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Epistasis between SNPs in genes involved in lipoprotein metabolism influences high- and low-density lipoprotein cholesterol levels

Abstract

Although genome-wide association (GWA) studies have provided valuable insights into the genetic architecture of human disease, they have elucidated relatively little of the heritability of complex traits. A significant part of the missing heritability might be explained by rare combinations of common SNPs. We hypothesized that epistasis among 15 genes (148 SNPs) involved in lipoprotein metabolism would influence HDL-cholesterol (HDL-C) and LDL-cholesterol (LDL-C) levels. Using SNPwinter software with the various epistatic models, we identified 58 association signals with HDL-C levels for SNPs in eleven genes and 118 associations with LDL-C for SNPs in fourteen genes. These associations were discovered in the urban Ansan cohort (n = 4,102) and replicated in a rural cohort (n = 3,434), the Ansung. We found replicated associations with new genes (SOAT1, APOB, HMGCR, and FDFT1 for HDL-C, and SOAT1, FDFT1, LPL, SQLE, ABCA1, LRP1, SCARB1, and PLTP for LDL-C), in addition to those (CETP, LIPC, LPL, ABCA1, PLTP, SCARB1, and LRP1 for HDL-C, and CETP, LIPC, LDLR, APOB, CYP7A1, and HMGCR for LDL-C) identified by GWA studies, through investigating pairwise interactions between candidate genes of biological and clinical importance. Interestingly, we found that some genes were more likely to be involved in epistatic interactions (ABCA1 and LIPC for HDL-C, and ABCA1, SCARB1, and LIPC for LDL-C).

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Acknowledgments

This study was supported by a grant from the Korea Health Technology R&D Project, Ministry of Health & Welfare, Republic of Korea (A110749), grants from Korea Centers for Disease Control and Prevention (4845-301, 4851-302, 4851-307), and Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education (No. 2009-0093821).

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The authors have no conflict of interest.

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Correspondence to Jeong-Jae Ko or KyuBum Kwack.

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Kim, S., Shin, C., Cho, N.H. et al. Epistasis between SNPs in genes involved in lipoprotein metabolism influences high- and low-density lipoprotein cholesterol levels. Genes Genom 36, 809–817 (2014). https://doi.org/10.1007/s13258-014-0216-7

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  • DOI: https://doi.org/10.1007/s13258-014-0216-7

Keywords

  • Epistatic interaction
  • Lipoprotein
  • Metabolism
  • Single nucleotide polymorphism (SNP)
  • SNPwinter