Contribution of rare and common genetic variants to plasma lipid levels and carotid stiffness and geometry – a substudy of the Paris Prospective Study 3 Short title: Genetic variants and carotid stiffness

Carole Proust (1) , Jean-Philippe Empana (2) , Pierre Boutouyrie (2) , Maureen Alivon (2) , Pascal Challande (3) , Nicolas Danchin (4) , Guillaume Escriou (1, 2) , Ulrike Esslinger (1) , Stéphane Laurent (2) , Zhenlin Li (5) , Bruno Pannier (6) , Veronique Regnault (7) , Frederique Thomas (6) , Xavier Jouven (2) , François Cambien (1) , Patrick Lacolley (7)

1 ICAN - Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Research Unit on Cardiovascular and Metabolic Diseases
2 PARCC - UMR-S U970 - Paris-Centre de Recherche Cardiovasculaire
3 DALEMBERT - Institut Jean Le Rond d'Alembert
4 HEGP - Hôpital Européen Georges Pompidou [APHP]
5 B2A - Adaptation Biologique et Vieillissement = Biological Adaptation and Ageing
6 CIPC - Centre d'Investigations Préventives et Cliniques
7 DCAC - Défaillance Cardiovasculaire Aiguë et Chronique

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. Methods and results: Measurements were obtained from 2283 men and 1398 women, and after filtering and exclusion of monomorphic variants, 32827 common (minor allele frequency >0.01) and 68770 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)/Vp=31.4%, P<3.1×10-11) and HDLc (V(G)/Vp=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, however this study had limited power to detect an effect of rare variants at the gene level. 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 (GWAS). We observed a strong association between the plasma lipids gene-set and plasma lipid variables but none of the 3 GWAS gene-sets was associated with the carotid parameters. Significant V(G)/Vp 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). Conclusion: 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.

Mots clés: exome; genetic hypertension; heritability; lipids; wall thickness

Domaines: Génétique humaine; Cardiologie et système cardiovasculaire

Carole Proust, Jean-Philippe Empana, Pierre Boutouyrie, Maureen Alivon, Pascal Challande, et al.. Contribution of rare and common genetic variants to plasma lipid levels and carotid stiffness and geometry – a substudy of the Paris Prospective Study 3 Short title: Genetic variants and carotid stiffness. Circulation: Cardiovascular Genetics, 2015, 8 (4), pp.628-636. ⟨10.1161/CIRCGENETICS.114.000979⟩. ⟨hal-01433651⟩