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Gain-of-function lipoprotein lipase variant rs13702 modulates lipid traits through disruption of a microRNA-410 seed site.

TitleGain-of-function lipoprotein lipase variant rs13702 modulates lipid traits through disruption of a microRNA-410 seed site.
Publication TypeJournal Article
Year of Publication2013
AuthorsRichardson K, Nettleton JA, Rotllan N, Tanaka T, Smith CE, Lai C-Q, Parnell LD, Lee Y-C, Lahti J, Lemaitre RN, Manichaikul A, Keller M, Mikkilä V, Ngwa J, van Rooij FJA, Ballantyne CM, Borecki IB, L Cupples A, Garcia M, Hofman A, Ferrucci L, Mozaffarian D, Perälä M-M, Raitakari O, Tracy RP, Arnett DK, Bandinelli S, Boerwinkle E, Eriksson JG, Franco OH, Kähönen M, Nalls M, Siscovick DS, Houston DK, Psaty BM, Viikari J, Witteman JCM, Goodarzi MO, Lehtimäki T, Liu Y, Zillikens CM, Chen Y-DI, Uitterlinden AG, Rotter JI, Fernandez-Hernando C
Secondary AuthorsOrdovas JM
JournalAm J Hum Genet
Volume92
Issue1
Pagination5-14
Date Published2013 Jan 10
ISSN1537-6605
KeywordsCholesterol, HDL, Dietary Fats, Gene Expression Regulation, Humans, Linkage Disequilibrium, Lipid Metabolism, Lipids, Lipoprotein Lipase, MicroRNAs, Polymorphism, Single Nucleotide, Triglycerides
Abstract

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 × 10(-42)) and high-density lipoprotein cholesterol (HDL-C) (p = 1.35 × 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.

DOI10.1016/j.ajhg.2012.10.020
Alternate JournalAm J Hum Genet
PubMed ID23246289
PubMed Central IDPMC3542456
Grant ListR01 HL091357 / HL / NHLBI NIH HHS / United States
UL1 TR000124 / TR / NCATS NIH HHS / United States
R01 HL105756 / HL / NHLBI NIH HHS / United States
P30 DK063491 / DK / NIDDK NIH HHS / United States
U01 HL072524 / HL / NHLBI NIH HHS / United States
L60 MD003562 / MD / NIMHD NIH HHS / United States