A1 Refereed original research article in a scientific journal
Gain-of-Function Lipoprotein Lipase Variant rs13702 Modulates Lipid Traits through Disruption of a MicroRNA-410 Seed Site
Authors: Richardson K, Nettleton JA, Rotllan N, Tanaka T, Smith CE, Lai CQ, Parne LD, Lee YC, Lahti J, Lemaitre RN, Manichaikul A, Keller M, Mikkila V, Ngwa J, van Rooij FJA, Ballentyne CM, Borecki IB, Cupples LA, Garcia M, Hofman A, Ferrucci L, Mozaffarian D, Perala MM, Raitakari O, Tracy RP, Arnett DK, Bandinelli S, Boerwinkle E, Eriksson JG, Franco OH, Kahonen M, Nalls M, Siscovick DS, Houston DK, Psaty BM, Viikari J, Witteman JCM, Goodarzi MO, Lehtimaki T, Liu YM, Zillikens MC, Chen YDI, Uitterlinden AG, Rotter JI, Fernandez-Hernando C, Ordovas JM
Publisher: CELL PRESS
Publication year: 2013
Journal: American Journal of Human Genetics
Journal name in source: AMERICAN JOURNAL OF HUMAN GENETICS
Journal acronym: AM J HUM GENET
Number in series: 1
Volume: 92
Issue: 1
First page : 5
Last page: 14
Number of pages: 10
ISSN: 0002-9297
DOI: https://doi.org/10.1016/j.ajhg.2012.10.020
Genome-wide association studies (GWAS) have identified hundreds of genetic variants that are associated with lipid phenotypes. However, data supporting a functional role for these variants in the context of lipid metabolism are scarce. We investigated the association of the lipoprotein lipase (LPL) variant rs13702 with plasma lipids and explored its potential for functionality The rs13702 minor allele had been predicted to disrupt a microRNA (miR) recognition element (MRE) seed site (MRESS) for the human microRNA-410 (miR-410). Furthermore, rs13702 is in linkage disequilibrium (LD) with several SNPs identified by GWAS. We performed a meta-analysis across ten cohorts of participants that showed a statistically significant association of rs13702 with triacylglycerols (TAG) (p = 3.18 x 10(-42))and high-density lipoprotein cholesterol (HDL-C) (p = 1.35 x 10(-32)) with each copy of the minor allele associated with 0.060 mmol/l lower TAG and 0.041 mmol/l higher HDL-C. Our data showed that an LPL 3' UTR luciferase reporter carrying the rs13702 major T allele was reduced by 40% in response to a miR-410 mimic. We also evaluated the interaction between intake of dietary fatty acids and rs13702. Meta-analysis demonstrated a significant interaction between rs13702 and dietary polyunsaturated fatty acid (PUFA) with respect to TAG concentrations (p = 0.00153), with the magnitude of the inverse association between dietary PUFA intake and TAG concentration showing -0.007 mmol/l greater reduction. Our results suggest that rs13702 induces the allele-specific regulation of LPL by miR-410 in humans. This work provides biological and potential clinical relevance for previously reported GWAS variants associated with plasma lipid phenotypes.
