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


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.

SUBMITTER: Richardson K 

PROVIDER: S-EPMC3542456 | biostudies-literature | 2013 Jan

REPOSITORIES: biostudies-literature

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

Richardson Kris K   Nettleton Jennifer A JA   Rotllan Noemi N   Tanaka Toshiko T   Smith Caren E CE   Lai Chao-Qiang CQ   Parnell Laurence D LD   Lee Yu-Chi YC   Lahti Jari J   Lemaitre Rozenn N RN   Manichaikul Ani A   Keller Margaux M   Mikkilä Vera V   Ngwa Julius J   van Rooij Frank J A FJ   Ballentyne Christie M CM   Borecki Ingrid B IB   Cupples L Adrienne LA   Garcia Melissa M   Hofman Albert A   Ferrucci Luigi L   Mozaffarian Dariush D   Perälä Mia-Maria MM   Raitakari Olli O   Tracy Russell P RP   Arnett Donna K DK   Bandinelli Stefania S   Boerwinkle Eric E   Eriksson Johan G JG   Franco Oscar H OH   Kähönen Mika M   Nalls Michael M   Siscovick David S DS   Houston Denise K DK   Psaty Bruce M BM   Viikari Jorma J   Witteman Jacqueline C M JC   Goodarzi Mark O MO   Lehtimäki Terho T   Liu Yongmei Y   Zillikens M Carola MC   Chen Yii-Der I YD   Uitterlinden André G AG   Rotter Jerome I JI   Fernandez-Hernando Carlos C   Ordovas Jose M JM  

American journal of human genetics 20121213 1


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  ...[more]

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