ProfessorPhilippeFroguel

Bar N, Korem T, Weissbrod O, Zeevi D, Rothschild D, Leviatan S, Kosower N, Lotan-Pompan M, Weinberger A, Le Roy CI, Menni C, Visconti A, Falchi M, Spector TD, Adamski J, Franks PW, Pedersen O, Segal Eet al., 2020, A reference map of potential determinants for the human serum metabolome, NATURE, Vol: 588, Pages: 135-140, ISSN: 0028-0836

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• Citations: 154

Marselli L, Piron A, Suleiman M, Colli ML, Yi X, Khamis A, Carrat GR, Rutter GA, Bugliani M, Giusti L, Ronci M, Ibberson M, Turatsinze J-V, Boggi U, De Simone P, De Tata V, Lopes M, Nasteska D, De Luca C, Tesi M, Bosi E, Singh P, Campani D, Schulte AM, Solimena M, Hecht P, Rady B, Bakaj I, Pocai A, Norquay L, Thorens B, Canouil M, Froguel P, Eizirik DL, Cnop M, Marchetti Pet al., 2020, Persistent or transient human β cell dysfunction induced by metabolic stress: specific signatures and shared gene expression with type 2 diabetes, Cell Reports, Vol: 33, ISSN: 2211-1247

Pancreatic β cell failure is key to type 2 diabetes (T2D) onset and progression. Here, we assess whether human β cell dysfunction induced by metabolic stress is reversible, evaluate the molecular pathways underlying persistent or transient damage, and explore the relationships with T2D islet traits. Twenty-six islet preparations are exposed to several lipotoxic/glucotoxic conditions, some of which impair insulin release, depending on stressor type, concentration, and combination. The reversal of dysfunction occurs after washout for some, although not all, of the lipoglucotoxic insults. Islet transcriptomes assessed by RNA sequencing and expression quantitative trait loci (eQTL) analysis identify specific pathways underlying β cell failure and recovery. Comparison of a large number of human T2D islet transcriptomes with those of persistent or reversible β cell lipoglucotoxicity show shared gene expression signatures. The identification of mechanisms associated with human β cell dysfunction and recovery and their overlap with T2D islet traits provide insights into T2D pathogenesis, fostering the development of improved β cell-targeted therapeutic strategies.

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Vaxillaire M, Bonnefond A, Liatis S, Hachmi LBS, Jotic A, Boissel M, Gaget S, Durand E, Vaillant E, Derhourhi M, Larcher N, Allegaert F, Medlej R, Chadli A, Arbouche Z, Belhadj A, Chaieb M, Raposo J, Ilkova H, Loizou D, Lalic N, Vassallo J, Marre M, Froguel Pet al., 2020, Monogenic diabetes gene screening in a transnational multicenter study from eleven countries of the Mediterranean area, Publisher: SPRINGERNATURE, Pages: 683-684, ISSN: 1018-4813

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Saeed S, Arslan M, Manzoor J, Janjua QM, Ayesha H, Durand E, Khan WI, Butt TA, Bonnefond A, Froguel Pet al., 2020, Genetic aetiology of early onset severe obesity revealed in half of the affected cases from a consanguineous population of Pakistan, Publisher: SPRINGERNATURE, Pages: 568-569, ISSN: 1018-4813

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El Shamieh S, Stathopoulou MG, Bonnefond A, Ndiaye NC, Lecoeur C, Meyre D, Dade S, Chedid P, Salami A, Shahabi P, Dedoussis G, Froguel P, Visvikis-Siest Set al., 2020, Obesity status modifies the association between rs7556897T&gt;C in the intergenic region <i>SLC19A3</i>-<i>CCL20</i> and blood pressure in French children, CLINICAL CHEMISTRY AND LABORATORY MEDICINE, Vol: 58, Pages: 1819-1827, ISSN: 1434-6621

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• Citations: 1

Imam A, Winnebeck EC, Buchholz N, Froguel P, Bonnefond A, Solimena M, Ivanova A, Bouvier M, Plouffe B, Charpentier G, Karamitri A, Jockers R, Roenneberg T, Vetter Cet al., 2020, Circadian, Sleep and Caloric Intake Phenotyping in Type 2 Diabetes Patients With Rare Melatonin Receptor 2 Mutations and Controls: A Pilot Study, FRONTIERS IN PHYSIOLOGY, Vol: 11, ISSN: 1664-042X

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• Citations: 9

Baron M, Froguel P, Bonnefond A, 2020, Something new in the genetics of monogenic obesity and its insights into pathophysiology, M S-MEDECINE SCIENCES, Vol: 36, Pages: 859-865, ISSN: 0767-0974

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• Citations: 1

Vogelezang S, Bradfield JP, Ahluwalia TS, Curtin JA, Lakka TA, Grarup N, Scholz M, van der Most PJ, Monnereau C, Stergiakouli E, Heiskala A, Horikoshi M, Fedko IO, Vilor-Tejedor N, Cousminer DL, Standl M, Wang CA, Viikari J, Geller F, iniguez C, Pitkanen N, Chesi A, Bacelis J, Yengo L, Torrent M, Ntalla I, Helgeland O, Selzam S, Vonk JM, Zafarmand MH, Heude B, Farooqi IS, Alyass A, Beaumont RN, Have CT, Rzehak P, Bilbao JR, Schnurr TM, Barroso I, Bonnelykke K, Beilin LJ, Carstensen L, Charles M-A, Chawes B, Clement K, Closa-Monasterolo R, Custovic A, Eriksson JG, Escribano J, Groen-Blokhuis M, Grote V, Gruszfeld D, Hakonarson H, Hansen T, Hattersley AT, Hollensted M, Hottenga J-J, Hypponen E, Johansson S, Joro R, Kahonen M, Karhunen V, Kiess W, Knight BA, Koletzko B, Kuehnapfel A, Landgraf K, Langhendries J-P, Lehtimaki T, Leinonen JT, Li A, Lindi V, Lowry E, Bustamante M, Medina-Gomez C, Melbye M, Michaelsen KF, Morgen CS, Mori TA, Nielsen TRH, Niinikoski H, Oldehinkel AJ, Pahkala K, Panoutsopoulou K, Pedersen O, Pennell CE, Power C, Reijneveld SA, Rivadeneira F, Simpson A, Sly PD, Stokholm J, Teo KK, Thiering E, Timpson NJ, Uitterlinden AG, van Beijsterveldt CEM, van Schaik BDC, Vaudel M, Verduci E, Vinding RK, Vogel M, Zeggini E, Sebert S, Lind MV, Brown CD, Santa-Marina L, Reischl E, Frithioff-Bojsoe C, Meyre D, Wheeler E, Ong K, Nohr EA, Vrijkotte TGM, Koppelman GH, Plomin R, Njolstad PR, Dedoussis GD, Froguel P, Sorensen TIA, Jacobsson B, Freathy RM, Zemel BS, Raitakari O, Vrijheid M, Feenstra B, Lyytikainen L-P, Snieder H, Kirsten H, Holt PG, Heinrich J, Widen E, Sunyer J, Boomsma DI, Jarvelin M-R, Koerner A, Davey Smith G, Holm J-C, Atalay M, Murray C, Bisgaard H, McCarthy MI, Jaddoe VWV, Grant SFA, Felix JFet al., 2020, Novel loci for childhood body mass index and shared heritability with adult cardiometabolic traits, PLoS Genetics, Vol: 16, Pages: 1-26, ISSN: 1553-7390

The genetic background of childhood body mass index (BMI), and the extent to which the well-known associations of childhood BMI with adult diseases are explained by shared genetic factors, are largely unknown. We performed a genome-wide association study meta-analysis of BMI in 61,111 children aged between 2 and 10 years. Twenty-five independent loci reached genome-wide significance in the combined discovery and replication analyses. Two of these, located near NEDD4L and SLC45A3, have not previously been reported in relation to either childhood or adult BMI. Positive genetic correlations of childhood BMI with birth weight and adult BMI, waist-to-hip ratio, diastolic blood pressure and type 2 diabetes were detected (Rg ranging from 0.11 to 0.76, P-values <0.002). A negative genetic correlation of childhood BMI with age at menarche was observed. Our results suggest that the biological processes underlying childhood BMI largely, but not completely, overlap with those underlying adult BMI. The well-known observational associations of BMI in childhood with cardio-metabolic diseases in adulthood may reflect partial genetic overlap, but in light of previous evidence, it is also likely that they are explained through phenotypic continuity of BMI from childhood into adulthood.

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Bonnefond A, Boissel M, Bolze A, Durand E, Toussaint B, Vaillant E, Gaget S, De Graeve F, Dechaume A, Allegaert F, Le Guilcher D, Yengo L, Dhennin V, Borys J-M, Lu JT, Cirulli ET, Elhanan G, Roussel R, Balkau B, Marre M, Franc S, Charpentier G, Vaxillaire M, Canouil M, Washington NL, Grzymski JJ, Froguel Pet al., 2020, Pathogenic variants in actionable MODY genes are associated with type 2 diabetes, NATURE METABOLISM, Vol: 2, Pages: 1126-+

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• Citations: 26

Jacob A, Pasquier J, Carapito R, Aurade F, Molitor A, Froguel P, Fakhro K, Halabi N, Viot G, Bahram S, Rafii Aet al., 2020, A de novo synonymous variant in<i>EFTUD2</i>disrupts normal splicing and causes mandibulofacial dysostosis with microcephaly: case report, BMC MEDICAL GENETICS, Vol: 21

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• Citations: 6

Hu M, Cebola I, Carrat G, Nawaz S, Khamis A, Canouil M, Froguel P, Schulte A, Solimena M, Ibberson M, Marchetti P, Gadue P, Hastoy B, McMahon H, Rutter Get al., 2020, Chromatin 3D interaction analysis of the STARD10 locus unveils FCHSD2 as a new regulator of insulin secretion, Publisher: SPRINGER

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Kahoul Y, Oger F, Montaigne J, Froguel P, Breton C, Annicotte J-Set al., 2020, Emerging Roles for the <i>INK4a/ARF</i> (<i>CDKN2A</i>) Locus in Adipose Tissue: Implications for Obesity and Type 2 Diabetes, BIOMOLECULES, Vol: 10

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• Citations: 10

Khamis A, Canouil M, Marselli L, Boutry R, Suleiman M, Jonckheere N, Schulte AM, Solimena M, Bonnefond A, Van Seuningen I, Ibberson M, Joerns A, Lenzen S, Marchetti P, Froguel Pet al., 2020, Pnliprp1 hypermethylation in human exocrine pancreas reveals a link between diabetes and pancreatic cancer, 56th Annual Meeting of the European-Association-for-the-Study-of-Diabetes (EASD), Publisher: SPRINGER, Pages: S109-S109, ISSN: 0012-186X

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Saeed S, Arslan M, Manzoor J, Din SM, Janjua QM, Ayesha H, Ain Q-T, Inam L, Lobbens S, Vaillant E, Durand E, Derhourhi M, Amanzougarene S, Badreddine A, Berberian L, Gaget S, Khan WI, Butt TA, Bonnefond A, Froguel Pet al., 2020, Genetic Causes of Severe Childhood Obesity: A Remarkably High Prevalence in an Inbred Population of Pakistan, DIABETES, Vol: 69, Pages: 1424-1438, ISSN: 0012-1797

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• Citations: 14

Zheng Y, Huang T, Wang T, Mei Z, Sun Z, Zhang T, Ellervik C, Chai J-F, Sim X, van Dam RM, Tai E-S, Koh W-P, Dorajoo R, Saw S-M, Sabanayagam C, Wong TY, Gupta P, Rossing P, Ahluwalia TS, Vinding RK, Bisgaard H, Bonnelykke K, Wang Y, Graff M, Voortman T, van Rooij FJA, Hofman A, van Heemst D, Noordam R, Estampador AC, Varga TV, Enzenbach C, Scholz M, Thiery J, Burkhardt R, Orho-Melander M, Schulz C-A, Ericson U, Sonestedt E, Kubo M, Akiyama M, Zhou A, Kilpelainen TO, Hansen T, Kleber ME, Delgado G, McCarthy M, Lemaitre RN, Felix JF, Jaddoe VWV, Wu Y, Mohlke KL, Lehtimaki T, Wang CA, Pennell CE, Schunkert H, Kessler T, Zeng L, Willenborg C, Peters A, Lieb W, Grote V, Rzehak P, Koletzko B, Erdmann J, Munz M, Wu T, He M, Yu C, Lecoeur C, Froguel P, Corella D, Moreno LA, Lai C-Q, Pitkanen N, Boreham CA, Ridker PM, Rosendaal FR, de Mutsert R, Power C, Paternoster L, Sorensen TIA, Tjonneland A, Overvad K, Djousse L, Rivadeneira F, Lee NR, Raitakari OT, Kahonen M, Viikari J, Langhendries J-P, Escribano J, Verduci E, Dedoussis G, Koenig I, Balkau B, Coltell O, Dallongeville J, Meirhaeghe A, Amouyel P, Gottrand F, Pahkala K, Niinikoski H, Hypponen E, Maerz W, Mackey DA, Gruszfeld D, Tucker KL, Fumeron F, Estruch R, Ordovas JM, Arnett DK, Mook-Kanamori DO, Mozaffarian D, Psaty BM, North KE, Chasman D, Qi Let al., 2020, Mendelian randomization analysis does not support causal associations of birth weight with hypertension risk and blood pressure in adulthood, EUROPEAN JOURNAL OF EPIDEMIOLOGY, Vol: 35, Pages: 685-697, ISSN: 0393-2990

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• Citations: 6

Lemoine S, Eladari D, Juillard L, Bonnefond A, Froguel P, Dubourg Let al., 2020, Hypokalemia and severe renal loss of sodium - Pendred syndrome mimicking Gitelman syndrome, KIDNEY INTERNATIONAL, Vol: 97, Pages: 1305-1306, ISSN: 0085-2538

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• Citations: 7

Thomas CE, Haussler RS, Hong M-G, Raverdy V, Dale M, Canouil M, Mazzoni G, Vinuela A, Froguel P, Brunak S, Schwenk JMet al., 2020, Individual and Longitudinal Effects of Gastric Bypass Surgery on the Circulating Proteome, 80th Scientific Sessions of the American-Diabetes-Association (ADA), Publisher: AMER DIABETES ASSOC, ISSN: 0012-1797

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Khamis A, Boutry R, Canouil M, Mathew S, Lobbens S, Crouch H, Andrew T, Abderrahmani A, Tamanini F, Froguel Pet al., 2020, Histone deacetylase 9 promoter hypomethylation associated with adipocyte dysfunction is a statin-related metabolic effect, Clinical Epigenetics, Vol: 12, Pages: 1-12, ISSN: 1868-7083

BackgroundAdipogenesis, the process whereby preadipocytes differentiate into mature adipocytes, is crucial for maintaining metabolic homeostasis. Cholesterol-lowering statins increase type 2 diabetes (T2D) risk possibly by affecting adipogenesis and insulin resistance but the (epi)genetic mechanisms involved are unknown. Here, we characterised the effects of statin treatment on adipocyte differentiation using in vitro human preadipocyte cell model to identify putative effective genes.ResultsStatin treatment during adipocyte differentiation caused a reduction in key genes involved in adipogenesis, such as ADIPOQ, GLUT4 and ABCG1. Using Illumina’s Infinium ‘850K’ Methylation EPIC array, we found a significant hypomethylation of cg14566882, located in the promoter of the histone deacetylase 9 (HDAC9) gene, in response to two types of statins (atorvastatin and mevastatin), which correlates with an increased HDAC9 mRNA expression. We confirmed that HDAC9 is a transcriptional repressor of the cholesterol efflux ABCG1 gene expression, which is epigenetically modified in obesity and prediabetic states. Thus, we assessed the putative impact of ABCG1 knockdown in mimicking the effect of statin in adipogenesis. ABCG1 KD reduced the expression of key genes involved in adipocyte differentiation and decreased insulin signalling and glucose uptake. In human blood cells from two cohorts, ABCG1 expression was impaired in response to statins, confirming that ABCG1 is targeted in vivo by these drugs.ConclusionsWe identified an epigenetic link between adipogenesis and adipose tissue insulin resistance in the context of T2D risk associated with statin use, which has important implications as HDAC9 and ABCG1 are considered potential therapeutic targets for obesity and metabolic diseases.

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de las Fuentes L, Sung YJ, Noordam R, Winkler T, Feitosa MF, Schwander K, Bentley AR, Brown MR, Guo X, Manning A, Chasman DI, Aschard H, Bartz TM, Bielak LF, Campbell A, Cheng C-Y, Dorajoo R, Hartwig FP, Horimoto ARVR, Li C, Li-Gao R, Liu Y, Marten J, Musani SK, Ntalla I, Rankinen T, Richard M, Sim X, Smith AV, Tajuddin SM, Tayo BO, Vojinovic D, Warren HR, Xuan D, Alver M, Boissel M, Chai J-F, Chen X, Christensen K, Divers J, Evangelou E, Gao C, Girotto G, Harris SE, He M, Hsu F-C, Kuehnel B, Laguzzi F, Li X, Lyytikainen L-P, Nolte IM, Poveda A, Rauramaa R, Riaz M, Rueedi R, Shu X-O, Snieder H, Sofer T, Takeuchi F, Verweij N, Ware EB, Weiss S, Yanek LR, Amin N, Arking DE, Arnett DK, Bergmann S, Boerwinkle E, Brody JA, Broeckel U, Brumat M, Burke G, Cabrera CP, Canouil M, Chee ML, Chen Y-DI, Cocca M, Connell J, de Silva HJ, de Vries PS, Eiriksdottir G, Faul JD, Fisher V, Forrester T, Fox EF, Friedlander Y, Gao H, Gigante B, Giulianini F, Gu CC, Gu D, Harris TB, He J, Heikkinen S, Heng C-K, Hunt S, Ikram MA, Irvin MR, Kahonen M, Kavousi M, Khor CC, Kilpelainen TO, Koh W-P, Komulainen P, Kraja AT, Krieger JE, Langefeld CD, Li Y, Liang J, Liewald DCM, Liu C-T, Liu J, Lohman KK, Magi R, McKenzie CA, Meitinger T, Metspalu A, Milaneschi Y, Milani L, Mook-Kanamori DO, Nalls MA, Nelson CP, Norris JM, O'Connell J, Ogunniyi A, Padmanabhan S, Palmer ND, Pedersen NL, Perls T, Peters A, Petersmann A, Peyser PA, Polasek O, Porteous DJ, Raffel LJ, Rice TK, Rotter JI, Rudan I, Rueda-Ochoa O-L, Sabanayagam C, Salako BL, Schreiner PJ, Shikany JM, Sidney SS, Sims M, Sitlani CM, Smith JA, Starr JM, Strauch K, Swertz MA, Teumer A, Tham YC, Uitterlinden AG, Vaidya D, van der Ende MY, Waldenberger M, Wang L, Wang Y-X, Wei W-B, Weir DR, Wen W, Yao J, Yu B, Yu C, Yuan J-M, Zhao W, Zonderman AB, Becker DM, Bowden DW, Deary IJ, Doerr M, Esko T, Freedman BI, Froguel P, Gasparini P, Gieger C, Jonas JB, Kammerer CM, Kato N, Lakka TA, Leander K, Lehtimaki T, Magnusson PKE, Marques-Vidal P, Penninxet al., 2020, Gene-educational attainment interactions in a multi-ancestry genome-wide meta-analysis identify novel blood pressure loci, Molecular Psychiatry, Vol: 26, Pages: 2111-2125, ISSN: 1359-4184

Educational attainment is widely used as a surrogate for socioeconomic status (SES). Low SES is a risk factor for hypertension and high blood pressure (BP). To identify novel BP loci, we performed multi-ancestry meta-analyses accounting for gene-educational attainment interactions using two variables, “Some College” (yes/no) and “Graduated College” (yes/no). Interactions were evaluated using both a 1 degree of freedom (DF) interaction term and a 2DF joint test of genetic and interaction effects. Analyses were performed for systolic BP, diastolic BP, mean arterial pressure, and pulse pressure. We pursued genome-wide interrogation in Stage 1 studies (N = 117 438) and follow-up on promising variants in Stage 2 studies (N = 293 787) in five ancestry groups. Through combined meta-analyses of Stages 1 and 2, we identified 84 known and 18 novel BP loci at genome-wide significance level (P < 5 × 10-8). Two novel loci were identified based on the 1DF test of interaction with educational attainment, while the remaining 16 loci were identified through the 2DF joint test of genetic and interaction effects. Ten novel loci were identified in individuals of African ancestry. Several novel loci show strong biological plausibility since they involve physiologic systems implicated in BP regulation. They include genes involved in the central nervous system-adrenal signaling axis (ZDHHC17, CADPS, PIK3C2G), vascular structure and function (GNB3, CDON), and renal function (HAS2 and HAS2-AS1, SLIT3). Collectively, these findings suggest a role of educational attainment or SES in further dissection of the genetic architecture of BP.

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Gloaguen E, Dizier M-H, Boissel M, Rocheleau G, Canouil M, Froguel P, Tichet J, Roussel R, Julier C, Balkau B, Mathieu F, Ducimetiere P, Eschwege E, Alhenc-Gelas F, Fumeron F, Marre M, Gallois Y, Girault A, Bonnet F, Bonnefond A, Cauchi S, Alencon A, Blois C, Chartres C, Cholet LM, Orleans T, Cogneau J, Born C, Caces E, Cailleau M, Copin N, Lantieri O, Moreau J-G, Rakotozafy F, Vol Set al., 2020, General regression model: A "model-free" association test for quantitative traits allowing to test for the underlying genetic model, ANNALS OF HUMAN GENETICS, Vol: 84, Pages: 280-290, ISSN: 0003-4800

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Canouil M, Bouland GA, Bonnefond A, Froguel P, 't Hart LM, Slieker RCet al., 2020, <i>NACHO:</i> an R package for quality control of NanoString nCounter data, BIOINFORMATICS, Vol: 36, Pages: 970-971, ISSN: 1367-4803

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• Citations: 8

Mishra R, Akerlund M, Cousminer DL, Ahlqvist E, Bradfield JP, Chesi A, Hodge KM, Guy VC, Brillon DJ, Pratley RE, Rickels MR, Vella A, Ovalle F, Harris RI, Melander O, Varvel S, Hakonarson H, Froguel P, Lonsdale JT, Mauricio D, Schloot NC, Khunti K, Greenbaum CJ, Yderstraede KB, Tuomi T, Voight BF, Schwartz S, Boehm BO, Groop L, Leslie RD, Grant SFAet al., 2020, Genetic Discrimination Between LADA and Childhood-Onset Type 1 Diabetes Within the MHC, DIABETES CARE, Vol: 43, Pages: 418-425, ISSN: 0149-5992

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• Citations: 20

Ndiaye FK, Huyvaert M, Ortalli A, Canouil M, Lecoeur C, Verbanck M, Lobbens S, Khamis A, Marselli L, Marchetti P, Kerr-Conte J, Pattou F, Marre M, Roussel R, Balkau B, Froguel P, Bonnefond Aet al., 2020, The expression of genes in top obesity-associated loci is enriched in insula and substantia nigra brain regions involved in addiction and reward, INTERNATIONAL JOURNAL OF OBESITY, Vol: 44, Pages: 539-543, ISSN: 0307-0565

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• Citations: 26

Imam A, Winnebeck E, Buchholz N, Froguel P, Bonnefond A, Solimena M, Ivanova A, Bouvier M, Plouffe B, Charpentier G, Karamitri A, Jockers R, Roenneberg T, Vetter Cet al., 2019, FUNCTIONAL CIRCADIAN AND SLEEP PHENOTYPING OF TYPE 2 DIABETES PATIENTS WITH MELATONIN RECEPTOR 2 MUTATIONS AND CONTROLS: A PILOT STUDY, Publisher: ELSEVIER, Pages: S166-S167, ISSN: 1389-9457

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Lecoutre S, Montel V, Vallez E, Pourpe C, Delmont A, Eury E, Verbanck M, Dickes-Coopman A, Daubersies P, Lesage J, Laborie C, Tailleux A, Staels B, Froguel P, Breton C, Vieau Det al., 2019, Transcription profiling in the liver of undernourished male rat offspring reveals altered lipid metabolism pathways and predisposition to hepatic steatosis, AMERICAN JOURNAL OF PHYSIOLOGY-ENDOCRINOLOGY AND METABOLISM, Vol: 317, Pages: E1094-E1107, ISSN: 0193-1849

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• Citations: 5

Mitchell RN, Ashar FN, Jarvelin M-R, Froguel P, Sotoodehnia N, Brody JA, Sebert S, Huikuri H, Rioux J, Goyette P, Newcomb CE, Junttila MJ, Arking DEet al., 2019, Effect of sex and underlying disease on the genetic association of QT interval and sudden cardiac death, Journal of the American Heart Association, Vol: 8, Pages: 1-27, ISSN: 2047-9980

BackgroundSudden cardiac death (SCD) accounts for ≈300 000 deaths annually in the United States. Men have a higher risk of SCD and are more likely to have underlying coronary artery disease, while women are more likely to have arrhythmic events in the setting of inherited or acquired QT prolongation. Moreover, there is evidence of sex differences in the genetics of QT interval duration. Using sex‐ and coronary artery disease–stratified analyses, we assess differences in genetic association between longer QT interval and SCD risk.Methods and ResultsWe examined 2282 SCD subjects and 3561 Finnish controls. The SCD subjects were stratified by underlying disease (ischemic versus nonischemic) and by sex. We used logistic regression to test for association between the top QT interval–associated single‐nucleotide polymorphism, rs12143842 (in the NOS1AP locus), and SCD risk. We also performed Mendelian randomization to test for causal association of QT interval in the various subgroups. No statistically significant differences were observed between the sexes for associations with rs12143842, despite the odds ratio being higher in females across all subgroup analyses. Consistent with our hypothesis, female non‐ischemics had the highest odds ratio point estimate for association between rs12143842 and SCD risk and male ischemics the lowest odds ratio point estimate (P=0.036 for difference). Similar trends were observed for the Mendelian randomization analysis.ConclusionsWhile individual subgroup comparisons did not achieve traditional criteria for statistical significance, this study is consistent with the hypothesis that the causal association of longer QT interval on SCD risk is stronger in women and nonischemic individuals.

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Meyre D, Andress EJ, Sharma T, Snippe M, Asif H, Maharaj A, Vatin V, Gaget S, Besnard P, Choquet H, Froguel P, Linton KJet al., 2019, Contribution of rare coding mutations in <i>CD36</i> to type 2 diabetes and cardio-metabolic complications, SCIENTIFIC REPORTS, Vol: 9, ISSN: 2045-2322

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• Citations: 5

Baron M, Maillet J, Huyvaert M, Dechaume A, Boutry R, Loiselle H, Durand E, Toussaint B, Vaillant E, Philippe J, Thomas J, Ghulam A, Franc S, Charpentier G, Borys J-M, Lévy-Marchal C, Tauber M, Scharfmann R, Weill J, Aubert C, Kerr-Conte J, Pattou F, Roussel R, Balkau B, Marre M, Boissel M, Derhourhi M, Gaget S, Canouil M, Froguel P, Bonnefond Aet al., 2019, Loss-of-function mutations in <i>MRAP2</i> are pathogenic in hyperphagic obesity with hyperglycemia and hypertension, NATURE MEDICINE, Vol: 25, Pages: 1733-+, ISSN: 1078-8956

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• Citations: 39

Schmidt AF, Holmes MV, Preiss D, Swerdlow DI, Denaxas S, Fatemifar G, Faraway R, Finan C, Valentine D, Fairhurst-Hunter Z, Hartwig FP, Horta BL, Hypponen E, Power C, Moldovan M, van Iperen E, Hovingh K, Demuth I, Norman K, Steinhagen-Thiessen E, Demuth J, Bertram L, Lill CM, Coassin S, Willeit J, Kiechl S, Willeit K, Mason D, Wright J, Morris R, Wanamethee G, Whincup P, Ben-Shlomo Y, McLachlan S, Price JF, Kivimaki M, Welch C, Sanchez-Galvez A, Marques-Vidal P, Nicolaides A, Panayiotou AG, Onland-Moret NC, van der Schouw YT, Matullo G, Fiorito G, Guarrera S, Sacerdote C, Wareham NJ, Langenberg C, Scott RA, Luan J, Bobak M, Malyutina S, Pająk A, Kubinova R, Tamosiunas A, Pikhart H, Grarup N, Pedersen O, Hansen T, Linneberg A, Jess T, Cooper J, Humphries SE, Brilliant M, Kitchner T, Hakonarson H, Carrell DS, McCarty CA, Lester KH, Larson EB, Crosslin DR, de Andrade M, Roden DM, Denny JC, Carty C, Hancock S, Attia J, Holliday E, Scott R, Schofield P, O'Donnell M, Yusuf S, Chong M, Pare G, van der Harst P, Said MA, Eppinga RN, Verweij N, Snieder H, Lifelines Cohort authors, Christen T, Mook-Kanamori DO, ICBP Consortium, Gustafsson S, Lind L, Ingelsson E, Pazoki R, Franco O, Hofman A, Uitterlinden A, Dehghan A, Teumer A, Baumeister S, Dörr M, Lerch MM, Völker U, Völzke H, Ward J, Pell JP, Meade T, Christophersen IE, Maitland-van der Zee AH, Baranova EV, Young R, Ford I, Campbell A, Padmanabhan S, Bots ML, Grobbee DE, Froguel P, Thuillier D, Roussel R, Bonnefond A, Cariou B, Smart M, Bao Y, Kumari M, Mahajan A, Hopewell JC, Seshadri S, METASTROKE Consortium of the ISGC, Dale C, Costa RPE, Ridker PM, Chasman DI, Reiner AP, Ritchie MD, Lange LA, Cornish AJ, Dobbins SE, Hemminki K, Kinnersley B, Sanson M, Labreche K, Simon M, Bondy M, Law P, Speedy H, Allan J, Li N, Went M, Weinhold N, Morgan G, Sonneveld P, Nilsson B, Goldschmidt H, Sud A, Engert A, Hansson M, Hemingway H, Asselbergs FW, Patel RS, Keating BJ, Sattar N, Houlston R, Casas JP, Hingorani ADet al., 2019, Phenome-wide association analysis of LDL-cholesterol lowering genetic variants in PCSK9, BMC Cardiovascular Disorders, Vol: 19, ISSN: 1471-2261

BACKGROUND: We characterised the phenotypic consequence of genetic variation at the PCSK9 locus and compared findings with recent trials of pharmacological inhibitors of PCSK9. METHODS: Published and individual participant level data (300,000+ participants) were combined to construct a weighted PCSK9 gene-centric score (GS). Seventeen randomized placebo controlled PCSK9 inhibitor trials were included, providing data on 79,578 participants. Results were scaled to a one mmol/L lower LDL-C concentration. RESULTS: The PCSK9 GS (comprising 4 SNPs) associations with plasma lipid and apolipoprotein levels were consistent in direction with treatment effects. The GS odds ratio (OR) for myocardial infarction (MI) was 0.53 (95% CI 0.42; 0.68), compared to a PCSK9 inhibitor effect of 0.90 (95% CI 0.86; 0.93). For ischemic stroke ORs were 0.84 (95% CI 0.57; 1.22) for the GS, compared to 0.85 (95% CI 0.78; 0.93) in the drug trials. ORs with type 2 diabetes mellitus (T2DM) were 1.29 (95% CI 1.11; 1.50) for the GS, as compared to 1.00 (95% CI 0.96; 1.04) for incident T2DM in PCSK9 inhibitor trials. No genetic associations were observed for cancer, heart failure, atrial fibrillation, chronic obstructive pulmonary disease, or Alzheimer's disease - outcomes for which large-scale trial data were unavailable. CONCLUSIONS: Genetic variation at the PCSK9 locus recapitulates the effects of therapeutic inhibition of PCSK9 on major blood lipid fractions and MI. While indicating an increased risk of T2DM, no other possible safety concerns were shown; although precision was moderate.

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Thériault S, Dina C, Messika-Zeitoun D, Le Scouarnec S, Capoulade R, Gaudreault N, Rigade S, Li Z, Simonet F, Lamontagne M, Clavel MA, Arsenault BJ, Boureau AS, Lecointe S, Baron E, Bonnaud S, Karakachoff M, Charpentier E, Fellah I, Roussel JC, Philippe Verhoye J, Baufreton C, Probst V, Roussel R, Redon R, Dagenais F, Pibarot P, Mathieu P, Le Tourneau T, Schott JJ, Thériault S, Messika-Zeitoun D, Li Z, Bossé Y, Balkau B, Ducimetière P, Eschwège E, Alhenc-Gelas F, Girault A, Fumeron F, Marre M, Bonnet F, Bonnefond A, Froguel P, Rancière F, Cogneau J, Born C, Caces E, Cailleau M, Lantieri O, Moreau JG, Rakotozafy F, Tichet J, Vol Set al., 2019, Genetic Association Analyses Highlight IL6, ALPL, and NAV1 As 3 New Susceptibility Genes Underlying Calcific Aortic Valve Stenosis, Circulation: Genomic and Precision Medicine, Vol: 12, Pages: 431-441

Background: Calcific aortic valve stenosis (CAVS) is a frequent and life-threatening cardiovascular disease for which there is currently no medical treatment available. To date, only 2 genes, LPA and PALMD, have been identified as causal for CAVS. We aimed to identify additional susceptibility genes for CAVS. Methods: A GWAS (genome-wide association study) meta-analysis of 4 cohorts, totaling 5115 cases and 354 072 controls of European descent, was performed. A TWAS (transcriptome-wide association study) was completed to integrate transcriptomic data from 233 human aortic valves. A series of post-GWAS analyses were performed, including fine-mapping, colocalization, phenome-wide association studies, pathway, and tissue enrichment as well as genetic correlation with cardiovascular traits. Results: In the GWAS meta-analysis, 4 loci achieved genome-wide significance, including 2 new loci: IL6 (interleukin 6) on 7p15.3 and ALPL (alkaline phosphatase) on 1p36.12. A TWAS integrating gene expression from 233 human aortic valves identified NAV1 (neuron navigator 1) on 1q32.1 as a new candidate causal gene. The CAVS risk alleles were associated with higher mRNA expression of NAV1 in valve tissues. Fine-mapping identified rs1800795 as the most likely causal variant in the IL6 locus. The signal identified colocalizes with the expression of the IL6 RNA antisense in various tissues. Phenome-wide association analyses in the UK Biobank showed colocalized associations between the risk allele at the IL6 lead variant and higher eosinophil count, pulse pressure, systolic blood pressure, and carotid artery procedures, implicating modulation of the IL6 pathways. The risk allele at the NAV1 lead variant colocalized with higher pulse pressure and higher prevalence of carotid artery stenosis. Association results at the genome-wide scale indicated genetic correlation between CAVS, coronary artery disease, and cardiovascular risk factors. Conclusions: Our study implicates 3 new genetic loci i

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• Citations: 39