The Interplay of Genes and Diet in Metabolic Diseases and Aging: Studies on Obesity, Osteoporosis and Survival

Obesity and osteoporosis are common and complex disorders with important consequences for human health and for society. The two conditions are intimately linked, as evidenced by epidemiological studies showing that obesity protects from osteoporosis while low body weight poses a strong risk factor 1, 2. Obesity, defined as a body mass index (BMI) of 30 kg/m2 and over, has become a global epidemic and represents an important risk factor for type 2 diabetes mellitus, hypertension, cardiovascular disease, stroke, some types of cancer and disability. Osteoporosis, a skeletal disorder characterized by loss of bone strength and proneness to fractures, is a major health threat to hundreds of millions of elderly individuals worldwide and prevalence will continue to rise as populations age. Osteoporosis and obesity result from an interaction between genetic factors and environment. Although the growing prevalence of obesity is most likely driven by changing lifestyles encompassing increased caloric intake and decreased energy expenditure through physical activity, individual susceptibility varies widely and is strongly influenced by genetic factors. Heritability estimates for BMI, the most widely used parameter of obesity, range from 30 to 70% in family- and twin studies 3. There are also genetic influences on obesity-related traits like total body fat mass, lean mass and measures of fat distribution 4-8, but the heritability of these parameters is less clear than that of BMI. A large contribution of genes has also been documented for the susceptibly to develop osteoporosis. Heritability estimates for bone mineral density (BMD), the most widely used parameter for osteoporosis, range between 50 and 85% 9. The age-adjusted heritability of osteoporotic fractures is smaller (between 25 and 50%) and may be independent to that of BMD 10, possibly due to other important factors associated with fractures such as falls

A Large Skull Defect Due to Gorham-Stout Disease: Case Report and Literature Review on Pathogenesis, Diagnosis, and Treatment

A 24-year old man was referred to the Erasmus MC Bone Center because of an asymptomatic increasing skull defect of the left parietal bone. The defect was first noticed at the age of six, and gradually increased over the years. His medical history was unremarkable, without any known trauma and a negative family history for bone diseases. Laboratory tests showed a low vitamin D level without other abnormalities. Particularly, there was no increase in markers of inflammation or bone turnover. CT-scans of the skull showed an osteolytic region of the parietal skull bone, with a two-centimeter increase in diameter over 9 years. Contrast enhanced MRI showed lymphangiogenic invasion, which was compatible with our suspicion of Gorham-Stout disease. The patient was referred to the neurosurgeon for treatment with a bone graft while considering additional drug treatment. Gorham-Stout or vanishing bone disease is a rare entity characterized by progressive osteolysis with lymphangiogenic bone invasion. Although already reported in 1838, currently the diagnosis and treatment of Gorham-Stout disease is still challenging. The underlying pathophysiology is not clarified yet and several theories exist. The disease usually affects persons younger than 40 years and the majority present with bone disease of the maxillofacial region, the upper extremities or the torso. The clinical presentation includes most frequently pain, swelling, and functional impairment of the affected region, but the disease can also be asymptomatic. Laboratory investigations are usually normal, and diagnosis is based upon imaging and sometimes pathology examination of affected bone tissue. Treatment is experimental and there is no general consensus about the best option due to lack of randomized controlled trials. Case reports showed patients treated with bisphosphonates, interferon-alpha, anti-VEGF therapy, mTOR inhibitors, and radiotherapy. There are some reports of surgery with prosthetic or bone grafts but no long-term follow-up data exist. This paper describes a unique case of Gorham-Stout disease of the parietal skull bone and discusses the current state of knowledge about this rare bone disease

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

Genetic Risk Factors for Atypical Femoral Fractures (AFFs): A Systematic Review

Atypical femoral fractures (AFFs) are uncommon and have been associated particularly with long-term antiresorptive therapy, including bisphosphonates. Although the pathogenesis of AFFs is unknown, their identification in bisphosphonate-naïve individuals and in monogenetic bone disorders has led to the hypothesis that genetic factors predispose to AFF. Our aim was to review and summarize the evidence for genetic factors in individuals with AFF. We conducted structured literature searches and hand-searching of conference abstracts/reference lists for key words relating to AFF and identified 2566 citations. Two individuals independently reviewed citations for (i) cases of AFF in monogenetic bone diseases and (ii) genetic studies in individuals with AFF. AFFs were reported in 23 individuals with the following 7 monogenetic bone disorders (gene): osteogenesis imperfecta (COL1A1/COL1A2), pycnodysostosis (CTSK), hypophosphatasia (ALPL), X-linked osteoporosis (PLS3), osteopetrosis, X-linked hypophosphatemia (PHEX), and osteoporosis pseudoglioma syndrome (LRP5). In 8 cases (35%), the monogenetic bone disorder was uncovered after the AFF occurred. Cases of bisphosphonate-naïve AFF were reported in pycnodysostosis, hypophosphatasia, osteopetrosis, X-linked hypophosphatemia, and osteoporosis pseudoglioma syndrome. A pilot study in 13 AFF patients and 268 controls identified a greater number of rare variants in AFF cases using exon array analysis. A whole-exome sequencing study in 3 sisters with AFFs showed, among 37 shared genetic variants, a p.Asp188Tyr mutation in the GGPS1 gene in the mevalonate pathway, critical to osteoclast function, which is also inhibited by bisphosphonates. Two studies completed targeted ALPL gene sequencing, an ALPL heterozygous mutation was found in 1 case of a cohort of 11 AFFs, whereas the second study comprising 10 AFF cases did not find mutations in ALPL. Targeted sequencing of ALPL, COL1A1, COL1A2, and SOX9 genes in 5 cases of AFF identified a variant in COL1A2 in 1 case. These findings suggest a genetic susceptibility for AFFs.

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

Heritability of serum iron, ferritin and transferrin saturation in a genetically isolated population, the Erasmus Rucphen Family (ERF) study

Background: Iron has been implicated in the pathogenesis of various disorders. Mutations in the HFE gene are associated with an increase in serum iron parameters. The aim of this study was to estimate the heritability in serum iron parameters explained by HFE. Methods: Ninety families (980 subjects) were included in the present analysis. Heritability estimation was conducted using the variance component method. The likelihood ratio test was used to compare models. Phenotypic and genetic correlations between serum iron parameters were calculated. Results: The heritability (h 2 ± SE) estimates were 0.23 ± 0.07 (p < 0.0001) for iron, 0.29 ± 0.09 (p < 0.0001) for ferritin and 0.28 ± 0.07 (p < 0.0001) for transferrin saturation while adjusting for age, age 2 and sex. The HFE genotypes explained between 2 to 6% of the sex and age-adjusted variance in serum iron, ferritin and transferrin saturation. There was a high genetic correlation between serum iron parameters, suggesting pleiotropy between these traits. Conclusion: A substantial proportion of the variance of iron, ferritin and transferrin saturation can be explained by additive genetic effects, independent of sex and age. The HFE genotypes explained a considerable proportion of serum iron parameters and may be an important factor in the complex iron network. Copyrigh

Bone health and coronary artery calcification: The Rotterdam Study

Objectives: Vascular calcification has been associated inconsistently to low bone mineral density and fractures. The aims of the present study were to investigate the associations between coronary artery calcification (CAC) and BMD change, BMD and fracture risk in elderly subjects of the population-based Rotterdam Study. Methods: BMD was assessed through dual-energy X-ray absorptiometry and CAC through Electron-Beam Computed Tomography in 582 men and 694 women. We investigated the associations between BMD change (6.4 years follow-up) and CAC at follow-up and between BMD and CAC (measured simultaneously). In sensitivity analyses we stratified analyses for estradiol levels in women. The association between CAC and fracture risk (9 years follow-up) was tested through competing-risks models. Models were sex-stratified and adjusted for age, body mass index, smoking, bisphosphonate use and age at menopause. Results: There was no association between BMD change and CAC in men. In women, each 1% increase in annual BMD loss was significantly associated with higher follow-up CAC [β = 0.22 (0.06-0.38), p. =. 0.006; prevalence ratio: 4%]. Stratified analyses showed significant associations between BMD loss and follow-up CAC only in women with lower estradiol levels. We found no association between CAC and fracture risk and no association between BMD and CAC cross-sectionally. Conclusions: BMD loss was associated with higher follow-up CAC in women, which might be related to low estrogen levels. No association between CAC and BMD or fracture risk was found. Further studies are required to elucidate the mechanisms that might underlie the association between BMD change and coronary calcification in women

Hypercalcemia during pregnancy: management and outcomes for mother and child

Diagnosing and treating hypercalcemia during pregnancy can be challenging due to both the physiological changes in calcium homeostasis and the underlying cause for the hypercalcemia. During pregnancy and lactation there is increased mobilization of calcium in the mother to meet the fetus’ calcium requirements. Here we discuss the diagnostic challenges, management, and patient perspective of hypercalcemia during pregnancy in two particular cases and in other rare conditions causing hypercalcemia

Hydroxychloroquine decreases human MSC-derived osteoblast differentiation and mineralization in vitro

We recently showed that patients with primary Sjögren Syndrome (pSS) have significantly higher bone mineral density (BMD) compared to healthy controls. The majority of those patients (69%) was using hydroxychloroquine (HCQ), which may have favourable effects on BMD. To study the direct effects of HCQ on human MSC-derived osteoblast activity. Osteoblasts were cultured from human mesenchymal stromal cells (hMSCs). Cultures were treated with different HCQ doses (control, 1 and 5 µg/ml). Alkaline phosphatase activity and calcium measurements were performed to evaluate osteoblast differentiation and activity, respectively. Detailed microarray analysis was performed in 5 µg/ml HCQ-treated cells and controls followed by qPCR validation. Additional cultures were performed using the cholesterol synthesis inhibitor simvastatin (SIM) to evaluate a potential mechanism of action. We showed that HCQ inhibits both MSC-derived osteoblast differentiation and mineralization in vitro. Microarray analysis and additional PCR validation reveale

単離した分裂酵母変異体は、MAPキナーゼシグナルとステロール合成に異常を示した

博士（医学）神戸大