Garg Gaurav, Kumar Jitender, McGuigan Fiona E, Ridderstråle Martin, Gerdhem Paul, Luthman Holger, Åkesson Kristina
Clinical and Molecular Osteoporosis Research Unit, Department of Clinical Sciences, Lund University and Department of Orthopaedics, Skåne University Hospital, Malmö, Sweden.
Department of Medical Sciences, Molecular Epidemiology and Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
PLoS One. 2014 Feb 6;9(2):e88565. doi: 10.1371/journal.pone.0088565. eCollection 2014.
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.
骨质疏松症的特征是骨矿物质密度（BMD）降低和骨折风险增加。脂肪量是骨强度的一个决定因素，且这两种表型都有很强的遗传成分。在本研究中，我们检测了肥胖相关单核苷酸多态性（SNP）与肥胖和骨质疏松症的身体成分、骨密度、超声（QUS）、骨折及生物标志物（同型半胱氨酸（Hcy）、叶酸、维生素D和维生素B12）之间的关联。对瑞典女性的两个队列进行了5个常见变异的基因分型：rs17782313和rs1770633（黑皮质素4受体（MC4R））；rs7566605（胰岛素诱导基因2（INSIG2））；rs9939609和rs1121980（脂肪量和肥胖相关基因（FTO）），这两个队列分别是PEAK - 25（25岁，n = 1061）和OPRA（75岁，n = 1044）。在两个队列中，体重指数（BMI）、全身脂肪和瘦体重与QUS和骨密度均呈强正相关（r² = 0.2 - 0.6）。在OPRA队列中，MC4R rs17782313与QUS相关，与T等位基因纯合子相比，携带次要C等位基因的个体QUS值更高（TT vs. CT vs. CC：宽带超声衰减（BUA）：100 vs. 103 vs. 103；p = 0.002）；（声速（SOS）：1521 vs. 1526 vs. 1524；p = 0.008）；（硬度指数：69 vs. 73 vs. 74；p = 0.0006），校正混杂因素后。他们的叶酸水平也较低（18 vs. 17 vs. 16；p = 0.03），维生素D水平较低（93 vs. 91 vs. 90；p = 0.03），同型半胱氨酸水平较高（13.7 vs 14.4 vs. 14.5；p = 0.06）。C等位基因女性的骨折发生率较低（52% vs. 58%；p = 0.067）。在OPRA或PEAK - 25中，MC4R的变异与骨密度或身体成分均无关联。靠近FTO和INSIG2的SNP在两个队列中均与任何骨表型无关，且FTO SNP仅在PEAK - 25中与身体成分相关（p≤0.001）。我们的结果表明，靠近MC4R的基因变异与定量超声及骨折风险相关。
