No Consistent Effect of ADRB2 Haplotypes on Obesity,Hypertension and Quantitative Traits of Body Fatness and Blood Pressure among 6,514 Adult Danes

Background

Evidence regarding the association of variation within ADRB2, the gene encoding the beta-adrenergic receptor 2 (ADRB2) with obesity and hypertension is exceedingly ambiguous. Despite negative reports, functional impacts of individual genetic variants have been reported. Also, functional haplotypes as well as haplotype combinations affecting expression levels in vivo of ADRB2 mRNA and protein as well as receptor sensitivity have been reported. The aim of the present study was therefore to evaluate if variations within ADRB2 as haplotypes or as haplotype combinations confer an increased prevalence of obesity and hypertension among adults.

Methodology/Principal Findings

We genotyped five variants required to capture common variation in a region including the ADRB2 locus in a population-based study of 6,514 unrelated, middle-aged Danes. Phases of the genotypes were estimated in silico. The variations were then investigated for their combined association with obesity, hypertension and related quantitative traits. The present study did not find consistent evidence for an association of ADRB2 variants with either obesity or hypertension when variations were analysed in a case-control study. The same lack of impact was also seen in the quantitative trait analyses, apart from nominal differences on waist-to-hip ratio and systolic blood pressure between specific haplotype combinations.

Conclusions/Significance

In a population-based sample of 6,514 Danes we found no consistent associations between five common variants which tag the ADRB2 locus and prevalence of obesity or hypertension neither when analysed as individual haplotypes nor as haplotype pairs.     

Do Gene Variants Influencing Adult Adiposity Affect Birth Weight? A Population-Based Study of 24 Loci in 4,744 Danish Individuals

Background

Several obesity risk alleles affecting adult adiposity have been identified by the recent wave of genome wide association studies. We aimed to examine the potential effect of these variants on fetal body composition by investigating the variants in relation to birth weight and ponderal index of the newborn.

Methodology/Principal Findings

Midwife records from the Danish State Archives provided information on mother''s age, parity, as well as birth weight, birth length and prematurity of the newborn in 4,744 individuals of the population-based Inter99 study. Twenty-four risk alleles showing genome-wide associations with adult BMI and/or waist circumference were genotyped. None of the 24 risk variants tested showed an association with birth weight or ponderal index after correction for multiple testing. Birth weight was divided into three categories low (≤10^th percentile), normal (10^th–90^th percentile) and high birth weight (≥90th percentile) to allow for non-linear associations. There was no difference in the number of risk alleles between the groups (p = 0.57). No interactions between each risk allele and birth weight in the prediction of adult BMI were observed. An obesity risk score was created by summing up risk alleles. The risk score did not associate with fetal body composition. Moreover there was no interaction between the risk score and birth weight/ponderal index in the prediction of adult BMI.

Conclusion

24 common variants associated with adult adiposity did not affect or interact with birth weight among Danes suggesting that the effects of these variants predominantly arise in the post-natal life.     

The Association between Genetic Variations of CHI3L1, Levels of the Encoded Glycoprotein YKL-40 and the Lipid Profile in a Danish Population

Background

The inflammatory biomarker YKL-40 seems to play a role in atherosclerosis and is elevated in patients with obesity, cardiovascular disease and type 2 diabetes. Single nucleotide polymorphisms (SNPs) of the YKL-40 encoding gene, CHI3L1, are associated with inter-individual YKL-40 levels. One study has described an association between a promoter polymorphism of CHI3L1 and levels of low density lipoprotein. The objective of this study was to evaluate the influence of YKL-40 on lipid parameters by determining the association between polymorphisms of CHI3L1, serum YKL-40 and levels of the differentiated lipid profile in a Danish general population.

Methodology/Principle Findings

12 SNPs of CHI3L1 were genotyped, and serum YKL-40 and parameters of the lipid profile were measured in 2,656 Danes. Lipid profile and genotypes were available in another Danish population (n = 6,784) for replication. Cholesterol and triglyceride levels increased with increasing YKL-40 quartile (both p<0.0001), and YKL-40 correlated with triglyceride levels (β = 0.15, p<0.0001). Low density lipoprotein levels increased slightly from the 1^st to the 3^rd quartile (p = 0.006). The highest YKL-40 quartile was associated with a greater risk of hypercholesterolemia compared to the lowest YKL-40 quartile (odds ratio 1.36, p = 0.009). Minor homozygosity of rs12123883 was associated with higher triglyceride levels (p = 0.022) and a higher prevalence of low high density lipoprotein (p = 0.012), but these associations could not be confirmed in the replication population.

Conclusions/Significance

Serum YKL-40 correlates with triglyceride levels in a representative group of the general Danish population. No consistent associations between SNPs of CHI3L1 and lipid levels could be documented.     

Association of LIN28B with Adult Adiposity-Related Traits in Females

Context

Pubertal timing is under strong genetic control and its early onset associates with several adverse health outcomes in adulthood, including obesity, type 2 diabetes and cardiovascular disease. Recent data indicate strong association between pubertal timing and genetic variants near LIN28B, but it is currently unknown whether the gene contributes to the association between puberty and adult disease.

Objective

To elucidate the putative genetic link between early puberty and adult disease risk, we examined the association of two genetic variants near LIN28B with adult body size and metabolic profiles in randomly ascertained adult Finnish males and females.

Methods

Two single nucleotide polymorphisms (SNPs), rs7759938, the lead SNP previously associated with pubertal timing and height, and rs314279, previously also associated with menarcheal age but only partially correlated with rs7759938 (r² = 0.30), were genotyped in 26,636 study subjects participating in the Finnish population survey FINRISK. Marker associations with adult height, weight, body mass index (BMI), hip and waist circumference, blood glucose, serum insulin and lipid/lipoprotein levels were determined by linear regression analyses.

Results

Both rs7759938 and rs314279 associated with adult height in both sexes (p = 2×10⁻⁶ and p = 0.001). Furthermore, rs314279 associated with increased weight in females (p = 0.001). Conditioned analyses including both SNPs in the regression model verified that rs314279 independently associates with adult female weight, BMI and hip circumference (p<0.005). Neither SNP associated with glucose, lipid, or lipoprotein levels.

Conclusion

Genetic variants near the puberty-associated gene LIN28B associate with adult weight and body shape in females, suggesting that the gene may tag molecular pathways influencing adult adiposity-related traits.     

Bioinformatics-driven identification and examination of candidate genes for non-alcoholic fatty liver disease

Objective

Candidate genes for non-alcoholic fatty liver disease (NAFLD) identified by a bioinformatics approach were examined for variant associations to quantitative traits of NAFLD-related phenotypes.

Research Design and Methods

By integrating public database text mining, trans-organism protein-protein interaction transferal, and information on liver protein expression a protein-protein interaction network was constructed and from this a smaller isolated interactome was identified. Five genes from this interactome were selected for genetic analysis. Twenty-one tag single-nucleotide polymorphisms (SNPs) which captured all common variation in these genes were genotyped in 10,196 Danes, and analyzed for association with NAFLD-related quantitative traits, type 2 diabetes (T2D), central obesity, and WHO-defined metabolic syndrome (MetS).

Results

273 genes were included in the protein-protein interaction analysis and EHHADH, ECHS1, HADHA, HADHB, and ACADL were selected for further examination. A total of 10 nominal statistical significant associations (P<0.05) to quantitative metabolic traits were identified. Also, the case-control study showed associations between variation in the five genes and T2D, central obesity, and MetS, respectively. Bonferroni adjustments for multiple testing negated all associations.

Conclusions

Using a bioinformatics approach we identified five candidate genes for NAFLD. However, we failed to provide evidence of associations with major effects between SNPs in these five genes and NAFLD-related quantitative traits, T2D, central obesity, and MetS.     

Prospective Analysis of the Association of a Common Variant of FTO (rs9939609) with Adiposity in Children: Results of the IDEFICS Study

Objectives

We investigated cross-sectionally and longitudinally the relationship between FTO rs9939609 and obesity-related characteristics in the European children of the IDEFICS project and the interaction of this variant with a lifestyle intervention.

Population and Methods

A cohort of 16224 children (2–9 years) was recruited into a population-based survey (T0) from eight European countries. A second survey (T1) reassessed the children two years later. A random sample of 4405 children was extracted for genetic studies. 3168 children were re-examined two years later. Half of them underwent a lifestyle intervention program. The FTO rs9939609 was genotyped. Weight, height, waist circumference, triceps and subscapular skinfolds were measured at T0 and T1.

Results

At T0, the risk A allele of rs9939609 was significantly associated with higher values of body mass index (BMI), waist circumference and skinfolds (age, sex, and country-adjusted p-values: all p<0.001) and with a statistically significant increased risk of overweight/obesity.Over the two year follow-up, no interaction between genotype and intervention was observed. The A allele was associated to a significantly higher increase in all the anthropometric variables examined at T0 independently from the study group (intervention versus control) (p-values: all p<0.002, adjusted for age, sex, country, intervention/control study group, T0 values, and individual time interval between T0 and T1). Over the two-year follow–up, 210 new cases of overweight/obesity occurred. A statistically significant higher incidence of overweight/obesity was associated to the A allele [OR_A = 1.95, 95% CI = (1.29; 2.97)].

Conclusions

We confirmed the association between the FTO rs9939609 and body mass and overweight/obesity risk in European children. The main finding of the study is that the A allele carriers present higher increase of body mass and central adiposity over time and higher risk of developing overweight/obesity during growth, independently from intervention measures.     

Overexpression of CD151 Predicts Prognosis in Patients with Resected Gastric Cancer

Purpose

The tetraspanin CD151 acts as a promoter of metastasis and invasion in several tumors. However, the role of CD151 in human gastric cancer (HGC) remains unclear.

Methods

Twenty HGC specimens and matched nontumor samples, human gastric epithelial cells (HGEC), and four gastric cancer cell lines were used to analyze CD151 expression. Short hairpin RNA-mediated downregulation of CD151 expression in HGC cells was performed to examine the role of CD151 in the proliferation and metastasis/invasion of HGC cells in vivo and in vitro. The relationship of CD151 with integrin α3 in HGC cells was investigated by silencing integrin α3 followed by co-immunoprecipitation and immunofluorescence staining. Finally, the prognostic value of CD151 and integrin α3 was evaluated by immunohistochemistry in tissue microarrays of 76 HGC patients.

Results

CD151 was expressed at higher levels in HGC tissues and HGC cells than in nontumor tissues and HGEC cells. Down-regulation of CD151 by vshRNA-CD151 impaired metastasis and invasion of HGC-27 cells, but did not affect cell proliferation. CD151 formed a complex with integrin α3 in HGC cells. CD151-cDNA transfection rescued the metastatic potential and invasiveness of HGC-27-vshCD151 cells, but not those of HGC-27-vshintegrin α3 cells in vitro. Clinically, CD151 overexpression was significantly correlated with high TNM stage, depth of invasion and positive lymph node involvement (p<0.05), and high levels of integrin α3 were associated with large tumor size, high TNM stage, depth of invasion and lymph node involvement (p<0.05). Importantly, the postoperative 5-year overall survival of patients with CD151^low and/or integrin α3^low was higher than that of patients with CD151^high and/or integrin α3^high.

Conclusion

CD151 is positively associated with the invasiveness of HGC, and CD151 or the combination of CD151 and integrin α3 is a novel marker for predicting the prognosis of HGC patients and may be potential therapeutic targets.     

Studies of the association of Arg72Pro of tumor suppressor protein p53 with type 2 diabetes in a combined analysis of 55,521 Europeans

Aims

A study of 222 candidate genes in type 2 diabetes reported association of variants in RAPGEF1, ENPP1, TP53, NRF1, SLC2A2, SLC2A4 and FOXC2 with type 2 diabetes in 4,805 Finnish individuals. We aimed to replicate these associations in a Danish case-control study and to substantiate any replicated associations in meta-analyses. Furthermore, we evaluated the impact on diabetes-related intermediate traits in a population-based sample of middle-aged Danes.

Methods

We genotyped nine lead variants in the seven genes in 4,973 glucose-tolerant and 3,612 type 2 diabetes Danish individuals. In meta-analyses we combined case-control data from the DIAGRAM+ Consortium (n = 47,117) and the present genotyping results. The quantitative trait studies involved 5,882 treatment-naive individuals from the Danish Inter99 study.

Results

None of the nine investigated variants were significantly associated with type 2 diabetes in the Danish samples. However, for all nine variants the estimate of increase in type 2 diabetes risk was observed for the same allele as previously reported. In a meta-analysis of published and online data including 55,521 Europeans the G-allele of rs1042522 in TP53 showed significant association with type 2 diabetes (OR = 1.06 95% CI 1.02–1.11, p = 0.0032). No substantial associations with diabetes-related intermediary phenotypes were found.

Conclusion

The G-allele of TP53 rs1042522 is associated with an increased prevalence of type 2 diabetes in a combined analysis of 55,521 Europeans.     

Common Variants of FTO Are Associated with Childhood Obesity in a Cross-Sectional Study of 3,126 Urban Indian Children

Background

FTO variants are robustly associated with obesity and related traits in many population and shown to have variable impact during life course. Although studies have shown association of FTO variants with adiposity in adult Indian, its association in Indian children is yet to be confirmed.

Methods

Here we examined association of FTO variants (rs9939609 and rs8050136) with obesity and related anthropometric and biochemical traits in 3,126 Indian children (aged 11–17 years) including 2,230 normal-weight and 896 over-weight/obese children. We also compared effects observed in the present study with that observed in previous studies on South Asian adults and children of other ethnic groups.

Results

The variant rs9939609 showed significant association with risk of obesity [OR = 1.21, P = 2.5×10⁻³] and its measures BMI, weight, waist circumference and hip circumference [β range = 0.11 to 0.14 Z-score units; P range = 1.3×10⁻⁴ to 1.6×10⁻⁷] in children. The observed effect sizes in Indian children were similar to those reported for European children. Variant rs9939609 explained 0.88% of BMI variance in Indian children. The effect sizes of rs9939609 on BMI and WC were ∼2 fold higher in children than adults. Interestingly rs9939609 was also associated with serum levels of thyroid stimulating hormone (TSH) [β = 0.10 Z-score, P = 5.8×10⁻³]. The other variant rs8050136 was in strong linkage disequilibrium with rs9939609 (r² = 0.97) and provided similar association results.

Conclusion

The study provides first report of association of FTO variants with obesity and related anthropometric traits in Indian children with higher impact in children compared to adults. We also demonstrated association of FTO variant with serum levels of TSH, indicating putative influence of FTO in hypothalamic-pituitary-thyroid axis.     

Association of the Hepatocyte Growth Factor Gene with Keratoconus in an Australian Population

Purpose

A previous study has indicated suggestive association of the hepatocyte growth factor (HGF) gene with Keratoconus. We wished to assess this association in an independent Caucasian cohort as well as assess its association with corneal curvature.

Participants

Keratoconus patients were recruited from private and public clinics in Melbourne, Australia. Non-keratoconic individuals were identified from the Genes in Myopia (GEM) study from Australia. A total of 830 individuals were used for the analysis including 157 keratoconic and 673 non keratoconic subjects.

Methods

Tag single nucleotide polymorphisms (tSNPs) were chosen to encompass the hepatocyte growth factor gene as well as 2 kb upstream of the start codon through to 2 kb downstream of the stop codon. Logistic and linear regression including age and gender as covariates were applied in statistical analysis with subsequent Bonferroni correction.

Results

Ten tSNPs were genotyped. Following statistical analysis and multiple testing correction, a statistically significant association was found for the tSNP rs2286194 {p = 1.1×10-³ Odds Ratio 0.52, 95% CI - 0.35, 0.77} for keratoconus. No association was found between the 10 tSNPs and corneal curvature.

Conclusions

These findings provide additional evidence of significant association of the HGF gene with Keratoconus. This association does not appear to act through the corneal curvature route.     

Pregnancy Weight Gain and Childhood Body Weight: A Within-Family Comparison

Background

Excessive pregnancy weight gain is associated with obesity in the offspring, but this relationship may be confounded by genetic and other shared influences. We aimed to examine the association of pregnancy weight gain with body mass index (BMI) in the offspring, using a within-family design to minimize confounding.

Methods and Findings

In this population-based cohort study, we matched records of all live births in Arkansas with state-mandated data on childhood BMI collected in public schools (from August 18, 2003 to June 2, 2011). The cohort included 42,133 women who had more than one singleton pregnancy and their 91,045 offspring. We examined how differences in weight gain that occurred during two or more pregnancies for each woman predicted her children''s BMI and odds ratio (OR) of being overweight or obese (BMI≥85th percentile) at a mean age of 11.9 years, using a within-family design. For every additional kg of pregnancy weight gain, childhood BMI increased by 0.0220 (95% CI 0.0134–0.0306, p<0.0001) and the OR of overweight/obesity increased by 1.007 (CI 1.003–1.012, p = 0.0008). Variations in pregnancy weight gain accounted for a 0.43 kg/m² difference in childhood BMI. After adjustment for birth weight, the association of pregnancy weight gain with childhood BMI was attenuated but remained statistically significant (0.0143 kg/m² per kg of pregnancy weight gain, CI 0.0057–0.0229, p = 0.0007).

Conclusions

High pregnancy weight gain is associated with increased body weight of the offspring in childhood, and this effect is only partially mediated through higher birth weight. Translation of these findings to public health obesity prevention requires additional study. Please see later in the article for the Editors'' Summary     

Identification of the Tyrosine-Protein Phosphatase Non-Receptor Type 2 as a Rheumatoid Arthritis Susceptibility Locus in Europeans

Objectives

Genome-wide association studies have facilitated the identification of over 30 susceptibility loci for rheumatoid arthritis (RA). However, evidence for a number of potential susceptibility genes have not so far reached genome-wide significance in studies of Caucasian RA.

Methods

A cohort of 4286 RA patients from across Europe and 5642 population matched controls were genotyped for 25 SNPs, then combined in a meta-analysis with previously published data.

Results

Significant evidence of association was detected for nine SNPs within the European samples. When meta-analysed with previously published data, 21 SNPs were associated with RA susceptibility. Although SNPs in the PTPN2 gene were previously reported to be associated with RA in both Japanese and European populations, we show genome-wide evidence for a different SNP within this gene associated with RA susceptibility in an independent European population (rs7234029, P = 4.4×10⁻⁹).

Conclusions

This study provides further genome-wide evidence for the association of the PTPN2 locus (encoding the T cell protein tyrosine phosphastase) with Caucasian RA susceptibility. This finding adds to the growing evidence for PTPN2 being a pan-autoimmune susceptibility gene.     

Genetic variant of AMD1 is associated with obesity in urban Indian children

Background

Hyperhomocysteinemia is regarded as a risk factor for cardiovascular diseases, diabetes and obesity. Manifestation of these chronic metabolic disorders starts in early life marked by increase in body mass index (BMI). We hypothesized that perturbations in homocysteine metabolism in early life could be a link between childhood obesity and adult metabolic disorders. Thus here we investigated association of common variants from homocysteine metabolism pathway genes with obesity in 3,168 urban Indian children.

Methodology/Principal Findings

We genotyped 90 common variants from 18 genes in 1,325 children comprising of 862 normal-weight (NW) and 463 over-weight/obese (OW/OB) children in stage 1. The top signal obtained was replicated in an independent sample set of 1843 children (1,399 NW and 444 OW/OB) in stage 2. Stage 1 association analysis revealed association between seven variants and childhood obesity at P<0.05, but association of only rs2796749 in AMD1 [OR = 1.41, P = 1.5×10^-4] remained significant after multiple testing correction. Association of rs2796749 with childhood obesity was validated in stage 2 [OR = 1.28, P = 4.2×10^-3] and meta-analysis [OR = 1.35, P = 1.9×10^-6]. AMD1 variant rs2796749 was also associated with quantitative measures of adiposity and plasma leptin levels that was also replicated and corroborated in combined analysis.

Conclusions/Significance

Our study provides first evidence for the association of AMD1 variant with obesity and plasma leptin levels in children. Further studies to confirm this association, its functional significance and mechanism of action need to be undertaken.     

Association between Common Polymorphism near the MC4R Gene and Obesity Risk: A Systematic Review and Meta-Analysis

Background

Genome-wide association studies on Europeans have shown that two polymorphisms (rs17782313, rs12970134) near the melanocortin 4 receptor (MC4R) gene were associated with increased risk of obesity. Subsequently studies among different ethnic populations have shown mixed results with some confirming and others showing inconsistent results, especially among East Asians and Africans. We performed a comprehensive meta-analysis of various studies from different ethnic populations to assess the association of the MC4R polymorphism with obesity risk.

Methods

We retrieved all published literature that investigated association of MC4R variants with obesity from PubMed and Embase. Pooled odds ratio (OR) with 95% confidence interval (CI) was calculated using fixed- or random-effects model.

Results

A total of 61 studies (80,957 cases/220,223 controls) for rs17782313 polymorphism (or proxy) were included in the meta-analysis. The results suggested that rs17782313 polymorphism was significantly associated with obesity risk (OR = 1.18, 95%CI = 1.15–1.21, p<0.001). Similar trends were observed among subgroups of Europeans and East Asians, adults and children, studies with high quality score, and for each five MC4R polymorphisms independently.

Conclusions

The present meta-analysis confirms the significant association of MC4R polymorphism with risk of obesity. Further studies should be conducted to identify the causal variant and the underlying mechanisms of the identified association.     

Genome-Wide Association Studies of Asthma in Population-Based Cohorts Confirm Known and Suggested Loci and Identify an Additional Association near HLA

Rationale

Asthma has substantial morbidity and mortality and a strong genetic component, but identification of genetic risk factors is limited by availability of suitable studies.

Objectives

To test if population-based cohorts with self-reported physician-diagnosed asthma and genome-wide association (GWA) data could be used to validate known associations with asthma and identify novel associations.

Methods

The APCAT (Analysis in Population-based Cohorts of Asthma Traits) consortium consists of 1,716 individuals with asthma and 16,888 healthy controls from six European-descent population-based cohorts. We examined associations in APCAT of thirteen variants previously reported as genome-wide significant (P<5x10⁻⁸) and three variants reported as suggestive (P<5×10⁻⁷). We also searched for novel associations in APCAT (Stage 1) and followed-up the most promising variants in 4,035 asthmatics and 11,251 healthy controls (Stage 2). Finally, we conducted the first genome-wide screen for interactions with smoking or hay fever.

Main Results

We observed association in the same direction for all thirteen previously reported variants and nominally replicated ten of them. One variant that was previously suggestive, rs11071559 in RORA, now reaches genome-wide significance when combined with our data (P = 2.4×10⁻⁹). We also identified two genome-wide significant associations: rs13408661 near IL1RL1/IL18R1 (P _{Stage1+Stage2} = 1.1x10⁻⁹), which is correlated with a variant recently shown to be associated with asthma (rs3771180), and rs9268516 in the HLA region (P _{Stage1+Stage2} = 1.1x10⁻⁸), which appears to be independent of previously reported associations in this locus. Finally, we found no strong evidence for gene-environment interactions with smoking or hay fever status.

Conclusions

Population-based cohorts with simple asthma phenotypes represent a valuable and largely untapped resource for genetic studies of asthma.     

Role of Haptoglobin in Polycystic Ovary Syndrome (PCOS), Obesity and Disorders of Glucose Tolerance in Premenopausal Women

Background

Hp² alleles of the haptoglobin α–chain polymorphism reduce the anti-oxidant properties and increase the pro-inflammatory actions of this acute-phase protein in a gene-dosage fashion. We hypothesized that the haptoglobin polymorphism might contribute to the increased oxidative stress and low-grade chronic inflammation frequently associated with polycystic ovary syndrome, obesity, and abnormalities of glucose tolerance.

Methodology/Principal Findings

Serum haptoglobin and the haptoglobin α–chain polymorphism were determined in 141 patients with polycystic ovary syndrome and 102 non-hyperandrogenic women. Of the whole group of 243 premenopausal women, 117 were obese and 51 showed abnormal glucose tolerance. Although serum haptoglobin concentrations were similar in PCOS patients and controls, the former presented with an increased frequency of Hp² alleles (62% vs. 52%, P = 0.023). Circulating haptoglobin levels increased with obesity (P<0.001), yet no association was found between obesity and haptoglobin genotypes. No differences were observed in haptoglobin levels or genotype frequencies depending on glucose tolerance. Fifty percent of the variation in serum haptoglobin concentrations was explained by the variability in serum C-reactive protein concentrations, BMI, insulin sensitivity and haptoglobin genotypes.

Conclusions/Significance

Serum haptoglobin concentrations in premenopausal women are largely dependent on the haptoglobin polymorphism and on the presence of obesity, with insulin resistance and chronic inflammation possibly modulating this relationship. The association of polycystic ovary syndrome with Hp² alleles suggests that the anti-oxidant and anti-inflammatory properties of haptoglobin may be reduced in these patients.     

Impact of Glucocorticoid Receptor Gene Polymorphisms on the Metabolic Profile of Adult Patients with the Classical Form of 21-Hydroxylase Deficiency

Background

CAH patients have an increased risk of cardiovascular disease, and it remains unknown if lifelong glucocorticoid (GC) treatment is a contributing factor. In the general population, glucocorticoid receptor gene (NR3C1) polymorphisms are associated with an adverse metabolic profile. Our aim was to analyze the association between the NR3C1 polymorphisms and the metabolic profile of CAH patients.

Methodology

Sixty-eight adult patients (34SV/34SW) with a mean age of 28.4±9 years received dexamethasone (mean 0.27±0.11 mg/day) to obtain normal androgen levels. SW patients also received fludrocortisone (50 µg/day). Metabolic syndrome (MetS) was defined by the NCEP ATPIII criteria and obesity by BMI ≥30 kg/m². NR3C1 alleles were genotyped, and association analyses with phenotype were carried out with Chi-square, t-test and regression analysis.

Results

Obesity and MetS were observed in 23.5% and 7.3% of patients, respectively, and were not correlated with GC doses and treatment duration. BMI was positively correlated with blood pressure (BP), triglycerides (TG), LDL-c levels and HOMA-IR and inversely correlated with HDL-c levels. BclI and A3669G variants were found in 26.4% and 9.6% of alleles, respectively. Heterozygotes for the BclI polymorphism presented with higher BMI (29 kg/m²±5.3 vs. 26 kg/m²±5.3, respectively) and waist circumference (89 cm±12.7 vs. 81 cm±13, respectively) compared to wild-type subjects. Hypertension was found in 12% of patients and heterozygotes for the BclI polymorphism presented higher systolic BP than wild type subjects. Low HDL-c and high TG levels were identified in 30% and 10% of patients, respectively, and were not associated with the NR3C1 polymorphisms. A3669G carriers and non-carriers did not differ.

Conclusion

In addition to GC therapy, the BclI GR variant might play an important role in obesity susceptibility in CAH patients. Genotyping of GR polymorphisms could result in the identification of a subgroup at risk patients, allowing for the establishment of personalized treatment and the avoidance of long-term adverse consequences.     

Impact of Obesity on the Clinical Profile of a Population-Based Sample with Chronic Obstructive Pulmonary Disease

Aims

To characterize the distribution of BMI in a population-based sample of COPD patients and to evaluate the impact of obesity on their health status, exercise tolerance, systemic inflammation and comorbidity.

Methods

A population-based sample of 3,797 subjects aged 40–80 years from the EPI-SCAN study was selected. Subjects were categorized according their body mass index (BMI) as underweight (<18.5 kg/m²), normal weight (18.5–24.9 kg/m²), overweight (25.0–29.9 kg/m²) or obese (BMI≥30.0 kg/m²). Subjects were evaluated with post-bronchodilator spirometry and 6-minute walk tests. Smoking habits, respiratory symptoms, generic and specific quality of life, daily physical activities, comorbidities and systemic inflammatory biomarkers were recorded.

Results

The prevalence of obesity or being overweight was higher in the 382 COPD patients than in the subjects without airflow limitation (29.4%, 95%CI 24.8–33.9% vs. 24.3, 95%CI 22.9–25.8; and 44.7%, 95%CI 39.7–49.6% vs. 43.0%, 95%CI 41.3–44.6, respectively; p = 0.020). In the COPD subgroup, obese subjects presented more dyspnea and less chronic cough, chronic bronchitis or chronic phlegm than normal-weight patients, as well as a worse health status. Moreover, reduced exercise tolerance and higher plasmatic C-reactive protein levels were found in the obese patients, who also presented a greater prevalence of cardiovascular disease (adjusted odds ratio 4.796, 95%CI 1.806–12.736, p = 0.002).

Conclusions

In a population-based sample, obesity is more prevalent in COPD patients than in subjects without airflow limitation. Furthermore, obesity affects the clinical manifestations, quality of life and exercise tolerance of COPD patients, and it may contribute to a phenotype characterized by increased systemic inflammation and greater frequency of cardiovascular comorbidity.     

Biomarkers of Endocannabinoid System Activation in Severe Obesity

Background

Obesity is a worldwide epidemic, and severe obesity is a risk factor for many diseases, including diabetes, heart disease, stroke, and some cancers. Endocannabinoid system (ECS) signaling in the brain and peripheral tissues is activated in obesity and plays a role in the regulation of body weight. The main research question here was whether quantitative measurement of plasma endocannabinoids, anandamide, and related N-acylethanolamines (NAEs), combined with genotyping for mutations in fatty acid amide hydrolase (FAAH) would identify circulating biomarkers of ECS activation in severe obesity.

Methodology/Principal Findings

Plasma samples were obtained from 96 severely obese subjects with body mass index (BMI) of ≥40 kg/m², and 48 normal weight subjects with BMI of ≤26 kg/m². Triple-quadrupole mass spectroscopy methods were used to measure plasma ECS analogs. Subjects were genotyped for human FAAH gene mutations. The principal analysis focused on the FAAH 385 C→A (P129T) mutation by comparing plasma ECS metabolite levels in the FAAH 385 minor A allele carriers versus wild-type C/C carriers in both groups. The main finding was significantly elevated mean plasma levels of anandamide (15.1±1.4 pmol/ml) and related NAEs in study subjects that carried the FAAH 385 A mutant alleles versus normal subjects (13.3±1.0 pmol/ml) with wild-type FAAH genotype (p = 0.04), and significance was maintained after controlling for BMI.

Conclusions/Significance

Significantly increased levels of the endocannabinoid anandamide and related NAEs were found in carriers of the FAAH 385 A mutant alleles compared with wild-type FAAH controls. This evidence supports endocannabinoid system activation due to the effect of FAAH 385 mutant A genotype on plasma AEA and related NAE analogs. This is the first study to document that FAAH 385 A mutant alleles have a direct effect on elevated plasma levels of anandamide and related NAEs in humans. These biomarkers may indicate risk for severe obesity and may suggest novel ECS obesity treatment strategies.