Adipose Tissue Expression and Genetic Variants of the Bone Morphogenetic Protein Receptor 1A Gene (BMPR1A) Are Associated With Human Obesity

OBJECTIVE

Members of the family of bone morphogenetic proteins (BMPs) are important regulators of adipogenesis. We examined the role of the BMP receptor 1A gene (BMPR1A) in the pathophysiology of human obesity.

RESEARCH DESIGN AND METHODS

We measured BMPR1A mRNA expression in paired samples of visceral and subcutaneous adipose tissue from 297 subjects and sequenced the BMPR1A in 48 nonrelated white subjects. Twenty-one representative variants including HapMap tagging single nucleotide polymorphisms (SNPs) were then genotyped for association studies in German whites (n = 1,907). For replication analyses, we used a population of Sorbs from Germany (n = 900) and German childhood cohorts (n = 1,029 schoolchildren and 270 obese children).

RESULTS

mRNA expression of the BMPR1A was significantly increased in both visceral and subcutaneous adipose tissue of overweight and obese subjects compared with lean subjects (P < 0.05). In a case-control study, four SNPs (rs7095025, rs11202222, rs10788528, and rs7922846) were nominally associated with obesity (adjusted P < 0.05). For three SNPs (rs7095025, rs11202222, and rs10788528), the association with obesity was confirmed in the independent cohort of Sorbs (adjusted P < 0.005). Consistent with this, BMPR1A SNPs were nominally associated with obesity-related quantitative traits in nondiabetic subjects in both adult cohorts. Furthermore, homozygous carriers of the obesity risk alleles had higher BMPR1A mRNA expression in fat than noncarriers.

CONCLUSIONS

Our data suggest that genetic variation in the BMPR1A may play a role in the pathophysiology of human obesity, possibly mediated through effects on mRNA expression.Recent advances in the field of genetics of complex diseases succeeded in identification of novel genes associated with human obesity (1–6). However, in contrast to fat mass and obesity associated (FTO) that turned out to be the first robustly replicated susceptibility signal for polygenic obesity (1,2), several other genes such as GAD2 and INSIG2 failed to “survive” replication efforts following initial studies (7,8). Therefore, along with the highly powered genome-wide association studies highlighting both expected and unexpected genes/variants, the candidate gene approach focusing on genes with plausible functional relevance can still substantially contribute to a better understanding of the etiology of complex disorders such as obesity and its sequelae.Bone morphogenetic proteins (BMPs) are members of the transforming growth factor-β (TGF-β) superfamily and are involved in control of multiple key steps of embryonic development and differentiation (9–11). BMPs have been shown to have different roles in adipogenesis depending on the differentiation stage, the concentrations of BMP, as well as the presence of other extracellular and intracellular factors (12–15). Cellular responses to BMPs have been shown to be mediated by the formation of a hetero-oligomeric complex of the type 1 and type 2 BMP receptors (16–18). Among different isoforms, three type 1 receptors (BMPR1A/ALK3, BMPR1B/ALK6, and ACVR1A/ALK2) and three type 2 receptors (BMPR2, ACTR2A, and ACTR2B) mediate most of the effects of BMPs (9). Of the different BMPR isoforms, BMPR1A is particularly interesting to adipocyte biology since it has been shown to specialize in adipocyte differentiation in vitro (19). Therefore, BMPR1A seems to be a convincing candidate gene possibly involved in the pathogenesis of human obesity and type 2 diabetes.Here, we examined the role of BMPR1A in the pathophysiology of human obesity. We measured mRNA expression of BMPR1A in paired samples of visceral and subcutaneous adipose tissue and examined its relation with anthropometric traits such as BMI, waist-to-hip ratio (WHR), and measures of glucose metabolism. Further, we investigated whether genetic variation within the BMPR1A might affect adipose tissue BMPR1A mRNA expression. Twenty-one representative variants including HapMap tagging single nucleotide polymorphisms (SNPs) were initially genotyped for association studies in German whites. For replication analyses, we used a population of Sorbs from Germany and German children cohorts (schoolchildren and obese children).     

Choosing event‐driven and daily HIV pre‐exposure prophylaxis – data from two European PrEP demonstration projects among men who have sex with men

IntroductionDaily and event‐driven PrEP are both efficacious in reducing the risk for HIV infection. However, the practice of event‐driven PrEP (edPrEP) is less well studied, in particular when provided as an alternative to daily PrEP. We studied regimen preferences and switches, and sexually transmitted infection (STI) incidence.MethodsWe analysed pooled data from two prospective cohort studies among MSM: Be‐PrEP‐ared, Belgium and AMPrEP, the Netherlands. In both projects, participants could choose between daily and edPrEP at three‐monthly study visits, when they were also screened for sexually transmitted infections including hepatitis C (HCV). We assessed the proportion choosing each regimen, and the determinants of choosing edPrEP at baseline. Additionally, we compared the incidence rates (IRs) of HCV, syphilis and chlamydia or gonorrhoea between regimens using Poisson regression. The study period was from 3 August 2015 until 24 September 2018.Results and discussionWe included 571 MSM, of whom 148 (25.9%) chose edPrEP at baseline. 31.7% of participants switched regimen at least once. After 28 months, 23.5% used edPrEP. Older participants (adjusted odds ratio (aOR) = 1.38 per 10 years, 95% confidence interval (CI) = 1.15 to 1.64) and those unemployed (aOR = 1.68, 95% CI = 1.03 to 1.75) were more likely to initially choose edPrEP. IR of HCV and syphilis did not differ between regimens, but the IR of chlamydia/gonorrhoea was higher among daily users (adjusted incidence rate ratio = 1.61, 95% CI = 1.35 to 1.94).ConclusionsA quarter of participants chose edPrEP at baseline and at 28 months this proportion was similar. Although the IR of HCV and syphilis were similar in the two regimens, the lower incidence of chlamydia and gonorrhoea among edPrEP users may suggest that less frequent STI testing of this group could be considered.     

Deviant neurophysiological responses to phonological regularities in speech in dyslexic children

Developmental dyslexia is strongly associated with a phonological deficit. Yet, implicit phonological processing (in)capacities in dyslexia remain relatively unexplored. Here we use a neurophysiological response sensitive to experience-dependent auditory memory traces, the mismatch negativity (MMN), to investigate implicit phonological processing of natural speech in dyslexic and normally reading children. In a modified passive oddball design that minimizes the contribution of acoustic processes, we presented non-words that differed by the degree of phonotactic probability, i.e. the distributional frequency of phoneme combinations in a given language. Overall morphology of ERP responses to the non-words indicated comparable processing of acoustic-phonetic stimulus differences in both children groups. Consistent with previous findings in adults, normally reading children showed a significantly stronger MMN response to the non-word with high phonotactic probability (notsel) as compared to the non-word with low phonotactic probability (notkel), suggesting auditory cortical tuning to statistical regularities of phoneme combinations. In contrast, dyslexic children did not show this sensitivity to phonotactic probability. These findings indicate that the phonological problems often reported in dyslexia relate to a subtle deficit in the implicit phonetic-phonological processing of natural speech.     

Contrast sensitivity--an unnoticed factor of visual perception in children with developmental delay: normal data of the Cambridge Low Contrast Gratings test in children

Contrast sensitivity is one of several factors necessary to obtain good visual quality. The aim of this study was to develop normal data on the Cambridge Low Contrast Gratings test in children and to compare these data with data from a group of children with developmental delay. Ninety-nine normal children (aged 2-14 years) and 146 children with developmental delay were tested with the contrast sensitivity test. All children had normal visual acuity and stereopsis. The normal children had an age-dependent development in contrast sensitivity, and adult level was reached after the age of 10 years. A significantly lower score was found in children with developmental delay compared to normal children. The Cambridge Low Contrast Gratings test is suitable for preschool children and children with developmental delay because of its simplicity, and it might be a valuable tool in diagnosing ophthalmologic diseases in children with developmental delay.     

Common variable immune deficiency and lung transplantation

We report on a male patient with bronchiectasis secondary to common variable immune deficiency (CVID) receiving lung transplantation. The patient had been diagnosed with CVID many y prior to right-sided single lung transplantation and was receiving appropriate immunoglobulin substitution therapy. He received antithymocyte globulin induction and maintenance triple therapy with cyclosporine, azathioprine and prednisolone. The early post-operative course was complicated by the development of severe acute cellular rejection and organizing pneumonia. Despite immunoglobulin replacement and antifungal prophylaxis and treatment, Aspergillus fumigatus was repeatedly cultured from bronchoalveolar lavage fluid, 18 months after transplantation. The patient died following a protracted period of repeated hospital admissions, 46 months after transplantation. A review of the literature suggests that many CVID patients appear to have had a complicated post-operative course after lung- and other solid-organ transplantation, and highlights the need for the establishment of international registries for transplanted patients with uncommon conditions.     

Gut microbiota composition and development of atopic manifestations in infancy: the KOALA Birth Cohort Study

BACKGROUND AND AIMS: Perturbations in intestinal microbiota composition due to lifestyle changes may be involved in the development of atopic diseases. We examined gut microbiota composition in early infancy and the subsequent development of atopic manifestations and sensitisation. METHODS: The faeces of 957 infants aged 1 month and participating in the KOALA Birth Cohort Study were analysed using quantitative real-time PCR. Information on atopic symptoms (eczema, wheeze) and potential confounders was acquired through repeated questionnaires. Total and specific IgE were measured in venous blood samples collected during home visits when the infant was 2 years old. During these home visits a clinical diagnosis of atopic dermatitis was made according to the UK-Working Party criteria. RESULTS: The presence of Escherichia coli was associated with a higher risk of developing eczema (OR(adj) = 1.87; 95% CI 1.15 to 3.04), this risk being increased with increasing numbers of E coli (p(for trend) = 0.016). Infants colonised with Clostridium difficile were at higher risk of developing eczema (OR(adj) = 1.40; 95% CI 1.02 to 1.91), recurrent wheeze (OR(adj) = 1.75; 95% CI 1.09 to 2.80) and allergic sensitisation (OR(adj) = 1.54; 95% CI 1.02 to 2.31). Furthermore, the presence of C difficile was also associated with a higher risk of a diagnosis of atopic dermatitis during the home visit (OR(adj) = 1.73; 95% CI 1.08 to 2.78). CONCLUSION: This study demonstrates that differences in gut microbiota composition precede the development of atopy. Since E coli was only associated with eczema and C difficile was associated with all atopic outcomes, the underlying mechanisms explaining these association may be different.     

The cost of treating patients with COPD in Denmark--a population study of COPD patients compared with non-COPD controls

This paper describes a population-based study of health care resource use of patients with chronic obstructive pulmonary disease (COPD) compared to non-COPD controls. Through a screening of the Danish Patient Registry for patients admitted with COPD diagnoses for a 5-year period, 1998-2002, 66,000 individuals with COPD still alive at the beginning of 2002 were identified. Their use of health care resources in 2002 were compared with equivalent data, stratified for age, sex and mortality rates, for a control population without COPD based on data for the 300,000 remaining patients on the Danish Patient Registry in 2002. Results indicated that the gross cost of treating patients with COPD in the Danish somatic hospital and primary health care sector corresponded to 10% of the total cost of treating patients of 40 years or more. The net cost for COPD patients was 1.9 billion DKK (256 million euro), 6% of the total annual costs of treating the population of 40 years or more. The gross cost related to any disease and the net cost reflected the resource use which could be attributed to COPD and its related diagnoses. The incidence of inpatient hospital admissions was almost four times higher in the COPD population than in the control group. COPD patients contacted their general practitioner 12 times more per year than non-COPD controls, but for specialist and paramedic treatment in the primary care sector there was no significant difference between COPD patients and non-COPD controls. Only one third of the COPD costs were due to treatment of COPD as the primary diagnosis. The remaining two-thirds of the COPD-related costs were mainly due to admissions for other diseases such as cardio-vascular diseases, other respiratory diseases, and cancer.     

Impact of type 2 diabetes on nitric oxide and adrenergic modulation of myocardial perfusion

Type 2 diabetic patients are characterized by a reduced adenosine-induced hyperemic myocardial perfusion, which may contribute to their increased cardiovascular morbidity. We hypothesized that the reduced hyperemia can be explained by functional changes in endothelial or autonomic nervous regulation. In 12 type 2 diabetic patients without signs of ischemic heart disease and 14 age-matched control subjects, myocardial perfusion was measured at rest, during adenosine, and during adenosine and alpha-receptor blockade (phentolamine) using positron emission tomography on two separate days: 1) with, and 2) without nitric oxide (NO) inhibition with N(G)-nitro-L-arginine methyl ester. Myocardial perfusion during adenosine was lower in type 2 diabetic patients compared with control subjects (P = 0.05). No significant effect of NO inhibition on myocardial perfusion during adenosine was found in any of the groups. In control subjects, alpha-receptor blockade increased hyperemic myocardial vascular resistance during NO inhibition, whereas no effect was observed in type 2 diabetic patients. At rest, a significant correlation was observed between rate-pressure product and myocardial perfusion in control subjects. NO inhibition and type 2 diabetes abolished this correlation. Endothelial and cardiac autonomic nerve function seems to play only a minimal role in the reduced hyperemic myocardial perfusion in type 2 diabetic patients. However, the linear correlation between resting perfusion and cardiac work appears to be abolished in type 2 diabetes and during NO synthase inhibition.     

Genetic,molecular and functional analyses of complement factor I deficiency

Complete deficiency of complement inhibitor factor I (FI) results in secondary complement deficiency due to uncontrolled spontaneous alternative pathway activation leading to susceptibility to infections. Current genetic examination of two patients with near complete FI deficiency and three patients with no detectable serum FI and also close family members revealed homozygous or compound heterozygous mutations in several domains of FI. These mutations were introduced into recombinant FI and the resulting proteins were purified for functional studies, while transient transfection was used to analyze expression and secretion. The G170V mutation resulted in a protein that was not expressed, whereas the mutations Q232K, C237Y, S250L, I339M and H400L affected secretion. Furthermore, the C237Y and the S250L mutants did not degrade C4b and C3b as efficiently as the WT. The truncated Q336x mutant could be expressed, in vitro, but was not functional because it lacks the serine protease domain. Furthermore, this truncated FI was not detected in serum of the patient. Structural investigations using molecular modeling were performed to predict the potential impact the mutations have on FI structure. This is the first study that investigates, at the functional level, the consequences of molecular defects identified in patients with full FI deficiency.     

Prevalence and characteristics of significant social anxiety in children aged 8–13 years

Background  Social anxiety has been frequently studied in both population- and clinical-based adult and adolescent samples. Corresponding research in children is scarce and is dominated by clinical studies. The aim of the present population-based study was to examine the prevalence of significant social anxiety (SSA) in preadolescent children and compare their characteristics with those of children without SSA. The spectrum of social anxiety is explored by comparing children with different levels of social anxiety, as defined by 1–2 versus 3–5 social situations feared. Method  The sample consisted of 14,497 parents and their 3rd–7th grade children (8–13 years old) who participated in a health profile study, including questions covering DSM-IV criteria A–D for social anxiety disorder (SAD). Socio-demographic data, social and school functioning, somatic complaints, parent–child relationships, and use of health services were added to a logistic regression model to explore characteristics associated with children with, and without SSA. Associated emotional and behavioural problems were measured by the Strengths and Difficulties Questionnaire (SDQ) using parent and self-report. Results  Parents described 2.3% of all children as significantly socially anxious and 0.9% feared at least three social situations. The majority of children with SSA managed their everyday life well. However, compared with children without SSA, children with SSA struggled more often in different areas of life and showed a significantly higher prevalence of associated emotional and behavioural symptoms. Our findings also support the notion of social anxiety as a spectrum concept. Conclusions  Social anxiety problems start in childhood and can be impairing, even in non-clinical populations and in reasonably young age groups. Increased awareness of different aspects of social anxiety is needed to identify children who are at risk and to devise appropriate interventions to improve the immediate and long-term outcome.