Radiology and imaging determinants of bone mass

Osteoporosis is a disease that shows no symptoms until fractures occur, and for that reason, relatively few diagnoses are made in time for effective therapy to be administered. Consequently, a large number of individuals experience the pain, expense, disability, and decreased quality of life caused by these age-related fractures. Sufficient diagnosis should result in decreased morbidity from osteoporotic fractures, and for that purpose determinations of bone mass and rate of bone loss are important. This review briefly outlines the most recent developments in this area with special attention to the issues on which those in the field today are in general agreement.     

Hormonal determinants of bone turnover before and after attainment of peak bone mass

Introduction Bone turnover decreases from adolescence into adulthood, but does not reach a nadir until the fourth decade. Biochemical markers of bone turnover reflect different processes before and after peak bone mass, so hormonal influences on bone turnover may differ before and after peak bone mass. Objectives To describe the changes in bone turnover and hormones relevant to bone metabolism from adolescence into adulthood, and to identify which hormones correlate with bone turnover before and after peak bone mass. Design/participants Two measurements of bone turnover markers and hormones were obtained 5–9 years apart in 116 healthy males and females recruited from secondary schools and general practices. Correlations were examined cross‐sectionally and longitudinally. Results Dehydroepiandrosterone sulphate (DHEAS) correlated negatively with bone turnover cross‐sectionally and longitudinally (r?0·59 to ?0·69) in males and females under the age of 25 years. IGF‐1 correlated positively with aminoterminal propeptide of type I procollagen (PINP) cross‐sectionally and longitudinally (r 0·35) in women over the age of 25 years. After correction for change in BMI, there were significant longitudinal correlations between DHEAS and bone turnover in women under 25 years (r?0·62, ?0·66) and IGF‐1 and PINP in women over 25 years (r 0·56). Conclusions We have described changes in bone turnover and hormones from adolescence into adulthood. Dehydroepiandrosterone sulphate correlates with bone turnover before peak bone mass which may represent a direct effect on bone metabolism or the role of dehydroepiandrosterone sulphate as a substrate for conversion to other sex steroids. IGF‐1 is correlated with aminoterminal propeptide of type I procollagen in women after peak bone mass, which may reflect an influence on cortical modelling.     

Clinical determinants of bone mass and bone ultrasonometry in patients with systemic sclerosis

OBJECTIVE: The aim of this study was to evaluate bone mass and bone ultrasonometry in patients affected with systemic sclerosis (SSc). METHODS: Fifty-five patients (mean age 54.1 +/- 14.1 years; 25 premenopausal, and 30 postmenopausal women) affected with SSc (in a limited, intermediate or diffused form) and 60 age-matched healthy controls (30 premenopausal, and 30 postmenopausal women) were studied for Bone Mineral Density (BMD) measured by fan-beam x-ray densitometry, Stiffness Index (SI) measured by ultrasonometry of the heel, inflammation indices (erithrocyte sedimentation rate, C-reactive protein), and autoantibodies (ANA, ENA). Examinations were also carried out in order to determine any internal organ involvement. None of the patients had previously received steroid treatment. RESULTS: BMD was significantly lower in the SSc group than in the control group, whether it was expressed in g/cm2 (lumbar spine: 0.980 vs 1.241, p < 0.01; femoral neck: 0.832 vs 0.955, p < 0.05; total body 1.050 vs 1.168, p < 0.01) or by T- and Z-score (lumbar spine: T = -2.48; Z = -1.10; femoral neck: T = -1.69; Z = -0.55; total body: T = -1.11; Z = -0.48). SI was also altered (75.8 vs 96.2, p < 0.01; T = -2.10, Z = -1.12). BMD and SI were lower in women with the diffuse form of skin involvement. BMD and SI were lower in women in whom one or more internal organs were involved. CONCLUSION: SSc patients had reduced BMD and SI that was more marked in the diffuse form and in those with internal organ involvement and that became more marked with age and estrogen deficiency. This demineralisation was not related to the inflammation indices, disease duration, or to the immunological pattern.     

Genetic determinants of urolithiasis

Urolithiasis affects approximately 10% of individuals in Western societies by the seventh decade of life. The most common form, idiopathic calcium oxalate urolithiasis, results from the interaction of multiple genes and their interplay with dietary and environmental factors. To date, considerable progress has been made in identifying the metabolic risk factors that predispose to this complex trait, among which hypercalciuria predominates. The specific genetic and epigenetic factors involved in urolithiasis have remained less clear, partly owing to the candidate gene and linkage methods that have been available until now, being inherently low in their power of resolution and in assessing modest effects in complex traits. However, together with investigations of rare, Mendelian forms of urolithiasis associated with various metabolic risk factors, these methods have afforded insights into biological pathways that seem to underlie the development of stones in the urinary tract. Monogenic diseases account for a greater proportion of stone formers in children and adolescents than in adults. Early diagnosis of monogenic forms of urolithiasis is of importance owing to associated renal injury and other potentially treatable disease manifestations, but diagnosis is often delayed because of a lack of familiarity with these rare disorders. In this Review, we will discuss advances in the understanding of the genetics underlying polygenic and monogenic forms of urolithiasis.     

Genetic determinants of osteoporosis

PURPOSE OF REVIEW: Osteoporosis is a common disease with a strong genetic component characterised by reduced bone mass and an increased risk of fragility fractures. Several advances have been made over recent years in understanding the genetic basis of susceptibility to osteoporosis. This paper will review recent developments in this area. RECENT FINDINGS: Twin studies have shown that genetic factors contribute to osteoporosis by influencing bone mineral density and other determinants of fracture risk such as ultrasound properties of bone, skeletal geometry, and bone turnover. In the normal population, many different genes contribute to the regulation of these phenotypes by interacting with environmental factors such as diet and exercise. Whereas the effect size of individual genes is small, meta-analysis has been successfully used in many cases to define the role of individual polymorphisms in predisposing to osteoporosis. Linkage studies in humans and experimental animals have identified several quantitative trait loci that regulate osteoporosis-related phenotypes, and many genes that cause monogenic bone diseases have been identified by use of this approach. It has been found that subtle polymorphisms in some of these genes also contribute to regulation of bone mass in the normal population. SUMMARY: Research has recently begun to clarify the genes and genetic variants that predispose to osteoporosis and regulation of bone mass. Clinical applications of this research include the identification of genetic markers for assessment of fracture risk and the identification of novel molecular targets for the design of drugs that can be used to treat bone disease.     

骨密度和骨折风险的遗传决定因素——发展现状和未来方向

全基因组关联研究(GWAS)的大规模应用,启动了寻找常见疾病(如骨质疏松和骨折)相关基因的热潮.本文目的为讨论目前各种遗传学方法的基本设想和优缺点;概述那些经GWAS鉴定的与骨密度(BMD)和骨折有关的基因及其功能,以及将来如何提高骨质疏松的遗传学研究水平.     

Genetic determinants of vascular reactivity

Blood pressure is controlled by a complex combination of processes that influence cardiac output and peripheral vascular resistance. Multiple genes potentially influence each parameter involved in the control of blood pressure, and individuals with the same blood pressor level do not necessarily have the same genotype at relevant loci, nor do individuals with the same genotype at particular loci necessarily have the same blood pressure. Nevertheless, pharmacogenetic studies of vascular reactivity will certainly allow the analysis of the mechanisms affected by genes, and lead to a better understanding of the epidemiologic observations seen in large groups of patients. Polymorphisms in the genes of the renin-angiotensin system allow definition of the “genetic profile” associated with a higher risk of cardiovascular disease, and can also be linked to significant changes in vascular reactivity in arteries isolated from patients carrying the polymorphisms.     

Genetic determinants of nonmodulating hypertension

We sought to determine whether genes of the renin-angiotensin-aldosterone system can predict the nonmodulating intermediate phenotype in essential hypertension. Aldosterone responses to angiotensin II were assessed in 298 subjects with hypertension. Subjects were genotyped at the angiotensinogen M235T, angiotensin-converting enzyme I/D, aldosterone synthase C-344 T, renin, angiotensin II type 1 receptor, and adducin loci. The data were analyzed by Student t test, ANOVA, stepwise linear regression and general linear model or GENMOD regression techniques, and chi2 analysis odds ratios (ORs). Aldosterone response varied by genotype for angiotensin and aldosterone synthase but not for the other loci. The combination of angiotensinogen 235 TT and angiotensin-converting enzyme DD showed further reduction (P=0.0377) when compared with angiotensinogen 235 TT alone, an example of genetic epistasis. When the subject was required also to possess the CYP11B2 -344 TT genotype, there was a further substantial reduction. Of these 3 loci, only angiotensinogen 235 TT significantly increased the OR of predicting the nonmodulating hypertensive phenotype (OR, 2.00; 95% confidence interval, 1.152 to 3.51). However, when angiotensin-converting enzyme DD was combined with angiotensinogen 235 TT, the OR nearly doubled to 3.74, with a further increase to 5.36-fold when the subject possessed all 3 genotypes. Thus, the angiotensinogen, angiotensin-converting enzyme, and aldosterone synthase genotypes identified individuals with the nonmodulating phenotype with an increasing degree of fidelity. For this subclass of essential hypertension, it is likely that genotyping can be substituted for complex phenotyping for therapeutic and preventive decision making.     

Genetic determinants of C-reactive protein

C-reactive protein (CRP) levels are a complex phenotype with both genetic and environmental determinants. Recent work has highlighted the impact of genetic variants within the CRP gene as well as other candidate genes, often chosen for their role in the inflammatory pathway, on CRP levels. Emerging work shows the association of such genetic variants in CRP not only to CRP levels, but also to variation of CRP levels in the acute phase response. Work on the relation of genetic variants within CRP to cardiovascular disease has had varied results. Whole-genome association studies to investigate the genetic determinants of CRP levels in an unbiased manner are ongoing.     

Genetic determinants of plasma lipoproteins

The search for common genetic determinants of plasma lipoproteins began in the early 1980s. Despite some exceptions, these efforts have not yet yielded a set of biological markers that can be used in clinical practice. By contrast, successes in defining the molecular basis of rare single-gene disorders, such as familial hypoalphalipoproteinemia, have shown the value of experimental designs that focus on genomic analysis of individuals within the tails of Gaussian distributions of quantitative lipoprotein traits. For example, this strategy showed that a small but relevant proportion of individuals within the <5% tail of plasma HDL-cholesterol distribution have mutations in genes that cause familial hypoalphalipoproteinemia. The value of clinical testing for genomic variants as an adjunct to a biochemical measurement of plasma lipoproteins, however, is at best questionable. A more direct impact of genetic studies is that definitions of 'common' and 'large genetic effects' have become more tempered, reflecting perhaps the biological reality that plasma lipoproteins are probably determined by the aggregate of numerous modest and occasional large genetic effects in addition to environmental factors. Here, we review recent progress on genomic variants and cholesterol metabolism, and discuss the impact these genetic studies will have on clinical cardiology.     

Genetic determinants of arterial thrombosis

Arterial thrombosis is a complex disorder that involves multiple genetic and environmental factors interacting to produce the characteristic phenotype. In the past decades, investigators have focused on the molecular genetics of arterial vascular disorders and have identified numerous polymorphisms and mutations in genes related to the hemostatic system and to enzymes involved in the synthesis and bioavailability of nitric oxide (NO); however, the relation between most polymorphisms and the risk of coronary artery disease, ischemic stroke, and peripheral vascular disease remains highly controversial. In this review, we describe the most common genetic variations involved in the pathogenesis of arterial thrombosis, their functional implications, and their association with disease risk. Specifically, we consider polymorphisms in coagulation factors (fibrinogen, prothrombin, FV Leiden, FVII, and FXIII); fibrinolytic factors (tissue-type plasminogen activator, plasminogen activator inhibitor-1, and thrombin-activatable fibrinolysis inhibitor); platelet surface receptors; methylenetetrahydrofolate reductase; endothelial NO synthase; and the antioxidant enzymes paraoxonase and plasma glutathione peroxidase. Overall, there seems to be a modest contribution of individual genetic variants in the hemostatic and antioxidant systems to the risk of arterial thrombosis. Thus, future research ought to focus on identifying novel genetic determinants and on the interaction of these genetic risk factors with each other and the environment to understand better the pathobiology and susceptibility to arterial thrombotic disease.     

Genetic determinants of cardiac hypertrophy

PURPOSE OF REVIEW: Cardiac hypertrophy is a common phenotypic response of the heart to stimulants. It is associated with increased morbidity and mortality in various cardiovascular disorders. Genetic factors are important determinants of phenotypic expression of cardiac hypertrophy, whether in single-gene disorders or in complex traits. We focus on the molecular genetics of cardiac hypertrophy in various conditions with an emphasis on hypertrophic cardiomyopathy, a genetic paradigm of cardiac hypertrophic response. RECENT FINDINGS: The molecular genetic basis of cardiac hypertrophy in single-gene disorders has been partially elucidated. Likewise, the impact of genetics on the expression of cardiac hypertrophy in the general population has been demonstrated. Identification of mutations in the Z disk proteins has expanded the spectrum of causal mutations beyond the thin and thick filaments of the sarcomeres. In addition, modifier loci have been mapped and shown to impart considerable effects on the expression of cardiac hypertrophy in hypertrophic cardiomyopathy. Elucidation of the molecular genetics of sarcomeric hypertrophic cardiomyopathy and many of the phenocopies has highlighted the limitations of clinical diagnosis as a determinant of management and prognostic advice. The findings have raised the importance of diagnosis and treatment algorithms, which are based on both genotype and phenotype information. SUMMARY: Cardiac hypertrophy, regardless of the cause, is the phenotypic consequence of complex interactions between genetic and nongenetic factors.     

Genetic determinants of alcoholic liver disease

Alcoholic liver disease (ALD) accounts for the majority of chronic liver disease in Western countries. The spectrum of ALD includes steatosis with or without fibrosis in virtually all individuals with an alcohol consumption of >80 g/day, alcoholic steatohepatitis of variable severity in 10-35% and liver cirrhosis in approximately 15% of patients. Once cirrhosis is established, there is an annual risk for hepatocellular carcinoma of 1-2%. Environmental factors such as drinking patterns, coexisting liver disease, obesity, diet composition and comedication may modify the natural course of ALD. Twin studies have revealed a substantial contribution of genetic factors to the evolution of ALD, as demonstrated by a threefold higher disease concordance between monozygotic twins and dizygotic twins. With genotyping becoming widely available, a large number of genetic case-control studies evaluating candidate gene variants coding for proteins involved in the degradation of alcohol, mediating antioxidant defence, the evolution and counteraction of necroinflammation and formation and degradation of extracellular matrix have been published with largely unconfirmed, impeached or even disproved associations. Recently, whole genome analyses of large numbers of genetic variants in several chronic liver diseases including gallstone disease, primary sclerosing cholangitis and non-alcoholic fatty liver disease (NAFLD) have identified novel yet unconsidered candidate genes. Regarding the latter, a sequence variation within the gene coding for patatin-like phospholipase encoding 3 (PNPLA3, rs738409) was found to modulate steatosis, necroinflammation and fibrosis in NAFLD. Subsequently, the same variant was repeatedly confirmed as the first robust genetic risk factor for progressive ALD.     

Genetic determinants of plasma total homocysteine

Hyperhomocysteinemia (Hhcy) is an established risk factor for various pathologies including arterial vascular disease and venous thrombosis, congenital malformations and other pregnancy complications, and dementia. Homocysteine remethylation, transsulfuration, and export to the blood/extracellular compartment determine homocysteine concentrations. Any disturbance in these routes may lead to Hhcy and potentially increase risk of disease. In this report, we aim to review all known polymorphisms involved in homocysteine and B-vitamin metabolism that have been assessed for their effect on tHcy. In the last section, we summarize the polymorphisms, for which the obtained data provides evidence for their involvement in Hhcy at the population level, and discuss how to continue our search for genetic determinants of tHcy.     

Genetic determinants of blood pressure regulation

Hypertension is a multifactorial disorder that probably results from the inheritance of a number of susceptibility genes and involves multiple environmental determinants. Existing evidence suggests that the genetic contribution to blood pressure variation is about 30-50%. Although a number of candidate genes have been studied in different ethnic populations, results from genetic analysis are still inconsistent and specific causes of hypertension remain unclear. Furthermore, the abundance of data in the literature makes it difficult to piece together the puzzle of hypertension and to define candidate genes involved in the dynamic of blood pressure regulation. In this review, we attempt to highlight the genetic basis of hypertension pathogenesis, focusing on the most important existing genetic variations of candidate genes and their potential role in the development of this disease. Our objective is to review current knowledge and discuss limitations to clinical applications of genotypic information in the diagnosis, evaluation and treatment of hypertension. Finally, some principles of pharmacogenomics are presented here along with future perspectives of hypertension.     

Genetic determinants of phenotype in beta-thalassemia

Abstract

Modifier genes are defined as inherited genetic variation that leads to a qualitative or quantitative difference in disease phenotype. This has made the prediction of the phenotype based upon the genotype more difficult. Beta-thalassemia phenotype is modified by co-existent other genetic alterations. Changes α/β-globin ratio can either ameliorate the disease phenotype or increase the severity of the disease in β-thalassemia. Primary modifiers primarily affecting the clinical presentation include alpha gene changes, XmnI polymorphism and hereditary persistence of fetal hemoglobin (HPFH) variants. 'Thalassemia intermedia' is a heterogenous group with interplay of several genetic factors. The nature of the beta-genotype as well as the knowledge of the presence or absence of alleviating factors help the physician to decide on commencement of a regular transfusion regime or other lines of management including hydroxyurea therapy. The secondary modifiers affect the severity of jaundice, bone disease, cardiac and thrombotic complications. The present review gives a concise discussion of various modifying genes and the influence on the phenotype of β-thalassemia.