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Title:
Combined effects of MC4R and FTO common genetic variants on obesity in European general populations | Journal of Molecular Medicine
Description:
Genome-wide association scans recently identified common polymorphisms, in intron 1 of FTO and 188 kb downstream MC4R, that modulate body mass index (BMI) and associate with increased risk of obesity. Although their individual contribution to obesity phenotype is modest, their combined effects and their interactions with environmental factors remained to be evaluated in large general populations from birth to adulthood. In the present study, we analyzed independent and combined effects of the FTO rs1421085 and MC4R rs17782313 risk alleles on BMI, fat mass, prevalence and incidence of obesity and subsequent type 2 diabetes (T2D) as well as their interactions with physical activity levels and gender in two European prospective population-based cohorts of 4,762 Finnish adolescents (NFBC 1986) and 3,167 French adults (D.E.S.I.R.). Compared to participants carrying neither FTO nor MC4R risk allele (20–24% of the populations), subjects with three or four risk alleles (7–10% of the populations) had a 3-fold increased susceptibility of developing obesity during childhood. In adults, their combined effects were more modest (~1.8-fold increased risk) and associated with a 1.27% increase in fat mass (P = 0.001). Prospectively, we demonstrated that each FTO and MC4R risk allele increased obesity and T2D incidences by 24% (P = 0.02) and 21% (P = 0.02), respectively. However, the effect on T2D disappeared after adjustment for BMI. The Z-BMI and ponderal index of newborns homozygous for the rs1421085 C allele were 0.1 units (P = 0.02) and 0.27 g/cm3 (P = 0.005) higher, respectively, than in those without FTO risk allele. The MC4R rs17782313 C allele was more associated with obesity and fat mass deposition in males than in females (P = 0.003 and P = 0.03, respectively) and low physical activity accentuated the effect of the FTO polymorphism on BMI increase and obesity prevalence (P = 0.008 and P = 0.01, respectively). In European general populations, the combined effects of common polymorphisms in FTO and MC4R are therefore additive, predictive of obesity and T2D, and may be influenced by interactions with physical activity levels and gender, respectively.
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Keywords {🔍}
article, obesity, google, scholar, fto, pubmed, cas, gene, risk, mcr, mass, fat, diabetes, association, common, variants, effects, study, physical, activity, genetic, desir, genet, france, institute, health, oulu, general, body, adults, finland, analysis, european, combined, populations, bmi, med, university, doc, privacy, cookies, content, journal, marre, balkau, marjoriitta, järvelin, philippe, froguel, index,
Topics {✒️}
genome wide association dual-energy x-ray absorptiometry month download article/chapter norwegian population-based cohort professor leena peltonen-palotie case–control studies anna-liisa hartikainen �fondation de france” mc4r genetic variants full article pdf privacy choices/manage cookies molecular medicine aims philippe froguel cross-regional institute obesity-related traits french epidemiological study genetic variants common variation melanocortin-4 receptor results melanocortin-4 receptor deficiency european economic area european general populations obesity related phenotypes body fat accumulation common polymorphisms 3-fold increased susceptibility 8-fold increased risk tuija tammelin jaana laitinen arturo gonzalez-izquierdo environmental factors remained stender-petersen kl asian indian sikhs proopiomelanocortin gene expression bioelectrical impedance accuracy st-onge mp du cane road electronic supplementary material genetic analysis attributable risk percent large general populations fat mass deposition michel marre common obesity variant conditions privacy policy carrying increasing numbers article cauchi fto variants confer age-dependent penetrance dna bank management
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headline:Combined effects of MC4R and FTO common genetic variants on obesity in European general populations
description:Genome-wide association scans recently identified common polymorphisms, in intron 1 of FTO and 188 kb downstream MC4R, that modulate body mass index (BMI) and associate with increased risk of obesity. Although their individual contribution to obesity phenotype is modest, their combined effects and their interactions with environmental factors remained to be evaluated in large general populations from birth to adulthood. In the present study, we analyzed independent and combined effects of the FTO rs1421085 and MC4R rs17782313 risk alleles on BMI, fat mass, prevalence and incidence of obesity and subsequent type 2 diabetes (T2D) as well as their interactions with physical activity levels and gender in two European prospective population-based cohorts of 4,762 Finnish adolescents (NFBC 1986) and 3,167 French adults (D.E.S.I.R.). Compared to participants carrying neither FTO nor MC4R risk allele (20–24% of the populations), subjects with three or four risk alleles (7–10% of the populations) had a 3-fold increased susceptibility of developing obesity during childhood. In adults, their combined effects were more modest (~1.8-fold increased risk) and associated with a 1.27% increase in fat mass (P = 0.001). Prospectively, we demonstrated that each FTO and MC4R risk allele increased obesity and T2D incidences by 24% (P = 0.02) and 21% (P = 0.02), respectively. However, the effect on T2D disappeared after adjustment for BMI. The Z-BMI and ponderal index of newborns homozygous for the rs1421085 C allele were 0.1 units (P = 0.02) and 0.27 g/cm3 (P = 0.005) higher, respectively, than in those without FTO risk allele. The MC4R rs17782313 C allele was more associated with obesity and fat mass deposition in males than in females (P = 0.003 and P = 0.03, respectively) and low physical activity accentuated the effect of the FTO polymorphism on BMI increase and obesity prevalence (P = 0.008 and P = 0.01, respectively). In European general populations, the combined effects of common polymorphisms in FTO and MC4R are therefore additive, predictive of obesity and T2D, and may be influenced by interactions with physical activity levels and gender, respectively.
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headline:Combined effects of MC4R and FTO common genetic variants on obesity in European general populations
description:Genome-wide association scans recently identified common polymorphisms, in intron 1 of FTO and 188 kb downstream MC4R, that modulate body mass index (BMI) and associate with increased risk of obesity. Although their individual contribution to obesity phenotype is modest, their combined effects and their interactions with environmental factors remained to be evaluated in large general populations from birth to adulthood. In the present study, we analyzed independent and combined effects of the FTO rs1421085 and MC4R rs17782313 risk alleles on BMI, fat mass, prevalence and incidence of obesity and subsequent type 2 diabetes (T2D) as well as their interactions with physical activity levels and gender in two European prospective population-based cohorts of 4,762 Finnish adolescents (NFBC 1986) and 3,167 French adults (D.E.S.I.R.). Compared to participants carrying neither FTO nor MC4R risk allele (20–24% of the populations), subjects with three or four risk alleles (7–10% of the populations) had a 3-fold increased susceptibility of developing obesity during childhood. In adults, their combined effects were more modest (~1.8-fold increased risk) and associated with a 1.27% increase in fat mass (P = 0.001). Prospectively, we demonstrated that each FTO and MC4R risk allele increased obesity and T2D incidences by 24% (P = 0.02) and 21% (P = 0.02), respectively. However, the effect on T2D disappeared after adjustment for BMI. The Z-BMI and ponderal index of newborns homozygous for the rs1421085 C allele were 0.1 units (P = 0.02) and 0.27 g/cm3 (P = 0.005) higher, respectively, than in those without FTO risk allele. The MC4R rs17782313 C allele was more associated with obesity and fat mass deposition in males than in females (P = 0.003 and P = 0.03, respectively) and low physical activity accentuated the effect of the FTO polymorphism on BMI increase and obesity prevalence (P = 0.008 and P = 0.01, respectively). In European general populations, the combined effects of common polymorphisms in FTO and MC4R are therefore additive, predictive of obesity and T2D, and may be influenced by interactions with physical activity levels and gender, respectively.
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address:
name:INSERM U780–IFR69, Villejuif, France
type:PostalAddress
type:Organization
name:University of Paris-Sud
address:
name:University of Paris-Sud, Paris, France
type:PostalAddress
type:Organization
name:Marjo-Riitta Järvelin
affiliation:
name:Imperial College London
address:
name:Epidemiology and Public Health, Imperial College London, London, UK
type:PostalAddress
type:Organization
name:University of Oulu
address:
name:Institute of Health Sciences and Biocenter Oulu, University of Oulu, Oulu, Finland
type:PostalAddress
type:Organization
name:National Public Health Institute
address:
name:Department of Child and Adolescent Health, National Public Health Institute, Helsinki, Finland
type:PostalAddress
type:Organization
name:Philippe Froguel
affiliation:
name:Pasteur Institute
address:
name:CNRS 8090—Institute of Biology, Pasteur Institute, Lille, France
type:PostalAddress
type:Organization
name:Imperial College London
address:
name:Genomic Medicine, Hammersmith Hospital, Imperial College London, London, UK
type:PostalAddress
type:Organization
email:[email protected]
PostalAddress:
name:CNRS 8090—Institute of Biology, Pasteur Institute, Lille, France
name:CNRS 8090—Institute of Biology, Pasteur Institute, Lille, France
name:CNRS 8090—Institute of Biology, Pasteur Institute, Lille, France
name:CNRS 8090—Institute of Biology, Pasteur Institute, Lille, France
name:Public Health Science and General Practice, University of Oulu, Oulu, Finland
name:Epidemiology and Public Health, Imperial College London, London, UK
name:Department of Clinical Sciences/Obstetrics and Gynecology, University of Oulu, Oulu, Finland
name:INSERM U695, Paris, France
name:René Diderot–Paris 7 University, Paris, France
name:Endocrinology–Diabetology and Nutrition, Bichat Claude Bernard Hospital, Paris, France
name:Regional Institute for Health, La Riche, France
name:Finnish Institute of Occupational Health, Helsinki, Finland
name:Finnish Institute of Occupational Health, Helsinki, Finland
name:Epidemiology and Public Health, Imperial College London, London, UK
name:Genomic Medicine, Hammersmith Hospital, Imperial College London, London, UK
name:Epidemiology and Public Health, Imperial College London, London, UK
name:CNRS 8090—Institute of Biology, Pasteur Institute, Lille, France
name:INSERM U780–IFR69, Villejuif, France
name:University of Paris-Sud, Paris, France
name:Epidemiology and Public Health, Imperial College London, London, UK
name:Institute of Health Sciences and Biocenter Oulu, University of Oulu, Oulu, Finland
name:Department of Child and Adolescent Health, National Public Health Institute, Helsinki, Finland
name:CNRS 8090—Institute of Biology, Pasteur Institute, Lille, France
name:Genomic Medicine, Hammersmith Hospital, Imperial College London, London, UK
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