title: Variation in the MC4R gene is associated with bone phenotypes in elderly Swedish women.
abstract: Osteoporosis is characterized by reduced bone mineral density (BMD) and increased fracture risk. Fat mass is a determinant of bone strength and both phenotypes have a strong genetic component. In this study, we examined the association between obesity associated polymorphisms (SNPs) with body composition, BMD, Ultrasound (QUS), fracture and biomarkers (Homocysteine (Hcy), folate, Vitamin D and Vitamin B12) for obesity and osteoporosis. Five common variants: rs17782313 and rs1770633 (melanocortin 4 receptor (MC4R); rs7566605 (insulin induced gene 2 (INSIG2); rs9939609 and rs1121980 (fat mass and obesity associated (FTO) were genotyped in 2 cohorts of Swedish women: PEAK-25 (age 25, n = 1061) and OPRA (age 75, n = 1044). Body mass index (BMI), total body fat and lean mass were strongly positively correlated with QUS and BMD in both cohorts (r(2) = 0.2-0.6). MC4R rs17782313 was associated with QUS in the OPRA cohort and individuals with the minor C-allele had higher values compared to T-allele homozygotes (TT vs. CT vs.
  100 vs. 103 vs. 103; p = 0.002); (SOS: 1521 vs. 1526 vs. 1524; p = 0.008); (Stiffness index: 69 vs. 73 vs. 74; p = 0.0006) after adjustment for confounders. They also had low folate (18 vs. 17 vs. 16; p = 0.03) and vitamin D (93 vs. 91 vs. 90; p = 0.03) and high Hcy levels (13.7 vs 14.4 vs. 14.5; p = 0.06). Fracture incidence was lower among women with the C-allele, (52% vs. 58%; p = 0.067). Variation in MC4R was not associated with BMD or body composition in either OPRA or PEAK-25. SNPs close to FTO and INSIG2 were not associated with any bone phenotypes in either cohort and FTO SNPs were only associated with body composition in PEAK-25 (p≤0.001). Our results suggest that genetic variation close to MC4R is associated with quantitative ultrasound and risk of fracture.
authors: Clinical and Molecular Osteoporosis Research Unit, Department of Clinical Sciences, Lund University and Department of Orthopaedics, Skåne University Hospital, Malmö, Sweden.
authors: Gaurav
authors: G
authors: Garg
authors: Department of Medical Sciences, Molecular Epidemiology and Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
authors: Jitender
authors: J
authors: Kumar
authors: Clinical and Molecular Osteoporosis Research Unit, Department of Clinical Sciences, Lund University and Department of Orthopaedics, Skåne University Hospital, Malmö, Sweden.
authors: Fiona E
authors: FE
authors: McGuigan
authors: Clinical Obesity Research, Department of Endocrinology, Skåne University Hospital, Malmö, Sweden.
authors: Martin
authors: M
authors: Ridderstråle
authors: Department of Clinical Science, Intervention and Technology, Karolinska Institutet, Department of Orthopaedics, Karolinska University Hospital, Stockholm, Sweden.
authors: Paul
authors: P
authors: Gerdhem
authors: Medical Genetics Unit, Department of Clinical Sciences, Lund University, Malmö, Sweden.
authors: Holger
authors: H
authors: Luthman
authors: Clinical and Molecular Osteoporosis Research Unit, Department of Clinical Sciences, Lund University and Department of Orthopaedics, Skåne University Hospital, Malmö, Sweden.
authors: Kristina
authors: K
authors: Åkesson
mesh_terms: D050154:Adiposity / Q000235:genetics; D000368:Aged; D000071516:Alpha-Ketoglutarate-Dependent Dioxygenase FTO; D015415:Biomarkers / Q000378:metabolism; D001823:Body Composition / Q000235:genetics; D001842:Bone and Bones / Q000000981:diagnostic imaging / Q000473:pathology*; D015331:Cohort Studies; D005260:Female; D050723:Fractures, Bone / Q000150:complications / Q000235:genetics / Q000473:pathology; D005787:Gene Frequency / Q000235:genetics; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006710:Homocysteine / Q000378:metabolism; D006801:Humans; D009765:Obesity / Q000150:complications / Q000235:genetics; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D011506:Proteins / Q000235:genetics; D044105:Receptor, Melanocortin, Type 4 / Q000235:genetics*; D013548:Sweden; D014463:Ultrasonography
chemical_list: D015415:Biomarkers; C470072:MC4R protein, human; D011506:Proteins; D044105:Receptor, Melanocortin, Type 4; D006710:Homocysteine; D000071516:Alpha-Ketoglutarate-Dependent Dioxygenase FTO; C526492:FTO protein, human