Osteoporosis from genes to phenotypes

Osteoporosis is a leading public health problem in our rapidly growing, aging population. It is a systemic skeletal disease characterized by reduced bone mass and microarchitectural deterioration of bone tissue, with a consequent increase in bone fragility and susceptibility to fracture. Family and twin studies have shown that osteoporosis and its associated phenotypes are under strong genetic control. In addition, it has been shown than not one major locus is responsible of the susceptibility to develop osteoporosis; instead, diverse genetic and environmental factors involved with the disease have confi rmed its complex multifactorial nature

Genomic Medicine: Lessons Learned From Monogenic and Complex Bone Disorders

Current genetic studies of monogenic and complex bone diseases have broadened our understanding of disease pathophysiology, highlighting the need for medical interventions and treatments tailored to the characteristics of patients. As genomic research progresses, novel insights into the molecular mechanisms are starting to provide support to clinical decision-making; now offering ample opportunities for disease screening, diagnosis, prognosis and treatment. Drug targets holding mechanisms with genetic support are more likely to be successful. Therefore, implementing genetic information to the drug development process and a molecular redefinition of skeletal disease can help overcoming current shortcomings in pharmaceutical research, including failed attempts and appalling costs. This review summarizes the achievements of genetic studies in the bone field and their application to clinical care, illustrating the imminent advent of the genomic medicine era

Using Mendelian Randomization to Decipher Mechanisms of Bone Disease

Purpose of Review: This review summarizes the basic principles of Mendelian randomization (MR) and provides evidence for the causal effect of multiple modifiable factors on bone outcomes. Recent Findings: Several studies using MR approach have provided support for the causal effect of obesity on bone mineral density (BMD). Strikingly, studies have failed to prove a causal association between elevated 25(OH) D concentrations and higher BMD in community-dwelling individuals. Summary: The MR approach has been successfully used to evaluate multiple factors related to bone mineral density variation and/or fracture risk. The MR approach avoids some of the classical observational study limitations and provides more robust causal evidence, ensuring bigger success of the clinical trials. The selection of interventions based on genetic evidence could have a substantial impact on clinical practice

Genetics of Bone and Muscle Interactions in Humans

Purpose of Review To summarize the evidence from recent studies on the shared genetics between bone and muscle in humans. Recent Findings Genome-wide association studies (GWAS) have successfully identified a multitude of loci influencing the variability of different bone or muscle parameters, with multiple loci overlapping between the traits. In addition, joint analyses of multiple correlated musculoskeletal traits (i.e., multivariate GWAS) have underscored several genes with possible pleiotropic effects on both bone and muscle including MEF2C and SREBF1. Notably, several of the proposed pleiotropic genes have been validated using human cells or animal models. Summary It is clear that the study of pleiotropy may provide novel insights into disease pathophysiology potentially leading to the identification of new treatment strategies that simultaneously prevent or treat both osteoporosis and sarcopenia. However, the role of muscle factors (myokines) that stimulate bone metabolism, as well as osteokines that affect muscles, is in its earliest stage of understandin

Diabetes, Diabetic Complications, and Fracture Risk

Diabetes and osteoporosis are both common diseases with increasing prevalences in the aging population. There is increasing evidence corroborating an association between diabetes mellitus and bone. This review will discuss the disease complications of diabetes on the skeleton, highlighting findings from epidemiological, molecular, and imaging studies in animal models and humans. Compared to control subjects, decreased bone mineral dens

Genome-wide association studies in economics and entrepreneurship research: promises and limitations

The recently developed genome-wide association study (GWAS) design enables the identification of genes specifically associated with economic outcomes such as occupational and other choices. This is a promising new approach for economics research which we aim to apply to the choice for entrepreneurship. However, due to multiple testing issues, very large sample sizes are needed to differentiate between true and false positives. For a GWAS on entrepreneurship, we expect that a sample size of at least 30,000 observations is required

Heritability of fasting glucose levels in a young genetically isolated population

Aims/hypothesis: The heritability of fasting glucose levels in Northern European populations has been examined previously in twins and samples of small pedigrees. In this study the heritability of fasting plasma glucose (FPG) was estimated in participants in the Erasmus Rucphen Family study, who were members of a single pedigree from a young genetic isolate. We also studied the relationship between FPG and components of the metabolic syndrome. Methods: FPG, lipid, blood pressure and body composition measurements were completed for 852 participants without diabetic medication. The most significant predictors of FPG were used as covariates in heritability estimation. The sibship effect, which is a composite of genetic dominance and shared early-life environmental effects, was included as a random effect. Results: The age- and sex-adjusted heritability of log normal-transformed FPG was 36.6%. When further adjusted for metabolic risk factors, namely body composition parameters, systolic blood pressure, triglycerides and cholesterol:HDL ratio, the heritability estimate rose to 42.8%. After adjustment for the sibship effect, the additive component of heritability was estimated to be 28.3% (age-and sex-adjusted) and 24.9% (full model). Conclusions/ interpretation: Genes control a significant proportion of the variance in FPG levels. Adjustment for other metabolic risk factors did not substantially change the heritability estimate, which suggests that a large part of the variance in FPG levels is due to genes that act through pathways that are independent of those controlling body composition, blood pressure and lipid levels

Dietary patterns in an elderly population and their relation with bone mineral density: the Rotterdam Study

Purpose: Our aim was to identify dietary patterns that are associated with bone mineral density (BMD) against a background of relatively high dairy intake in elderly Dutch subjects. Methods: Participants were 55 years of age and older (n = 5144) who were enrolled in The Rotterdam Study, a population-based prospective cohort study. Baseline intake of 28 pre-defined food groups was determined using a validated food frequency questionnaire. Dietary patterns were identified using principal component analysis. BMD was measured using dual-energy X-ray absorptiometry at baseline and at three subsequent visits (between 1993 and 2004). Linear mixed modelling was used to longitudinally analyse associations of adherence to each pattern with repeatedly measured BMD (both in Z scores). Results: After adjustment for confounders, two dietary patterns were associated with high BMD: a “Traditional” pattern, characterized by high intake of potatoes, meat and fat (β = 0.06; 95 % CI 0.03, 0.09) and a “Health conscious” pattern, characterized by high intake of fruits, vegetables, poultry and fish (β = 0.06; 95 % CI 0.04, 0.08). The “Processed” pattern, characterized by high intake of processed meat and alcohol, was associated with low BMD (β = −0.03; 95 % CI −0.06, −0.01). Associations of adherence to the “Health conscious” and “Processed” pattern with BMD were independent of body weight and height, whereas the association between adherence to the “Traditional” pattern with BMD was not. Conclusions: Against a background of high dairy intake and independent of anthropometrics, a “Health conscious” dietary pattern may have benefits for BMD, whereas a “Processed” dietary pattern may pose a risk for low BMD

Association between an insulin-like growth factor I gene promoter polymorphism and bone mineral density in the elderly: the Rotterdam Study

Studies of the roles of variants of the IGF-I gene in the regulation of bone mineral density (BMD) have yielded conflicting results. We examined the role of a microsatellite repeat polymorphism in one of the promoter regions of the IGF-I gene in relation to femoral BMD in elderly women and men from the Rotterdam Study. We studied 5648 and 4134 individuals at baseline and follow-up ( approximately 2 yr later), respectively. Femoral BMD measurements were performed using dual energy x-ray absorptiometry. In women, baseline BMD levels were, on the average, 0.02 g/cm(2) [95% confidence interval (CI) for difference, -0.03, -0.00 g/cm(2)] lower in individuals without the 192-bp allele as compared with the homozygotes for the allele (P = 0.03). The mean rate of BMD change from baseline to follow-up was -6.9 mg/cm(2) (95% CI, -10.8, -3.0), -4.5 mg/cm(2) (95% CI, -6.4, -2.5), and -2.3 mg/cm(2) (95% CI, -4.2, 0.3) in noncarriers, heterozygotes, and homozygotes for the 192-bp allele, respectively (P trend = 0.03). Adjustment for age and body mass index did not essentially change this relation. No such effects were observed in men. Our findings suggest that this promoter polymorphism or another functional polymorphism in linkage disequilibrium may be a genetic determinant of BMD levels and rate of bone loss in postmenopausal women

Fetal and childhood growth patterns associated with bone mass in school-age children: The generation R study

Low birth weight is associated with lower bone accrual in children and peak bone mass in adults. We assessed how different patterns of longitudinal fetal and early childhood growth influence bone properties at school age. In 5431 children participating in a population-based prospective cohort study, we measured fetal growth by ultrasound at 20 and 30 weeks gestation, and childhood growth at birth, 1, 2, 3, and 4 years of age. We analy