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Title: The PLIN4 variant rs8887 modulates obesity related phenotypes in humans through creation of a novel miR-522 seed site

Author
item Richardson, Kris
item LOUIE-GAO, QIONG - Boston University
item ARNETT, DONNA K. - University Of Alabama
item Parnell, Laurence
item Lai, Chao Qiang
item DAVALOS, ALBERTO - Non ARS Employee
item FOX, CAROLINE S. - Framingham Heart Study
item DEMISSIE, SERKALEM - Boston University
item CUPPLES, L. ADRIENNE - Boston University
item FERNANDEZ-HERNANDO, CARLOS - New York University
item ORDOVAS, JOSE M. - Jean Mayer Human Nutrition Research Center On Aging At Tufts University

Submitted to: PLoS ONE
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 2/16/2011
Publication Date: 4/20/2011
Citation: Richardson, K., Louie-Gao, Q., Arnett, D., Parnell, L.D., Lai, C., Davalos, A., Fox, C., Demissie, S., Cupples, L., Fernandez-Hernando, C., Ordovas, J. 2011. The PLIN4 variant rs8887 modulates obesity related phenotypes in humans through creation of a novel miR-522 seed site. PLoS One. 6(4):e17944.

Interpretive Summary: It has long been recognized that individuals may respond differently to similar dietary exposures. We investigated whether genetic variation in the human PLIN4 gene can modulate anthropometrics in response to dietary polyunsaturated fatty acids (PUFA). We identified a common variant, rs8887, in the PLIN4 gene that associates with a constellation of anthropometric traits. Furthermore, our gene-by-diet interaction analyses suggest rs8887 can modulate anthropometrics in response to dietary polyunsaturated fatty acid (PUFA) N3. The minor A allele of rs8887 creates a perfectly complementary binding site for the mammalian specific regulatory molecule, microRNA-522. Using laboratory techniques we demonstrate that rs8887 is able to bind and suppress PLIN4 levels through the microRNA-522 site. This is the first example of a human genetic variant creating a regulatory microRNA target site resulting in the modulation of obesity related traits. This work may help to enable health professionals to better tailor an effective weight-loss regimen based on a patients DNA profile.

Technical Abstract: PLIN4 is a member of the PAT family of lipid storage droplet (LSD) proteins. Associations between seven single nucleotide polymorphisms (SNPs) at human PLIN4 with obesity related phenotypes were investigated using meta-analysis followed by a determination if these phenotypes are modulated by interactions between PLIN4 SNPs and dietary PUFA. Samples consisted of subjects from two populations of European ancestry. We demonstrated association of rs8887 with anthropometrics. Meta-analysis demonstrated significant interactions between the rs8887 minor allele with PUFA n3 modulating anthropometrics. rs884164 showed interaction with both n3 and n6 PUFA modulating anthropometric and lipid phenotypes. In silico analysis of the PLIN4 3'UTR sequence surrounding the rs8887 minor A allele predicted a seed site for the human microRNA-522 (miR-522), suggesting a functional mechanism. Our data showed that a PLIN4 3'UTR luciferase reporter carrying the A allele of rs8887 was reduced in response to miR-522 mimics compared to the G allele. These results suggest variation at the PLIN4 locus, and its interaction with PUFA as a modulator of obesity related phenotypes, acts in part through creation of a miR-522 regulatory site.