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1.  The TCF7L2 rs7903146 polymorphism, dietary intakes and type 2 diabetes risk in an Algerian population 
BMC Genetics  2014;15(1):134.
The transcription factor 7-like 2 (TCF7L2) gene is the most significant genetic risk factor for type 2 diabetes (T2D). Association analyses were performed on participants (n = 751, aged between 30 and 64) in the ISOR population-based study in the city of Oran. Dietary intakes were estimated using a weekly food frequency questionnaire.
The T allele of the rs7903146 single nucleotide polymorphism (SNP) was associated with lower body weight (p = 0.02), lower BMI (p = 0.009), lower waist circumference (p = 0.01) and a lower waist-to-hip ratio (p = 0.02). The T allele was associated with a significantly higher risk of T2D (odds ratio (OR) (95% confidence interval) = 1.55 (1.09–2.20), p = 0.01) and this association was independent of BMI. When considering the T2D risk, there were nominal interactions between the rs7903146 SNP and dessert (p = 0.05) and milk intakes (p = 0.01). The T2D risk was greater in T allele carriers with high dessert and milk intakes (OR = 2.61 (1.51-4.52), p = 0.0006, and 2.46 (1.47-4.12), p = 0.0006, respectively). In subjects with a high dessert intake, the T allele was also associated with higher fasting plasma glucose concentrations (4.89 ± 0.46 mmol/L in TT subjects, 4.72 ± 0.48 mmol/L in CT subjects and 4.78 ± 0.51 mmol/L in CC subjects; p = 0.03).
The T allele of the rs7903146 SNP is associated with a significantly higher risk of T2D in an Algerian population. This association was further strengthened by a high dessert intake, suggesting that gene-diet interactions increase the T2D risk.
PMCID: PMC4266211  PMID: 25491720
Diabetes; Gene-diet interaction; Polymorphism; TCF7L2; ISOR study
2.  Combined effect of established BMI loci on obesity-related traits in an Algerian population sample 
BMC Genetics  2014;15(1):128.
Genome-wide association studies have identified variants associated with BMI in populations of European descent. We sought to establish whether genetic variants that are robustly associated with BMI could modulate anthropometric traits and the obesity risk in an Algerian population sample, the ISOR study.
The ISOR study of 787 adult subjects (aged between 30 and 64) provided a representative sample of the population living in the city of Oran (north-west of Algeria). We investigated the combined effect of 29 BMI established genetic variants using a genetic predisposition score (GPS) on anthropometric traits and obesity risk in 740 subjects.
We found that each additional risk allele in the GPS was associated with an increment in the mean [95% CI] for BMI of 0.15 [0.06 - 0.24] kg/m2 (p = 0.001). Although the GPS was also associated with higher waist (p = 0.02) and hip (p = 0.02) circumferences, these associations were in fact driven by BMI. The GPS was also associated with an 11% higher risk of obesity (OR [95%CI] = 1.11 [1.05 - 1.18], p = 0.0004).
Our data showed that a GPS comprising 29 BMI established loci developed from Europeans seems to be a valid score in a North African population. Our findings contribute to a better understanding of the genetic susceptibility to obesity in Algeria.
Electronic supplementary material
The online version of this article (doi:10.1186/s12863-014-0128-1) contains supplementary material, which is available to authorized users.
PMCID: PMC4247883  PMID: 25422053
Genetic predisposition score; Polymorphism; BMI; Obesity; Algerian population; ISOR study
3.  Hypomethylation of the promoter of the catalytic subunit of protein phosphatase 2A in response to hyperglycemia 
Physiological Reports  2014;2(7):e12076.
In order to identify epigenetic mechanisms through which hyperglycemia can affect gene expression durably in β cells, we screened DNA methylation changes induced by high glucose concentrations (25 mmol/L) in the BTC3 murine cell line, using an epigenome‐wide approach. Exposure of BTC3 cells to high glucose modified the expression of 1612 transcripts while inducing significant methylation changes in 173 regions. Among these 173 glucose‐sensitive differentially methylated regions (DMRs), 14 were associated with changes in gene expression, suggesting an epigenetic effect of high glucose on gene transcription at these loci. Among these 14 DMRs, we selected for further study Pp2ac, a gene previously suspected to play a role in β‐cell physiology and type 2 diabetes. Using RT‐qPCR and bisulfite pyrosequencing, we confirmed our previous observations in BTC3 cells and found that this gene was significantly demethylated in the whole blood cells (WBCs) of type 2 diabetic patients compared to controls.
In order to identify epigenetic mechanisms through which hyperglycemia can affect gene expression durably in β cells, we screened DNA methylation changes induced by high glucose concentration in the BTC3 murine cell line. We identified one interesting gene, PP2AC, and confirmed it in type 2 diabetic patients.
PMCID: PMC4187575  PMID: 25347859
β cells; DNA methylation; gene expression; hyperglycemia; type 2 diabetes
4.  Effects of established BMI-associated loci on obesity-related traits in a French representative population sample 
BMC Genetics  2014;15:62.
Genome-wide association studies have identified variants associated with obesity-related traits, such as the body mass index (BMI). We sought to determine how the combination of 31 validated, BMI-associated loci contributes to obesity- and diabetes-related traits in a French population sample. The MONA LISA Lille study (1578 participants, aged 35–74) constitutes a representative sample of the population living in Lille (northern France). Genetic variants were considered both individually and combined into a genetic predisposition score (GPS).
Individually, 25 of 31 SNPs showed directionally consistent effects on BMI. Four loci (FTO, FANCL, MTIF3 and NUDT3) reached nominal significance (p ≤ 0.05) for their association with anthropometric traits. When considering the combined effect of the 31 SNPs, each additional risk allele of the GPS was significantly associated with an increment in the mean [95% CI] BMI of 0.13 [0.07-0.20] kg/m2 (p = 6.3x10-5) and a 3% increase in the risk of obesity (p = 0.047). The GPS explained 1% of the variance in the BMI. Furthermore, the GPS was associated with higher fasting glycaemia (p = 0.04), insulinaemia (p = 0.008), HbA1c levels (p = 0.01) and HOMA-IR scores (p = 0.0003) and a greater risk of type 2 diabetes (OR [95% CI] = 1.06 [1.00-1.11], p = 0.03). However, these associations were no longer statistically significant after adjustment for BMI.
Our results show that the GPS was associated with a higher BMI and an insulin-resistant state (mediated by BMI) in a population in northern France.
PMCID: PMC4035696  PMID: 24885863
Genetic predisposition score; Polymorphism; BMI; Obesity; General population
5.  Genetic and Molecular Insights Into the Role of PROX1 in Glucose Metabolism 
Diabetes  2013;62(5):1738-1745.
Genome-wide association studies have shown that the rs340874 single nucleotide polymorphism (SNP) in PROX1 is a genetic susceptibility factor for type 2 diabetes. We conducted genetic and molecular studies to better understand the role of PROX1 in type 2 diabetes. We assessed the impact of the whole common genetic variability of PROX1 (80 SNPs) on type 2 diabetes–related biochemical traits in the HELENA (Healthy Lifestyle in Europe by Nutrition in Adolescence) study (n = 1,155). Three SNPs (rs340838, rs340837, and rs340836) were significantly associated with fasting plasma insulin levels (P ≤ 0.00295). We evaluated the impact of nine PROX1 SNPs (the three insulin-associated SNPs plus six SNPs in strong linkage disequilibrium) on luciferase reporter gene expression. The insulin-lowering alleles of rs340874, rs340873, and rs340835 were associated with lower luciferase activity in MIN6 and HepG2 cells (except for rs340874, which was in HepG2 cells only). Electrophoretic mobility shift assays indicated that specific nuclear protein bindings occur at the three SNPs in HepG2 cells, with allele-binding differences for rs340874. We also showed that the knockdown of Prox1 expression by small interfering RNAs in INS-1E cells resulted in a 1.7-fold reduction in glucose-stimulated insulin secretion. All together, we propose that reduced expression of PROX1 by cis-regulatory variants results in altered β-cell insulin secretion and thereby confers susceptibility to type 2 diabetes.
PMCID: PMC3636631  PMID: 23274905
6.  Impact of APOE gene polymorphisms on the lipid profile in an Algerian population 
The importance of apolipoprotein E (APOE) in lipid and lipoprotein metabolism is well established. However, the impact of APOE polymorphisms has never been investigated in an Algerian population. This study assessed, for the fist time, the relationships between three APOE polymorphisms (epsilon, rs439401, rs4420638) and plasma lipid concentrations in a general population sample from Algeria.
The association analysis was performed in the ISOR study, a representative sample of the population living in Oran (787 subjects aged between 30 and 64). Polymorphisms were considered both individually and as haplotypes.
In the ISOR sample, APOE ϵ4 allele carriers had higher plasma triglyceride (p=0.0002), total cholesterol (p=0.009) and LDL-cholesterol (p=0.003) levels than ϵ3 allele carriers. No significant associations were detected for the rs4420638 and rs439401 SNPs. Linkage disequilibrium and haplotype analyses confirmed the respectively deleterious and protective impacts of the ϵ4 and ϵ2 alleles on LDL-cholesterol levels and showed that the G allele of the rs4420638 polymorphism may exert a protective effect on LDL-cholesterol levels in subjects bearing the APOE epsilon 4 allele.
Our results showed that (i) the APOE epsilon polymorphism has the expected impact on the plasma lipid profile and (ii) the rs4420638 G allele may counterbalance the deleterious effect of the ϵ4 allele on LDL-cholesterol levels in an Algerian population.
PMCID: PMC4231468  PMID: 24160669
APOE; Polymorphism; Algerian population; Lipid parameters; Cardiovascular risk; General population sample; North Africa
7.  New loci associated with birth weight identify genetic links between intrauterine growth and adult height and metabolism 
Horikoshi, Momoko | Yaghootkar, Hanieh | Mook-Kanamori, Dennis O. | Sovio, Ulla | Taal, H. Rob | Hennig, Branwen J. | Bradfield, Jonathan P. | St. Pourcain, Beate | Evans, David M. | Charoen, Pimphen | Kaakinen, Marika | Cousminer, Diana L. | Lehtimäki, Terho | Kreiner-Møller, Eskil | Warrington, Nicole M. | Bustamante, Mariona | Feenstra, Bjarke | Berry, Diane J. | Thiering, Elisabeth | Pfab, Thiemo | Barton, Sheila J. | Shields, Beverley M. | Kerkhof, Marjan | van Leeuwen, Elisabeth M. | Fulford, Anthony J. | Kutalik, Zoltán | Zhao, Jing Hua | den Hoed, Marcel | Mahajan, Anubha | Lindi, Virpi | Goh, Liang-Kee | Hottenga, Jouke-Jan | Wu, Ying | Raitakari, Olli T. | Harder, Marie N. | Meirhaeghe, Aline | Ntalla, Ioanna | Salem, Rany M. | Jameson, Karen A. | Zhou, Kaixin | Monies, Dorota M. | Lagou, Vasiliki | Kirin, Mirna | Heikkinen, Jani | Adair, Linda S. | Alkuraya, Fowzan S. | Al-Odaib, Ali | Amouyel, Philippe | Andersson, Ehm Astrid | Bennett, Amanda J. | Blakemore, Alexandra I.F. | Buxton, Jessica L. | Dallongeville, Jean | Das, Shikta | de Geus, Eco J. C. | Estivill, Xavier | Flexeder, Claudia | Froguel, Philippe | Geller, Frank | Godfrey, Keith M. | Gottrand, Frédéric | Groves, Christopher J. | Hansen, Torben | Hirschhorn, Joel N. | Hofman, Albert | Hollegaard, Mads V. | Hougaard, David M. | Hyppönen, Elina | Inskip, Hazel M. | Isaacs, Aaron | Jørgensen, Torben | Kanaka-Gantenbein, Christina | Kemp, John P. | Kiess, Wieland | Kilpeläinen, Tuomas O. | Klopp, Norman | Knight, Bridget A. | Kuzawa, Christopher W. | McMahon, George | Newnham, John P. | Niinikoski, Harri | Oostra, Ben A. | Pedersen, Louise | Postma, Dirkje S. | Ring, Susan M. | Rivadeneira, Fernando | Robertson, Neil R. | Sebert, Sylvain | Simell, Olli | Slowinski, Torsten | Tiesler, Carla M.T. | Tönjes, Anke | Vaag, Allan | Viikari, Jorma S. | Vink, Jacqueline M. | Vissing, Nadja Hawwa | Wareham, Nicholas J. | Willemsen, Gonneke | Witte, Daniel R. | Zhang, Haitao | Zhao, Jianhua | Wilson, James F. | Stumvoll, Michael | Prentice, Andrew M. | Meyer, Brian F. | Pearson, Ewan R. | Boreham, Colin A.G. | Cooper, Cyrus | Gillman, Matthew W. | Dedoussis, George V. | Moreno, Luis A | Pedersen, Oluf | Saarinen, Maiju | Mohlke, Karen L. | Boomsma, Dorret I. | Saw, Seang-Mei | Lakka, Timo A. | Körner, Antje | Loos, Ruth J.F. | Ong, Ken K. | Vollenweider, Peter | van Duijn, Cornelia M. | Koppelman, Gerard H. | Hattersley, Andrew T. | Holloway, John W. | Hocher, Berthold | Heinrich, Joachim | Power, Chris | Melbye, Mads | Guxens, Mònica | Pennell, Craig E. | Bønnelykke, Klaus | Bisgaard, Hans | Eriksson, Johan G. | Widén, Elisabeth | Hakonarson, Hakon | Uitterlinden, André G. | Pouta, Anneli | Lawlor, Debbie A. | Smith, George Davey | Frayling, Timothy M. | McCarthy, Mark I. | Grant, Struan F.A. | Jaddoe, Vincent W.V. | Jarvelin, Marjo-Riitta | Timpson, Nicholas J. | Prokopenko, Inga | Freathy, Rachel M.
Nature genetics  2012;45(1):76-82.
Birth weight within the normal range is associated with a variety of adult-onset diseases, but the mechanisms behind these associations are poorly understood1. Previous genome-wide association studies identified a variant in the ADCY5 gene associated both with birth weight and type 2 diabetes, and a second variant, near CCNL1, with no obvious link to adult traits2. In an expanded genome-wide association meta-analysis and follow-up study (up to 69,308 individuals of European descent from 43 studies), we have now extended the number of genome-wide significant loci to seven, accounting for a similar proportion of variance to maternal smoking. Five of the loci are known to be associated with other phenotypes: ADCY5 and CDKAL1 with type 2 diabetes; ADRB1 with adult blood pressure; and HMGA2 and LCORL with adult height. Our findings highlight genetic links between fetal growth and postnatal growth and metabolism.
PMCID: PMC3605762  PMID: 23202124
8.  Physical Activity Attenuates the Effect of Low Birth Weight on Insulin Resistance in Adolescents 
Diabetes  2011;60(9):2295-2299.
To examine whether physical activity influences the association between birth weight and insulin resistance in adolescents.
The study comprised adolescents who participated in two cross-sectional studies: the Healthy Lifestyle in Europe by Nutrition in Adolescence (HELENA) study (n = 520, mean age = 14.6 years) and the Swedish part of the European Youth Heart Study (EYHS) (n = 269, mean age = 15.6 years). Participants had valid data on birth weight (parental recall), BMI, sexual maturation, maternal education, breastfeeding, physical activity (accelerometry, counts/minute), fasting glucose, and insulin. Insulin resistance was assessed by homeostasis model assessment–insulin resistance (HOMA-IR). Maternal education level and breastfeeding duration were reported by the mothers.
There was a significant interaction of physical activity in the association between birth weight and HOMA-IR (logarithmically transformed) in both the HELENA study and the EYHS (P = 0.05 and P = 0.03, respectively), after adjusting for sex, age, sexual maturation, BMI, maternal education level, and breastfeeding duration. Stratified analyses by physical activity levels (below/above median) showed a borderline inverse association between birth weight and HOMA-IR in the low-active group (standardized β = −0.094, P = 0.09, and standardized β = −0.156, P = 0.06, for HELENA and EYHS, respectively), whereas no evidence of association was found in the high-active group (standardized β = −0.031, P = 0.62, and standardized β = 0.053, P = 0.55, for HELENA and EYHS, respectively).
Higher levels of physical activity may attenuate the adverse effects of low birth weight on insulin sensitivity in adolescents. More observational data, from larger and more powerful studies, are required to test these findings.
PMCID: PMC3161315  PMID: 21752955
9.  A genome-wide association meta-analysis identifies new childhood obesity loci 
Bradfield, Jonathan P. | Taal, H. Rob | Timpson, Nicholas J. | Scherag, André | Lecoeur, Cecile | Warrington, Nicole M. | Hypponen, Elina | Holst, Claus | Valcarcel, Beatriz | Thiering, Elisabeth | Salem, Rany M. | Schumacher, Fredrick R. | Cousminer, Diana L. | Sleiman, Patrick M.A. | Zhao, Jianhua | Berkowitz, Robert I. | Vimaleswaran, Karani S. | Jarick, Ivonne | Pennell, Craig E. | Evans, David M. | St. Pourcain, Beate | Berry, Diane J. | Mook-Kanamori, Dennis O | Hofman, Albert | Rivadeinera, Fernando | Uitterlinden, André G. | van Duijn, Cornelia M. | van der Valk, Ralf J.P. | de Jongste, Johan C. | Postma, Dirkje S. | Boomsma, Dorret I. | Gauderman, William J. | Hassanein, Mohamed T. | Lindgren, Cecilia M. | Mägi, Reedik | Boreham, Colin A.G. | Neville, Charlotte E. | Moreno, Luis A. | Elliott, Paul | Pouta, Anneli | Hartikainen, Anna-Liisa | Li, Mingyao | Raitakari, Olli | Lehtimäki, Terho | Eriksson, Johan G. | Palotie, Aarno | Dallongeville, Jean | Das, Shikta | Deloukas, Panos | McMahon, George | Ring, Susan M. | Kemp, John P. | Buxton, Jessica L. | Blakemore, Alexandra I.F. | Bustamante, Mariona | Guxens, Mònica | Hirschhorn, Joel N. | Gillman, Matthew W. | Kreiner-Møller, Eskil | Bisgaard, Hans | Gilliland, Frank D. | Heinrich, Joachim | Wheeler, Eleanor | Barroso, Inês | O'Rahilly, Stephen | Meirhaeghe, Aline | Sørensen, Thorkild I.A. | Power, Chris | Palmer, Lyle J. | Hinney, Anke | Widen, Elisabeth | Farooqi, I. Sadaf | McCarthy, Mark I. | Froguel, Philippe | Meyre, David | Hebebrand, Johannes | Jarvelin, Marjo-Riitta | Jaddoe, Vincent W.V. | Smith, George Davey | Hakonarson, Hakon | Grant, Struan F.A.
Nature Genetics  2012;44(5):526-531.
Multiple genetic variants have been associated with adult obesity and a few with severe obesity in childhood; however, less progress has been made to establish genetic influences on common early-onset obesity. We performed a North American-Australian-European collaborative meta-analysis of fourteen studies consisting of 5,530 cases (≥95th percentile of body mass index (BMI)) and 8,318 controls (<50th percentile of BMI) of European ancestry. Taking forward the eight novel signals yielding association with P < 5×10−6 in to nine independent datasets (n = 2,818 cases and 4,083 controls) we observed two loci that yielded a genome wide significant combined P-value, namely near OLFM4 on 13q14 (rs9568856; P=1.82×10−9; OR=1.22) and within HOXB5 on 17q21 (rs9299; P=3.54×10−9; OR=1.14). Both loci continued to show association when including two extreme childhood obesity cohorts (n = 2,214 cases and 2,674 controls). Finally, these two loci yielded directionally consistent associations in the GIANT meta-analysis of adult BMI1.
PMCID: PMC3370100  PMID: 22484627
10.  Physical Activity Attenuates the Influence of FTO Variants on Obesity Risk: A Meta-Analysis of 218,166 Adults and 19,268 Children 
Kilpeläinen, Tuomas O. | Qi, Lu | Brage, Soren | Sharp, Stephen J. | Sonestedt, Emily | Demerath, Ellen | Ahmad, Tariq | Mora, Samia | Kaakinen, Marika | Sandholt, Camilla Helene | Holzapfel, Christina | Autenrieth, Christine S. | Hyppönen, Elina | Cauchi, Stéphane | He, Meian | Kutalik, Zoltan | Kumari, Meena | Stančáková, Alena | Meidtner, Karina | Balkau, Beverley | Tan, Jonathan T. | Mangino, Massimo | Timpson, Nicholas J. | Song, Yiqing | Zillikens, M. Carola | Jablonski, Kathleen A. | Garcia, Melissa E. | Johansson, Stefan | Bragg-Gresham, Jennifer L. | Wu, Ying | van Vliet-Ostaptchouk, Jana V. | Onland-Moret, N. Charlotte | Zimmermann, Esther | Rivera, Natalia V. | Tanaka, Toshiko | Stringham, Heather M. | Silbernagel, Günther | Kanoni, Stavroula | Feitosa, Mary F. | Snitker, Soren | Ruiz, Jonatan R. | Metter, Jeffery | Larrad, Maria Teresa Martinez | Atalay, Mustafa | Hakanen, Maarit | Amin, Najaf | Cavalcanti-Proença, Christine | Grøntved, Anders | Hallmans, Göran | Jansson, John-Olov | Kuusisto, Johanna | Kähönen, Mika | Lutsey, Pamela L. | Nolan, John J. | Palla, Luigi | Pedersen, Oluf | Pérusse, Louis | Renström, Frida | Scott, Robert A. | Shungin, Dmitry | Sovio, Ulla | Tammelin, Tuija H. | Rönnemaa, Tapani | Lakka, Timo A. | Uusitupa, Matti | Rios, Manuel Serrano | Ferrucci, Luigi | Bouchard, Claude | Meirhaeghe, Aline | Fu, Mao | Walker, Mark | Borecki, Ingrid B. | Dedoussis, George V. | Fritsche, Andreas | Ohlsson, Claes | Boehnke, Michael | Bandinelli, Stefania | van Duijn, Cornelia M. | Ebrahim, Shah | Lawlor, Debbie A. | Gudnason, Vilmundur | Harris, Tamara B. | Sørensen, Thorkild I. A. | Mohlke, Karen L. | Hofman, Albert | Uitterlinden, André G. | Tuomilehto, Jaakko | Lehtimäki, Terho | Raitakari, Olli | Isomaa, Bo | Njølstad, Pål R. | Florez, Jose C. | Liu, Simin | Ness, Andy | Spector, Timothy D. | Tai, E. Shyong | Froguel, Philippe | Boeing, Heiner | Laakso, Markku | Marmot, Michael | Bergmann, Sven | Power, Chris | Khaw, Kay-Tee | Chasman, Daniel | Ridker, Paul | Hansen, Torben | Monda, Keri L. | Illig, Thomas | Järvelin, Marjo-Riitta | Wareham, Nicholas J. | Hu, Frank B. | Groop, Leif C. | Orho-Melander, Marju | Ekelund, Ulf | Franks, Paul W. | Loos, Ruth J. F.
PLoS Medicine  2011;8(11):e1001116.
Ruth Loos and colleagues report findings from a meta-analysis of multiple studies examining the extent to which physical activity attenuates effects of a specific gene variant, FTO, on obesity in adults and children. They report a fairly substantial attenuation by physical activity on the effects of this genetic variant on the risk of obesity in adults.
The 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 Findings
All studies identified to have data on the FTO rs9939609 variant (or any proxy [r2>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 (pinteraction  = 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.
The 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.
Please see later in the article for the Editors' Summary
Editors’ Summary
Two in three Americans are overweight, of whom half are obese, and the trend towards increasing obesity is now seen across developed and developing countries. There has long been interest in understanding the impact of genes and environment when it comes to apportioning responsibility for obesity. Carrying a change in the FTO gene is common (found in three-quarters of Europeans and North Americans) and is associated with a 20%–30% increased risk of obesity. Some overweight or obese individuals may feel that the dice are loaded and there is little point in fighting the fat; it has been reported that those made aware of their genetic susceptibility to obesity may still choose a poor diet. A similar fatalism may occur when overweight and obese people consider physical activity. But disentangling the influence of physical activity on those genetically susceptible to obesity from other factors that might impact weight is not straightforward, as it requires large sample sizes, could be subject to publication bias, and may rely on less than ideal self-reporting methods.
Why Was This Study Done?
The public health ramifications of understanding the interaction between genetic susceptibility to obesity and physical activity are considerable. Tackling the rising prevalence of obesity will inevitably include interventions principally aimed at changing dietary intake and/or increasing physical activity, but the evidence for these with regards to those genetically susceptible has been lacking to date. The authors of this paper set out to explore the interaction between the commonest genetic susceptibility trait and physical activity using a rigorous meta-analysis of a large number of studies.
What Did the Researchers Do and Find?
The authors were concerned that a meta-analysis of published studies would be limited both by the data available to them and by possible bias. Instead of this more widely used approach, they took the literature search as their starting point, identified other studies through their collaborators’ network, and then undertook a meta-analysis of all available studies using a new and standardized analysis plan. This entailed an extremely large number of authors mining their data afresh to extract the relevant data points to enable such a meta-analysis. Physical activity was identified in the original studies in many different ways, including by self-report or by using an external measure of activity or heart rate. In order to perform the meta-analysis, participants were labeled as physically active or inactive in each study. For studies that had used a continuous scale, the authors decided that the bottom 20% of the participants were inactive (10% for children and adolescents). Using data from over 218,000 adults, the authors found that carrying a copy of the susceptibility gene increased the odds of obesity by 1.23-fold. But the size of this influence was 27% less in the genetically susceptible adults who were physically active (1.22-fold) compared to those who were physically inactive (1.30-fold). In a smaller study of about 19,000 children, no such effect of physical activity was seen.
What Do these Findings Mean?
This study demonstrates that people who carry the susceptibility gene for obesity can benefit from physical activity. This should inform health care professionals and the wider public that the view of genetically determined obesity not being amenable to exercise is incorrect and should be challenged. Dissemination, implementation, and ensuring uptake of effective physical activity programs remains a challenge and deserves further consideration. That the researchers treated “physically active” as a yes/no category, and how they categorized individuals, could be criticized, but this was done for pragmatic reasons, as a variety of means of assessing physical activity were used across the studies. It is unlikely that the findings would have changed if the authors had used a different method of defining physically active. Most of the studies included in the meta-analysis looked at one time point only; information about the influence of physical activity on weight changes over time in genetically susceptible individuals is only beginning to emerge.
Additional Information
Please access these websites via the online version of this summary at
This study is further discussed in a PLoS Medicine Perspective by Lennert Veerman
The US Centers for Disease Control and Prevention provides obesity-related statistics, details of prevention programs, and an overview on public health strategy in the United States
A more worldwide view is given by the World Health Organization
The UK National Health Service website gives information on physical activity guidelines for different age groups, while similar information can also be found from US sources
PMCID: PMC3206047  PMID: 22069379
11.  Mendelian Randomization Study of B-Type Natriuretic Peptide and Type 2 Diabetes: Evidence of Causal Association from Population Studies 
PLoS Medicine  2011;8(10):e1001112.
Using mendelian randomization, Roman Pfister and colleagues demonstrate a potentially causal link between low levels of B-type natriuretic peptide (BNP), a hormone released by damaged hearts, and the development of type 2 diabetes.
Genetic and epidemiological evidence suggests an inverse association between B-type natriuretic peptide (BNP) levels in blood and risk of type 2 diabetes (T2D), but the prospective association of BNP with T2D is uncertain, and it is unclear whether the association is confounded.
Methods and Findings
We analysed the association between levels of the N-terminal fragment of pro-BNP (NT-pro-BNP) in blood and risk of incident T2D in a prospective case-cohort study and genotyped the variant rs198389 within the BNP locus in three T2D case-control studies. We combined our results with existing data in a meta-analysis of 11 case-control studies. Using a Mendelian randomization approach, we compared the observed association between rs198389 and T2D to that expected from the NT-pro-BNP level to T2D association and the NT-pro-BNP difference per C allele of rs198389. In participants of our case-cohort study who were free of T2D and cardiovascular disease at baseline, we observed a 21% (95% CI 3%–36%) decreased risk of incident T2D per one standard deviation (SD) higher log-transformed NT-pro-BNP levels in analysis adjusted for age, sex, body mass index, systolic blood pressure, smoking, family history of T2D, history of hypertension, and levels of triglycerides, high-density lipoprotein cholesterol, and low-density lipoprotein cholesterol. The association between rs198389 and T2D observed in case-control studies (odds ratio = 0.94 per C allele, 95% CI 0.91–0.97) was similar to that expected (0.96, 0.93–0.98) based on the pooled estimate for the log-NT-pro-BNP level to T2D association derived from a meta-analysis of our study and published data (hazard ratio = 0.82 per SD, 0.74–0.90) and the difference in NT-pro-BNP levels (0.22 SD, 0.15–0.29) per C allele of rs198389. No significant associations were observed between the rs198389 genotype and potential confounders.
Our results provide evidence for a potential causal role of the BNP system in the aetiology of T2D. Further studies are needed to investigate the mechanisms underlying this association and possibilities for preventive interventions.
Please see later in the article for the Editors' Summary
Editors' Summary
Worldwide, nearly 250 million people have diabetes, and this number is increasing rapidly. Diabetes is characterized by dangerous amounts of sugar (glucose) in the blood. Blood sugar levels are normally controlled by insulin, a hormone that the pancreas releases after meals (digestion of food produces glucose). In people with type 2 diabetes (the most common form of diabetes), blood sugar control fails because the fat and muscle cells that usually respond to insulin by removing sugar from the blood become insulin resistant. Type 2 diabetes can be controlled with diet and exercise, and with drugs that help the pancreas make more insulin or that make cells more sensitive to insulin. The long-term complications of diabetes, which include kidney failure and an increased risk of cardiovascular problems such as heart disease and stroke, reduce the life expectancy of people with diabetes by about 10 years compared to people without diabetes.
Why Was This Study Done?
Because the causes of type 2 diabetes are poorly understood, it is hard to devise ways to prevent the condition. Recently, B-type natriuretic peptide (BNP, a hormone released by damaged hearts) has been implicated in type 2 diabetes development in cross-sectional studies (investigations in which data are collected at a single time point from a population to look for associations between an illness and potential risk factors). Although these studies suggest that high levels of BNP may protect against type 2 diabetes, they cannot prove a causal link between BNP levels and diabetes because the study participants with low BNP levels may share some another unknown factor (a confounding factor) that is the real cause of both diabetes and altered BNP levels. Here, the researchers use an approach called “Mendelian randomization” to examine whether reduced BNP levels contribute to causing type 2 diabetes. It is known that a common genetic variant (rs198389) within the genome region that encodes BNP is associated with a reduced risk of type 2 diabetes. Because gene variants are inherited randomly, they are not subject to confounding. So, by investigating the association between BNP gene variants that alter NT-pro-BNP (a molecule created when BNP is being produced) levels and the development of type 2 diabetes, the researchers can discover whether BNP is causally involved in this chronic condition.
What Did the Researchers Do and Find?
The researchers analyzed the association between blood levels of NT-pro-BNP at baseline in 440 participants of the EPIC-Norfolk study (a prospective population-based study of lifestyle factors and the risk of chronic diseases) who subsequently developed diabetes and in 740 participants who did not develop diabetes. In this prospective case-cohort study, the risk of developing type 2 diabetes was associated with lower NT-pro-BNP levels. They also genotyped (sequenced) rs198389 in the participants of three case-control studies of type 2 diabetes (studies in which potential risk factors for type 2 diabetes were examined in people with type 2 diabetes and matched controls living in the East of England), and combined these results with those of eight similar published case-control studies. Finally, the researchers showed that the association between rs198389 and type 2 diabetes measured in the case-control studies was similar to the expected association calculated from the association between NT-pro-BNP level and type 2 diabetes obtained from the prospective case-cohort study and the association between rs198389 and BNP levels obtained from the EPIC-Norfolk study and other published studies.
What Do These Findings Mean?
The results of this Mendelian randomization study provide evidence for a causal, protective role of the BNP hormone system in the development of type 2 diabetes. That is, these findings suggest that low levels of BNP are partly responsible for the development of type 2 diabetes. Because the participants in all the individual studies included in this analysis were of European descent, these findings may not be generalizable to other ethnicities. Moreover, they provide no explanation of how alterations in the BNP hormone system might affect the development of type 2 diabetes. Nevertheless, the demonstration of a causal link between the BNP hormone system and type 2 diabetes suggests that BNP may be a potential target for interventions designed to prevent type 2 diabetes, particularly since the feasibility of altering BNP levels with drugs has already been proven in patients with cardiovascular disease.
Additional Information
Please access these websites via the online version of this summary at
The International Diabetes Federation provides information about all aspects of diabetes
The US National Diabetes Information Clearinghouse provides detailed information about diabetes for patients, health-care professionals, and the general public (in English and Spanish)
The UK National Health Service Choices website also provides information for patients and carers about type 2 diabetes and includes people's stories about diabetes
MedlinePlus provides links to further resources and advice about diabetes (in English and Spanish)
Wikipedia has pages on BNP and on Mendelian randomization (note: Wikipedia is a free online encyclopedia that anyone can edit; available in several languages)
The charity Healthtalkonline has interviews with people about their experiences of diabetes; the charity Diabetes UK has a further selection of stories from people with diabetes
PMCID: PMC3201934  PMID: 22039354
12.  Breast-Feeding Modulates the Influence of the Peroxisome Proliferator–Activated Receptor-γ (PPARG2) Pro12Ala Polymorphism on Adiposity in Adolescents 
Diabetes Care  2009;33(1):190-196.
The peroxisome proliferator–activated receptor-γ2 (PPARG2) Pro12Ala polymorphism has been associated with a higher BMI and a lower risk of type 2 diabetes in adulthood. The association between adiposity and PPARG variants can be influenced by environmental factors such as early growth, dietary fat, and (as recently shown) breast-feeding. The objectives of this study were to assess 1) the influence of the PPARG2 Pro12Ala polymorphism on adiposity markers in adolescents and 2) a possible modulating effect of breast-feeding on these associations.
Data on breast-feeding duration, BMI, and genotypes for the Pro12Ala polymorphism were available for 945 adolescents (mean age 14.7 years). The breast-feeding duration was obtained from parental records. We measured weight, height, waist circumference, and six skinfold thicknesses.
No significant associations between the Pro12Ala polymorphism and any of the above-mentioned anthropometric parameters were found. There were significant interactions between the PPARG2 Pro12Ala polymorphism and breast-feeding with regard to adiposity measurements (all adjusted P < 0.05). Indeed, in children who had not been breast-fed, Ala12 allele carriers had higher adiposity parameters (e.g., Δ BMI +1.88 kg/m2, adjusted for age, sex, and center, P = 0.007) than Pro12Pro adolescents. In contrast, in breast-fed subjects, there was no significant difference between Ala12 allele carriers and Pro12Pro children in terms of adiposity measurements, whatever the duration of breast-feeding.
Breast-feeding appears to counter the deleterious effect of the PPARG2 Pro12Ala polymorphism on anthropometric parameters in adolescents.
PMCID: PMC2797971  PMID: 19846795
13.  Early Life Programming of Abdominal Adiposity in Adolescents: The HELENA Study 
Diabetes Care  2009;32(11):2120-2122.
To examine the relationship between birth weight and abdominal adiposity in adolescents.
A total of 284 adolescents (49.3% of whom were female) aged 14.9 ± 1.2 years were included in the study. Birth weight and gestational age were obtained from parental records. Abdominal adiposity (in three regions: R1, R2, and R3) and trunk and total body fat mass were measured by dual-energy X-ray absorptiometry. Regional fat mass indexes (FMIs) were thereafter calculated as fat mass divided by the square of height (Trunk FMI and abdominal FMI R1, R2, and R3).
Birth weight was negatively associated with abdominal FMI R1, R2, and R3 independently of total fat mass, gestational age, sex, breast-feeding duration, pubertal stage, physical activity, and socioeconomic status (all P < 0.01).
Our study shows an inverse association between birth weight and abdominal adiposity in adolescents independently of total fat mass and other potential confounders. These findings suggest that fetal nutrition, as reflected by birth weight, may have a programming effect on abdominal adiposity later in life.
PMCID: PMC2768211  PMID: 19641158
14.  Suggestive evidence of associations between liver X receptor β polymorphisms with type 2 diabetes mellitus and obesity in three cohort studies: HUNT2 (Norway), MONICA (France) and HELENA (Europe) 
BMC Medical Genetics  2010;11:144.
The liver X receptors (LXR) α and β regulate lipid and carbohydrate homeostasis and inflammation. Lxrβ-/- mice are glucose intolerant and at the same time lean. We aimed to assess the associations between single nucleotide polymorphisms (SNPs) in LXRβ and risk of type 2 diabetes mellitus (T2DM), obesity and related traits in 3 separate cohort studies.
Twenty LXRβ SNPs were identified by sequencing and genotyped in the HUNT2 adult nested case-control study for T2DM (n = 835 cases/1986 controls). Five tag-SNPs (rs17373080, rs2695121, rs56151148, rs2303044 and rs3219281), covering 99.3% of the entire common genetic variability of the LXRβ gene were identified and genotyped in the French MONICA adult study (n = 2318) and the European adolescent HELENA cross-sectional study (n = 1144). In silico and in vitro functionality studies were performed.
We identified suggestive or significant associations between rs17373080 and the risk of (i) T2DM in HUNT2 (OR = 0.82, p = 0.03), (ii) obesity in MONICA (OR = 1.26, p = 0.05) and (iii) overweight/obesity in HELENA (OR = 1.59, p = 0.002). An intron 4 SNP (rs28514894, a perfect proxy for rs17373080) could potentially create binding sites for hepatic nuclear factor 4 alpha (HNF4α) and nuclear factor 1 (NF1). The C allele of rs28514894 was associated with ~1.25-fold higher human LXRβ basal promoter activity in vitro. However, no differences between alleles in terms of DNA binding and reporter gene transactivation by HNF4α or NF1 were observed.
Our results suggest that rs17373080 in LXRβ is associated with T2DM and obesity, maybe via altered LXRβ expression.
PMCID: PMC2958901  PMID: 20939869
15.  Peroxisome Proliferator-Activated Receptor Gamma Polymorphisms and Coronary Heart Disease 
PPAR Research  2009;2009:543746.
Single nucleotide polymorphisms (SNPs) in the peroxisome proliferator-activated receptor γ (PPARG) gene have been associated with cardiovascular risk factors, particularly obesity and diabetes. We assessed the relationship between 4 PPARG SNPs (C-681G, C-689T, Pro12Ala, and C1431T) and coronary heart disease (CHD) in the PRIME (249 cases/494 controls, only men) and ADVANCE (1,076 cases/805 controls, men or women) studies. In PRIME, homozygote individuals for the minor allele of the PPARG C-689T, Pro12Ala, and C1431T SNPs tended to have a higher risk of CHD than homozygote individuals for the frequent allele (adjusted OR [95% CI] = 3.43 [0.96–12.27], P = .058, 3.41 [0.95–12.22], P = .060 and 5.10 [0.99–26.37], P = .050, resp.). No such association could be detected in ADVANCE. Haplotype distributions were similar in cases and control in both studies. A meta-analysis on the Pro12Ala SNP, based on our data and 11 other published association studies (6,898 CHD cases/11,287 controls), revealed that there was no evidence for a significant association under the dominant model (OR = 0.99 [0.92–1.07], P = .82). However, there was a borderline association under the recessive model (OR = 1.29 [0.99–1.67], P = .06) that became significant when considering men only (OR = 1.73 [1.20–2.48], P = .003). In conclusion, the PPARG Ala12Ala genotype might be associated with a higher CHD risk in men but further confirmation studies are needed.
PMCID: PMC2792957  PMID: 20016803
16.  The APOA5 Trp19 allele is associated with metabolic syndrome via its association with plasma triglycerides 
BMC Medical Genetics  2008;9:84.
The goal of the present study was to assess the effect of genetic variability at the APOA5/A4/C3/A1 cluster locus on the risk of metabolic syndrome.
The APOA5 Ser19Trp, APOA5 -12,238T>C, APOA4 Thr347Ser, APOC3 -482C>T and APOC3 3238C>G (SstI) polymorphisms were analyzed in a representative population sample of 3138 men and women from France, including 932 individuals with metabolic syndrome and 2206 without metabolic syndrome, as defined by the NCEP criteria.
Compared with homozygotes for the common allele, the odds ratio (OR) [95% CI] for metabolic syndrome was 1.30 [1.03–1.66] (p = 0.03) for APOA5 Trp19 carriers, 0.81 [0.69–0.95] (p = 0.01) for APOA5 -12,238C carriers and 0.84 [0.70–0.99] (p = 0.04) for APOA4 Ser347 carriers. Adjustment for plasma triglycerides, (but not for waist girth, HDL, blood pressure or glycemia – the other components of metabolic syndrome) abolished these associations and suggests that triglyceride levels explain the association with metabolic syndrome. There was no association between the APOC3 -482C>T or APOC3 3238C>G polymorphisms and metabolic syndrome. The decreased risk of metabolic syndrome observed in APOA5 -12,238C and APOA4 Ser347 carriers merely reflected the fact that the APOA5 Trp19 allele was in negative linkage disequilibrium with the common alleles of APOA5 -12,238T>C and APOA4 Thr347Ser polymorphisms.
The APOA5 Trp19 allele increased susceptibility to metabolic syndrome via its impact on plasma triglyceride levels.
PMCID: PMC2551592  PMID: 18789138
17.  Ablation of PGC-1β Results in Defective Mitochondrial Activity, Thermogenesis, Hepatic Function, and Cardiac Performance 
PLoS Biology  2006;4(11):e369.
The transcriptional coactivator peroxisome proliferator-activated receptor-gamma coactivator-1β (PGC-1β) has been implicated in important metabolic processes. A mouse lacking PGC-1β (PGC1βKO) was generated and phenotyped using physiological, molecular, and bioinformatic approaches. PGC1βKO mice are generally viable and metabolically healthy. Using systems biology, we identified a general defect in the expression of genes involved in mitochondrial function and, specifically, the electron transport chain. This defect correlated with reduced mitochondrial volume fraction in soleus muscle and heart, but not brown adipose tissue (BAT). Under ambient temperature conditions, PGC-1β ablation was partially compensated by up-regulation of PGC-1α in BAT and white adipose tissue (WAT) that lead to increased thermogenesis, reduced body weight, and reduced fat mass. Despite their decreased fat mass, PGC1βKO mice had hypertrophic adipocytes in WAT. The thermogenic role of PGC-1β was identified in thermoneutral and cold-adapted conditions by inadequate responses to norepinephrine injection. Furthermore, PGC1βKO hearts showed a blunted chronotropic response to dobutamine stimulation, and isolated soleus muscle fibres from PGC1βKO mice have impaired mitochondrial function. Lack of PGC-1β also impaired hepatic lipid metabolism in response to acute high fat dietary loads, resulting in hepatic steatosis and reduced lipoprotein-associated triglyceride and cholesterol content. Altogether, our data suggest that PGC-1β plays a general role in controlling basal mitochondrial function and also participates in tissue-specific adaptive responses during metabolic stress.
The authors conduct an in-depth analysis of a PGC-1β knockout mouse; these animals posses specific defects in basal mitochondrial function and adaptation to metabolic stress.
PMCID: PMC1634886  PMID: 17090215
18.  Study of the impact of perilipin polymorphisms in a French population 
Perilipins are proteins localized at the surface of the lipid droplet in adipocytes, steroid-producing cells and ruptured atherosclerotic plaques playing a role in the regulation of triglyceride deposition and mobilization. We investigated whether perilipin gene polymorphisms were associated with obesity, type 2 diabetes, and their related variables (anthropometric variables, plasma leptin, lipids, glucose and insulin concentrations) in a cross-sectional random sample of 1120 French men and women aged 35 to 65 years old, including 227 obese (BMI ≥ 30 kg/m2) and 275 type 2 diabetes subjects.
Among 7 perilipin polymorphisms tested, only 2 (rs4578621 and rs894160) of them were frequent enough to be fully investigated and we genotyped the sample using the PCR-RFLP method. No significant associations could be found between any of these polymorphisms and the studied phenotypes.
The rs4578621 and rs894160 polymorphisms of the perilipin gene are not major genetic determinants of obesity and type 2 diabetes-related phenotypes in a random sample of French men and women.
PMCID: PMC1538627  PMID: 16836753
19.  A study of the relationships between KLF2 polymorphisms and body weight control in a French population 
BMC Medical Genetics  2006;7:26.
Factors governing adipose tissue differentiation play a major role in obesity development in humans. The Krüppel-like zinc finger transcription factor KLF2/Lung KLF (LKLF) is a negative regulator of adipocyte differentiation. In this study, we sequenced the human KLF2 gene and several common polymorphisms were found, among them the Pro104Leu and 3'UTR 1239C>A polymorphisms.
To evaluate the impact of these polymorphisms on anthropometric variables in humans, we genotyped a general population composed of 1155 French individuals (including 232 obese subjects) for these polymorphisms and looked for potential statistical associations with obesity-related variables.
The frequency of the Leu104 and 1239A alleles were 0.22 and 0.18 respectively. Genotype and allele frequencies of the two polymorphisms were comparable in obese, overweight and normal weight subjects. No association between the rare alleles of the polymorphisms and anthropometric variables (BMI, weight, waist and hip circumferences, waist-to-hip ratio and plasma leptin levels) could be detected. Haplotype analyses did not reveal further significant associations.
These data indicate that the Pro104Leu and 3'UTR 1239C>A polymorphisms in KLF2 are not associated with obesity and obesity-related traits in humans.
PMCID: PMC1431513  PMID: 16542423

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