title: Molecular Characterization of the Lipid Genome-Wide Association Study Signal on Chromosome 18q11.2 Implicates HNF4A-Mediated Regulation of the TMEM241 Gene.
abstract: We recently identified a locus on chromosome 18q11.2 for high serum triglycerides in Mexicans. We hypothesize that the lead genome-wide association study single-nucleotide polymorphism rs9949617, or its linkage disequilibrium proxies, regulates 1 of the 5 genes in the triglyceride-associated region.
  
  
  
  We performed a linkage disequilibrium analysis and found 9 additional variants in linkage disequilibrium (r(2)>0.7) with the lead single-nucleotide polymorphism. To select the variants for functional analyses, we annotated the 10 variants using DNase I hypersensitive sites, transcription factor and chromatin states and identified rs17259126 as the lead candidate variant for functional in vitro validation. Using luciferase transcriptional reporter assay in liver HepG2 cells, we found that the G allele exhibits a significantly lower effect on transcription (P<0.05). The electrophoretic mobility shift and ChIPqPCR (chromatin immunoprecipitation coupled with quantitative polymerase chain reaction) assays confirmed that the minor G allele of rs17259126 disrupts an hepatocyte nuclear factor 4 α-binding site. To find the regional candidate gene, we performed a local expression quantitative trait locus analysis and found that rs17259126 and its linkage disequilibrium proxies alter expression of the regional transmembrane protein 241 (TMEM241) gene in 795 adipose RNAs from the Metabolic Syndrome In Men (METSIM) cohort (P=6.11×10(-07)-5.80×10(-04)). These results were replicated in expression profiles of TMEM241 from the Multiple Tissue Human Expression Resource (MuTHER; n=856).
  
  
  
  The Mexican genome-wide association study signal for high serum triglycerides on chromosome 18q11.2 harbors a regulatory single-nucleotide polymorphism, rs17259126, which disrupts normal hepatocyte nuclear factor 4 α binding and decreases the expression of the regional TMEM241 gene. Our data suggest that decreased transcript levels of TMEM241 contribute to increased triglyceride levels in Mexicans.
authors.affiliation: From the Department of Human Genetics, David Geffen School of Medicine (A.R., L.G., A.K., M.A., Z.M., Y.B., E.N., P.P.), Molecular Biology Institute (A.K., P.P.), and Bioinformatics Interdepartmental Program (P.P.), University of California, Los Angeles; Instituto Nacional de Ciencias Médicas y Nutrición, Salvador Zubiran, Mexico City, Mexico (I.C.-B., O.A.-C., L.L.M.-H., M.-L. O.-S., R.R.-G., T.T.-L., C.A.A.-S.); Department of Genetics, University of North Carolina, Chapel Hill (K.L.M.); Department of Medicine, University of Eastern Finland and Kuopio University Hospital (M.L.); and Instituto de Investigaciones Biomédicas de la UNAM, Mexico City, Mexico (T.T.-L.).
authors.forename: Alejandra
authors.initials: A
authors.lastname: Rodríguez
authors.affiliation: From the Department of Human Genetics, David Geffen School of Medicine (A.R., L.G., A.K., M.A., Z.M., Y.B., E.N., P.P.), Molecular Biology Institute (A.K., P.P.), and Bioinformatics Interdepartmental Program (P.P.), University of California, Los Angeles; Instituto Nacional de Ciencias Médicas y Nutrición, Salvador Zubiran, Mexico City, Mexico (I.C.-B., O.A.-C., L.L.M.-H., M.-L. O.-S., R.R.-G., T.T.-L., C.A.A.-S.); Department of Genetics, University of North Carolina, Chapel Hill (K.L.M.); Department of Medicine, University of Eastern Finland and Kuopio University Hospital (M.L.); and Instituto de Investigaciones Biomédicas de la UNAM, Mexico City, Mexico (T.T.-L.).
authors.forename: Luis
authors.initials: L
authors.lastname: Gonzalez
authors.affiliation: From the Department of Human Genetics, David Geffen School of Medicine (A.R., L.G., A.K., M.A., Z.M., Y.B., E.N., P.P.), Molecular Biology Institute (A.K., P.P.), and Bioinformatics Interdepartmental Program (P.P.), University of California, Los Angeles; Instituto Nacional de Ciencias Médicas y Nutrición, Salvador Zubiran, Mexico City, Mexico (I.C.-B., O.A.-C., L.L.M.-H., M.-L. O.-S., R.R.-G., T.T.-L., C.A.A.-S.); Department of Genetics, University of North Carolina, Chapel Hill (K.L.M.); Department of Medicine, University of Eastern Finland and Kuopio University Hospital (M.L.); and Instituto de Investigaciones Biomédicas de la UNAM, Mexico City, Mexico (T.T.-L.).
authors.forename: Arthur
authors.initials: A
authors.lastname: Ko
authors.affiliation: From the Department of Human Genetics, David Geffen School of Medicine (A.R., L.G., A.K., M.A., Z.M., Y.B., E.N., P.P.), Molecular Biology Institute (A.K., P.P.), and Bioinformatics Interdepartmental Program (P.P.), University of California, Los Angeles; Instituto Nacional de Ciencias Médicas y Nutrición, Salvador Zubiran, Mexico City, Mexico (I.C.-B., O.A.-C., L.L.M.-H., M.-L. O.-S., R.R.-G., T.T.-L., C.A.A.-S.); Department of Genetics, University of North Carolina, Chapel Hill (K.L.M.); Department of Medicine, University of Eastern Finland and Kuopio University Hospital (M.L.); and Instituto de Investigaciones Biomédicas de la UNAM, Mexico City, Mexico (T.T.-L.).
authors.forename: Marcus
authors.initials: M
authors.lastname: Alvarez
authors.affiliation: From the Department of Human Genetics, David Geffen School of Medicine (A.R., L.G., A.K., M.A., Z.M., Y.B., E.N., P.P.), Molecular Biology Institute (A.K., P.P.), and Bioinformatics Interdepartmental Program (P.P.), University of California, Los Angeles; Instituto Nacional de Ciencias Médicas y Nutrición, Salvador Zubiran, Mexico City, Mexico (I.C.-B., O.A.-C., L.L.M.-H., M.-L. O.-S., R.R.-G., T.T.-L., C.A.A.-S.); Department of Genetics, University of North Carolina, Chapel Hill (K.L.M.); Department of Medicine, University of Eastern Finland and Kuopio University Hospital (M.L.); and Instituto de Investigaciones Biomédicas de la UNAM, Mexico City, Mexico (T.T.-L.).
authors.forename: Zong
authors.initials: Z
authors.lastname: Miao
authors.affiliation: From the Department of Human Genetics, David Geffen School of Medicine (A.R., L.G., A.K., M.A., Z.M., Y.B., E.N., P.P.), Molecular Biology Institute (A.K., P.P.), and Bioinformatics Interdepartmental Program (P.P.), University of California, Los Angeles; Instituto Nacional de Ciencias Médicas y Nutrición, Salvador Zubiran, Mexico City, Mexico (I.C.-B., O.A.-C., L.L.M.-H., M.-L. O.-S., R.R.-G., T.T.-L., C.A.A.-S.); Department of Genetics, University of North Carolina, Chapel Hill (K.L.M.); Department of Medicine, University of Eastern Finland and Kuopio University Hospital (M.L.); and Instituto de Investigaciones Biomédicas de la UNAM, Mexico City, Mexico (T.T.-L.).
authors.forename: Yash
authors.initials: Y
authors.lastname: Bhagat
authors.affiliation: From the Department of Human Genetics, David Geffen School of Medicine (A.R., L.G., A.K., M.A., Z.M., Y.B., E.N., P.P.), Molecular Biology Institute (A.K., P.P.), and Bioinformatics Interdepartmental Program (P.P.), University of California, Los Angeles; Instituto Nacional de Ciencias Médicas y Nutrición, Salvador Zubiran, Mexico City, Mexico (I.C.-B., O.A.-C., L.L.M.-H., M.-L. O.-S., R.R.-G., T.T.-L., C.A.A.-S.); Department of Genetics, University of North Carolina, Chapel Hill (K.L.M.); Department of Medicine, University of Eastern Finland and Kuopio University Hospital (M.L.); and Instituto de Investigaciones Biomédicas de la UNAM, Mexico City, Mexico (T.T.-L.).
authors.forename: Elina
authors.initials: E
authors.lastname: Nikkola
authors.affiliation: From the Department of Human Genetics, David Geffen School of Medicine (A.R., L.G., A.K., M.A., Z.M., Y.B., E.N., P.P.), Molecular Biology Institute (A.K., P.P.), and Bioinformatics Interdepartmental Program (P.P.), University of California, Los Angeles; Instituto Nacional de Ciencias Médicas y Nutrición, Salvador Zubiran, Mexico City, Mexico (I.C.-B., O.A.-C., L.L.M.-H., M.-L. O.-S., R.R.-G., T.T.-L., C.A.A.-S.); Department of Genetics, University of North Carolina, Chapel Hill (K.L.M.); Department of Medicine, University of Eastern Finland and Kuopio University Hospital (M.L.); and Instituto de Investigaciones Biomédicas de la UNAM, Mexico City, Mexico (T.T.-L.).
authors.forename: Ivette
authors.initials: I
authors.lastname: Cruz-Bautista
authors.affiliation: From the Department of Human Genetics, David Geffen School of Medicine (A.R., L.G., A.K., M.A., Z.M., Y.B., E.N., P.P.), Molecular Biology Institute (A.K., P.P.), and Bioinformatics Interdepartmental Program (P.P.), University of California, Los Angeles; Instituto Nacional de Ciencias Médicas y Nutrición, Salvador Zubiran, Mexico City, Mexico (I.C.-B., O.A.-C., L.L.M.-H., M.-L. O.-S., R.R.-G., T.T.-L., C.A.A.-S.); Department of Genetics, University of North Carolina, Chapel Hill (K.L.M.); Department of Medicine, University of Eastern Finland and Kuopio University Hospital (M.L.); and Instituto de Investigaciones Biomédicas de la UNAM, Mexico City, Mexico (T.T.-L.).
authors.forename: Olimpia
authors.initials: O
authors.lastname: Arellano-Campos
authors.affiliation: From the Department of Human Genetics, David Geffen School of Medicine (A.R., L.G., A.K., M.A., Z.M., Y.B., E.N., P.P.), Molecular Biology Institute (A.K., P.P.), and Bioinformatics Interdepartmental Program (P.P.), University of California, Los Angeles; Instituto Nacional de Ciencias Médicas y Nutrición, Salvador Zubiran, Mexico City, Mexico (I.C.-B., O.A.-C., L.L.M.-H., M.-L. O.-S., R.R.-G., T.T.-L., C.A.A.-S.); Department of Genetics, University of North Carolina, Chapel Hill (K.L.M.); Department of Medicine, University of Eastern Finland and Kuopio University Hospital (M.L.); and Instituto de Investigaciones Biomédicas de la UNAM, Mexico City, Mexico (T.T.-L.).
authors.forename: Linda L
authors.initials: LL
authors.lastname: Muñoz-Hernández
authors.affiliation: From the Department of Human Genetics, David Geffen School of Medicine (A.R., L.G., A.K., M.A., Z.M., Y.B., E.N., P.P.), Molecular Biology Institute (A.K., P.P.), and Bioinformatics Interdepartmental Program (P.P.), University of California, Los Angeles; Instituto Nacional de Ciencias Médicas y Nutrición, Salvador Zubiran, Mexico City, Mexico (I.C.-B., O.A.-C., L.L.M.-H., M.-L. O.-S., R.R.-G., T.T.-L., C.A.A.-S.); Department of Genetics, University of North Carolina, Chapel Hill (K.L.M.); Department of Medicine, University of Eastern Finland and Kuopio University Hospital (M.L.); and Instituto de Investigaciones Biomédicas de la UNAM, Mexico City, Mexico (T.T.-L.).
authors.forename: Maria-Luisa
authors.initials: ML
authors.lastname: Ordóñez-Sánchez
authors.affiliation: From the Department of Human Genetics, David Geffen School of Medicine (A.R., L.G., A.K., M.A., Z.M., Y.B., E.N., P.P.), Molecular Biology Institute (A.K., P.P.), and Bioinformatics Interdepartmental Program (P.P.), University of California, Los Angeles; Instituto Nacional de Ciencias Médicas y Nutrición, Salvador Zubiran, Mexico City, Mexico (I.C.-B., O.A.-C., L.L.M.-H., M.-L. O.-S., R.R.-G., T.T.-L., C.A.A.-S.); Department of Genetics, University of North Carolina, Chapel Hill (K.L.M.); Department of Medicine, University of Eastern Finland and Kuopio University Hospital (M.L.); and Instituto de Investigaciones Biomédicas de la UNAM, Mexico City, Mexico (T.T.-L.).
authors.forename: Rosario
authors.initials: R
authors.lastname: Rodriguez-Guillen
authors.affiliation: From the Department of Human Genetics, David Geffen School of Medicine (A.R., L.G., A.K., M.A., Z.M., Y.B., E.N., P.P.), Molecular Biology Institute (A.K., P.P.), and Bioinformatics Interdepartmental Program (P.P.), University of California, Los Angeles; Instituto Nacional de Ciencias Médicas y Nutrición, Salvador Zubiran, Mexico City, Mexico (I.C.-B., O.A.-C., L.L.M.-H., M.-L. O.-S., R.R.-G., T.T.-L., C.A.A.-S.); Department of Genetics, University of North Carolina, Chapel Hill (K.L.M.); Department of Medicine, University of Eastern Finland and Kuopio University Hospital (M.L.); and Instituto de Investigaciones Biomédicas de la UNAM, Mexico City, Mexico (T.T.-L.).
authors.forename: Karen L
authors.initials: KL
authors.lastname: Mohlke
authors.affiliation: From the Department of Human Genetics, David Geffen School of Medicine (A.R., L.G., A.K., M.A., Z.M., Y.B., E.N., P.P.), Molecular Biology Institute (A.K., P.P.), and Bioinformatics Interdepartmental Program (P.P.), University of California, Los Angeles; Instituto Nacional de Ciencias Médicas y Nutrición, Salvador Zubiran, Mexico City, Mexico (I.C.-B., O.A.-C., L.L.M.-H., M.-L. O.-S., R.R.-G., T.T.-L., C.A.A.-S.); Department of Genetics, University of North Carolina, Chapel Hill (K.L.M.); Department of Medicine, University of Eastern Finland and Kuopio University Hospital (M.L.); and Instituto de Investigaciones Biomédicas de la UNAM, Mexico City, Mexico (T.T.-L.).
authors.forename: Markku
authors.initials: M
authors.lastname: Laakso
authors.affiliation: From the Department of Human Genetics, David Geffen School of Medicine (A.R., L.G., A.K., M.A., Z.M., Y.B., E.N., P.P.), Molecular Biology Institute (A.K., P.P.), and Bioinformatics Interdepartmental Program (P.P.), University of California, Los Angeles; Instituto Nacional de Ciencias Médicas y Nutrición, Salvador Zubiran, Mexico City, Mexico (I.C.-B., O.A.-C., L.L.M.-H., M.-L. O.-S., R.R.-G., T.T.-L., C.A.A.-S.); Department of Genetics, University of North Carolina, Chapel Hill (K.L.M.); Department of Medicine, University of Eastern Finland and Kuopio University Hospital (M.L.); and Instituto de Investigaciones Biomédicas de la UNAM, Mexico City, Mexico (T.T.-L.).
authors.forename: Teresa
authors.initials: T
authors.lastname: Tusie-Luna
authors.affiliation: From the Department of Human Genetics, David Geffen School of Medicine (A.R., L.G., A.K., M.A., Z.M., Y.B., E.N., P.P.), Molecular Biology Institute (A.K., P.P.), and Bioinformatics Interdepartmental Program (P.P.), University of California, Los Angeles; Instituto Nacional de Ciencias Médicas y Nutrición, Salvador Zubiran, Mexico City, Mexico (I.C.-B., O.A.-C., L.L.M.-H., M.-L. O.-S., R.R.-G., T.T.-L., C.A.A.-S.); Department of Genetics, University of North Carolina, Chapel Hill (K.L.M.); Department of Medicine, University of Eastern Finland and Kuopio University Hospital (M.L.); and Instituto de Investigaciones Biomédicas de la UNAM, Mexico City, Mexico (T.T.-L.).
authors.forename: Carlos A
authors.initials: CA
authors.lastname: Aguilar-Salinas
authors.affiliation: From the Department of Human Genetics, David Geffen School of Medicine (A.R., L.G., A.K., M.A., Z.M., Y.B., E.N., P.P.), Molecular Biology Institute (A.K., P.P.), and Bioinformatics Interdepartmental Program (P.P.), University of California, Los Angeles; Instituto Nacional de Ciencias Médicas y Nutrición, Salvador Zubiran, Mexico City, Mexico (I.C.-B., O.A.-C., L.L.M.-H., M.-L. O.-S., R.R.-G., T.T.-L., C.A.A.-S.); Department of Genetics, University of North Carolina, Chapel Hill (K.L.M.); Department of Medicine, University of Eastern Finland and Kuopio University Hospital (M.L.); and Instituto de Investigaciones Biomédicas de la UNAM, Mexico City, Mexico (T.T.-L.). ppajukanta@mednet.ucla.edu.
authors.forename: Päivi
authors.initials: P
authors.lastname: Pajukanta
mesh_terms: D000368:Aged; D001665:Binding Sites; D002887:Chromosomes, Human, Pair 18; D005387:Finland; D017930:Genes, Reporter; D005819:Genetic Markers; D055106:Genome-Wide Association Study; D005838:Genotype; D056945:Hep G2 Cells; D051557:Hepatocyte Nuclear Factor 4 / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D015810:Linkage Disequilibrium; D050356:Lipid Metabolism / Q000235:genetics*; D008297:Male; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism; D008800:Mexico; D008875:Middle Aged; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D040641:Quantitative Trait Loci; D014158:Transcription, Genetic; D014162:Transfection; D014280:Triglycerides / Q000097:blood*; D014481:United States; D015854:Up-Regulation
chemical_list: D005819:Genetic Markers; C496592:HNF4A protein, human; D051557:Hepatocyte Nuclear Factor 4; D008565:Membrane Proteins; C000620514:TMEM241 protein, human; D014280:Triglycerides
keywords: chromatin; dyslipidemias; functional genomics; gene expression and regulation; genome-wide association study; mechanisms; triglycerides