on November 6, 2008
Published online before print November 6, 2008, doi: 10.1161/ATVBAHA.108.178533
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Submitted on July 29, 2008
Accepted on October 23, 2008
Galanin Preproprotein Is Associated With Elevated Plasma Triglycerides
Christopher L. Plaisier ;
From the Department of Human Genetics, David Geffen School of Medicine at UCLA (C.L.P., M.K., D.W.-V., J.S.S, A.H.-V., P.P.), the Departments of Biomathematics and Biostatistics (J.S.S.), University of California Los Angeles; Molecular Biology and Genomic Medicine Unit (L.R., S.R.-J., T.T.-L.), Department of Endocrinology and Metabolism (I.C.-B., C.A.-S.), and Surgery Division (M.F.H.), Instituto de Investigaciones Biomédicas de la UNAM, Instituto Nacional de Ciencias Médicas y Nutrición, Salvador Zubirán, Mexico City, Mexico; the Department of Medicine and Cardiovascular Research Institute Maastricht (T.W.A.B., C.J.H.K.), Academic Hospital Maastricht, Maastricht, The Netherlands; GlaxoSmithKline R&D (T.W.A.B), Durham, NC; the Department of Physiological Nursing, School of Nursing (B.E.A., C.R.P.), Institute for Human Genetics (B.E.A.), and Cardiovascular Research Institute (C.R.P., M.J.M., J.P.K.), University of California San Francisco; the Department of Medicine (J.K., M.L.), University of Kuopio and Kuopio University Hospital, Finland; and the Department of Medicine (M.-R.T.), Helsinki University Central Hospital, Finland.
* To whom correspondence should be addressed. E-mail: ppajukanta{at}mednet.ucla.edu.
Objective—There is increasing physiological evidence in rodents connecting the neuropeptide galanin to triglyceride (TG) levels. We hypothesized that variation in the galanin preproprotein (GAL) gene may contribute to hypertriglyceridemia (HTG) in humans.
Methods and Results—We investigated GAL as a TG candidate gene by genotyping 4 tagSNPs in Dutch, Finnish, and Mexican familial combined hyperlipidemia (FCHL) families as well as in white combined hyperlipidemia cases/controls (n=2471). The common allele of rs2187331, residing in the promoter region of GAL, was significantly associated with HTG (probability value=0.00038). In an unascertained population sample of 4463 Finnish males, the rare allele of rs2187331 was associated with higher TGs (probability value=0.0028 to 0.00016). We also observed an allele specific difference with rs2187331 in reporter gene expression and nuclear factor binding in vitro. Furthermore, we detected differential expression of many key lipid genes in adipose tissue based on rs2187331 genotypes.
Conclusions—The SNP rs2187331 is associated with HTG in FCHL and white combined hyperlipidemia cases/controls and influences TG levels in the population. Further studies are warranted to elucidate the allelic difference observed between FCHL and the general population. Functional evidence shows that rs2187331 has an allele specific cis-regulatory function and influences the expression of lipid related genes in adipose.