title: Contribution of Rare and Common Genetic Variants to Plasma Lipid Levels and Carotid Stiffness and Geometry: A Substudy of the Paris Prospective Study 3.
abstract: BACKGROUND
  We assess the contribution of common and rare putatively functional genetic variants (most of them coding) present on the Illumina exome Beadchip to the variability of plasma lipids and stiffness of the common carotid artery.
  
  
  RESULTS
  Measurements were obtained from 2283 men and 1398 women, and after filtering and exclusion of monomorphic variants, 32,827 common (minor allele frequency >0.01) and 68,770 rare variants were analyzed. A large fraction of the heritability of plasma lipids is attributable to variants present on the array, especially for triglycerides (fraction of variance attributable to measured genotypes: V(G)/V(p)=31.4%, P<3.1×10(-11)) and high-density lipoprotein cholesterol (V(G)/V(p)=26.4%, P<4.2×10(-12)). Plasma lipids were associated with common variants located in known candidate genes, but no implication of rare variants could be established. Gene sets for plasma lipids, blood pressure, and coronary artery disease were defined on the basis of recent meta-analyses of genome-wide association studies. We observed a strong association between the plasma lipids gene set and plasma lipid variables, but none of the 3 genome-wide association studies gene sets was associated with the carotid parameters. Significant V(G)/V(p) ratios were observed for external (14.5%, P<2.7×10(-5)) and internal diameter (13.4%, P<4.3×10(-4)), stiffness (12.5%, P<8.0×10(-4)), intima-media thickness (10.6%, P<7.9×10(-4)), and wall cross-sectional area (13.2%, P<2.4×10(-5)). A significant association was observed between the common rs2903692 polymorphism of the CLEC16A gene and the internal diameter (P<4.3×10(-7)).
  
  
  CONCLUSIONS
  These results suggest an involvement of CLEC16A, a gene that has been reported to be associated with immune disorders, in the modulation of carotid vasodilatation.
authors.affiliation: From the Inserm, UMR_S 1166 (C.P., G.E., U.E., F.C.), CNRS UMR 7190 (P.C.), and CNRS, UMR 8256 (Z.L.), Sorbonne Universités, UPMC Univ Paris 06; Inserm, UMR_S 970, Sorbonne Paris Cité (J.-P.E., P.B., M.A., G.E., S.L., X.J.); Department of Cardiology, European Hospital of Georges Pompidou, Université Paris Descartes (N.D.); Centre d'Investigations Préventives et Cliniques (IPC Center), Paris, France (B.P., F.T.); and Inserm, UMR_S 1116; Université de Lorraine, Nancy, France (V.R., P.L.).
authors.forename: Carole
authors.initials: C
authors.lastname: Proust
authors.affiliation: From the Inserm, UMR_S 1166 (C.P., G.E., U.E., F.C.), CNRS UMR 7190 (P.C.), and CNRS, UMR 8256 (Z.L.), Sorbonne Universités, UPMC Univ Paris 06; Inserm, UMR_S 970, Sorbonne Paris Cité (J.-P.E., P.B., M.A., G.E., S.L., X.J.); Department of Cardiology, European Hospital of Georges Pompidou, Université Paris Descartes (N.D.); Centre d'Investigations Préventives et Cliniques (IPC Center), Paris, France (B.P., F.T.); and Inserm, UMR_S 1116; Université de Lorraine, Nancy, France (V.R., P.L.).
authors.forename: Jean-Philippe
authors.initials: JP
authors.lastname: Empana
authors.affiliation: From the Inserm, UMR_S 1166 (C.P., G.E., U.E., F.C.), CNRS UMR 7190 (P.C.), and CNRS, UMR 8256 (Z.L.), Sorbonne Universités, UPMC Univ Paris 06; Inserm, UMR_S 970, Sorbonne Paris Cité (J.-P.E., P.B., M.A., G.E., S.L., X.J.); Department of Cardiology, European Hospital of Georges Pompidou, Université Paris Descartes (N.D.); Centre d'Investigations Préventives et Cliniques (IPC Center), Paris, France (B.P., F.T.); and Inserm, UMR_S 1116; Université de Lorraine, Nancy, France (V.R., P.L.).
authors.forename: Pierre
authors.initials: P
authors.lastname: Boutouyrie
authors.affiliation: From the Inserm, UMR_S 1166 (C.P., G.E., U.E., F.C.), CNRS UMR 7190 (P.C.), and CNRS, UMR 8256 (Z.L.), Sorbonne Universités, UPMC Univ Paris 06; Inserm, UMR_S 970, Sorbonne Paris Cité (J.-P.E., P.B., M.A., G.E., S.L., X.J.); Department of Cardiology, European Hospital of Georges Pompidou, Université Paris Descartes (N.D.); Centre d'Investigations Préventives et Cliniques (IPC Center), Paris, France (B.P., F.T.); and Inserm, UMR_S 1116; Université de Lorraine, Nancy, France (V.R., P.L.).
authors.forename: Maureen
authors.initials: M
authors.lastname: Alivon
authors.affiliation: From the Inserm, UMR_S 1166 (C.P., G.E., U.E., F.C.), CNRS UMR 7190 (P.C.), and CNRS, UMR 8256 (Z.L.), Sorbonne Universités, UPMC Univ Paris 06; Inserm, UMR_S 970, Sorbonne Paris Cité (J.-P.E., P.B., M.A., G.E., S.L., X.J.); Department of Cardiology, European Hospital of Georges Pompidou, Université Paris Descartes (N.D.); Centre d'Investigations Préventives et Cliniques (IPC Center), Paris, France (B.P., F.T.); and Inserm, UMR_S 1116; Université de Lorraine, Nancy, France (V.R., P.L.).
authors.forename: Pascal
authors.initials: P
authors.lastname: Challande
authors.affiliation: From the Inserm, UMR_S 1166 (C.P., G.E., U.E., F.C.), CNRS UMR 7190 (P.C.), and CNRS, UMR 8256 (Z.L.), Sorbonne Universités, UPMC Univ Paris 06; Inserm, UMR_S 970, Sorbonne Paris Cité (J.-P.E., P.B., M.A., G.E., S.L., X.J.); Department of Cardiology, European Hospital of Georges Pompidou, Université Paris Descartes (N.D.); Centre d'Investigations Préventives et Cliniques (IPC Center), Paris, France (B.P., F.T.); and Inserm, UMR_S 1116; Université de Lorraine, Nancy, France (V.R., P.L.).
authors.forename: Nicolas
authors.initials: N
authors.lastname: Danchin
authors.affiliation: From the Inserm, UMR_S 1166 (C.P., G.E., U.E., F.C.), CNRS UMR 7190 (P.C.), and CNRS, UMR 8256 (Z.L.), Sorbonne Universités, UPMC Univ Paris 06; Inserm, UMR_S 970, Sorbonne Paris Cité (J.-P.E., P.B., M.A., G.E., S.L., X.J.); Department of Cardiology, European Hospital of Georges Pompidou, Université Paris Descartes (N.D.); Centre d'Investigations Préventives et Cliniques (IPC Center), Paris, France (B.P., F.T.); and Inserm, UMR_S 1116; Université de Lorraine, Nancy, France (V.R., P.L.).
authors.forename: Guillaume
authors.initials: G
authors.lastname: Escriou
authors.affiliation: From the Inserm, UMR_S 1166 (C.P., G.E., U.E., F.C.), CNRS UMR 7190 (P.C.), and CNRS, UMR 8256 (Z.L.), Sorbonne Universités, UPMC Univ Paris 06; Inserm, UMR_S 970, Sorbonne Paris Cité (J.-P.E., P.B., M.A., G.E., S.L., X.J.); Department of Cardiology, European Hospital of Georges Pompidou, Université Paris Descartes (N.D.); Centre d'Investigations Préventives et Cliniques (IPC Center), Paris, France (B.P., F.T.); and Inserm, UMR_S 1116; Université de Lorraine, Nancy, France (V.R., P.L.).
authors.forename: Ulrike
authors.initials: U
authors.lastname: Esslinger
authors.affiliation: From the Inserm, UMR_S 1166 (C.P., G.E., U.E., F.C.), CNRS UMR 7190 (P.C.), and CNRS, UMR 8256 (Z.L.), Sorbonne Universités, UPMC Univ Paris 06; Inserm, UMR_S 970, Sorbonne Paris Cité (J.-P.E., P.B., M.A., G.E., S.L., X.J.); Department of Cardiology, European Hospital of Georges Pompidou, Université Paris Descartes (N.D.); Centre d'Investigations Préventives et Cliniques (IPC Center), Paris, France (B.P., F.T.); and Inserm, UMR_S 1116; Université de Lorraine, Nancy, France (V.R., P.L.).
authors.forename: Stéphane
authors.initials: S
authors.lastname: Laurent
authors.affiliation: From the Inserm, UMR_S 1166 (C.P., G.E., U.E., F.C.), CNRS UMR 7190 (P.C.), and CNRS, UMR 8256 (Z.L.), Sorbonne Universités, UPMC Univ Paris 06; Inserm, UMR_S 970, Sorbonne Paris Cité (J.-P.E., P.B., M.A., G.E., S.L., X.J.); Department of Cardiology, European Hospital of Georges Pompidou, Université Paris Descartes (N.D.); Centre d'Investigations Préventives et Cliniques (IPC Center), Paris, France (B.P., F.T.); and Inserm, UMR_S 1116; Université de Lorraine, Nancy, France (V.R., P.L.).
authors.forename: Zhenlin
authors.initials: Z
authors.lastname: Li
authors.affiliation: From the Inserm, UMR_S 1166 (C.P., G.E., U.E., F.C.), CNRS UMR 7190 (P.C.), and CNRS, UMR 8256 (Z.L.), Sorbonne Universités, UPMC Univ Paris 06; Inserm, UMR_S 970, Sorbonne Paris Cité (J.-P.E., P.B., M.A., G.E., S.L., X.J.); Department of Cardiology, European Hospital of Georges Pompidou, Université Paris Descartes (N.D.); Centre d'Investigations Préventives et Cliniques (IPC Center), Paris, France (B.P., F.T.); and Inserm, UMR_S 1116; Université de Lorraine, Nancy, France (V.R., P.L.).
authors.forename: Bruno
authors.initials: B
authors.lastname: Pannier
authors.affiliation: From the Inserm, UMR_S 1166 (C.P., G.E., U.E., F.C.), CNRS UMR 7190 (P.C.), and CNRS, UMR 8256 (Z.L.), Sorbonne Universités, UPMC Univ Paris 06; Inserm, UMR_S 970, Sorbonne Paris Cité (J.-P.E., P.B., M.A., G.E., S.L., X.J.); Department of Cardiology, European Hospital of Georges Pompidou, Université Paris Descartes (N.D.); Centre d'Investigations Préventives et Cliniques (IPC Center), Paris, France (B.P., F.T.); and Inserm, UMR_S 1116; Université de Lorraine, Nancy, France (V.R., P.L.).
authors.forename: Veronique
authors.initials: V
authors.lastname: Regnault
authors.affiliation: From the Inserm, UMR_S 1166 (C.P., G.E., U.E., F.C.), CNRS UMR 7190 (P.C.), and CNRS, UMR 8256 (Z.L.), Sorbonne Universités, UPMC Univ Paris 06; Inserm, UMR_S 970, Sorbonne Paris Cité (J.-P.E., P.B., M.A., G.E., S.L., X.J.); Department of Cardiology, European Hospital of Georges Pompidou, Université Paris Descartes (N.D.); Centre d'Investigations Préventives et Cliniques (IPC Center), Paris, France (B.P., F.T.); and Inserm, UMR_S 1116; Université de Lorraine, Nancy, France (V.R., P.L.).
authors.forename: Frederique
authors.initials: F
authors.lastname: Thomas
authors.affiliation: From the Inserm, UMR_S 1166 (C.P., G.E., U.E., F.C.), CNRS UMR 7190 (P.C.), and CNRS, UMR 8256 (Z.L.), Sorbonne Universités, UPMC Univ Paris 06; Inserm, UMR_S 970, Sorbonne Paris Cité (J.-P.E., P.B., M.A., G.E., S.L., X.J.); Department of Cardiology, European Hospital of Georges Pompidou, Université Paris Descartes (N.D.); Centre d'Investigations Préventives et Cliniques (IPC Center), Paris, France (B.P., F.T.); and Inserm, UMR_S 1116; Université de Lorraine, Nancy, France (V.R., P.L.).
authors.forename: Xavier
authors.initials: X
authors.lastname: Jouven
authors.affiliation: From the Inserm, UMR_S 1166 (C.P., G.E., U.E., F.C.), CNRS UMR 7190 (P.C.), and CNRS, UMR 8256 (Z.L.), Sorbonne Universités, UPMC Univ Paris 06; Inserm, UMR_S 970, Sorbonne Paris Cité (J.-P.E., P.B., M.A., G.E., S.L., X.J.); Department of Cardiology, European Hospital of Georges Pompidou, Université Paris Descartes (N.D.); Centre d'Investigations Préventives et Cliniques (IPC Center), Paris, France (B.P., F.T.); and Inserm, UMR_S 1116; Université de Lorraine, Nancy, France (V.R., P.L.).
authors.forename: François
authors.initials: F
authors.lastname: Cambien
authors.affiliation: From the Inserm, UMR_S 1166 (C.P., G.E., U.E., F.C.), CNRS UMR 7190 (P.C.), and CNRS, UMR 8256 (Z.L.), Sorbonne Universités, UPMC Univ Paris 06; Inserm, UMR_S 970, Sorbonne Paris Cité (J.-P.E., P.B., M.A., G.E., S.L., X.J.); Department of Cardiology, European Hospital of Georges Pompidou, Université Paris Descartes (N.D.); Centre d'Investigations Préventives et Cliniques (IPC Center), Paris, France (B.P., F.T.); and Inserm, UMR_S 1116; Université de Lorraine, Nancy, France (V.R., P.L.). patrick.lacolley@inserm.fr.
authors.forename: Patrick
authors.initials: P
authors.lastname: Lacolley
mesh_terms: D000368:Aged; D017536:Carotid Artery, Common / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D059168:Carotid Intima-Media Thickness; D008076:Cholesterol, HDL / Q000097:blood; D003324:Coronary Artery Disease / Q000235:genetics / Q000503:physiopathology; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D014644:Genetic Variation; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D037181:Lectins, C-Type / Q000235:genetics; D008055:Lipids / Q000097:blood*; D008297:Male; D008875:Middle Aged; D009004:Monosaccharide Transport Proteins / Q000235:genetics; D010297:Paris; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D011446:Prospective Studies; D014280:Triglycerides / Q000097:blood; D059289:Vascular Stiffness / Q000235:genetics*
chemical_list: C522505:CLEC16A protein, human; D008076:Cholesterol, HDL; D037181:Lectins, C-Type; D008055:Lipids; D009004:Monosaccharide Transport Proteins; D014280:Triglycerides
keywords: exome; genetic hypertension; heritability; lipids; wall thickness