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

Kris Richardson, Jennifer A. Nettleton, Noemi Rotllan, Toshiko Tanaka, Caren E. Smith, Chao Qiang Lai, Laurence D. Parnell, Yu Chi Lee, Jari Lahti, Rozenn N. Lemaitre, Ani Manichaikul, Margaux Keller, Vera Mikkilä, Julius Ngwa, Frank J A Van Rooij, Christie M. Ballentyne, Ingrid B. Borecki, L. Adrienne Cupples, Melissa Garcia, Albert HofmanLuigi Ferrucci, Dariush Mozaffarian, Mia Maria Perälä, Olli Raitakari, Russell P. Tracy, Donna K. Arnett, Stefania Bandinelli, Eric Boerwinkle, Johan G. Eriksson, Oscar H. Franco, Mika Kähönen, Michael Nalls, David S. Siscovick, Denise K. Houston, Bruce M. Psaty, Jorma Viikari, Jacqueline C M Witteman, Mark O. Goodarzi, Terho Lehtimäki, Yongmei Liu, M. Carola Zillikens, Yii Der I Chen, André G. Uitterlinden, Jerome I. Rotter, Carlos Fernandez-Hernando, Jose M. Ordovas

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)5-14
Number of pages10
JournalAmerican Journal of Human Genetics
Volume92
Issue number1
DOIs
StatePublished - Jan 10 2013
Externally publishedYes

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Lipoprotein Lipase
MicroRNAs
Genome-Wide Association Study
Seeds
Triglycerides
Alleles
Lipids
Unsaturated Fatty Acids
Meta-Analysis
Phenotype
Linkage Disequilibrium
3' Untranslated Regions
Luciferases
Lipid Metabolism
HDL Cholesterol
Single Nucleotide Polymorphism
Fatty Acids
human MIRN410 microRNA

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

Cite this

Gain-of-function lipoprotein lipase variant rs13702 modulates lipid traits through disruption of a MicroRNA-410 seed site. / Richardson, Kris; Nettleton, Jennifer A.; Rotllan, Noemi; Tanaka, Toshiko; Smith, Caren E.; Lai, Chao Qiang; Parnell, Laurence D.; Lee, Yu Chi; Lahti, Jari; Lemaitre, Rozenn N.; Manichaikul, Ani; Keller, Margaux; Mikkilä, Vera; Ngwa, Julius; Van Rooij, Frank J A; Ballentyne, Christie M.; Borecki, Ingrid B.; Cupples, L. Adrienne; Garcia, Melissa; Hofman, Albert; Ferrucci, Luigi; Mozaffarian, Dariush; Perälä, Mia Maria; Raitakari, Olli; Tracy, Russell P.; Arnett, Donna K.; Bandinelli, Stefania; Boerwinkle, Eric; Eriksson, Johan G.; Franco, Oscar H.; Kähönen, Mika; Nalls, Michael; Siscovick, David S.; Houston, Denise K.; Psaty, Bruce M.; Viikari, Jorma; Witteman, Jacqueline C M; Goodarzi, Mark O.; Lehtimäki, Terho; Liu, Yongmei; Zillikens, M. Carola; Chen, Yii Der I; Uitterlinden, André G.; Rotter, Jerome I.; Fernandez-Hernando, Carlos; Ordovas, Jose M.

In: American Journal of Human Genetics, Vol. 92, No. 1, 10.01.2013, p. 5-14.

Research output: Contribution to journalArticle

Richardson, K, Nettleton, JA, Rotllan, N, Tanaka, T, Smith, CE, Lai, CQ, Parnell, LD, Lee, YC, Lahti, J, Lemaitre, RN, Manichaikul, A, Keller, M, Mikkilä, V, Ngwa, J, Van Rooij, FJA, Ballentyne, CM, Borecki, IB, Cupples, LA, Garcia, M, Hofman, A, Ferrucci, L, Mozaffarian, D, Perälä, MM, 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, MC, Chen, YDI, Uitterlinden, AG, Rotter, JI, Fernandez-Hernando, C & Ordovas, JM 2013, 'Gain-of-function lipoprotein lipase variant rs13702 modulates lipid traits through disruption of a MicroRNA-410 seed site', American Journal of Human Genetics, vol. 92, no. 1, pp. 5-14. https://doi.org/10.1016/j.ajhg.2012.10.020
Richardson, Kris ; Nettleton, Jennifer A. ; Rotllan, Noemi ; Tanaka, Toshiko ; Smith, Caren E. ; Lai, Chao Qiang ; Parnell, Laurence D. ; Lee, Yu Chi ; Lahti, Jari ; Lemaitre, Rozenn N. ; Manichaikul, Ani ; Keller, Margaux ; Mikkilä, Vera ; Ngwa, Julius ; Van Rooij, Frank J A ; Ballentyne, Christie M. ; Borecki, Ingrid B. ; Cupples, L. Adrienne ; Garcia, Melissa ; Hofman, Albert ; Ferrucci, Luigi ; Mozaffarian, Dariush ; Perälä, Mia Maria ; Raitakari, Olli ; Tracy, Russell P. ; Arnett, Donna K. ; Bandinelli, Stefania ; Boerwinkle, Eric ; Eriksson, Johan G. ; Franco, Oscar H. ; Kähönen, Mika ; Nalls, Michael ; Siscovick, David S. ; Houston, Denise K. ; Psaty, Bruce M. ; Viikari, Jorma ; Witteman, Jacqueline C M ; Goodarzi, Mark O. ; Lehtimäki, Terho ; Liu, Yongmei ; Zillikens, M. Carola ; Chen, Yii Der I ; Uitterlinden, André G. ; Rotter, Jerome I. ; Fernandez-Hernando, Carlos ; Ordovas, Jose M. / Gain-of-function lipoprotein lipase variant rs13702 modulates lipid traits through disruption of a MicroRNA-410 seed site. In: American Journal of Human Genetics. 2013 ; Vol. 92, No. 1. pp. 5-14.
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T1 - Gain-of-function lipoprotein lipase variant rs13702 modulates lipid traits through disruption of a MicroRNA-410 seed site

AU - Richardson, Kris

AU - Nettleton, Jennifer A.

AU - Rotllan, Noemi

AU - Tanaka, Toshiko

AU - Smith, Caren E.

AU - Lai, Chao Qiang

AU - Parnell, Laurence D.

AU - Lee, Yu Chi

AU - Lahti, Jari

AU - Lemaitre, Rozenn N.

AU - Manichaikul, Ani

AU - Keller, Margaux

AU - Mikkilä, Vera

AU - Ngwa, Julius

AU - Van Rooij, Frank J A

AU - Ballentyne, Christie M.

AU - Borecki, Ingrid B.

AU - Cupples, L. Adrienne

AU - Garcia, Melissa

AU - Hofman, Albert

AU - Ferrucci, Luigi

AU - Mozaffarian, Dariush

AU - Perälä, Mia Maria

AU - Raitakari, Olli

AU - Tracy, Russell P.

AU - Arnett, Donna K.

AU - Bandinelli, Stefania

AU - Boerwinkle, Eric

AU - Eriksson, Johan G.

AU - Franco, Oscar H.

AU - Kähönen, Mika

AU - Nalls, Michael

AU - Siscovick, David S.

AU - Houston, Denise K.

AU - Psaty, Bruce M.

AU - Viikari, Jorma

AU - Witteman, Jacqueline C M

AU - Goodarzi, Mark O.

AU - Lehtimäki, Terho

AU - Liu, Yongmei

AU - Zillikens, M. Carola

AU - Chen, Yii Der I

AU - Uitterlinden, André G.

AU - Rotter, Jerome I.

AU - Fernandez-Hernando, Carlos

AU - Ordovas, Jose M.

PY - 2013/1/10

Y1 - 2013/1/10

N2 - 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.

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