Variation in the MC4R Gene Is Associated with Bone Phenotypes in Elderly Swedish Women

Gaurav Garg,Kristina Åkesson,Fiona E Mcguigan,Paul Gerdhem,Martin Ridderstråle,Holger Luthman,Jitender Kumar

doi:10.1371/journal.pone.0088565

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 (r2 = 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. CC: BUA: 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.

Highlights

Osteoporosis and obesity are both multifactorial disorders that in recent years have become major public health problems
All single nucleotide polymorphisms (SNPs) conformed to HWE (p.0.05). Both SNPs from the FTO gene were in strong Linkage disequilibrium (LD) (OPRA, D9 = 0.98, r2 = 0.84; PEAK-25, D9 = 0.99, r2 = 0.87) only rs9939609 was used for further analysis
No LD was observed for the MC4R SNPs (D9 = 0.45, r2 = 0.13)

Summary

Introduction

Osteoporosis and obesity are both multifactorial disorders that in recent years have become major public health problems. Epidemiological studies have shown that increased body weight is positively associated with bone mass, while low body weight is a risk factor for bone loss and osteoporosis [3]. The positive effect of body weight on bone mass may be attributable to a number of factors: increased mechanical load which has an anabolic effect on bone [4]; conversion of steroid precursors to estrogen in peripheral adipose tissue [5] or through the secretion of bone active hormones from b-cells in the pancreas and adipocytes themselves [6]. Elevated levels of Hcy and low levels of vitamin D are strong and independent risk factors for osteoporotic fracture risk [11,12]

Methods

Results

Conclusion