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

Publication ,  Journal Article
Richardson, K; Nettleton, JA; Rotllan, N; Tanaka, T; Smith, CE; Lai, C-Q; Parnell, LD; Lee, Y-C; Lahti, J; Lemaitre, RN; Manichaikul, A ...
Published in: Am J Hum Genet
January 10, 2013

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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Published In

Am J Hum Genet

DOI

EISSN

1537-6605

Publication Date

January 10, 2013

Volume

92

Issue

1

Start / End Page

5 / 14

Location

United States

Related Subject Headings

  • Triglycerides
  • Polymorphism, Single Nucleotide
  • MicroRNAs
  • Lipoprotein Lipase
  • Lipids
  • Lipid Metabolism
  • Linkage Disequilibrium
  • Humans
  • Genetics & Heredity
  • Gene Expression Regulation
 

Citation

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Richardson, K., Nettleton, J. A., Rotllan, N., Tanaka, T., Smith, C. E., Lai, C.-Q., … Ordovas, J. M. (2013). Gain-of-function lipoprotein lipase variant rs13702 modulates lipid traits through disruption of a microRNA-410 seed site. Am J Hum Genet, 92(1), 5–14. https://doi.org/10.1016/j.ajhg.2012.10.020
Richardson, Kris, Jennifer A. Nettleton, Noemi Rotllan, Toshiko Tanaka, Caren E. Smith, Chao-Qiang Lai, Laurence D. Parnell, et al. “Gain-of-function lipoprotein lipase variant rs13702 modulates lipid traits through disruption of a microRNA-410 seed site.Am J Hum Genet 92, no. 1 (January 10, 2013): 5–14. https://doi.org/10.1016/j.ajhg.2012.10.020.
Richardson K, Nettleton JA, Rotllan N, Tanaka T, Smith CE, Lai C-Q, et al. Gain-of-function lipoprotein lipase variant rs13702 modulates lipid traits through disruption of a microRNA-410 seed site. Am J Hum Genet. 2013 Jan 10;92(1):5–14.
Richardson, Kris, et al. “Gain-of-function lipoprotein lipase variant rs13702 modulates lipid traits through disruption of a microRNA-410 seed site.Am J Hum Genet, vol. 92, no. 1, Jan. 2013, pp. 5–14. Pubmed, doi:10.1016/j.ajhg.2012.10.020.
Richardson 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, Ballentyne CM, Borecki IB, Cupples LA, 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 MC, Chen Y-DI, Uitterlinden AG, Rotter JI, Fernandez-Hernando C, Ordovas JM. Gain-of-function lipoprotein lipase variant rs13702 modulates lipid traits through disruption of a microRNA-410 seed site. Am J Hum Genet. 2013 Jan 10;92(1):5–14.
Journal cover image

Published In

Am J Hum Genet

DOI

EISSN

1537-6605

Publication Date

January 10, 2013

Volume

92

Issue

1

Start / End Page

5 / 14

Location

United States

Related Subject Headings

  • Triglycerides
  • Polymorphism, Single Nucleotide
  • MicroRNAs
  • Lipoprotein Lipase
  • Lipids
  • Lipid Metabolism
  • Linkage Disequilibrium
  • Humans
  • Genetics & Heredity
  • Gene Expression Regulation