TY - JOUR
T1 - An exome-wide sequencing study of the GOLDN cohort reveals novel associations of coding variants and fasting plasma lipids
AU - Geng, Xin
AU - Irvin, Marguerite R.
AU - Hidalgo, Bertha
AU - Aslibekyan, Stella
AU - Srinivasasainagendra, Vinodh
AU - An, Ping
AU - Frazier-Wood, Alexis C.
AU - Tiwari, Hemant K.
AU - Dave, Tushar
AU - Ryan, Kathleen
AU - Ordovas, Jose M.
AU - Straka, Robert J.
AU - Feitosa, Mary F.
AU - Hopkins, Paul N.
AU - Borecki, Ingrid
AU - Province, Michael A.
AU - Mitchell, Braxton D.
AU - Arnett, Donna K.
AU - Zhi, Degui
N1 - Publisher Copyright:
© 2019 Geng, Irvin, Hidalgo, Aslibekyan, Srinivasasainagendra, An, Frazier-Wood, Tiwari, Dave, Ryan, Ordovas, Straka, Feitosa, Hopkins, Borecki, Province, Mitchell, Arnett and Zhi.
PY - 2019
Y1 - 2019
N2 - 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.
AB - 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.
KW - Cholesterol
KW - Epidemiology
KW - Genetics
KW - HDL
KW - LDL
KW - Rare variant
KW - Triglyceride
KW - Whole exome sequencing
UR - http://www.scopus.com/inward/record.url?scp=85065816821&partnerID=8YFLogxK
U2 - 10.3389/fgene.2019.00158
DO - 10.3389/fgene.2019.00158
M3 - Article
C2 - 30863429
AN - SCOPUS:85065816821
SN - 1664-8021
VL - 10
JO - Frontiers in Genetics
JF - Frontiers in Genetics
IS - feburay
M1 - 158
ER -