cholesterol. These results were replicated in other populations, such as the 3,183 African American samples from Hypertension Genetic Epidemiology Network (HyperGEN) and the Genetic Epidemiology Network of Arteriopathy (GENOA). In GOLDN, mRNA levels of ITGA7 and SLCO2A1 were associated with fasting triglycerides, supporting the functional relevance of our findings. In conclusion, in this study, we present evidence about the importance of rare variants as determinants of fasting lipids. Our findings may inform novel biomarkers of disease risk and treatment targets.

Technical Abstract: Background: 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. Results: 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 ITGA7) was associated with fasting triglyceride levels (P = 7.66E-08), explaining approximately 3.2% of the total trait variance. In gene-based tests, we found statistically significant associations between ITGA7 (P = 1.77E-07) and SLCO2A1 (P = 7.18E-07) and triglycerides, as well as between POT1 (P = 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 P-values of 0.04 (ITGA7), 0.08 (SLCO2A1), and 0.02 (POT1). In GOLDN, gene transcript levels of ITGA7 and SLCO2A1 were associated with fasting triglycerides (P = 0.07 and P = 0.02), highlighting functional relevance of our findings. Conclusion: 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.