Gain-of-Function Lipoprotein Lipase Variant rs13702 Modulates Lipid Traits through Disruption of a MicroRNA-410 Seed Site

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• 作者：Kris Richardson¹ ; ^{kris.richardson@ars.usda.gov} ; Jennifer A. Nettleton² ; Noemi Rotllan³ ; Toshiko Tanaka⁴ ; Caren E. Smith¹ ; Chao-Qiang Lai¹ ; Laurence D. Parnell¹ ; Yu-Chi Lee¹ ; Jari Lahti⁵ ; Rozenn N. Lemaitre⁶ ; Ani Manichaikul⁷ ; Margaux Keller⁸ ; ⁹ ; Vera Mikkil&auml ; ¹⁰ ; Julius Ngwa¹¹ ; Frank J.A. van Rooij¹² ; ¹³ ; Christie M. Ballentyne¹⁴ ; Ingrid B. Borecki¹⁵ ; L. Adrienne Cupples¹¹ ; ¹⁶ ; Melissa Garcia¹⁷ ; Albert Hofman¹² ; ¹³ ; Luigi Ferrucci⁴ ; Dariush Mozaffarian¹⁸ ; ¹⁹ ; Mia-Maria Per&auml ; l&auml ; ²⁰ ; Olli Raitakari²¹ ; Russell P. Tracy²² ; Donna K. Arnett²³ ; Stefania Bandinelli²⁴ ; Eric Boerwinkle² ; ²⁵ ; Johan G. Eriksson²⁶ ; ²⁷ ; ²⁸ ; ²⁹ ; Oscar H. Franco¹² ; ¹³ ; Mika K&auml ; h&ouml ; nen³⁰ ; Michael Nalls⁹ ; David S. Siscovick⁶ ; Denise K. Houston³¹ ; Bruce M. Psaty⁶ ; ³² ; Jorma Viikari³³ ; Jacqueline C.M. Witteman¹² ; ¹³ ; Mark O. Goodarzi³⁴ ; ³⁵ ; Terho Lehtim&auml ; ki³⁶ ; Yongmei Liu³¹ ; M. Carola Zillikens¹² ; ¹³ ; ³⁷ ; Yii-Der I. Chen³⁴ ; André ; G. Uitterlinden¹² ; ¹³ ; ³⁷ ; Jerome I. Rotter³⁴ ; Carlos Fernandez-Hernando³ ; Jose M. Ordovas¹ ; ³⁸ ; ³⁹
• 刊名：The American Journal of Human Genetics
• 出版年：2013
• 出版时间：10 January, 2013
• 年：2013
• 卷：92
• 期：1
• 页码：5-14
• 全文大小：444 K

文摘

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 (m>LPLm>) 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?¡Á 10^?42) and high-density lipoprotein cholesterol (HDL-C) (p = 1.35?¡Á 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 m>LPLm> 3¡ä 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 m>LPLm> by miR-410 in humans. This work provides biological and potential clinical relevance for previously reported GWAS variants associated with plasma lipid phenotypes.