Adrenoceptor Beta Research Articles

Using Big Data Analytics to "Back Engineer" Protein Conformational Selection Mechanisms.

In the living cells, proteins bind small molecules (or “ligands”) through a “conformational selection” mechanism, where a subset of protein structures are capable of binding the small molecules well while most other protein structures are not capable of such binding. The present work uses machine learning approaches to identify, in a very large amount of protein:ligand complexes, what protein properties are associated with their capacity to bind small molecules. In order to do so, we calculate 40 physicochemical properties on about 1.5 millions of protein conformations: ligand and protein conformations. This work describes a machine learning approach to identify the unique physico-chemical descriptors of a protein that maximize the prediction rate of potential protein molecular conformations for the test case proteins ADORA2A (Adenosine A2a Receptor), ADRB2 (Adrenoceptor Beta 2) and OPRK1 (Opioid Receptor Kappa 1). We find adequate machine learning techniques can increase by an order of magnitude the identification of “binding protein conformations” in an otherwise very large ensemble of protein conformations, compared to random selection of protein conformations. This opens the door to the systematic identification of such “binding conformations” for proteins and provides a big data approach to the conformational selection mechanism.

Network Pharmacology and Molecular Docking Analysis on Molecular Mechanism and Key Targets of Xiaoyao Powder in the Treatment of Irritable Bowel Syndrome

Ultra-processed food and psychological stress have led to an increase in the new incidence of irritable bowel syndrome. Xiaoyao powder is a classic traditional Chinese medicine formula for improving the secretion and transportation of the gastrointestinal tract as well as eliminating intestinal allergy in irritable bowel syndrome clinical treatment. To investigate the targets and mechanisms of action of Xiaoyao powder in the treatment of irritable bowel syndrome and in this study, we investigated the compound of Xiaoyao powder and the effects of it on irritable bowel syndrome by network pharmacology. Meanwhile, molecular docking method was used to verify the affinity of the top 20 active components to the targets (including master regulator of cell cycle entry and proliferative metabolism, adrenoceptor beta 2, Erb-B2 receptor tyrosine kinase 2). 146 active components and 628 drug targets of Xiaoyao powder were obtained from traditional Chinese medicine systems pharmacology database and analysis platform database. A total of 2498 irritable bowel syndrome differential genes were obtained from the Gene Expression Omnibus database. 737 items were obtained by gene ontology functional enrichment analysis. A total of 83 pathways were obtained by Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis. The results of molecular docking showed that the first 20 active components of Xiaoyao powder had strong affinity with their targets (master regulator of cell cycle entry and proliferative metabolism, adrenoceptor beta 2, Erb-B2 receptor tyrosine kinase 2). Our study showed that quercetin, polyporenic acid C and kaempferol in Xiaoyao powder were key potential active components treating irritable bowel syndrome. These compounds were strongly associated with core target proteins (such as master regulator of cell cycle entry and proliferative metabolism, adrenoceptor beta 2, Erb-B2 receptor tyrosine kinase 2 etc.). This study reveals that neuroactive ligand-receptor interaction, calcium signaling pathway and steroid hormone biosynthesis pathways mediate the therapeutic effects of Xiaoyao powder on irritable bowel syndrome.

Fat mass and obesity-associated protein regulates RNA methylation associated with depression-like behavior in mice

Post-transcriptional modifications of RNA, such as RNA methylation, can epigenetically regulate behavior, for instance learning and memory. However, it is unclear whether RNA methylation plays a critical role in the pathophysiology of major depression disorder (MDD). Here, we report that expression of the fat mass and obesity associated gene (FTO), an RNA demethylase, is downregulated in the hippocampus of patients with MDD and mouse models of depression. Suppressing Fto expression in the mouse hippocampus results in depression-like behaviors in adult mice, whereas overexpression of FTO expression leads to rescue of the depression-like phenotype. Epitranscriptomic profiling of N6-methyladenosine (m6A) RNA methylation in the hippocampus of Fto knockdown (KD), Fto knockout (cKO), and FTO-overexpressing (OE) mice allows us to identify adrenoceptor beta 2 (Adrb2) mRNA as a target of FTO. ADRB2 stimulation rescues the depression-like behaviors in mice and spine loss induced by hippocampal Fto deficiency, possibly via the modulation of hippocampal SIRT1 expression by c-MYC. Our findings suggest that FTO is a regulator of a mechanism underlying depression-like behavior in mice.

Effects of Four Lipid Metabolism-Related Polymorphisms on Body Composition Improvements After 12 Weeks of High-Intensity Interval Training and Dietary Energy Restriction in Overweight/Obese Adult Women: A Pilot Study.

Background: Polymorphisms in lipid metabolism-related genes have been associated with obesity and body composition, but these have been scarcely described concerning the magnitude of the response to exercise interventions in the overweight/obese population.Objective: To evaluate the association of perilipin 1 (PLIN1; rs1052700 and rs2304795), lipoprotein lipase (rs283), and adrenoceptor beta 3 (rs4994) polymorphisms with high and low responders (LoRes) to fat mass reduction after 12 weeks of high-intensity interval training (HIIT) and dietary energy restriction in overweight/obese adult women. In addition, we examined the effect of these genetic variants on body composition changes.Methods: Forty-three unrelated overweight/obese adult women were incorporated and genotyped, of which 30 women (age = 27.4 ± 7.9 years; BMI = 29.9 ± 3.3 kg/m2) successfully completed the 12-week supervised HIIT program plus an individually prescribed home hypocaloric diet.Results: An association was observed between the PLIN1 rs1052700 polymorphism with high and LoRes (χ2 = 8.138; 2 df; p = 0.01). Moreover, after the intervention, the carriers of TT genotype of PLIN1 rs1052700 as compared to AA and AT showed a greater reduction in absolute fat mass (Δ: −5.1 ± 1.8 vs. − 1.8 ± 1.4 vs. − 2.1 ± 2.3 kg; p = 0.04). The effect size of this fat mass reduction between TT and AT genotypes was a mean difference of −3.01 kg [95%IC − 4.88– − 1.1], and between TT and AA genotypes was −3.29 kg [95%IC − 4.86– − 1.65]. No differences were observed for other polymorphisms investigated.Conclusion: These results suggest that the rs1052700 (14995A>T) polymorphism of the PLIN1 gene is associated with a differential response to fat mass reduction after a 12-week intervention in overweight/obese adult women. In addition, women with the TT genotype of this genetic variant showed greater changes in fat mass than AA and AT genotypes. However, further studies are needed to confirm these findings.

Polygonum multiflorum Thunb. Hot Water Extract Reverses High-Fat Diet-Induced Lipid Metabolism of White and Brown Adipose Tissues in Obese Mice.

The purpose of the present study was to determine whether an anti-obesity effect of a Polygonum multiflorum Thunb. hot water extract (PW) was involved in the lipid metabolism of white adipose tissue (WAT) and brown adipose tissue (BAT) in high-fat diet (HFD)-induced C57BL/6N obese mice. Mice freely received a normal diet (NCD) or an HFD for 12 weeks; HFD-fed mice were orally given PW (100 or 300 mg/kg) or garcinia cambogia (GC, 200 mg/kg) once a day. After 12 weeks, PW (300 mg/kg) or GC significantly alleviated adiposity by reducing body weight, WAT weights, and food efficiency ratio. PW (300 mg/kg) improved hyperinsulinemia and enhanced insulin sensitivity. In addition, PW (300 mg/kg) significantly down-regulated expression of carbohydrate-responsive element-binding protein (ChREBP) and diacylglycerol O-acyltransferase 2 (DGAT2) genes in WAT compared with the untreated HFD group. HFD increased BAT gene levels such as adrenoceptor beta 3 (ADRB3), peroxisome proliferator-activated receptor γ (PPARγ), hormone-sensitive lipase (HSL), cluster of differentiation 36 (CD36), fatty acid-binding protein 4 (FABP4), PPARγ coactivator 1-α (PGC-1α), PPARα, and carnitine palmitoyltransferase 1B (CPT1B) compared with the NCD group; however, PW or GC effectively reversed those levels. These findings suggest that the anti-obesity activity of PW was mediated via suppression of lipogenesis in WAT, leading to the normalization of lipid metabolism in BAT.

Gene variants associated with obstructive sleep apnea (OSA) in relation to sudden infant death syndrome (SIDS)

BackgroundBoth obstructive sleep apnea (OSA) and (at least a fraction of) sudden infant death syndrome (SIDS) are associated with impaired respiration. For OSA, an association with several gene variants was identified. Therefore, our hypothesis is that these polymorphisms might be of relevance in SIDS as well.MethodsTwenty-four single nucleotide polymorphisms (SNPs) in 21 candidate genes connected to OSA, were genotyped in a total of 282 SIDS cases and 374 controls. Additionally, subgroups based on factors codetermining the SIDS risk (age, sex, season, and prone position) were established and compared as well.ResultsTwo of the analyzed SNPs showed nominally significant differences between SIDS and control groups: rs1042714 in ADRB2 (adrenoceptor beta 2) and rs1800541 in EDN1 (endothelin 1). In the subgroup analyses, 10 further SNPs gave significant results. Nevertheless, these associations did not survive adjustment for multiple testing.ConclusionsOur results suggest that there might be a link between SIDS and OSA and its resulting respiratory and cardiovascular problems, albeit this predisposition might be dependent on the combination with other, hitherto unknown gene variants. These findings may encourage replication studies to get a better understanding of this connection.

Kisspeptin and the Genetic Obesity Interactome.

Kisspeptin (encoded by the KISS1 gene in humans) is an excitatory neuromodulatory peptide implicated in multiple homeostatic systems, including anti-oxidation, glucose homeostasis, nutrition, locomotion, etc. Therefore, in the current obesity epidemic, kisspeptin is gaining increasing interest as a research objective. To construct an updated interactome of genetic obesity, including the kisspeptin signal transduction pathway. Kisspeptin and obesity-related genes or gene products were extracted from the biomedical literature, and a network of functional associations was created. The generated network contains 101 nodes corresponding to gene/gene products with known and/or predicted interactions. In this interactome, KISS1 and KISS1R are connected directly to the luteinizing hormone receptor (LHCGR), gonadotropin-releasing hormone receptor (GNRH1), and indirectly, through the latter, to proopiomelanocortin (POMC), glucagon, leptin (LEP), and/or pro-protein convertase subtilisin/kexin-type 1 (PCSK1), all of which are critically implicated in obesity disorders. Our updated obesidome includes kisspeptin and its connections to the genetic obesity signalosome with 12 major hubs: glucagon (GCG), insulin (INS), arginine vasopressin (AVP), G protein subunit beta 1 (GNB1) and proopiomelanocortin (POMC), melanocortin 4 receptor (MC4R), leptin (LEP), gonadotropin-releasing hormone 1 (GNRH1), adrenoceptor beta 2 and 3 (ADRB2-3), glucagon-like peptide 1 receptor (GLP1R), and melanocortin 3 receptor (MC3R) genes were identified as major "hubs" for genetic obesity, providing novel insight into the body's energy homeostasis.

MiR-7 mediates the signaling pathway of NE affecting FSH and LH synthesis in pig pituitary.

MicroRNA-7 (miR-7) is an important modulator of a plenty of gene expressions and the interrelated biological processes, highly expressed in porcine pituitary. Norepinephrine (NE), acting as an important neurotransmitter or/and a hormone secreted excessively under stress, affects the synthesis and secretion of various hormones, including pituitary follicle-stimulating hormone (FSH) and luteinizing hormone (LH), which are the key hormones which regulate sexual maturation and reproductive functions. However, the relationship among NE, miR-7 and gonadotropin needs to be elucidated. The aim of this study was to identify whether miR-7 involved in the NE-adrenoceptor signaling pathway affects the synthesis and secretion of FSH and LH in porcine pituitary. Our results showed that the NE intracerebroventricular injection increased pituitary miR-7 level and the synthesis and secretion of FSH and LH in porcine, whereas the inhibition of either endogenous miR-7 or β-adrenergic receptors hindered the rise of FSH and LH synthesis induced by NE in cultured primary porcine anterior pituitary cells. Further, we identified the molecular type of β-adrenergic receptors and the signaling pathway in porcine pituitary, and we found that NE played its roles relying on adrenoceptor beta 2 (β2AR) and the RAF/MEK/ERK1/2 signaling pathway. The phosphorylation of ERK1/2 upregulated miR-7 level which subsequently enhanced FSH and LH synthesis by targeting to Golgi glycoprotein 1 (GLG1). These suggest that miR-7 mediates NE's effect on promoting FSH and LH synthesis in porcine pituitary.

Targeting the highly abundant circular RNA circSlc8a1 in cardiomyocytes attenuates pressure overload induced hypertrophy.

We and others have previously described the expression landscape of circular RNA (circRNA) in mouse and human hearts. However, the functional relevance of many of these abundantly expressed cardiomyocyte circRNA remains to be fully explored. Among the most abundant circRNA, one stems from the sodium-calcium exchanger gene, Slc8a1, exon 2 locus. Because of its very high abundance in cardiomyocytes we investigated the possible role of circSlc8a1 in the heart. We performed a miRNA screen using an array of 752 miRNAs with RNA recovered from a pull-down of endogenous cardiomyocyte circSlc8a1. MicroRNA-133a (miR-133a), with a prior well-recognized role in cardiac hypertrophy, was highly enriched in the fraction of circSlc8a1 pull-down (adjusted P-value < 0.001). We, therefore, followed-up validation of the functional interaction between circSlc8a1 and miR-133 using luciferase assays and reciprocal pull-down assays. In vivo, AAV9-mediated RNAi knockdown of circSlc8a1 attenuates cardiac hypertrophy from pressure-overload, whereas forced cardiomyocyte specific overexpression of circSlc8a1 resulted in heart failure. Molecular analyses showed targets of miR-133a including serum response factor (Srf), connective tissue growth factor (Ctgf), adrenoceptor beta 1 (Adrb1), and adenylate cyclase 6 (Adcy6) to be regulated by circSlc8a1-directed intervention of knockdown and overexpression. In summary, circSlc8a1 can function as an endogenous sponge for miR-133a in cardiomyocytes. We propose that circSlc8a1 may serve as a novel therapeutic target for cardiac hypertrophy.

ADRB2 suppresses IL-13-induced allergic rhinitis inflammatory cytokine regulated by miR-15a-5p.

Allergic rhinitis (AR) is a common hypersensitive disease that troubles patients a lot. Nasal epithelial cells (NECs), as the outmost protection of inhalation, play an important role in AR allergic response. Adrenoceptor beta 2 (ADRB2) is an important gene in inflammatory response, which has become the hot spot for AR development and treatment in recent years. MiR-15a-5p has been proved to be involved in AR immune response as the upstream regulator of ADRB2. Human primary NECs were isolated and stimulated by IL-13. qRT-PCR assay was used to detect the RNA level of target genes. ELISA and Western blotting were applied to detect target protein levels. Luciferase reporter assay and biotin pull-down assay were performed to test molecules interaction. ADRB2 was highly expressed in nasal mucosa of AR patients and was positively correlated with IL-13 stimulation, and knockdown of ADRB2 inhibited IL-13-induced expression of GM-CSF, eotaxin, and MUC5AC in NECs. ADRB2 was directly targeted by miR-15a-5p, and miR-15a-5p inhibited IL-13-induced expression of GM-CSF, eotaxin, and MUC5AC in NECs. ADRB2 mediated the effect of miR-15a-5p on the regulation of nasal epithelial immune responses. ADRB2 is negatively regulated by miR-15a-5p, which inhibits IL-13-induced nasal epithelial inflammatory responses.

Identification of Suitable Reference Genes for Quantitative Gene Expression Analysis in Innervated and Denervated Adipose Tissue from Cafeteria Diet-Fed Rats.

Our previous studies show that cafeteria diet increases body adiposity, plasma insulin levels, and sympathetic activity to brown adipose tissue (BAT) and white adipose tissue (WAT) of Wistar rats, leading to rapid and progressive changes in the metabolic profile. The identification of suitable reference genes that are not affected by the experimental conditions is a critical step in accurate normalization of the reverse transcription quantitative real-time PCR (qRT-PCR), a commonly used assay to elucidate changes in the gene expression profile. In the present study, the effects of the cafeteria diet and sympathetic innervation on the gene expression of adrenoceptor beta 3 (Adrb3) from BAT and WAT were assessed using one of the most stable and one of the least stable genes as normalizers. Rats were fed the cafeteria diet and on the 17th day, interscapular BAT or retroperitoneal WAT was denervated and, 7 days after surgery, the contralateral innervated tissue was used as control. Ten reference genes were evaluated (18S, B2m, Actb, CypA, Gapdh, Hprt1, Rpl32, Tbp, Ubc, and Ywhaz) and ranked according to their stability using the following algorithms: geNorm, NormFinder, BestKeeper, and comparative delta threshold cycle (ΔC t ) method. According to the algorithms employed, the normalization of Adrb3 expression by the least stable genes produced opposite results compared with the most stable genes and literature data. In cafeteria and control diet-fed rats, the three most stable genes were Hprt1, Tbp, and Rpl32 for interscapular BAT and Tbp, B2m, and Hprt1 for retroperitoneal WAT, while the least stable genes were 18S, Actb, and Gapdh for both tissues.

Differences in the genetic backgrounds of patients with alcoholic liver disease and non-alcoholic fatty liver disease.

Background and AimAlcoholic liver disease (ALD) and non‐alcoholic fatty liver disease (NAFLD) have common hepatic histological features, but few studies have compared the genomic backgrounds of these two diseases. Here, we compared the genetic differences between ALD and NAFLD.MethodsThis study enrolled 318 Japanese patients with ALD (n = 118; male, 86%; median age, 62 years; liver cirrhosis, 58%; hepatocellular carcinoma [HCC], 31%) and NAFLD (n = 200; male, 55%; age, 61 years; cirrhosis, 19%; HCC, 12%). The genotype frequencies of 10 single nucleotide polymorphisms (SNPs) were analyzed.ResultsThe ADH1B genotype GG and ALDH2 genotype GG were observed more frequently, and the percentage of patients with the MTP genotype GG was lower in ALD compared with NAFLD patients (ADH1B, 16 vs 4%; ALDH2 84 vs 44%; MTP 62 vs 72%, respectively; all P < 0.01). Comparing noncirrhosis to cirrhosis, the frequency of the potassium voltage‐gated channel subfamily Q member 1 (KCNQ1) genotype TT and adrenoceptor beta 3 (ADRB3) genotype TT was increased significantly in ALD‐related cirrhosis. In contrast, the patatin‐like phospholipase 3 (PNPLA3) genotype CC was decreased significantly in NAFLD‐related cirrhosis. A comparison of patients with and without HCC demonstrated that the KCNQ1 genotype TT was increased significantly in both HCC groups. In addition, associations between the KCNJ15 genotype GG and ALD‐HCC and the G allele of PNPLA3 and NAFLD‐HCC were identified.ConclusionsSNPs in genes related to ethanol and lipid metabolism clearly differed between patients with ALD and NAFLD. KCNQ1 might affect the progression and hepatocarcinogenesis in both ALD and NAFLD.

Microarray analysis of obese women with polycystic ovary syndrome for key gene screening, key pathway identification and drug prediction

PurposeThis study aimed to screen key genes and pathways involved in obese polycystic ovary syndrome (PCOS), and predict drugs for treatment of obese PCOS via bioinformatics approaches. MethodsMicroarray dataset GSE10946 were downloaded from the Gene Expression Omnibus database, including 7 cumulus cell samples from obese PCOS patients and 6 lean control samples. Differentially expressed genes (DEGs) between obese PCOS and controls were obtained using Bayesian test after data preprocessing, followed by functional enrichment analyses for DEGs. Besides, protein-protein interaction (PPI) network and sub-network analyses were performed. Furthermore, drug prediction was carried out based on the DEGs. ResultsA total of 793 DEGs were identified in PCOS compared with control, including 352 up-regulated and 441 down-regulated DEGs. Specifically, upregulated RNA polymerase I subunit B (POLR1B), DNA polymerase epsilon 3, accessory subunit (POLE3), and DNA polymerase delta 3, accessory subunit (POLD3) were enriched in pathway of pyrimidine metabolism associated with obesity and PCOS, and 5-hydroxytryptamine receptor 2C (HTR2C) was enriched calcium signaling pathway. Additionally, 10 significant potential drugs, such as spironolactone targeting androgen receptor (AR), trimipramine targeting adrenoceptor beta 2 (ADRB2), and L-ornithine targeting ornithine decarboxylase antizyme 3 (OAZ3), were obtained. ConclusionsIn conclusion, POLR1B, POLE3, POLD3, and HTR2C might play important roles in obese PCOS via involvement of pyrimidine metabolism and calcium signaling pathway. Moreover, AR, ADRB2, and OAZ3 might be targets of spironolactone, trimipramine, and L-ornithine in the treatment of obese PCOS.

Genetic basis of obesity: a review

Obesity is a state of “positive” energy balance when energy intake in is much greater than energy expenditure. The familial aggregation of body size was first published by Sir Francis Galton in 1889, which become a well-established risk factor for childhood obesity. Obesity is often allied with insulin resistance, dyslipidemia and cardiovascular disease. Monogenic obesity includes the involvements of Leptin (LEP) gene, leptin receptor(LEPR), Proopiomelanocortin (POMC), Melanocortin-4 receptor (MC4R), single-minded gene 1 (SIM 1), Proprotein convertase subtilisin/ kexin type 1 (PCSK1), Neuropeptide Y (NPY). Polygenic obesity is due to Adrenoceptor beta 1 (ADRB1), ADRB2, ADRB3, Uncoupling protein 1(UCP1), UCP2, UCP3. Monogenic and polygenic obesity; pleiotropic syndromes, chromosomal rearrangement are different types of obesity with genetic cause. Surprisingly all “obesity genes” carriers do not become overweight, and exercise, maintaining healthy routine is a significant contributing factor to nullify genetic prediposition.Journal of Biomedical Sciences, Vol. 3, No.2, 2016, Page: 24-28

Further evidence for a role of the ADRB2 gene in risk for posttraumatic stress disorder

The aim of the present study was to attempt to replicate the recently reported finding associating rs2400707 of the Adrenoceptor Beta 2, Surface (ADRB2) gene and childhood trauma on PTSD symptoms. Participants included a predominantly veteran cohort of non-Hispanic blacks (NHB; n = 949) and a pre-dominantly veteran cohort of non-Hispanic whites (NHW; n = 759). No main effects were observed for rs2400707 on PTSD diagnosis. Among the NHB participants, we observed an interaction between rs2400707 and history of childhood trauma, whereby with each additional A allele, the odds of having PTSD increased by 1.31, but only among those who had experienced childhood trauma (p = 0.038). The interaction with rs2400707 and childhood trauma was not observed among the NHW study participants (p = 0.892). Taken together, the findings from the present research provide further evidence that the adrenergic system may be an important modulator of PTSD risk; however, additional work is still needed to clarify the exact nature of the relationship between PTSD and rs2400707 of the ADRB2 gene.

β-Adrenergic receptor gene expression in HIV-associated neurocognitive impairment and encephalitis: implications for MOR-1K subcellular localization.

We previously reported that mRNA expression of the unique alternatively spliced OPRM1 isoform μ-opioid receptor-1K (MOR-1K), which exhibits excitatory cellular signaling, is elevated in HIV-infected individuals with combined neurocognitive impairment (NCI) and HIV encephalitis (HIVE). It has recently been shown that the β2-adrenergic receptor (β2-AR) chaperones MOR-1K, normally localized intracellularly, to the cell surface. Here, we found mRNA expression of the adrenoceptor beta 2 (ADRB2) gene is also elevated in NCI-HIVE individuals, as well as that β2-AR protein expression is elevated in HIV-1-infected primary human astrocytes treated with morphine, and discuss the implications for MOR-1K subcellular localization in this condition.

Pharmacogenetic Associations of Antipsychotic Drug-Related Weight Gain: A Systematic Review and Meta-analysis.

Although weight gain is a serious but variable adverse effect of antipsychotics that has genetic underpinnings, a comprehensive meta-analysis of pharmacogenetics of antipsychotic-related weight gain is missing. In this review, random effects meta-analyses were conducted for dominant and recessive models on associations of specific single nucleotide polymorphisms (SNP) with prospectively assessed antipsychotic-related weight or body mass index (BMI) changes (primary outcome), or categorical increases in weight or BMI (≥7%; secondary outcome). Published studies, identified via systematic database search (last search: December 31, 2014), plus 3 additional cohorts, including 222 antipsychotic-naïve youth, and 81 and 141 first-episode schizophrenia adults, each with patient-level data at 3 or 4 months treatment, were meta-analyzed. Altogether, 72 articles reporting on 46 non-duplicated samples (n = 6700, mean follow-up = 25.1wk) with 38 SNPs from 20 genes/genomic regions were meta-analyzed (for each meta-analysis, studies = 2-20, n = 81-2082). Eleven SNPs from 8 genes were significantly associated with weight or BMI change, and 4 SNPs from 2 genes were significantly associated with categorical weight or BMI increase. Combined, 13 SNPs from 9 genes (Adrenoceptor Alpha-2A [ADRA2A], Adrenoceptor Beta 3 [ADRB3], Brain-Derived Neurotrophic Factor [BDNF], Dopamine Receptor D2 [DRD2], Guanine Nucleotide Binding Protein [GNB3], 5-Hydroxytryptamine (Serotonin) Receptor 2C [HTR2C], Insulin-induced gene 2 [INSIG2], Melanocortin-4 Receptor [MC4R], and Synaptosomal-associated protein, 25kDa [SNAP25]) were significantly associated with antipsychotic-related weight gain (P-values < .05-.001). SNPs in ADRA2A, DRD2, HTR2C, and MC4R had the largest effect sizes (Hedges' g's = 0.30-0.80, ORs = 1.47-1.96). Less prior antipsychotic exposure (pediatric or first episode patients) and short follow-up (1-2 mo) were associated with larger effect sizes. Individual antipsychotics did not significantly moderate effect sizes. In conclusion, antipsychotic-related weight gain is polygenic and associated with specific genetic variants, especially in genes coding for antipsychotic pharmacodynamic targets.

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Methacholine PC20 in African Americans and whites with asthma with homozygous genotypes at ADRB2 codon 16

BackgroundAfrican Americans have worse asthma outcomes compared to whites. Adrenoceptor beta 2, surface gene (ADRB2) Gly16Arg genotypes have been associated with β2-agonist bronchodilator response, asthma exacerbation rate, response to methacholine, and lung function decline but not specifically in African Americans. ObjectiveWe sought to compare the provocative concentration of methacholine that causes a 20% fall in FEV1 (PC20) in African Americans and whites with asthma who were ADRB2 homozygous at codon 16 (Arg16Arg or Gly16Gly). MethodsAfrican Americans and whites whose parents and grandparents were of the same race, aged ≥10 years, with baseline FEV1 of ≥60% predicted, and no upper or lower respiratory tract infection within the previous 2 weeks meeting genotype criteria were enrolled. PC20 was measured after withholding short-acting and long-acting β2-agonists for 8 and 12 h respectively, montelukast for 24 h, ipratropium bromide and inhaled corticosteroids for 12 h, and antihistamines for 72 h. Results423 participants were screened and 88 had a positive challenge. Participants were 32 yrs ± 19 yrs (mean ± SD), 70% female, 51% White (vs. African American), 6% Hispanic. Similar numbers of participants were using inhaled corticosteroids by race and genotype. There were significant differences in log PC20 between race/genotype groups (p = 0.012). African American Arg16Arg participants had a lower log PC20 than White Gly16Gly (p = 0.009) and African American Gly16Gly (p = 0.041) participants. Both race and genotype contributed significantly to the model (p = 0.037 and p = 0.014, respectively) but there was no interaction between race and genotype on log PC20. Conclusions and clinical relevanceAirway hyperresponsiveness is influenced by race and the ADRB2 codon 16 polymorphism. African Americans with the Arg16Arg genotype have increased airway reactivity and may be at risk for worse asthma outcomes. Inclusion of genetic information as an additional clinical tool may aid in the personalization of asthma management decisions.[ClinicalTrials.gov Identifier: NCT00708227]