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1. Investigation of Antihypertensive Properties of Chios Mastic via Monitoring microRNA-21 Expression Levels in the Plasma of Well-Controlled Hypertensive Patients

Author

Maria Tsota, Panagiota Giardoglou, Evangelia Mentsiou-Nikolaou, Panagiotis Symianakis, Ioanna Panagiota Kalafati, Anastasia-Areti Kyriazopoulou-Korovesi, Lasthenis Angelidakis, Maria Papaioannou, Christina Konstantaki, HYPER-MASTIC Consortium, Kimon Stamatelopoulos, and George V. Dedoussis

Subjects
hypertension, Chios mastic, biomarker, epigenetics, microRNA-21, Genetics, QH426-470
Abstract

Hypertension is a chronic, multifactorial disease, leading to high cardiovascular morbidity and mortality globally. Despite the advantages of pharmaceutical treatments, natural products have gained scientific interest due to their emerging phytotherapeutic properties. Chios mastic is a natural Greek product, consisting of bioactive compounds which modify microRNAs’ (small, expression-regulating molecules) expression. In this study, we investigated the antihypertensive properties of Chios mastic through the assessment of miR-21 levels. Herein, plasma samples of 57 individuals with hypertension, recruited for the purposes of the HYPER-MASTIC study, were analyzed. This was a clinical trial with Chios mastic supplements in which the patients were divided into groups receiving high and low mastic doses and placebo supplements, respectively. miR-21 was significantly upregulated in patients compared to normotensive individuals. Mean changes in miR-21 levels were statistically significant, after adjusting for sex and age, between the placebo and low-dose group and between the low- and high-dose group. Post-intervention miR-21 levels were positively associated with night-time systolic blood pressure, pulse pressure, and central systolic mean arterial pressure and negatively associated with night-time pulse wave velocity in the low-dose group. Our findings suggest a potential implication of miR-21 in the association of Chios mastic with night-time blood pressure measurements.

Published
2024
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2. Serum metabolomic profiling unveils distinct sex-related metabolic patterns in NAFLD

Author

Charalambos Fotakis, Ioanna-Panagiota Kalafati, Athina I. Amanatidou, Vasiliki Andreou, Manolis Matzapetakis, Maria Kafyra, Iraklis Varlamis, Maria Zervou, and George V. Dedoussis

Subjects
NMR metabolomics, NAFLD, serum metabolite markers, amino acids, sex, ketone bodies, Diseases of the endocrine glands. Clinical endocrinology, RC648-665
Abstract

ObjectiveObesity poses an increased risk for the onset of Nonalcoholic fatty liver disease (NAFLD). The influence of other factors, such as sex in the incidence and severity of this liver disease has not yet been fully elucidated. Thus, we aimed to identify the NAFLD serum metabolic signatures associated with sex in normal, overweight and obese patients and to associate the metabolite fluctuations across the increasing liver steatosis stages.Methods and resultsUsing nuclear magnetic resonance (NMR) serum samples of 210 NAFLD cases and control individuals diagnosed with liver U/S, our untargeted metabolomics enquiry provided a sex distinct metabolic bouquet. Increased levels of alanine, histidine and tyrosine are associated with severity of NAFLD in both men and women. Moreover, higher serum concentrations of valine, aspartic acid and mannose were positively associated with the progression of NAFLD among the male subjects, while a negative association was observed with the levels of creatine, phosphorylcholine and acetic acid. On the other hand, glucose was positively associated with the progression of NAFLD among the female subjects, while levels of threonine were negatively related. Fluctuations in ketone bodies acetoacetate and acetone were also observed among the female subjects probing a significant reduction in the circulatory levels of the former in NAFLD cases. A complex glycine response to hepatic steatosis of the female subjects deserves further investigation.ConclusionResults of this study aspire to address the paucity of data on sex differences regarding NAFLD pathogenesis. Targeted circulatory metabolome measurements could be used as diagnostic markers for the distinct stages of NAFLD in each sex and eventually aid in the development of novel sex-related therapeutic options.

Published
2023
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3. Plasma Amino Acids in NAFLD Patients with Obesity Are Associated with Steatosis and Fibrosis: Results from the MAST4HEALTH Study

Author

Athina I. Amanatidou, Eleni V. Mikropoulou, Charalampia Amerikanou, Maja Milanovic, Stefan Stojanoski, Mladen Bjelan, Lucia Cesarini, Jonica Campolo, Anastasia Thanopoulou, Rajarshi Banerjee, Mary Jo Kurth, Natasa Milic, Milica Medic-Stojanoska, Maria Giovanna Trivella, Sophie Visvikis-Siest, Amalia Gastaldelli, Maria Halabalaki, Andriana C. Kaliora, George V. Dedoussis, and on behalf of the Mast4Health consortium

Subjects
non-alcoholic fatty liver disease, magnetic resonance imaging, amino acids, metabolomics, inflammation, Microbiology, QR1-502
Abstract

Non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) have been linked to changes in amino acid (AA) levels. The objective of the current study was to examine the relationship between MRI parameters that reflect inflammation and fibrosis and plasma AA concentrations in NAFLD patients. Plasma AA levels of 97 NAFLD patients from the MAST4HEALTH study were quantified with liquid chromatography. Medical, anthropometric and lifestyle characteristics were collected and biochemical parameters, as well as inflammatory and oxidative stress biomarkers, were measured. In total, subjects with a higher MRI-proton density fat fraction (MRI-PDFF) exhibited higher plasma AA levels compared to subjects with lower PDFF. The concentrations of BCAAs (p-Value: 0.03), AAAs (p-Value: 0.039), L-valine (p-Value: 0.029), L-tyrosine (p-Value: 0.039) and L-isoleucine (p-Value: 0.032) were found to be significantly higher in the higher PDFF group compared to lower group. Plasma AA levels varied according to MRI-PDFF. Significant associations were also demonstrated between AAs and MRI-PDFF and MRI-cT1, showing the potential utility of circulating AAs as diagnostic markers of NAFLD.

Published
2023
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4. Sex-dimorphic genetic effects and novel loci for fasting glucose and insulin variability

Author

Vasiliki Lagou, Reedik Mägi, Jouke- Jan Hottenga, Harald Grallert, John R. B. Perry, Nabila Bouatia-Naji, Letizia Marullo, Denis Rybin, Rick Jansen, Josine L. Min, Antigone S. Dimas, Anna Ulrich, Liudmila Zudina, Jesper R. Gådin, Longda Jiang, Alessia Faggian, Amélie Bonnefond, Joao Fadista, Maria G. Stathopoulou, Aaron Isaacs, Sara M. Willems, Pau Navarro, Toshiko Tanaka, Anne U. Jackson, May E. Montasser, Jeff R. O’Connell, Lawrence F. Bielak, Rebecca J. Webster, Richa Saxena, Jeanette M. Stafford, Beate St Pourcain, Nicholas J. Timpson, Perttu Salo, So-Youn Shin, Najaf Amin, Albert V. Smith, Guo Li, Niek Verweij, Anuj Goel, Ian Ford, Paul C. D. Johnson, Toby Johnson, Karen Kapur, Gudmar Thorleifsson, Rona J. Strawbridge, Laura J. Rasmussen-Torvik, Tõnu Esko, Evelin Mihailov, Tove Fall, Ross M. Fraser, Anubha Mahajan, Stavroula Kanoni, Vilmantas Giedraitis, Marcus E. Kleber, Günther Silbernagel, Julia Meyer, Martina Müller-Nurasyid, Andrea Ganna, Antti-Pekka Sarin, Loic Yengo, Dmitry Shungin, Jian’an Luan, Momoko Horikoshi, Ping An, Serena Sanna, Yvonne Boettcher, N. William Rayner, Ilja M. Nolte, Tatijana Zemunik, Erik van Iperen, Peter Kovacs, Nicholas D. Hastie, Sarah H. Wild, Stela McLachlan, Susan Campbell, Ozren Polasek, Olga Carlson, Josephine Egan, Wieland Kiess, Gonneke Willemsen, Johanna Kuusisto, Markku Laakso, Maria Dimitriou, Andrew A. Hicks, Rainer Rauramaa, Stefania Bandinelli, Barbara Thorand, Yongmei Liu, Iva Miljkovic, Lars Lind, Alex Doney, Markus Perola, Aroon Hingorani, Mika Kivimaki, Meena Kumari, Amanda J. Bennett, Christopher J. Groves, Christian Herder, Heikki A. Koistinen, Leena Kinnunen, Ulf de Faire, Stephan J. L. Bakker, Matti Uusitupa, Colin N. A. Palmer, J. Wouter Jukema, Naveed Sattar, Anneli Pouta, Harold Snieder, Eric Boerwinkle, James S. Pankow, Patrik K. Magnusson, Ulrika Krus, Chiara Scapoli, Eco J. C. N. de Geus, Matthias Blüher, Bruce H. R. Wolffenbuttel, Michael A. Province, Goncalo R. Abecasis, James B. Meigs, G. Kees Hovingh, Jaana Lindström, James F. Wilson, Alan F. Wright, George V. Dedoussis, Stefan R. Bornstein, Peter E. H. Schwarz, Anke Tönjes, Bernhard R. Winkelmann, Bernhard O. Boehm, Winfried März, Andres Metspalu, Jackie F. Price, Panos Deloukas, Antje Körner, Timo A. Lakka, Sirkka M. Keinanen-Kiukaanniemi, Timo E. Saaristo, Richard N. Bergman, Jaakko Tuomilehto, Nicholas J. Wareham, Claudia Langenberg, Satu Männistö, Paul W. Franks, Caroline Hayward, Veronique Vitart, Jaakko Kaprio, Sophie Visvikis-Siest, Beverley Balkau, David Altshuler, Igor Rudan, Michael Stumvoll, Harry Campbell, Cornelia M. van Duijn, Christian Gieger, Thomas Illig, Luigi Ferrucci, Nancy L. Pedersen, Peter P. Pramstaller, Michael Boehnke, Timothy M. Frayling, Alan R. Shuldiner, Patricia A. Peyser, Sharon L. R. Kardia, Lyle J. Palmer, Brenda W. Penninx, Pierre Meneton, Tamara B. Harris, Gerjan Navis, Pim van der Harst, George Davey Smith, Nita G. Forouhi, Ruth J. F. Loos, Veikko Salomaa, Nicole Soranzo, Dorret I. Boomsma, Leif Groop, Tiinamaija Tuomi, Albert Hofman, Patricia B. Munroe, Vilmundur Gudnason, David S. Siscovick, Hugh Watkins, Cecile Lecoeur, Peter Vollenweider, Anders Franco-Cereceda, Per Eriksson, Marjo-Riitta Jarvelin, Kari Stefansson, Anders Hamsten, George Nicholson, Fredrik Karpe, Emmanouil T. Dermitzakis, Cecilia M. Lindgren, Mark I. McCarthy, Philippe Froguel, Marika A. Kaakinen, Valeriya Lyssenko, Richard M. Watanabe, Erik Ingelsson, Jose C. Florez, Josée Dupuis, Inês Barroso, Andrew P. Morris, Inga Prokopenko, and Meta-Analyses of Glucose and Insulin-related traits Consortium (MAGIC)

Subjects
Science
Abstract

Sex differences in fasting glucose and insulin have been identified, but the genetic loci underlying these differences have not. Here, the authors perform a meta-analysis of genome-wide association studies to detect sex-specific and sex-dimorphic loci associated with fasting glucose and insulin.

Published
2021
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5. Nutrigenetic Interactions Might Modulate the Antioxidant and Anti-Inflammatory Status in Mastiha-Supplemented Patients With NAFLD

Author

Stavroula Kanoni, Satish Kumar, Charalampia Amerikanou, Mary Jo Kurth, Maria G. Stathopoulou, Stephane Bourgeois, Christine Masson, Aimo Kannt, Lucia Cesarini, Maria-Spyridoula Kontoe, Maja Milanović, Francisco J. Roig, Mirjana Beribaka, Jonica Campolo, Nuria Jiménez-Hernández, Nataša Milošević, Carlos Llorens, Ilias Smyrnioudis, M. Pilar Francino, Nataša Milić, Andriana C. Kaliora, Maria Giovanna Trivella, Mark W. Ruddock, Milica Medić-Stojanoska, Amalia Gastaldelli, John Lamont, Panos Deloukas, George V. Dedoussis, and Sophie Visvikis-Siest

Subjects
non-alcoholic fatty liver disease, inflammation, oxidative stress, Mastiha, nutrigenetics, randomized clinical trial, Immunologic diseases. Allergy, RC581-607
Abstract

Non-alcoholic fatty liver disease (NAFLD) is the most common liver disease with no therapeutic consensus. Oxidation and inflammation are hallmarks in the progression of this complex disease, which also involves interactions between the genetic background and the environment. Mastiha is a natural nutritional supplement known to possess antioxidant and anti-inflammatory properties. This study investigated how a 6-month Mastiha supplementation (2.1 g/day) could impact the antioxidant and inflammatory status of patients with NAFLD, and whether genetic variants significantly mediate these effects. We recruited 98 patients with obesity (BMI ≥ 30 kg/m2) and NAFLD and randomly allocated them to either the Mastiha or the placebo group for 6 months. The anti-oxidative and inflammatory status was assessed at baseline and post-treatment. Genome-wide genetic data was also obtained from all participants, to investigate gene-by-Mastiha interactions. NAFLD patients with severe obesity (BMI > 35kg/m2) taking the Mastiha had significantly higher total antioxidant status (TAS) compared to the corresponding placebo group (P value=0.008). We did not observe any other significant change in the investigated biomarkers as a result of Mastiha supplementation alone. We identified several novel gene-by-Mastiha interaction associations with levels of cytokines and antioxidant biomarkers. Some of the identified genetic loci are implicated in the pathological pathways of NAFLD, including the lanosterol synthase gene (LSS) associated with glutathione peroxidase activity (Gpx) levels, the mitochondrial pyruvate carrier-1 gene (MPC1) and the sphingolipid transporter-1 gene (SPNS1) associated with hemoglobin levels, the transforming growth factor‐beta‐induced gene (TGFBI) and the micro-RNA 129-1 (MIR129-1) associated with IL-6 and the granzyme B gene (GZMB) associated with IL-10 levels. Within the MAST4HEALTH randomized clinical trial (NCT03135873, www.clinicaltrials.gov) Mastiha supplementation improved the TAS levels among NAFLD patients with severe obesity. We identified several novel genome-wide significant nutrigenetic interactions, influencing the antioxidant and inflammatory status in NAFLD.Clinical Trial RegistrationClinicalTrials.gov, identifier NCT03135873.

Published
2021
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6. A zebrafish forward genetic screen identifies an indispensable threonine residue in the kinase domain of PRKD2

Author

Panagiota Giardoglou, Despina Bournele, Misun Park, Stavroula Kanoni, George V. Dedoussis, Susan F. Steinberg, Panos Deloukas, and Dimitris Beis

Subjects
protein kinase d2, cardiovascular development, cardiac valves, zebrafish, Science, Biology (General), QH301-705.5
Abstract

Protein kinase D2 belongs to a family of evolutionarily conserved enzymes regulating several biological processes. In a forward genetic screen for zebrafish cardiovascular mutants, we identified a mutation in the prkd2 gene. Homozygous mutant embryos develop as wild type up to 36 h post-fertilization and initiate blood flow, but fail to maintain it, resulting in a complete outflow tract stenosis. We identified a mutation in the prkd2 gene that results in a T757A substitution at a conserved residue in the kinase domain activation loop (T714A in human PRKD2) that disrupts catalytic activity and drives this phenotype. Homozygous mutants survive without circulation for several days, allowing us to study the extreme phenotype of no intracardiac flow, in the background of a functional heart. We show dysregulation of atrioventricular and outflow tract markers in the mutants and higher sensitivity to the Calcineurin inhibitor, Cyclosporin A. Finally we identify TBX5 as a potential regulator of PRKD2. Our results implicate PRKD2 catalytic activity in outflow tract development in zebrafish. This article has an associated First Person interview with the first author of the paper.

Published
2021
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7. Publisher Correction: Sex-dimorphic genetic effects and novel loci for fasting glucose and insulin variability

Author

Vasiliki Lagou, Reedik Mägi, Jouke- Jan Hottenga, Harald Grallert, John R. B. Perry, Nabila Bouatia-Naji, Letizia Marullo, Denis Rybin, Rick Jansen, Josine L. Min, Antigone S. Dimas, Anna Ulrich, Liudmila Zudina, Jesper R. Gådin, Longda Jiang, Alessia Faggian, Amélie Bonnefond, Joao Fadista, Maria G. Stathopoulou, Aaron Isaacs, Sara M. Willems, Pau Navarro, Toshiko Tanaka, Anne U. Jackson, May E. Montasser, Jeff R. O’Connell, Lawrence F. Bielak, Rebecca J. Webster, Richa Saxena, Jeanette M. Stafford, Beate St Pourcain, Nicholas J. Timpson, Perttu Salo, So-Youn Shin, Najaf Amin, Albert V. Smith, Guo Li, Niek Verweij, Anuj Goel, Ian Ford, Paul C. D. Johnson, Toby Johnson, Karen Kapur, Gudmar Thorleifsson, Rona J. Strawbridge, Laura J. Rasmussen-Torvik, Tõnu Esko, Evelin Mihailov, Tove Fall, Ross M. Fraser, Anubha Mahajan, Stavroula Kanoni, Vilmantas Giedraitis, Marcus E. Kleber, Günther Silbernagel, Julia Meyer, Martina Müller-Nurasyid, Andrea Ganna, Antti-Pekka Sarin, Loic Yengo, Dmitry Shungin, Jian’an Luan, Momoko Horikoshi, Ping An, Serena Sanna, Yvonne Boettcher, N. William Rayner, Ilja M. Nolte, Tatijana Zemunik, Erik van Iperen, Peter Kovacs, Nicholas D. Hastie, Sarah H. Wild, Stela McLachlan, Susan Campbell, Ozren Polasek, Olga Carlson, Josephine Egan, Wieland Kiess, Gonneke Willemsen, Johanna Kuusisto, Markku Laakso, Maria Dimitriou, Andrew A. Hicks, Rainer Rauramaa, Stefania Bandinelli, Barbara Thorand, Yongmei Liu, Iva Miljkovic, Lars Lind, Alex Doney, Markus Perola, Aroon Hingorani, Mika Kivimaki, Meena Kumari, Amanda J. Bennett, Christopher J. Groves, Christian Herder, Heikki A. Koistinen, Leena Kinnunen, Ulf de Faire, Stephan J. L. Bakker, Matti Uusitupa, Colin N. A. Palmer, J. Wouter Jukema, Naveed Sattar, Anneli Pouta, Harold Snieder, Eric Boerwinkle, James S. Pankow, Patrik K. Magnusson, Ulrika Krus, Chiara Scapoli, Eco J. C. N. de Geus, Matthias Blüher, Bruce H. R. Wolffenbuttel, Michael A. Province, Goncalo R. Abecasis, James B. Meigs, G. Kees Hovingh, Jaana Lindström, James F. Wilson, Alan F. Wright, George V. Dedoussis, Stefan R. Bornstein, Peter E. H. Schwarz, Anke Tönjes, Bernhard R. Winkelmann, Bernhard O. Boehm, Winfried März, Andres Metspalu, Jackie F. Price, Panos Deloukas, Antje Körner, Timo A. Lakka, Sirkka M. Keinanen-Kiukaanniemi, Timo E. Saaristo, Richard N. Bergman, Jaakko Tuomilehto, Nicholas J. Wareham, Claudia Langenberg, Satu Männistö, Paul W. Franks, Caroline Hayward, Veronique Vitart, Jaakko Kaprio, Sophie Visvikis-Siest, Beverley Balkau, David Altshuler, Igor Rudan, Michael Stumvoll, Harry Campbell, Cornelia M. van Duijn, Christian Gieger, Thomas Illig, Luigi Ferrucci, Nancy L. Pedersen, Peter P. Pramstaller, Michael Boehnke, Timothy M. Frayling, Alan R. Shuldiner, Patricia A. Peyser, Sharon L. R. Kardia, Lyle J. Palmer, Brenda W. Penninx, Pierre Meneton, Tamara B. Harris, Gerjan Navis, Pim van der Harst, George Davey Smith, Nita G. Forouhi, Ruth J. F. Loos, Veikko Salomaa, Nicole Soranzo, Dorret I. Boomsma, Leif Groop, Tiinamaija Tuomi, Albert Hofman, Patricia B. Munroe, Vilmundur Gudnason, David S. Siscovick, Hugh Watkins, Cecile Lecoeur, Peter Vollenweider, Anders Franco-Cereceda, Per Eriksson, Marjo-Riitta Jarvelin, Kari Stefansson, Anders Hamsten, George Nicholson, Fredrik Karpe, Emmanouil T. Dermitzakis, Cecilia M. Lindgren, Mark I. McCarthy, Philippe Froguel, Marika A. Kaakinen, Valeriya Lyssenko, Richard M. Watanabe, Erik Ingelsson, Jose C. Florez, Josée Dupuis, Inês Barroso, Andrew P. Morris, Inga Prokopenko, and Meta-Analyses of Glucose and Insulin-related traits Consortium (MAGIC)

Subjects
Science
Abstract

A Correction to this paper has been published: https://doi.org/10.1038/s41467-021-21276-3

Published
2021
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8. Polygenic risk scores and personalized approaches to cardiometabolic disease prevention and treatment: A short review

Author

Maria Kafyra and George V. Dedoussis

Abstract

Accounting for the role of genetic variants in disease is increasingly gaining ground as a major contributing factor to the maximization of successful precision medicine and personalized nutrition approaches. An aggregated technique to quantifying genetic effect refers to the development and use of disease-specific Polygenic Risk Scores (PRSs) deriving from the sum of the weighted effects of multiple disease-related Single Nucleotide Polymorphisms (SNPs), mainly from Genome-Wide association studies (GWAS). Integration of PRS use in medical and nutritional practice is largely discussed in current literature, with special attention to: i) disease prediction accuracy after PRS consideration and their potential utility; ii) the role of current methodological approaches used to derive reliable results and the effect of limitations such as ancestry or population size; iii) the familiarization of healthcare professionals with the meaning of genetic information; and iv) the context-based interpretations of PRS results in the formation of personalized advice. In this context, the present short review aims to summarize current findings on PRS use and utility in cardiometabolic, weight-related disorders and discuss future directions for their potential integration in the practice of personalized nutrition.

Published
2023
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11. Quality Specific Associations of Carbohydrate Consumption and Frailty Index

Author

Toshiko Tanaka, Maria Kafyra, Yichen Jin, Chee W. Chia, George V. Dedoussis, Sameera A. Talegawkar, and Luigi Ferrucci

Subjects
Nutrition and Dietetics, Cross-Sectional Studies, Frailty, Glycemic Index, Dietary Carbohydrates, Glycemic Load, Humans, carbohydrate consumption, frailty index, aging, epidemiology, Female, Longitudinal Studies, Food Science
Abstract

Background: The quality of carbohydrate consumed may influence the risk of frailty. In this study, we tested the hypothesis that indices of carbohydrate intake are associated with trajectories of frailty in participants of the Baltimore Longitudinal Study of Aging (BLSA). Methods: Cross sectional and longitudinal analyses were conducted in 1024 BLSA participants to examine the association between usual intake of carbohydrate and frailty index. Seven measures of carbohydrate consumption were estimated using data derived from Food Frequency Questionnaires (FFQs) and examined in association with a 43-item Frailty Index (FI). Results: In cross-sectional analyses, there was a significant, positive association between higher tertiles of total carbohydrate, glycemic load, and non-whole grains and FI. Conversely, higher tertiles of fiber-to-carbohydrate ratio was associated with lower FI. These differences persisted over the follow-up period of up to 13.8 years. Women in the highest tertile of the fiber-to-carbohydrate ratio showed a less steep increase in FI over time. Conclusions: Carbohydrate intake was positively associated with increased frailty risk in the BLSA participants, whereas a higher fiber-to-carbohydrate ratio was related to reduced risk for frailty.

Published
2022
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13. Associations of VEGF-A-Related Variants with Adolescent Cardiometabolic and Dietary Parameters

Author

Maria Kafyra, Ioanna Panagiota Kalafati, Ioanna Gavra, Sophie Siest, and George V. Dedoussis

Subjects
Nutrition and Dietetics, vascular endothelial growth factor A (VEGF-A), cardiometabolic profile, genetic risk score, adolescents, dietary patterns, Food Science
Abstract

Previous research has allowed the identification of variants related to the vascular endothelial growth factor-A (VEGF-A) and their association with anthropometric, lipidemic and glycemic indices. The present study examined potential relations between key VEGF-A-related single-nucleotide polymorphisms (SNPs), cardiometabolic parameters and dietary habits in an adolescent cohort. Cross-sectional analyses were conducted using baseline data from 766 participants of the Greek TEENAGE study. Eleven VEGF-A-related SNPs were examined for associations with cardiometabolic indices through multivariate linear regressions after adjusting for confounding factors. A 9-SNP unweighted genetic risk score (uGRS) for increased VEGF-A levels was constructed to examine associations and the effect of its interactions with previously extracted dietary patterns for the cohort. Two variants (rs4416670, rs7043199) displayed significant associations (p-values < 0.005) with the logarithms of systolic and diastolic blood pressure (logSBP and logDBP). The uGRS was significantly associated with higher values of the logarithm of Body Mass Index (logBMI) and logSBP (p-values < 0.05). Interactions between the uGRS and specific dietary patterns were related to higher logDBP and logGlucose (p-values < 0.01). The present analyses constitute the first-ever attempt to investigate the influence of VEGF-A-related variants on teenage cardiometabolic determinants, unveiling several associations and the modifying effect of diet.

Published
2023
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14. TM6SF2-rs58542926 Genetic Variant Modifies the Protective Effect of a 'Prudent' Dietary Pattern on Serum Triglyceride Levels

Author

Ioanna Panagiota Kalafati, Maria Dimitriou, Konstantinos Revenas, Alexander Kokkinos, Panos Deloukas, and George V. Dedoussis

Subjects
MBOAT7, Nutrition and Dietetics, NAFLD, dietary patterns, interaction, genetics, triglycerides, TM6SF2, FLI, PNPLA3, GCKR, Food Science
Abstract

The epidemic prevalence of non-alcoholic fatty liver disease (NAFLD), despite extensive research in the field, underlines the importance of focusing on personalized therapeutic approaches. However, nutrigenetic effects on NAFLD are poorly investigated. To this end, we aimed to explore potential gene-dietary pattern interactions in a NAFLD case–control study. The disease was diagnosed with liver ultrasound and blood collection was performed after an overnight fast. Adherence to four a posteriori, data-driven, dietary patterns was used to investigate interactions with PNPLA3-rs738409, TM6SF2-rs58542926, MBOAT7-rs641738, and GCKR-rs738409 in disease and related traits. IBM SPSS Statistics/v21.0 and Plink/v1.07 were used for statistical analyses. The sample consisted of 351 Caucasian individuals. PNPLA3-rs738409 was positively associated with disease odds (OR = 1.575, p = 0.012) and GCKR-rs738409 with lnC-reactive protein (CRP) (beta = 0.098, p = 0.003) and Fatty Liver Index (FLI) levels (beta = 5.011, p = 0.007). The protective effect of a “Prudent” dietary pattern on serum triglyceride (TG) levels in this sample was significantly modified by TM6SF2-rs58542926 (pinteraction = 0.007). TM6SF2-rs58542926 carriers may not benefit from a diet rich in unsaturated fatty acids and carbohydrates in regard to TG levels, a commonly elevated feature in NAFLD patients.

Published
2023
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15. Robust Bioinformatics Approaches Result in the First Polygenic Risk Score for BMI in Greek Adults

Author

Maria Kafyra, Ioanna Panagiota Kalafati, Maria Dimitriou, Effimia Grigoriou, Alexandros Kokkinos, Loukianos Rallidis, Genovefa Kolovou, Georgios Trovas, Eirini Marouli, Panos Deloukas, Panagiotis Moulos, and George V. Dedoussis

Subjects
polygenic risk score (PRS), body mass index (BMI), Medicine (miscellaneous), Greek adults, bioinformatics
Abstract

Quantifying the role of genetics via construction of polygenic risk scores (PRSs) is deemed a resourceful tool to enable and promote effective obesity prevention strategies. The present paper proposes a novel methodology for PRS extraction and presents the first PRS for body mass index (BMI) in a Greek population. A novel pipeline for PRS derivation was used to analyze genetic data from a unified database of three cohorts of Greek adults. The pipeline spans various steps of the process, from iterative dataset splitting to training and test partitions, calculation of summary statistics and PRS extraction, up to PRS aggregation and stabilization, achieving higher evaluation metrics. Using data from 2185 participants, implementation of the pipeline enabled consecutive repetitions in splitting training and testing samples and resulted in a 343-single nucleotide polymorphism PRS yielding an R2 = 0.3241 (beta = 1.011, p-value = 4 × 10−193) for BMI. PRS-included variants displayed a variety of associations with known traits (i.e., blood cell count, gut microbiome, lifestyle parameters). The proposed methodology led to creation of the first-ever PRS for BMI in Greek adults and aims at promoting a facilitating approach to reliable PRS development and integration in healthcare practice.

Published
2023
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16. Association of Dietary Patterns with MRI Markers of Hepatic Inflammation and Fibrosis in the MAST4HEALTH Study

Author

Athina I. Amanatidou, Andriana C. Kaliora, Charalampia Amerikanou, Stefan Stojanoski, Natasa Milosevic, Chara Vezou, Mirjana Beribaka, Rajarshi Banerjee, Ioanna-Panagiota Kalafati, Ilias Smyrnioudis, Mary Jo Kurth, Aimo Kannt, M. Pilar Francino, Sophie Visvikis-Siest, Panos Deloukas, Carlos Llorens, Fernando Marascio, Natasa Milic, Milica Medic-Stojanoska, Amalia Gastaldelli, Maria Giovanna Trivella, George V. Dedoussis, and Publica

Subjects
Inflammation, Health, Toxicology and Mutagenesis, Public Health, Environmental and Occupational Health, NASH, dietary patterns, Fibrosis, Magnetic Resonance Imaging, NAFLD, MRI, MAST4HEALTH, Article, Diabetes Mellitus, Type 2, Liver, Non-alcoholic Fatty Liver Disease, Humans, Medicine
Abstract

Whereas the etiology of non-alcoholic fatty liver disease (NAFLD) is complex, the role of nutrition as a causing and preventive factor is not fully explored. The aim of this study is to associate dietary patterns with magnetic resonance imaging (MRI) parameters in a European population (Greece, Italy, and Serbia) affected by NAFLD. For the first time, iron-corrected T1 (cT1), proton density fat fraction (PDFF), and the liver inflammation fibrosis score (LIF) were examined in relation to diet. A total of 97 obese patients with NAFLD from the MAST4HEALTH study were included in the analysis. A validated semi-quantitative food frequency questionnaire (FFQ) was used to assess the quality of diet and food combinations. Other variables investigated include anthropometric measurements, total type 2 diabetes risk, physical activity level (PAL), and smoking status. Principal component analysis (PCA) was performed to identify dietary patterns. Six dietary patterns were identified, namely “High-Sugar”, “Prudent”, “Western”, “High-Fat and Salt”, “Plant-Based”, and “Low-Fat Dairy and Poultry”. The “Western” pattern was positively associated with cT1 in the unadjusted model (beta: 0.020, p-value: 0.025) and even after adjusting for age, sex, body mass index (BMI), PAL, smoking, the center of the study, and the other five dietary patterns (beta: 0.024, p-value: 0.020). On the contrary, compared with low-intake patients, those with medium intake of the “Low-Fat Dairy and Poultry” pattern were associated with lower values of cT1, PDFF, and LIF. However, patients with a “Low-Fat Dairy and Poultry” dietary pattern were negatively associated with MRI parameters (cT1: beta: −0.052, p-value: 0.046, PDFF: beta: −0.448, p-value: 0.030, LIF: beta: −0.408, p-value: 0.025). Our findings indicate several associations between MRI parameters and dietary patterns in NAFLD patients, highlighting the importance of diet in NAFLD.

Published
2022

17. The iMPROVE Study; Design, Dietary Patterns, and Development of a Lifestyle Index in Overweight and Obese Greek Adults

Author

Sophia Lambrinou, Ioanna P. Kalafati, Iraklis Varlamis, George V. Dedoussis, Efthymia A. Katsareli, Andriana C. Kaliora, and Maria Kafyra

Subjects
Blood Glucose, Male, Multivariate statistics, obesity, Index (economics), health status, Overweight, nutritional intervention, Body Mass Index, Weight management, adults, Health Status Indicators, Nutritional Physiological Phenomena, TX341-641, Prospective Studies, Principal Component Analysis, Nutrition and Dietetics, Anthropometry, Greece, Middle Aged, Weight Reduction Programs, Body Composition, Female, medicine.symptom, Adult, dietary patterns, Nutritional Status, Intra-Abdominal Fat, Diet Surveys, Article, Negatively associated, online assessment tool, Environmental health, medicine, Humans, overweight, Life Style, Caloric Restriction, business.industry, Nutrition. Foods and food supply, Feeding Behavior, Nutrients, medicine.disease, Obesity, weight management, lifestyle index, Linear Models, Lifestyle habits, business, Food Science
Abstract

Background: Dietary and lifestyle habits constitute a significant contributing factor in the formation of anthropometric and biochemical characteristics of overweight and obese populations. The iMPROVE study recruited overweight and obese Greek adults and investigated the effect of gene–diet interactions on weight management when adhering to a six-month, randomized nutritional trial including two hypocaloric diets of different macronutrient content. The present paper displays the design of the intervention and the baseline findings of the participants’ dietary habits and their baseline anthropometric and biochemical characteristics. Methods: Baseline available data for 202 participants were analyzed and patterns were extracted via principal component analysis (PCA) on 69-item Food-Frequency Questionnaires (FFQ). Relationships with indices at baseline were investigated by multivariate linear regressions. A Lifestyle Index of five variables was further constructed. Results: PCA provided 5 dietary patterns. The “Mixed” pattern displayed positive associations with logBMI and logVisceral fat, whereas the “Traditional, vegetarian-alike” pattern was nominally, negatively associated with body and visceral fat, but positively associated with HDL levels. The Lifestyle Index displayed protective effects in the formation of logBMI and logGlucose levels. Conclusions: Dietary patterns and a Lifestyle Index in overweight and obese, Greek adults highlighted associations between diet, lifestyle, and anthropometric and biochemical indices.

Published
2021

18. Mastiha has efficacy in immune-mediated inflammatory diseases through a microRNA-155 Th17 dependent action

Author

Charalampia Amerikanou, Efstathia Papada, Aristea Gioxari, Ilias Smyrnioudis, Stamatia-Angeliki Kleftaki, Evdokia Valsamidou, Victoria Bruns, Rajarshi Banerjee, Maria Giovanna Trivella, Natasa Milic, Milica Medić‐Stojanoska, Amalia Gastaldelli, Aimo Kannt, MAST4HEALTH, George V. Dedoussis, and Andriana C. Kaliora

Subjects
miR-155, immunity, Th17 cells, Mastiha, Non-alcoholic fatty liver disease, Inflammatory Bowel Diseases, inflammation
Abstract

Mastiha is a natural nutritional supplement with known anti-inflammatory properties. Non-alcoholic fatty liver disease (NAFLD) and Inflammatory bowel disease (IBD) are immune mediated inflammatory diseases that share common pathophysiological features. Mastiha has shown beneficial effects in both diseases. MicroRNAs have emerged as key regulators of inflammation and their modulation by phytochemicals have been extensively studied over the last years. Therefore, the aim of this study was to investigate whether a common route exists in the anti-inflammatory activity of Mastiha, specifically through the regulation of miRNA levels. Plasma miR-16, miR-21 and miR-155 were measured by Real-Time PCR before and after two double blinded and placebo-controlled randomized clinical trials with Mastiha. In NAFLD, miR-155 decreased in the placebo group (p=0.054) whereas it remained unchanged in the Mastiha group. In all IBD and particulary in ulcerative colitis patients in relapse, miR-155 increased in the placebo group (p=0.054) whereas this increase was prevented by Mastiha. The mean changes were different in the two groups even after adjusting for age, sex and BMI (p=0.024 for IBD and p=0.042 for ulcerative colitis patients in relapse). Our results propose a regulatory role for Mastiha in circulating levels of miR-155, a critical player in T helper-17 (Th17) differentiation and function.

Published
2021

19. Dietary Patterns, Blood Pressure and the Glycemic and Lipidemic Profile of Two Teenage, European Populations

Author

Ioanna P. Kalafati, Maria Spyridoula Kontoe, Maria Kafyra, Sophie Siest, George V. Dedoussis, Christine Masson, Satish Kumar, Interactions Gène-Environnement en Physiopathologie Cardio-Vasculaire (IGE-PCV), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), Harokopio University of Athens, This research was funded by 'La Région Grand Est, France-GUTENBERG chair 2018, grant number 18CP-1413'. Salary for S.K. was financed by the french PIA project «Lorraine Universite d’Excellence», reference ANR-15-IDEX-04-LUE and for M.S.K. and M.K. by 'Agence Nationale de la Recherche, Programme d’Investissements d’Avenir', grant number ANR-15RHU-0004, IMPACT GEENAGE, ANR-15-RHUS-0004,FIGHT-HF,Combattre l'insuffisance cardiaque(2015), and ANR-15-IDEX-0004,LUE (ISITE),Lorraine Université d'Excellence(2016)

Subjects
0301 basic medicine, Blood Glucose, Male, European populations, Adolescent, [SDV]Life Sciences [q-bio], Population, dietary patterns, lcsh:TX341-641, Article, Body Mass Index, Food group, 03 medical and health sciences, 0302 clinical medicine, Medicine, Humans, 030212 general & internal medicine, glucose, education, triglycerides, Glycemic, Retrospective Studies, 2. Zero hunger, Cardiometabolic risk, education.field_of_study, 030109 nutrition & dietetics, Nutrition and Dietetics, Greece, teenagers, business.industry, High protein, Confounding, blood pressure, cholesterol, Feeding Behavior, Dietary pattern, Dietary Fats, cardiometabolic risk factors, humanities, Diet, Blood pressure, Cross-Sectional Studies, Female, business, lcsh:Nutrition. Foods and food supply, Biomarkers, Food Science, Demography
Abstract

The present study sought to retrospectively investigate the dietary habits of two adolescent, European populations from the cross-sectional Greek TEENAGE Study and French STANISLAS Family Study. We aimed to explore the relation between the populations&rsquo, dietary patterns and blood pressure, glycemic and lipidemic profile. Dietary patterns were extracted via Principal Component Analysis (PCA), based on data collected from two 24 h dietary recalls for the TEENAGE study and a 3-day food consumption diary for the STANISLAS study. Multiple linear regressions and mixed models analyses, adjusting for confounding factors, were employed to investigate potential associations. A total of 766 Greek teenagers and 287 French teenagers, were included in analyses. Five dietary patterns were extracted for each population accounting for 49.35% and 46.69% of their respective total variance, with similarities regarding the consumption of specific food groups (i.e., western-type foods). In the TEENAGE Study, the &ldquo, chicken and sugars&rdquo, pattern was associated with lower CRP levels, after adjusting for confounding factors (p-value &lt, 0.01). The &ldquo, high protein and animal fat&rdquo, dietary pattern of the STANISLAS Family Study was related to higher BMI (p-value &lt, 0.01) and higher triglycerides levels (p-value &lt, 0.01). Our findings summarize the dietary habits of two teenage, European populations and their associations with cardiometabolic risk factors.

Published
2021
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20. Obesity status modifies the association between rs7556897T>C in the intergenic region SLC19A3-CCL20 and blood pressure in French children

Author

Maria G. Stathopoulou, George V. Dedoussis, Pia Chedid, Philippe Froguel, Sophie Visvikis-Siest, Said El Shamieh, Ndeye Coumba Ndiaye, Ali Salami, Payman Shahabi, Amélie Bonnefond, Cécile Lecoeur, Sébastien Dadé, David Meyre, Interactions Gène-Environnement en Physiopathologie Cardio-Vasculaire (IGE-PCV), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), Beirut Arab University [Beyrouth, Liban] (BAU), Metabolic functional (epi)genomics and molecular mechanisms involved in type 2 diabetes and related diseases - UMR 8199 - UMR 1283 (GI3M), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre National de la Recherche Scientifique (CNRS), McMaster University [Hamilton, Ontario], Harokopio University of Athens, Imperial College London, and Metabolic functional (epi)genomics and molecular mechanisms involved in type 2 diabetes and related diseases - UMR 8199 - UMR 1283 (EGENODIA (GI3M))

Subjects
Male, 0301 basic medicine, medicine.medical_specialty, Adolescent, [SDV]Life Sciences [q-bio], Clinical Biochemistry, Population, Gene Expression, Adipose tissue, Blood Pressure, Single-nucleotide polymorphism, Inflammation, 030204 cardiovascular system & hematology, Overweight, Polymorphism, Single Nucleotide, White People, Childhood obesity, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, medicine, Humans, Obesity, Child, education, ComputingMilieux_MISCELLANEOUS, education.field_of_study, Chemokine CCL20, business.industry, Biochemistry (medical), Membrane Transport Proteins, General Medicine, medicine.disease, 030104 developmental biology, Endocrinology, Blood pressure, Adipose Tissue, Leukocytes, Mononuclear, DNA, Intergenic, Female, France, medicine.symptom, business
Abstract

Background Growing evidence reports an association between inflammatory markers, obesity and blood pressure (BP). Specifically, the intergenic single nucleotide polymorphism (SNP) rs7556897T > C (MAF = 0.34) located between SLC19A3 and the CCL20 was shown to be associated with chronic inflammatory diseases. In addition, CCL20 expression was found increased in pancreatic islets of obese rodents and human pancreatic β cells under the influence of inflammation. In this study, we hypothesized that SNP rs7556897 could affect BP levels, thus providing a link between inflammation, BP and obesity. Methods BP was measured under supine position with a manual sphygmomanometer; values reported were the means of three readings. We analyzed rs7556897 in 577 normal weight and 689 obese French children. Using real-time polymerase chain reaction (PCR), we quantified CCL20 and SLC19A3 expression in adipose tissue and peripheral blood mononuclear cells (PBMCs) of normal weight and overweight children. Results The rs7556897C allele was negatively associated with diastolic BP in normal weight children (β = −0.012 ± 0.004, p = 0.006) but positively associated in obese children (β = 2.178 ± 0.71, p = 0.002). A significant interaction between rs7556897T > C and the obesity status (obese or normal weight) was detected (β = 3.49, p = 9.79 × 10−5) for BP in a combined population analysis. CCL20 mRNA was only expressed in the adipose tissue of overweight children, and its expression levels were 10.7× higher in PBMCs of overweight children than normal weight children. Finally, CCL20 mRNA levels were positively associated with rs7556897T > C in PBMCs of 58 normal weight children (β = 0.43, p = 0.002). SLC19A3 was not expressed in PBMCs, and in adipose tissue, it showed same levels of expression in normal weight and overweight children. The gene expression results may highlight a specific involvement of CCL20 via communicating obesity/inflammation pathways that regulate BP. Conclusions Childhood obesity reverses the effect of rs7556897T > C on diastolic BP, possibly via the modulation of CCL20 expression levels.

Published
2020
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21. Loss of Cardioprotective Effects at the ADAMTS7 Locus as a Result of Gene-Smoking Interactions

Author

Dominique Gauguier, Ruth McPherson, Anuj Goel, Donald W. Bowden, Nancy L. Pedersen, WeangKee Ho, Danish Saleheen, Nilesh J. Samani, Marcus Edi Kleber, Michael A. Province, Albert V. Smith, Christopher J. O'Donnell, Jeanette Erdmann, Hooman Allayee, Asif Rasheed, Mary F. Feitosa, Vilmundur Gudnason, Jaspal S. Kooner, Christopher P. Nelson, Muredach P. Reilly, Winfried März, George V. Dedoussis, Wei Zhao, Markus Perola, Alexandre F.R. Stewart, Veikko Salomaa, John C. Chambers, Alistair S. Hall, K. Stefansson, Robert C. Bauer, Panos Deloukas, Charles C. White, Daniel J. Rader, Eirini Marouli, Robert A. Scott, Sylvia T. Nurnberg, Stavroula Kanoni, Andrea Ganna, Anni Joensuu, Svati H. Shah, Juha Sinisalo, Gudmar Thorleifsson, Jing Hua Zhao, Lingyao Zeng, Kari Kuulasmaa, Nicholas J. Wareham, Rona J. Strawbridge, Jane F. Ferguson, Philippe M. Frossard, Weihua Zhang, Pierre Zalloua, Kristy Ou, Ulf de Faire, Martin Farrall, Sanaz Sedaghat, Robin Young, Amanda J. Cox, Lars Lind, Christina Willenborg, K. Kristiansson, Erik Ingelsson, Colin N. A. Palmer, Jaana Hartiala, Abbas Dehghan, Natalie van Zuydam, Sekar Kathiresan, John Thompson, Ron Do, Heribert Schunkert, Thorsten Kessler, Epidemiology, Clinicum, Kardiologian yksikkö, Department of Medicine, and Institute for Molecular Medicine Finland

Subjects
0301 basic medicine, SUSCEPTIBILITY LOCI, Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy), Genome-wide association study, Locus (genetics), smoking, AMYOTROPHIC-LATERAL-SCLEROSIS, Coronary artery disease, 03 medical and health sciences, Muscle cell migration, Physiology (medical), medicine, Genetic predisposition, Cardiac and Cardiovascular Systems, CORONARY-HEART-DISEASE, Gene–environment interaction, GENOME-WIDE ASSOCIATION, Medicinsk bioteknologi (med inriktning mot cellbiologi (inklusive stamcellsbiologi), molekylärbiologi, mikrobiologi, biokemi eller biofarmaci), Gene, METAANALYSIS, Genetics, RISK, Kardiologi, genome-wide association study, business.industry, MORTALITY, ADAMTS7 protein, MEN, medicine.disease, 3. Good health, gene-environment interaction, 030104 developmental biology, 3121 General medicine, internal medicine and other clinical medicine, Etiology, MUSCLE-CELL MIGRATION, CIGARETTE-SMOKING, Cardiology and Cardiovascular Medicine, business, coronary artery disease
Abstract

Background: Common diseases such as coronary heart disease (CHD) are complex in etiology. The interaction of genetic susceptibility with lifestyle factors may play a prominent role. However, gene-lifestyle interactions for CHD have been difficult to identify. Here, we investigate interaction of smoking behavior, a potent lifestyle factor, with genotypes that have been shown to associate with CHD risk. Methods: We analyzed data on 60 919 CHD cases and 80 243 controls from 29 studies for gene-smoking interactions for genetic variants at 45 loci previously reported to be associated with CHD risk. We also studied 5 loci associated with smoking behavior. Study-specific gene-smoking interaction effects were calculated and pooled using fixed-effects meta-analyses. Interaction analyses were declared to be significant at a P value of –3 (Bonferroni correction for 50 tests). Results: We identified novel gene-smoking interaction for a variant upstream of the ADAMTS7 gene. Every T allele of rs7178051 was associated with lower CHD risk by 12% in never-smokers ( P =1.3×10 –16 ) in comparison with 5% in ever-smokers ( P =2.5×10 –4 ), translating to a 60% loss of CHD protection conferred by this allelic variation in people who smoked tobacco (interaction P value=8.7×10 –5 ). The protective T allele at rs7178051 was also associated with reduced ADAMTS7 expression in human aortic endothelial cells and lymphoblastoid cell lines. Exposure of human coronary artery smooth muscle cells to cigarette smoke extract led to induction of ADAMTS7. Conclusions: Allelic variation at rs7178051 that associates with reduced ADAMTS7 expression confers stronger CHD protection in never-smokers than in ever-smokers. Increased vascular ADAMTS7 expression may contribute to the loss of CHD protection in smokers.

Published
2017

22. A genome-wide association study in Europeans and South Asians identifies five new loci for coronary artery disease

Author

Markku S. Nieminen, Engert Jc, Anders Hamsten, Mark I. McCarthy, Khan Shah Zaman, Nilesh J. Samani, Silvia Pietri, Nadeem Hayat Mallick, Robert Clarke, Anna Helgadottir, John C. Chambers, Peter Sleight, Lasse Folkersen, Simon C. Potter, Fazal-ur-Rehman Memon, Gonçalo R. Abecasis, Shapour Jalilzadeh, Louise Bowman, Anders Mälarstig, Abdus Samad, Veikko Salomaa, John F. Peden, Juha Sinisalo, Jane Armitage, Asif Rasheed, Simona Barlera, Eirini V. Theodoraki, Suthesh Sivapalaratnam, Halit Ongen, Alison Offer, Theodosios Kyriakou, Hugh Watkins, John J.P. Kastelein, Philippe Froguel, Emma Gray, Tim D. Spector, Panos Deloukas, Mai-Lis Hellénius, Anders Gabrielsen, Martin Farrall, Jemma C. Hopewell, Mark Lathrop, Nicole Soranzo, Nabeel Ahmed, Bruna Gigante, Roberto Marchioli, Muhammad Azhar, Danish Saleheen, Salim Yusuf, Simon Heath, Anders Franco-Cereceda, Ulf de Faire, James Scott, Ann-Christine Syvänen, Marc Delepine, Maria Samuel, John Öhrvik, M. Ishaq, Fiona Green, Leena Peltonen, Paul Elliott, Moazzam Zaidi, Gerd Assmann, Rhian Gwilliam, Gianni Tognoni, Nabi Shah, John Danesh, Jorg Hager, Weihua Zhang, Mark J. Caulfield, Jaspal S. Kooner, Angad S. Kooner, Suzannah Bumpstead, Richard Peto, Francesca Gori, Maria Grazia Franzosi, Anuj Goel, Sarah E. Hunt, Karin Leander, Ferdinand M. van't Hooft, Angela Silveira, Rory Collins, Samuli Ripatti, Muhammed Murtaza, Pamela Linksted, Per Eriksson, George V. Dedoussis, Sarah Edkins, Sonia S. Anand, Philippe M. Frossard, Tomas Axelsson, Ali Raza Gardezi, Peter Donnelly, Mieke D. Trip, Sarah Parish, Stephan Rust, Udo Seedorf, Gunnar O Olsson, Kathy Stirrups, Rona J. Strawbridge, Joban Sehmi, Derrick A Bennett, Other departments, ACS - Amsterdam Cardiovascular Sciences, Vascular Medicine, and Cardiology

Subjects
Adult, Male, South asia, Quantitative Trait Loci, ADAMTS7 Protein, Single-nucleotide polymorphism, Genome-wide association study, Coronary Artery Disease, Biology, 030204 cardiovascular system & hematology, Polymorphism, Single Nucleotide, Article, White People, Coronary artery disease, 03 medical and health sciences, 0302 clinical medicine, Asian People, Genotype, Genetics, Medicine, Humans, Genetic Predisposition to Disease, cardiovascular diseases, Myocardial infarction, Genotyping, Genetics (clinical), 030304 developmental biology, Genetic association, Aged, Oligonucleotide Array Sequence Analysis, Platelet-Derived Growth Factor, 0303 health sciences, Lymphokines, business.industry, Heritability, Middle Aged, Sterol Esterase, medicine.disease, ADAM Proteins, Case-Control Studies, Female, Cardiology and Cardiovascular Medicine, business, Imputation (genetics), Genome-Wide Association Study, Transcription Factors
Abstract

Study Hypothesis Recently, genome-wide association studies (GWAS) have identified several common variants associated with increased risk of coronary artery disease (CAD) and myocardial infarction (MI) by 10% to 30%. The authors state that these loci explain only a small proportion of the predicted genetic risk and that all of the current loci for CAD and MI by GWAS have been discovered in European populations. The authors hypothesized that discovery of new susceptibility loci of smaller effect sizes would be aided by conducting much larger studies in addition to an emphasis on early-onset CAD and clearly defined clinical end points. Therefore, they assembled the Coronary Artery Disease (C4D) Genetics Consortium.1 ### How Was the Hypothesis Tested? The authors performed a meta-analysis of 4 large GWAS of CAD, 2 of European ancestry (PROCARDIS and HPS) and 2 of South Asian ancestry (PROMIS and LOLLIPOP), with ≈575 000 genotyped single-nucleotide polymorphisms (SNPs) in a discovery data set comprising 15 420 individuals with CAD (cases) (8424 Europeans and 6996 South Asians) and 15 062 control subjects. They observed little evidence for ancestry-specific associations, supporting the use of combined analyses. Furthermore, the authors state that because all individuals were genotyped on the same platform (whole-genome Illumina BeadChips), a meta-analysis of actual genotypes rather than imputed data enabled analysis of low-frequency variants (1% to 5%), which have been excluded from GWAS either because of sample size or because imputation has been required to combine data from different genotyping platforms. After the meta-analysis, they selected 59 SNPs from 50 loci that showed potential new associations from the meta-analysis of the European and South Asian studies (41 SNPs; P

Published
2016

23. Common variants at 6q22 and 17q21 are associated with intracranial volume

Author

Julie A. Marsh, Meike W. Vernooij, Nicholas J. Timpson, Linda S. Adair, Maksim Struchalin, Kelly S. Benke, Alex P. Zijdenbos, Wiro J. Niessen, Dexter Hadley, André Scherag, Niina Siitonen, Johannes Hedebrand, Helena Schmidt, Iona Y. Millwood, Emily Oken, David S. Knopman, James F. Wilson, H. Rob Taal, Henri A. Vrooman, Karen L. Mohlke, Myriam Fornage, Vilmundur Gudnason, Leslie A. Lange, Sigurdur Sigurdsson, Maria M. Groen-Blokhuis, Diane J. Catellier, Stefan Ropele, Seang Mei Saw, Sylvain Sebert, Alexa S. Beiser, Lyle J. Palmer, Claudia Flexeder, Paul Elliott, George Davey Smith, John W. Holloway, Michel G. Nivard, Mike A. Nalls, Albert V. Smith, Cyrus Cooper, E Zeggini, Terho Lehtimäki, Struan F.A. Grant, Virpi Lindi, Romy Gaillard, B. Gwen Windham, Dennis O. Mook-Kanamori, Claus Holst, Timo A. Lakka, Stéphanie Debette, Liang Kee Goh, Ewan R. Pearson, Tamara B. Harris, Momoko Horikoshi, Jeffrey C. Murray, Mirna Kirin, M. Arfan Ikram, George V. Dedoussis, Anita L. DeStefano, Clifford R. Jack, Alex Lewin, Reedik Maggi, Vincent W. V. Jaddoe, Haukur Gudnason, Hakon Hakonarson, Thomas H. Mosley, Alina Rodriguez, Sudha Seshadri, William M. Meeks, Philip A. Wolf, Gonneke Willemsen, B. Valcarcel, Anke Hinney, Eric A.P. Steegers, Lenore J. Launer, Elina Hyppönen, Lachlan J. M. Coin, Elisabeth Thiering, Mustafa Atalay, W. T. Longstreth, Thorkild I. A. Sørensen, André G. Uitterlinden, Christel M. Middeldorp, Matthew W. Gillman, Ken K. Ong, Oliver S. P. Davis, Monique M.B. Breteler, Wei Ang, Ulla Sovio, Tuomas O. Kilpeläinen, Ioanna Ntalla, Marjo-Riitta Järvelin, Aad van der Lugt, Cornelia M. van Duijn, Cecilia M. Lindgren, Rany M. Salem, Laura H. Coker, Craig E. Pennell, Fernando Rivadeneira, Thomas S. Price, Charles DeCarli, Dorret I. Boomsma, Ellen Aagaard Nohr, Diane Berry, Rhoda Au, Yik Y. Teo, Ville Huikari, Jouke-Jan Hottenga, Matthew Kowgier, Joachim Heinrich, Nienke E. Bergen, Beate St Pourcain, Reinhold Schmidt, C Power, Kalliope Panoutsopoulou, Olli T. Raitakari, Albert Hofman, Mark I. McCarthy, Joel N. Hirschhorn, Olli Simell, Claire M. A. Haworth, Mark A. van Buchem, Anna-Liisa Hartikainen, Berthold Hocher, Debbie A Lawlor, Jennifer Pararajasingham, Toos C. E. M. van Beijsterveldt, David P. Strachan, Hanna Maaria Lakka, Timothy M. Frayling, Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium, Early Growth Genetics (EGG) Consortium, Ikram, M Afran, Fornage, Myriam, Smith, Albert V, Seshadri, Sudha, Hypponen, Elina Tuulikki, Wilson, James F, Biological Psychology, Radiology & Nuclear Medicine, Epidemiology, Erasmus MC other, Internal Medicine, Obstetrics & Gynecology, Public Health, and Medical Oncology

Subjects
Netherlands Twin Register (NTR), Genetic Markers, Male, medicine.medical_specialty, Medizin, Locus (genetics), Genome-wide association study, physiopathology [Brain], Biology, Bioinformatics, Polymorphism, Single Nucleotide, Article, genetics [Chromosomes, Human, Pair 17], 03 medical and health sciences, 0302 clinical medicine, ddc:570, Intracranial volume, Internal medicine, medicine, Genetics, Humans, 030304 developmental biology, Aged, Aged, 80 and over, 0303 health sciences, Haplotype, Chromosome, Brain, Infant, genetics [Chromosomes, Human, Pair 6], Microdeletion syndrome, ta3121, physiopathology [Head], Endocrinology, Genetic marker, Genetic Loci, Brain size, genetics [Polymorphism, Single Nucleotide], Institut für Ernährungswissenschaft, Chromosomes, Human, Pair 6, Female, Head, 030217 neurology & neurosurgery, Chromosomes, Human, Pair 17, Genome-Wide Association Study
Abstract

During aging, intracranial volume remains unchanged and represents maximally attained brain size, while various interacting biological phenomena lead to brain volume loss. Consequently, intracranial volume and brain volume in late life reflect different genetic influences. Our genome-wide association study (GWAS) in 8,175 community-dwelling elderly persons did not reveal any associations at genome-wide significance (P < 5 × 10 -8) for brain volume. In contrast, intracranial volume was significantly associated with two loci: rs4273712 (P = 3.4 × 10 -11), a known height-associated locus on chromosome 6q22, and rs9915547 (P = 1.5 × 10 -12), localized to the inversion on chromosome 17q21. We replicated the associations of these loci with intracranial volume in a separate sample of 1,752 elderly persons (P = 1.1 × 10 -3 for 6q22 and 1.2 × 10 -3 for 17q21). Furthermore, we also found suggestive associations of the 17q21 locus with head circumference in 10,768 children (mean age of 14.5 months). Our data identify two loci associated with head size, with the inversion at 17q21 also likely to be involved in attaining maximal brain size. © 2012 Nature America, Inc. All rights reserved.

Published
2012
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26. A Genome-Wide Association Study Identifies rs2000999 as a Strong Genetic Determinant of Circulating Haptoglobin Levels

Author

Paul Elliott, M. R. Järvelin, Amélie Bonnefond, Lars Sjöström, Andrew Walley, Anita Morandi, Mario Falchi, Aimo Ruokonen, Aurélie Dechaume, Philippe Froguel, Said El Shamieh, Lena M. S. Carlsson, Sophie Visvikis-Siest, Maria G. Stathopoulou, Rosa-Maria Guéant-Rodriguez, David Meyre, Leonardo Bottolo, Bernard Herbeth, Michel Langlois, George V. Dedoussis, Yann Labrune, Nabila Bouatia-Naji, Joris R. Delanghe, Cécile Lecoeur, Claudio Maffeis, Ndeye Coumba Ndiaye, Peter Jacobson, Gérard Siest, and Medical Research Council (MRC)

Subjects
Male, PEDIGREE ANALYSIS, Epidemiology, lcsh:Medicine, Genome-wide association study, 030204 cardiovascular system & hematology, PHENOTYPE, Pediatrics, genome-wide, 0302 clinical medicine, Risk Factors, Genotype, lcsh:Science, Child, HEMOGLOBIN, 0303 health sciences, Multidisciplinary, Haptoglobin, Genomics, haptoglobin, 3. Good health, ADIPOSE-TISSUE, Infectious Diseases, Cardiovascular Diseases, Science & Technology - Other Topics, Medicine, Female, Public Health, CHRONIC HEPATITIS-C, Research Article, Adult, children, General Science & Technology, Immunology, Single-nucleotide polymorphism, Biology, Polymorphism, Single Nucleotide, 03 medical and health sciences, INFLAMMATION, Genome Analysis Tools, Diagnostic Medicine, Diabetes mellitus, MD Multidisciplinary, medicine, Genetics, SNP, Humans, Genetic variability, Genotyping, 030304 developmental biology, Clinical Genetics, Science & Technology, Population Biology, Haptoglobins, MULTIDISCIPLINARY SCIENCES, lcsh:R, Immunity, Biology and Life Sciences, Computational Biology, Human Genetics, medicine.disease, POLYMORPHISM, PLASMA-GLUCOSE LEVELS, CARDIOVASCULAR-DISEASES, RISK-FACTORS, biology.protein, lcsh:Q, Clinical Immunology, Genome-Wide Association Study
Abstract

Haptoglobin is an acute phase inflammatory marker. Its main function is to bind hemoglobin released from erythrocytes to aid its elimination, and thereby haptoglobin prevents the generation of reactive oxygen species in the blood. Haptoglobin levels have been repeatedly associated with a variety of inflammation-linked infectious and non-infectious diseases, including malaria, tuberculosis, human immunodeficiency virus, hepatitis C, diabetes, carotid atherosclerosis, and acute myocardial infarction. However, a comprehensive genetic assessment of the inter-individual variability of circulating haptoglobin levels has not been conducted so far.We used a genome-wide association study initially conducted in 631 French children followed by a replication in three additional European sample sets and we identified a common single nucleotide polymorphism (SNP), rs2000999 located in the Haptoglobin gene (HP) as a strong genetic predictor of circulating Haptoglobin levels (P(overall) = 8.1 × 10(-59)), explaining 45.4% of its genetic variability (11.8% of Hp global variance). The functional relevance of rs2000999 was further demonstrated by its specific association with HP mRNA levels (β = 0.23 ± 0.08, P = 0.007). Finally, SNP rs2000999 was associated with decreased total and low-density lipoprotein cholesterol in 8,789 European children (P(total cholesterol) = 0.002 and P(LDL) = 0.0008).Given the central position of haptoglobin in many inflammation-related metabolic pathways, the relevance of rs2000999 genotyping when evaluating haptoglobin concentration should be further investigated in order to improve its diagnostic/therapeutic and/or prevention impact.

Published
2012
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27. Adipokine expression in adipose tissue and in peripheral blood mononuclear cells in children Correlation with BMI and fatty acid content

Author

George V, Dedoussis, Alexandra, Kapiri, Nick, Kalogeropoulos, Anastasia, Samara, Dimitris, Dimitriadis, Daniel, Lambert, Michele, Pfister, Gerard, Siest, and Sophie, Visvikis-Siest

Subjects
Inflammation, Leptin, Male, Blood Cells, Interleukin-6, Tumor Necrosis Factor-alpha, Fatty Acids, Body Mass Index, Adipokines, Adipose Tissue, Body Composition, Leukocytes, Mononuclear, Humans, Female, Child, Nicotinamide Phosphoribosyltransferase
Abstract

Adipose tissue contributes in energy, lipid homeostasis and inflammation, through the adipokines it releases. Our aim was to study the associations between adipose tissue (AT) fatty acid content, adipokines' expression in AT and PBMCs and BMI in children.Thirty-one (17 male) healthy children aged 10.9+/-1.8years and of BMI 19.3+/-3.5kg/m(2) were enrolled. Adipokines (TNF-alpha, IL-6, leptin and visfatin) expression was quantified by real-time quantitative PCR in AT and PBMCs. Serum levels were measured by ELISA and fatty acids (FA) from AT by gas chromatography.BMI was correlated with monounsaturated fatty acids (MUFAs) (beta=0.339, p=0.043), arachidonic (AA) (beta=0.576, por =0.001) and eicosapentaenoic acids (EPA) (beta=0.404, p=0.004) and negatively with stearic acid (beta=-0.577, por =0.001). TNF-alpha and visfatin expression from PBMCs were positively correlated with MUFAs (beta=0.271, p=0.027 and beta=0.214, p=0.020, respectively), n-9 fatty acids (beta=0.313, p=0.010 and beta=0.269 and p=0.024, respectively) and with docosahexaenoic acid (DHA) (beta=0.429, p=0.004 and beta=0.484, por =0.001, respectively), while negatively with the ratio n-6/n-3 (beta=-0.490, p=0.007 and beta=-0.374, p=0.044).A series of FA molecules were correlated with children's BMI and with TNF-alpha and visfatin expression from PBMCs indicating that AT fatty acid content, might have a role, as a potential regulator of PBMCs inflammatory gene expression.

Published
2009

28. Design and descriptive characteristics of the GHRAS: the Greek Health Randomized Aging Study

Author

Stavroula, Kanoni and George V, Dedoussis

Subjects
Aged, 80 and over, Male, Aging, Sex Characteristics, Greece, Health Status, Hypercholesterolemia, Smoking, Blood Pressure, Middle Aged, Health Surveys, Body Mass Index, Random Allocation, Cholesterol, Socioeconomic Factors, Cardiovascular Diseases, Health, Surveys and Questionnaires, Hypertension, Diabetes Mellitus, Humans, Female, Obesity, Life Style, Aged
Abstract

The "GHRAS" study is aimed at investigating the interactions among socioeconomic, lifestyle, dietary, psychological, and biochemical factors determining the health status of elderly Greeks. The design and baseline sociodemographic, clinical, and dietary characteristics of the participants are presented here.A total of 782 elderly (60 years of age) Greeks were randomly recruited in Athens. Standardized anthropometric, biochemical, and clinical procedures and extensive questionnaires were used to assess health parameters and lifestyle factors.A high prevalence of hypercholesterolemia was found in both men and women (78.7% vs. 90.1%, p0.001) as well as hypertension (81.3% vs. 71.8, p=0.005). Obesity was found in 43.6% of all participants and 42.7% was overweight. Elderly women demonstrated higher mean BMI values than the men (30.2+/-5.0 vs. 28.7+/-4.0, p0.001). Only 13.4% of all subjects reported current smoking. The majority of the women (77.5%) had never smoked, while most of the men (53.4%) were former smokers. The women appeared more physically active and less adherent to the Mediterranean diet than the men. 36.2% of the women and 21.0% of the men had mild to severe depressive symptoms (p0.001), while 28.4% of the women and 25.4% of the men had cognitive decline (p=0.430). A history of cardiovascular disease was present in 19.9% and diabetes in 13.9% of all participants.The prevalence of morbidity risk factors in this population is high. Further investigation is required, including the interaction of compromising factors, to clarify their impact on the health status of the elderly.

Published
2008

29. The STK33-linked SNP rs4929949 is associated with obesity and BMI in two independent cohorts of Swedish and Greek children.

Author

Mathias Rask-Andersen, George Moschonis, George P Chrousos, Claude Marcus, George V Dedoussis, Robert Fredriksson, and Helgi B Schiöth

Subjects
Medicine, Science
Abstract

Recent genome wide association studies (GWAS) have identified a locus on chromosome 11p15.5, closely associated with serine/threonine kinase 33 (STK33), to be associated with body mass. STK33, a relatively understudied protein, has been linked to KRAS mutation-driven cancers and explored as a potential antineoplastic drug target. The strongest association with body mass observed at this loci in GWAS was rs4929949, a single nucleotide polymorphism located within intron 1 of the gene encoding STK33. The functional implications of rs4929949 or related variants have not been explored as of yet. We have genotyped rs4929949 in two cohorts, an obesity case-control cohort of 991 Swedish children, and a cross-sectional cohort of 2308 Greek school children. We found that the minor allele of rs4929949 was associated with obesity in the cohort of Swedish children and adolescents (OR = 1.199 (95%CI: 1.002-1.434), p = 0.047), and with body mass in the cross-sectional cohort of Greek children (β = 0.08147 (95% CI: 0.1345-0.1618), p = 0.021). We observe the effects of rs4929949 on body mass to be detectable already at adolescence. Subsequent analysis did not detect any association of rs4929949 to phenotypic measurements describing body adiposity or to metabolic factors such as insulin levels, triglycerides and insulin resistance (HOMA).

Published
2013
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30. A genome-wide association study identifies rs2000999 as a strong genetic determinant of circulating haptoglobin levels.

Author

Philippe Froguel, Ndeye Coumba Ndiaye, Amélie Bonnefond, Nabila Bouatia-Naji, Aurélie Dechaume, Gérard Siest, Bernard Herbeth, Mario Falchi, Leonardo Bottolo, Rosa-Maria Guéant-Rodriguez, Cécile Lecoeur, Michel R Langlois, Yann Labrune, Aimo Ruokonen, Said El Shamieh, Maria G Stathopoulou, Anita Morandi, Claudio Maffeis, David Meyre, Joris R Delanghe, Peter Jacobson, Lars Sjöström, Lena M S Carlsson, Andrew Walley, Paul Elliott, Marjo-Riita Jarvelin, George V Dedoussis, and Sophie Visvikis-Siest

Subjects
Medicine, Science
Abstract

Haptoglobin is an acute phase inflammatory marker. Its main function is to bind hemoglobin released from erythrocytes to aid its elimination, and thereby haptoglobin prevents the generation of reactive oxygen species in the blood. Haptoglobin levels have been repeatedly associated with a variety of inflammation-linked infectious and non-infectious diseases, including malaria, tuberculosis, human immunodeficiency virus, hepatitis C, diabetes, carotid atherosclerosis, and acute myocardial infarction. However, a comprehensive genetic assessment of the inter-individual variability of circulating haptoglobin levels has not been conducted so far.We used a genome-wide association study initially conducted in 631 French children followed by a replication in three additional European sample sets and we identified a common single nucleotide polymorphism (SNP), rs2000999 located in the Haptoglobin gene (HP) as a strong genetic predictor of circulating Haptoglobin levels (P(overall) = 8.1 × 10(-59)), explaining 45.4% of its genetic variability (11.8% of Hp global variance). The functional relevance of rs2000999 was further demonstrated by its specific association with HP mRNA levels (β = 0.23 ± 0.08, P = 0.007). Finally, SNP rs2000999 was associated with decreased total and low-density lipoprotein cholesterol in 8,789 European children (P(total cholesterol) = 0.002 and P(LDL) = 0.0008).Given the central position of haptoglobin in many inflammation-related metabolic pathways, the relevance of rs2000999 genotyping when evaluating haptoglobin concentration should be further investigated in order to improve its diagnostic/therapeutic and/or prevention impact.

Published
2012
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31. Genome-wide association study to identify common variants associated with brachial circumference: a meta-analysis of 14 cohorts.

Author

Vesna Boraska, Aaron Day-Williams, Christopher S Franklin, Katherine S Elliott, Kalliope Panoutsopoulou, Ioanna Tachmazidou, Eva Albrecht, Stefania Bandinelli, Lawrence J Beilin, Murielle Bochud, Gemma Cadby, Florian Ernst, David M Evans, Caroline Hayward, Andrew A Hicks, Jennifer Huffman, Cornelia Huth, Alan L James, Norman Klopp, Ivana Kolcic, Zoltán Kutalik, Debbie A Lawlor, Arthur W Musk, Marina Pehlic, Craig E Pennell, John R B Perry, Annette Peters, Ozren Polasek, Beate St Pourcain, Susan M Ring, Erika Salvi, Sabine Schipf, Jan A Staessen, Alexander Teumer, Nicholas Timpson, Veronique Vitart, Nicole M Warrington, Hanieh Yaghootkar, Tatijana Zemunik, Lina Zgaga, Ping An, Verneri Anttila, Ingrid B Borecki, Jostein Holmen, Ioanna Ntalla, Aarno Palotie, Kirsi H Pietiläinen, Juho Wedenoja, Bendik S Winsvold, George V Dedoussis, Jaakko Kaprio, Michael A Province, John-Anker Zwart, Michel Burnier, Harry Campbell, Daniele Cusi, George Davey Smith, Timothy M Frayling, Christian Gieger, Lyle J Palmer, Peter P Pramstaller, Igor Rudan, Henry Völzke, H-Erich Wichmann, Alan F Wright, and Eleftheria Zeggini

Subjects
Medicine, Science
Abstract

Brachial circumference (BC), also known as upper arm or mid arm circumference, can be used as an indicator of muscle mass and fat tissue, which are distributed differently in men and women. Analysis of anthropometric measures of peripheral fat distribution such as BC could help in understanding the complex pathophysiology behind overweight and obesity. The purpose of this study is to identify genetic variants associated with BC through a large-scale genome-wide association scan (GWAS) meta-analysis. We used fixed-effects meta-analysis to synthesise summary results across 14 GWAS discovery and 4 replication cohorts comprising overall 22,376 individuals (12,031 women and 10,345 men) of European ancestry. Individual analyses were carried out for men, women, and combined across sexes using linear regression and an additive genetic model: adjusted for age and adjusted for age and BMI. We prioritised signals for follow-up in two-stages. We did not detect any signals reaching genome-wide significance. The FTO rs9939609 SNP showed nominal evidence for association (p

Published
2012
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32. A genome-wide association search for type 2 diabetes genes in African Americans.

Author

Nicholette D Palmer, Caitrin W McDonough, Pamela J Hicks, Bong H Roh, Maria R Wing, S Sandy An, Jessica M Hester, Jessica N Cooke, Meredith A Bostrom, Megan E Rudock, Matthew E Talbert, Joshua P Lewis, DIAGRAM Consortium, MAGIC Investigators, Assiamira Ferrara, Lingyi Lu, Julie T Ziegler, Michele M Sale, Jasmin Divers, Daniel Shriner, Adebowale Adeyemo, Charles N Rotimi, Maggie C Y Ng, Carl D Langefeld, Barry I Freedman, Donald W Bowden, Benjamin F Voight, Laura J Scott, Valgerdur Steinthorsdottir, Andrew P Morris, Christian Dina, Ryan P Welch, Eleftheria Zeggini, Cornelia Huth, Yurii S Aulchenko, Gudmar Thorleifsson, Laura J McCulloch, Teresa Ferreira, Harald Grallert, Najaf Amin, Guanming Wu, Cristen J Willer, Soumya Raychaudhuri, Steve A McCarroll, Claudia Langenberg, Oliver M Hofmann, Josée Dupuis, Lu Qi, Ayellet V Segrè, Mandy van Hoek, Pau Navarro, Kristin Ardlie, Beverley Balkau, Rafn Benediktsson, Amanda J Bennett, Roza Blagieva, Eric Boerwinkle, Lori L Bonnycastle, Kristina Bengtsson Boström, Bert Bravenboer, Suzannah Bumpstead, Noël P Burtt, Guillaume Charpentier, Peter S Chines, Marilyn Cornelis, David J Couper, Gabe Crawford, Alex S F Doney, Katherine S Elliott, Amanda L Elliott, Michael R Erdos, Caroline S Fox, Christopher S Franklin, Martha Ganser, Christian Gieger, Niels Grarup, Todd Green, Simon Griffin, Christopher J Groves, Candace Guiducci, Samy Hadjadj, Neelam Hassanali, Christian Herder, Bo Isomaa, Anne U Jackson, Paul R V Johnson, Torben Jørgensen, Wen H L Kao, Norman Klopp, Augustine Kong, Peter Kraft, Johanna Kuusisto, Torsten Lauritzen, Man Li, Aloysius Lieverse, Cecilia M Lindgren, Valeriya Lyssenko, Michel Marre, Thomas Meitinger, Kristian Midthjell, Mario A Morken, Narisu Narisu, Peter Nilsson, Katharine R Owen, Felicity Payne, John R B Perry, Ann-Kristin Petersen, Carl Platou, Christine Proença, Inga Prokopenko, Wolfgang Rathmann, N William Rayner, Neil R Robertson, Ghislain Rocheleau, Michael Roden, Michael J Sampson, Richa Saxena, Beverley M Shields, Peter Shrader, Gunnar Sigurdsson, Thomas Sparsø, Klaus Strassburger, Heather M Stringham, Qi Sun, Amy J Swift, Barbara Thorand, Jean Tichet, Tiinamaija Tuomi, Rob M van Dam, Timon W van Haeften, Thijs van Herpt, Jana V van Vliet-Ostaptchouk, G Bragi Walters, Michael N Weedon, Cisca Wijmenga, Jacqueline Witteman, Richard N Bergman, Stephane Cauchi, Francis S Collins, Anna L Gloyn, Ulf Gyllensten, Torben Hansen, Winston A Hide, Graham A Hitman, Albert Hofman, David J Hunter, Kristian Hveem, Markku Laakso, Karen L Mohlke, Andrew D Morris, Colin N A Palmer, Peter P Pramstaller, Igor Rudan, Eric Sijbrands, Lincoln D Stein, Jaakko Tuomilehto, Andre Uitterlinden, Mark Walker, Nicholas J Wareham, Richard M Watanabe, Goncalo R Abecasis, Bernhard O Boehm, Harry Campbell, Mark J Daly, Andrew T Hattersley, Frank B Hu, James B Meigs, James S Pankow, Oluf Pedersen, H-Erich Wichmann, Inês Barroso, Jose C Florez, Timothy M Frayling, Leif Groop, Rob Sladek, Unnur Thorsteinsdottir, James F Wilson, Thomas Illig, Philippe Froguel, Cornelia M van Duijn, Kari Stefansson, David Altshuler, Michael Boehnke, Mark I McCarthy, Nicole Soranzo, Eleanor Wheeler, Nicole L Glazer, Nabila Bouatia-Naji, Reedik Mägi, Joshua Randall, Toby Johnson, Paul Elliott, Denis Rybin, Peter Henneman, Abbas Dehghan, Jouke Jan Hottenga, Kijoung Song, Anuj Goel, Josephine M Egan, Taina Lajunen, Alex Doney, Stavroula Kanoni, Christine Cavalcanti-Proença, Meena Kumari, Nicholas J Timpson, Carina Zabena, Erik Ingelsson, Ping An, Jeffrey O'Connell, Jian'an Luan, Amanda Elliott, Steven A McCarroll, Rosa Maria Roccasecca, François Pattou, Praveen Sethupathy, Yavuz Ariyurek, Philip Barter, John P Beilby, Yoav Ben-Shlomo, Sven Bergmann, Murielle Bochud, Amélie Bonnefond, Knut Borch-Johnsen, Yvonne Böttcher, Eric Brunner, Suzannah J Bumpstead, Yii-Der Ida Chen, Peter Chines, Robert Clarke, Lachlan J M Coin, Matthew N Cooper, Laura Crisponi, Ian N M Day, Eco J C de Geus, Jerome Delplanque, Annette C Fedson, Antje Fischer-Rosinsky, Nita G Forouhi, Rune Frants, Maria Grazia Franzosi, Pilar Galan, Mark O Goodarzi, Jürgen Graessler, Scott Grundy, Rhian Gwilliam, Göran Hallmans, Naomi Hammond, Xijing Han, Anna-Liisa Hartikainen, Caroline Hayward, Simon C Heath, Serge Hercberg, Andrew A Hicks, David R Hillman, Aroon D Hingorani, Jennie Hui, Joe Hung, Antti Jula, Marika Kaakinen, Jaakko Kaprio, Y Antero Kesaniemi, Mika Kivimaki, Beatrice Knight, Seppo Koskinen, Peter Kovacs, Kirsten Ohm Kyvik, G Mark Lathrop, Debbie A Lawlor, Olivier Le Bacquer, Cécile Lecoeur, Yun Li, Robert Mahley, Massimo Mangino, Alisa K Manning, María Teresa Martínez-Larrad, Jarred B McAteer, Ruth McPherson, Christa Meisinger, David Melzer, David Meyre, Braxton D Mitchell, Sutapa Mukherjee, Silvia Naitza, Matthew J Neville, Ben A Oostra, Marco Orrù, Ruth Pakyz, Giuseppe Paolisso, Cristian Pattaro, Daniel Pearson, John F Peden, Nancy L Pedersen, Markus Perola, Andreas F H Pfeiffer, Irene Pichler, Ozren Polasek, Danielle Posthuma, Simon C Potter, Anneli Pouta, Michael A Province, Bruce M Psaty, Nigel W Rayner, Kenneth Rice, Samuli Ripatti, Fernando Rivadeneira, Olov Rolandsson, Annelli Sandbaek, Manjinder Sandhu, Serena Sanna, Avan Aihie Sayer, Paul Scheet, Udo Seedorf, Stephen J Sharp, Beverley Shields, Eric J G Sijbrands, Angela Silveira, Laila Simpson, Andrew Singleton, Nicholas L Smith, Ulla Sovio, Amy Swift, Holly Syddall, Ann-Christine Syvänen, Toshiko Tanaka, Anke Tönjes, André G Uitterlinden, Ko Willems van Dijk, Dhiraj Varma, Sophie Visvikis-Siest, Veronique Vitart, Nicole Vogelzangs, Gérard Waeber, Peter J Wagner, Andrew Walley, Kim L Ward, Hugh Watkins, Sarah H Wild, Gonneke Willemsen, Jaqueline C M Witteman, John W G Yarnell, Diana Zelenika, Björn Zethelius, Guangju Zhai, Jing Hua Zhao, M Carola Zillikens, Ingrid B Borecki, Ruth J F Loos, Pierre Meneton, Patrik K E Magnusson, David M Nathan, Gordon H Williams, Kaisa Silander, Veikko Salomaa, George Davey Smith, Stefan R Bornstein, Peter Schwarz, Joachim Spranger, Fredrik Karpe, Alan R Shuldiner, Cyrus Cooper, George V Dedoussis, Manuel Serrano-Ríos, Lars Lind, Lyle J Palmer, Paul W Franks, Shah Ebrahim, Michael Marmot, W H Linda Kao, Peter Paul Pramstaller, Alan F Wright, Michael Stumvoll, Anders Hamsten, Thomas A Buchanan, Timo T Valle, Jerome I Rotter, David S Siscovick, Brenda W J H Penninx, Dorret I Boomsma, Panos Deloukas, Timothy D Spector, Luigi Ferrucci, Antonio Cao, Angelo Scuteri, David Schlessinger, Manuela Uda, Aimo Ruokonen, Marjo-Riitta Jarvelin, Dawn M Waterworth, Peter Vollenweider, Leena Peltonen, Vincent Mooser, and Robert Sladek

Subjects
Medicine, Science
Abstract

African Americans are disproportionately affected by type 2 diabetes (T2DM) yet few studies have examined T2DM using genome-wide association approaches in this ethnicity. The aim of this study was to identify genes associated with T2DM in the African American population. We performed a Genome Wide Association Study (GWAS) using the Affymetrix 6.0 array in 965 African-American cases with T2DM and end-stage renal disease (T2DM-ESRD) and 1029 population-based controls. The most significant SNPs (n = 550 independent loci) were genotyped in a replication cohort and 122 SNPs (n = 98 independent loci) were further tested through genotyping three additional validation cohorts followed by meta-analysis in all five cohorts totaling 3,132 cases and 3,317 controls. Twelve SNPs had evidence of association in the GWAS (P

Published
2012
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33. Novel loci for adiponectin levels and their influence on type 2 diabetes and metabolic traits: a multi-ethnic meta-analysis of 45,891 individuals.

Author

Zari Dastani, Marie-France Hivert, Nicholas Timpson, John R B Perry, Xin Yuan, Robert A Scott, Peter Henneman, Iris M Heid, Jorge R Kizer, Leo-Pekka Lyytikäinen, Christian Fuchsberger, Toshiko Tanaka, Andrew P Morris, Kerrin Small, Aaron Isaacs, Marian Beekman, Stefan Coassin, Kurt Lohman, Lu Qi, Stavroula Kanoni, James S Pankow, Hae-Won Uh, Ying Wu, Aurelian Bidulescu, Laura J Rasmussen-Torvik, Celia M T Greenwood, Martin Ladouceur, Jonna Grimsby, Alisa K Manning, Ching-Ti Liu, Jaspal Kooner, Vincent E Mooser, Peter Vollenweider, Karen A Kapur, John Chambers, Nicholas J Wareham, Claudia Langenberg, Rune Frants, Ko Willems-Vandijk, Ben A Oostra, Sara M Willems, Claudia Lamina, Thomas W Winkler, Bruce M Psaty, Russell P Tracy, Jennifer Brody, Ida Chen, Jorma Viikari, Mika Kähönen, Peter P Pramstaller, David M Evans, Beate St Pourcain, Naveed Sattar, Andrew R Wood, Stefania Bandinelli, Olga D Carlson, Josephine M Egan, Stefan Böhringer, Diana van Heemst, Lyudmyla Kedenko, Kati Kristiansson, Marja-Liisa Nuotio, Britt-Marie Loo, Tamara Harris, Melissa Garcia, Alka Kanaya, Margot Haun, Norman Klopp, H-Erich Wichmann, Panos Deloukas, Efi Katsareli, David J Couper, Bruce B Duncan, Margreet Kloppenburg, Linda S Adair, Judith B Borja, DIAGRAM+ Consortium, MAGIC Consortium, GLGC Investigators, MuTHER Consortium, James G Wilson, Solomon Musani, Xiuqing Guo, Toby Johnson, Robert Semple, Tanya M Teslovich, Matthew A Allison, Susan Redline, Sarah G Buxbaum, Karen L Mohlke, Ingrid Meulenbelt, Christie M Ballantyne, George V Dedoussis, Frank B Hu, Yongmei Liu, Bernhard Paulweber, Timothy D Spector, P Eline Slagboom, Luigi Ferrucci, Antti Jula, Markus Perola, Olli Raitakari, Jose C Florez, Veikko Salomaa, Johan G Eriksson, Timothy M Frayling, Andrew A Hicks, Terho Lehtimäki, George Davey Smith, David S Siscovick, Florian Kronenberg, Cornelia van Duijn, Ruth J F Loos, Dawn M Waterworth, James B Meigs, Josee Dupuis, J Brent Richards, Benjamin F Voight, Laura J Scott, Valgerdur Steinthorsdottir, Christian Dina, Ryan P Welch, Eleftheria Zeggini, Cornelia Huth, Yurii S Aulchenko, Gudmar Thorleifsson, Laura J McCulloch, Teresa Ferreira, Harald Grallert, Najaf Amin, Guanming Wu, Cristen J Willer, Soumya Raychaudhuri, Steve A McCarroll, Oliver M Hofmann, Ayellet V Segrè, Mandy van Hoek, Pau Navarro, Kristin Ardlie, Beverley Balkau, Rafn Benediktsson, Amanda J Bennett, Roza Blagieva, Eric Boerwinkle, Lori L Bonnycastle, Kristina Bengtsson Boström, Bert Bravenboer, Suzannah Bumpstead, Noël P Burtt, Guillaume Charpentier, Peter S Chines, Marilyn Cornelis, Gabe Crawford, Alex S F Doney, Katherine S Elliott, Amanda L Elliott, Michael R Erdos, Caroline S Fox, Christopher S Franklin, Martha Ganser, Christian Gieger, Niels Grarup, Todd Green, Simon Griffin, Christopher J Groves, Candace Guiducci, Samy Hadjadj, Neelam Hassanali, Christian Herder, Bo Isomaa, Anne U Jackson, Paul R V Johnson, Torben Jørgensen, Wen H L Kao, Augustine Kong, Peter Kraft, Johanna Kuusisto, Torsten Lauritzen, Man Li, Aloysius Lieverse, Cecilia M Lindgren, Valeriya Lyssenko, Michel Marre, Thomas Meitinger, Kristian Midthjell, Mario A Morken, Narisu Narisu, Peter Nilsson, Katharine R Owen, Felicity Payne, Ann-Kristin Petersen, Carl Platou, Christine Proença, Inga Prokopenko, Wolfgang Rathmann, N William Rayner, Neil R Robertson, Ghislain Rocheleau, Michael Roden, Michael J Sampson, Richa Saxena, Beverley M Shields, Peter Shrader, Gunnar Sigurdsson, Thomas Sparsø, Klaus Strassburger, Heather M Stringham, Qi Sun, Amy J Swift, Barbara Thorand, Jean Tichet, Tiinamaija Tuomi, Rob M van Dam, Timon W van Haeften, Thijs van Herpt, Jana V van Vliet-Ostaptchouk, G Bragi Walters, Michael N Weedon, Cisca Wijmenga, Jacqueline Witteman, Richard N Bergman, Stephane Cauchi, Francis S Collins, Anna L Gloyn, Ulf Gyllensten, Torben Hansen, Winston A Hide, Graham A Hitman, Albert Hofman, David J Hunter, Kristian Hveem, Markku Laakso, Andrew D Morris, Colin N A Palmer, Igor Rudan, Eric Sijbrands, Lincoln D Stein, Jaakko Tuomilehto, Andre Uitterlinden, Mark Walker, Richard M Watanabe, Goncalo R Abecasis, Bernhard O Boehm, Harry Campbell, Mark J Daly, Andrew T Hattersley, Oluf Pedersen, Inês Barroso, Leif Groop, Rob Sladek, Unnur Thorsteinsdottir, James F Wilson, Thomas Illig, Philippe Froguel, Cornelia M van Duijn, Kari Stefansson, David Altshuler, Michael Boehnke, Mark I McCarthy, Nicole Soranzo, Eleanor Wheeler, Nicole L Glazer, Nabila Bouatia-Naji, Reedik Mägi, Joshua Randall, Paul Elliott, Denis Rybin, Abbas Dehghan, Jouke Jan Hottenga, Kijoung Song, Anuj Goel, Taina Lajunen, Alex Doney, Christine Cavalcanti-Proença, Meena Kumari, Nicholas J Timpson, Carina Zabena, Erik Ingelsson, Ping An, Jeffrey O'Connell, Jian'an Luan, Amanda Elliott, Steven A McCarroll, Rosa Maria Roccasecca, François Pattou, Praveen Sethupathy, Yavuz Ariyurek, Philip Barter, John P Beilby, Yoav Ben-Shlomo, Sven Bergmann, Murielle Bochud, Amélie Bonnefond, Knut Borch-Johnsen, Yvonne Böttcher, Eric Brunner, Suzannah J Bumpstead, Yii-Der Ida Chen, Peter Chines, Robert Clarke, Lachlan J M Coin, Matthew N Cooper, Laura Crisponi, Ian N M Day, Eco J C de Geus, Jerome Delplanque, Annette C Fedson, Antje Fischer-Rosinsky, Nita G Forouhi, Maria Grazia Franzosi, Pilar Galan, Mark O Goodarzi, Jürgen Graessler, Scott Grundy, Rhian Gwilliam, Göran Hallmans, Naomi Hammond, Xijing Han, Anna-Liisa Hartikainen, Caroline Hayward, Simon C Heath, Serge Hercberg, David R Hillman, Aroon D Hingorani, Jennie Hui, Joe Hung, Marika Kaakinen, Jaakko Kaprio, Y Antero Kesaniemi, Mika Kivimaki, Beatrice Knight, Seppo Koskinen, Peter Kovacs, Kirsten Ohm Kyvik, G Mark Lathrop, Debbie A Lawlor, Olivier Le Bacquer, Cécile Lecoeur, Yun Li, Robert Mahley, Massimo Mangino, María Teresa Martínez-Larrad, Jarred B McAteer, Ruth McPherson, Christa Meisinger, David Melzer, David Meyre, Braxton D Mitchell, Sutapa Mukherjee, Silvia Naitza, Matthew J Neville, Marco Orrù, Ruth Pakyz, Giuseppe Paolisso, Cristian Pattaro, Daniel Pearson, John F Peden, Nancy L Pedersen, Andreas F H Pfeiffer, Irene Pichler, Ozren Polasek, Danielle Posthuma, Simon C Potter, Anneli Pouta, Michael A Province, Nigel W Rayner, Kenneth Rice, Samuli Ripatti, Fernando Rivadeneira, Olov Rolandsson, Annelli Sandbaek, Manjinder Sandhu, Serena Sanna, Avan Aihie Sayer, Paul Scheet, Udo Seedorf, Stephen J Sharp, Beverley Shields, Gunnar Sigurðsson, Eric J G Sijbrands, Angela Silveira, Laila Simpson, Andrew Singleton, Nicholas L Smith, Ulla Sovio, Amy Swift, Holly Syddall, Ann-Christine Syvänen, Anke Tönjes, André G Uitterlinden, Ko Willems van Dijk, Dhiraj Varma, Sophie Visvikis-Siest, Veronique Vitart, Nicole Vogelzangs, Gérard Waeber, Peter J Wagner, Andrew Walley, Kim L Ward, Hugh Watkins, Sarah H Wild, Gonneke Willemsen, Jaqueline C M Witteman, John W G Yarnell, Diana Zelenika, Björn Zethelius, Guangju Zhai, Jing Hua Zhao, M Carola Zillikens, DIAGRAM Consortium, GIANT Consortium, Global B Pgen Consortium, Ingrid B Borecki, Pierre Meneton, Patrik K E Magnusson, David M Nathan, Gordon H Williams, Kaisa Silander, Stefan R Bornstein, Peter Schwarz, Joachim Spranger, Fredrik Karpe, Alan R Shuldiner, Cyrus Cooper, Manuel Serrano-Ríos, Lars Lind, Lyle J Palmer, Paul W Franks, Shah Ebrahim, Michael Marmot, W H Linda Kao, Peter Paul Pramstaller, Alan F Wright, Michael Stumvoll, Anders Hamsten, Procardis Consortium, Thomas A Buchanan, Timo T Valle, Jerome I Rotter, Brenda W J H Penninx, Dorret I Boomsma, Antonio Cao, Angelo Scuteri, David Schlessinger, Manuela Uda, Aimo Ruokonen, Marjo-Riitta Jarvelin, Leena Peltonen, Vincent Mooser, Robert Sladek, MAGIC investigators, GLGC Consortium, Kiran Musunuru, Albert V Smith, Andrew C Edmondson, Ioannis M Stylianou, Masahiro Koseki, James P Pirruccello, Daniel I Chasman, Christopher T Johansen, Sigrid W Fouchier, Gina M Peloso, Maja Barbalic, Sally L Ricketts, Joshua C Bis, Mary F Feitosa, Marju Orho-Melander, Olle Melander, Xiaohui Li, Mingyao Li, Yoon Shin Cho, Min Jin Go, Young Jin Kim, Jong-Young Lee, Taesung Park, Kyunga Kim, Xueling Sim, Rick Twee-Hee Ong, Damien C Croteau-Chonka, Leslie A Lange, Joshua D Smith, Andreas Ziegler, Weihua Zhang, Robert Y L Zee, John B Whitfield, John R Thompson, Ida Surakka, Tim D Spector, Johannes H Smit, Juha Sinisalo, James Scott, Juha Saharinen, Chiara Sabatti, Lynda M Rose, Robert Roberts, Mark Rieder, Alex N Parker, Guillaume Pare, Christopher J O'Donnell, Markku S Nieminen, Deborah A Nickerson, Grant W Montgomery, Wendy McArdle, David Masson, Nicholas G Martin, Fabio Marroni, Gavin Lucas, Robert Luben, Marja-Liisa Lokki, Guillaume Lettre, Lenore J Launer, Edward G Lakatta, Reijo Laaksonen, Kirsten O Kyvik, Inke R König, Kay-Tee Khaw, Lee M Kaplan, Åsa Johansson, A Cecile J W Janssens, Wilmar Igl, G Kees Hovingh, Christian Hengstenberg, Aki S Havulinna, Nicholas D Hastie, Tamara B Harris, Talin Haritunians, Alistair S Hall, Leif C Groop, Elena Gonzalez, Nelson B Freimer, Jeanette Erdmann, Kenechi G Ejebe, Angela Döring, Anna F Dominiczak, Serkalem Demissie, Panagiotis Deloukas, Ulf de Faire, Gabriel Crawford, Yii-der I Chen, Mark J Caulfield, S Matthijs Boekholdt, Themistocles L Assimes, Thomas Quertermous, Mark Seielstad, Tien Y Wong, E-Shyong Tai, Alan B Feranil, Christopher W Kuzawa, Herman A Taylor, Stacey B Gabriel, Hilma Holm, Vilmundur Gudnason, Ronald M Krauss, Jose M Ordovas, Patricia B Munroe, Jaspal S Kooner, Alan R Tall, Robert A Hegele, John J P Kastelein, Eric E Schadt, David P Strachan, Muredach P Reilly, Nilesh J Samani, Heribert Schunkert, L Adrienne Cupples, Manjinder S Sandhu, Paul M Ridker, Daniel J Rader, and Sekar Kathiresan

Subjects
Genetics, QH426-470
Abstract

Circulating levels of adiponectin, a hormone produced predominantly by adipocytes, are highly heritable and are inversely associated with type 2 diabetes mellitus (T2D) and other metabolic traits. We conducted a meta-analysis of genome-wide association studies in 39,883 individuals of European ancestry to identify genes associated with metabolic disease. We identified 8 novel loci associated with adiponectin levels and confirmed 2 previously reported loci (P = 4.5×10(-8)-1.2×10(-43)). Using a novel method to combine data across ethnicities (N = 4,232 African Americans, N = 1,776 Asians, and N = 29,347 Europeans), we identified two additional novel loci. Expression analyses of 436 human adipocyte samples revealed that mRNA levels of 18 genes at candidate regions were associated with adiponectin concentrations after accounting for multiple testing (p

Published
2012
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34. Physical activity attenuates the influence of FTO variants on obesity risk: a meta-analysis of 218,166 adults and 19,268 children.

Author

Tuomas O Kilpeläinen, Lu Qi, Soren Brage, Stephen J Sharp, Emily Sonestedt, Ellen Demerath, Tariq Ahmad, Samia Mora, Marika Kaakinen, Camilla Helene Sandholt, Christina Holzapfel, Christine S Autenrieth, Elina Hyppönen, Stéphane Cauchi, Meian He, Zoltan Kutalik, Meena Kumari, Alena Stančáková, Karina Meidtner, Beverley Balkau, Jonathan T Tan, Massimo Mangino, Nicholas J Timpson, Yiqing Song, M Carola Zillikens, Kathleen A Jablonski, Melissa E Garcia, Stefan Johansson, Jennifer L Bragg-Gresham, Ying Wu, Jana V van Vliet-Ostaptchouk, N Charlotte Onland-Moret, Esther Zimmermann, Natalia V Rivera, Toshiko Tanaka, Heather M Stringham, Günther Silbernagel, Stavroula Kanoni, Mary F Feitosa, Soren Snitker, Jonatan R Ruiz, Jeffery Metter, Maria Teresa Martinez Larrad, Mustafa Atalay, Maarit Hakanen, Najaf Amin, Christine Cavalcanti-Proença, Anders Grøntved, Göran Hallmans, John-Olov Jansson, Johanna Kuusisto, Mika Kähönen, Pamela L Lutsey, John J Nolan, Luigi Palla, Oluf Pedersen, Louis Pérusse, Frida Renström, Robert A Scott, Dmitry Shungin, Ulla Sovio, Tuija H Tammelin, Tapani Rönnemaa, Timo A Lakka, Matti Uusitupa, Manuel Serrano Rios, Luigi Ferrucci, Claude Bouchard, Aline Meirhaeghe, Mao Fu, Mark Walker, Ingrid B Borecki, George V Dedoussis, Andreas Fritsche, Claes Ohlsson, Michael Boehnke, Stefania Bandinelli, Cornelia M van Duijn, Shah Ebrahim, Debbie A Lawlor, Vilmundur Gudnason, Tamara B Harris, Thorkild I A Sørensen, Karen L Mohlke, Albert Hofman, André G Uitterlinden, Jaakko Tuomilehto, Terho Lehtimäki, Olli Raitakari, Bo Isomaa, Pål R Njølstad, Jose C Florez, Simin Liu, Andy Ness, Timothy D Spector, E Shyong Tai, Philippe Froguel, Heiner Boeing, Markku Laakso, Michael Marmot, Sven Bergmann, Chris Power, Kay-Tee Khaw, Daniel Chasman, Paul Ridker, Torben Hansen, Keri L Monda, Thomas Illig, Marjo-Riitta Järvelin, Nicholas J Wareham, Frank B Hu, Leif C Groop, Marju Orho-Melander, Ulf Ekelund, Paul W Franks, and Ruth J F Loos

Subjects
Medicine
Abstract

BackgroundThe FTO gene harbors the strongest known susceptibility locus for obesity. While many individual studies have suggested that physical activity (PA) may attenuate the effect of FTO on obesity risk, other studies have not been able to confirm this interaction. To confirm or refute unambiguously whether PA attenuates the association of FTO with obesity risk, we meta-analyzed data from 45 studies of adults (n = 218,166) and nine studies of children and adolescents (n = 19,268).Methods and findingsAll studies identified to have data on the FTO rs9939609 variant (or any proxy [r(2)>0.8]) and PA were invited to participate, regardless of ethnicity or age of the participants. PA was standardized by categorizing it into a dichotomous variable (physically inactive versus active) in each study. Overall, 25% of adults and 13% of children were categorized as inactive. Interaction analyses were performed within each study by including the FTO×PA interaction term in an additive model, adjusting for age and sex. Subsequently, random effects meta-analysis was used to pool the interaction terms. In adults, the minor (A-) allele of rs9939609 increased the odds of obesity by 1.23-fold/allele (95% CI 1.20-1.26), but PA attenuated this effect (p(interaction) = 0.001). More specifically, the minor allele of rs9939609 increased the odds of obesity less in the physically active group (odds ratio = 1.22/allele, 95% CI 1.19-1.25) than in the inactive group (odds ratio = 1.30/allele, 95% CI 1.24-1.36). No such interaction was found in children and adolescents.ConclusionsThe association of the FTO risk allele with the odds of obesity is attenuated by 27% in physically active adults, highlighting the importance of PA in particular in those genetically predisposed to obesity.

Published
2011
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