Obesity is a risk factor for poor response to treatment in early rheumatoid arthritis: a NORD-STAR study.

OBJECTIVE: This report from the NORD-STAR (Nordic Rheumatic Diseases Strategy Trials and Registries) trial aimed to determine if obesity is associated with response to conventional and biological antirheumatic treatment in early rheumatoid arthritis (RA). METHODS: This report included 793 participants with untreated early RA from the randomised, longitudinal NORD-STAR trial, all of whom had their body mass index (BMI) assessed at baseline. Obesity was defined as BMI ≥30 kg/m2. All participants were randomised 1:1:1:1 to one of four treatment arms: active conventional treatment, certolizumab-pegol, abatacept and tocilizumab. Clinical and laboratory measurements were performed at baseline and at 8, 12, 24 and 48-week follow-up. The primary endpoint for this report was response to treatment based on Clinical Disease Activity Index (CDAI) and Simple Disease Activity Index (SDAI) remission and Disease Activity Score with 28 joints using C-reactive protein (DAS28-CRP) <2.6 stratified by BMI. RESULTS: Out of 793 people included in the present report, 161 (20%) had obesity at baseline. During follow-up, participants with baseline obesity had higher disease activity compared with those with lower BMI, despite having similar disease activity at baseline. In survival analyses, obesity was associated with a lower likelihood of achieving response to treatment during follow-up for up to 48 weeks (CDAI remission, HR 0.84, 95% CI 0.67 to 1.05; SDAI, HR 0.77, 95% CI 0.62 to 0.97; DAS28-CRP <2.6, HR 0.78, 95% CI 0.64 to 0.95). The effect of obesity on response to treatment was not influenced by the treatment arms. CONCLUSION: In people with untreated early RA followed up for up to 48 weeks, obesity was associated with a lower likelihood of good treatment response, irrespective of the type of randomised treatment received. TRIAL REGISTRATION NUMBER: NCT01491815.

Adipokines and risk of rheumatoid arthritis: A two-sample multivariable Mendelian randomisation study.

Adiponectin, leptin, and resistin are thought to be involved in the pathogenesis of rheumatoid arthritis (RA). However, the causal relationship between these adipokines and the risk for RA is unclear. We performed a range of two-sample Mendelian randomisation (MR) analyses to assess the causal effect of circulating adiponectin, leptin, and resistin on RA risk in European and East Asian individuals. Different sets of adiponectin-, leptin-, and resistin-related genetic variants were used as instruments for genetically determined adipokine levels. As body mass index (BMI) is a risk factor for RA and affects adipokine levels, multivariable MR was used to calculate the causal effect of each adipokine on RA risk taking BMI into account. Several MR analyses revealed no evidence of a causal relationship between circulating adiponectin, leptin, or resistin levels and RA risk in either Europeans or East Asians. Similarly, multivariable MR did not provide evidence of any causal effect of adiponectin, leptin, or resistin on RA risk when taking BMI into account. This MR study shows for the first time that genetically determined levels of adiponectin, leptin, or resistin do not have a direct causal effect on the risk of developing RA after adjustment for BMI.

Risk variants of obesity associated genes demonstrate BMI raising effect in a large cohort.

Obesity is highly polygenic disease where several genetic variants have been reportedly associated with obesity in different ethnicities of the world. In the current study, we identified the obesity risk or protective association and BMI raising effect of the minor allele of adiponectin, C1Q and collagen domain containing (ADIPOQ), cholesteryl ester transfer protein (CEPT), FTO alpha-ketoglutarate dependent dioxygenase (FTO), leptin (LEP), and leptin receptor (LEPR) genes in a large cohort stratified into four BMI-based body weight categories i.e., normal weight, lean, over-weight, and obese. Based on selected candidate genetic markers, the genotyping of all study subjects was performed by PCR assays, and genotypes and allele frequencies were calculated. The minor allele frequencies (MAFs) of all genetic markers were computed for total and BMI-based body weight categories and compared with MAFs of global and South Asian (SAS) populations. Genetic associations of variants with obesity risk were calculated and BMI raising effect per copy of the minor allele were estimated. The genetic variants with higher MAFs in obese BMI group were; rs2241766 (G = 0.43), rs17817449 (G = 0.54), rs9939609 (A = 0.51), rs1421085 (C = 0.53), rs1558902 (A = 0.63), and rs1137101 (G = 0.64) respectively. All these variants were significantly associated with obesity (OR = 1.03-4.42) and showed a high BMI raising effect (ß = 0.239-0.31 Kg/m2) per copy of the risk allele. In contrast, the MAFs of three variants were higher in lean-normal BMI groups; rs3764261 A = 0.38, rs9941349 T = 0.43, and rs7799039 G = 0.40-0.43). These variants showed obesity protective associations (OR = 0.68-0.76), and a BMI lowering effect per copy of the protective allele (ß = -0.103-0.155 Kg/m2). The rs3764261 variant also showed significant and positive association with lean body mass (OR = 2.38, CI = 1.30-4.34). Overall, we report six genetic variants of ADIPOQ, FTO and LEPR genes as obesity-risk markers and a CETP gene variant as lean mass/obesity protective marker in studied Pakistani cohort.

N-Acetyl Cysteine, Selenium, and Ascorbic Acid Rescue Diabetic Cardiac Hypertrophy via Mitochondrial-Associated Redox Regulators.

Metabolic disorders often lead to cardiac complications. Metabolic deregulations during diabetic conditions are linked to mitochondrial dysfunctions, which are the key contributing factors in cardiac hypertrophy. However, the underlying mechanisms involved in diabetes-induced cardiac hypertrophy are poorly understood. In the current study, we initially established a diabetic rat model by alloxan-administration, which was validated by peripheral glucose measurement. Diabetic rats displayed myocardial stiffness and fibrosis, changes in heart weight/body weight, heart weight/tibia length ratios, and enhanced size of myocytes, which altogether demonstrated the establishment of diabetic cardiac hypertrophy (DCH). Furthermore, we examined the expression of genes associated with mitochondrial signaling impairment. Our data show that the expression of PGC-1α, cytochrome c, MFN-2, and Drp-1 was deregulated. Mitochondrial-signaling impairment was further validated by redox-system dysregulation, which showed a significant increase in ROS and thiobarbituric acid reactive substances, both in serum and heart tissue, whereas the superoxide dismutase, catalase, and glutathione levels were decreased. Additionally, the expression levels of pro-apoptotic gene PUMA and stress marker GATA-4 genes were elevated, whereas ARC, PPARα, and Bcl-2 expression levels were decreased in the heart tissues of diabetic rats. Importantly, these alloxan-induced impairments were rescued by N-acetyl cysteine, ascorbic acid, and selenium treatment. This was demonstrated by the amelioration of myocardial stiffness, fibrosis, mitochondrial gene expression, lipid profile, restoration of myocyte size, reduced oxidative stress, and the activation of enzymes associated with antioxidant activities. Altogether, these data indicate that the improvement of mitochondrial dysfunction by protective agents such as N-acetyl cysteine, selenium, and ascorbic acid could rescue diabetes-associated cardiac complications, including DCH.

Association between serum urate and CSF markers of Alzheimer's disease pathology in a population-based sample of 70-year-olds.

INTRODUCTION: The relationship between urate and biomarkers for Alzheimer's disease (AD) pathophysiology has not been investigated. METHODS: We examined whether serum concentration of urate was associated with cerebrospinal fluid biomarkers, amyloid beta (Aß)42, Aß40, phosphorylated tau (p-tau), total tau (t-tau), neurofilament light (NfL), and Aß42/Aß40 ratio, in cognitively unimpaired 70-year-old individuals from Gothenburg, Sweden. We also evaluated whether possible associations were modulated by the apolipoprotein E (APOE) ε4 allele. RESULTS: Serum urate was positively associated with Aß42 in males (ß = 0.55 pg/mL, P = .04). There was a positive urate-APOE ε4 interaction (1.24 pg/mL, P interaction = .02) in relation to Aß42 association. The positive urate and Aß42 association strengthened in male APOE ε4 carriers (ß = 1.28 pg/mL, P = .01). DISCUSSION: The positive association between urate and Aß42 in cognitively healthy men may suggest a protective effect of urate against deposition of amyloid protein in the brain parenchyma, and in the longer term, maybe against AD dementia.

The absolute risk of gout by clusters of gout-associated comorbidities and lifestyle factors-30 years follow-up of the Malmö Preventive Project.

BACKGROUND: Gout is predicted by a number of comorbidities and lifestyle factors. We aimed to identify discrete phenotype clusters of these factors in a Swedish population-based health survey. In these clusters, we calculated and compared the incidence and relative risk of gout. METHODS: Cluster analyses were performed to group variables with close proximity and to obtain homogenous clusters of individuals (n = 22,057) in the Malmö Preventive Project (MPP) cohort. Variables clustered included obesity, kidney dysfunction, diabetes mellitus (DM), hypertension, cardiovascular disease (CVD), dyslipidemia, pulmonary dysfunction (PD), smoking, and the use of diuretics. Incidence rates and hazard ratios (HRs) for gout, adjusted for age and sex, were computed for each cluster. RESULTS: Five clusters (C1-C5) were identified. Cluster C1 (n = 16,063) was characterized by few comorbidities. All participants in C2 (n = 750) had kidney dysfunction (100%), and none had CVD. In C3 (n = 528), 100% had CVD and most participants were smokers (74%). C4 (n = 3673) had the greatest fractions of obesity (34%) and dyslipidemia (74%). In C5 (n = 1043), proportions with DM (51%), hypertension (54%), and diuretics (52%) were highest. C1 was by far the most common in the population (73%), followed by C4 (17%). These two pathways included 86% of incident gout cases. The four smaller clusters (C2-C5) had higher incidence rates and a 2- to 3-fold increased risk for incident gout. CONCLUSIONS: Five distinct clusters based on gout-related comorbidities and lifestyle factors were identified. Most incident gout cases occurred in the cluster of few comorbidities, and the four comorbidity pathways had overall a modest influence on the incidence of gout.

On Topological Indices of OT [m, n] Octagonal Tillings and TiO2 Nanotubes.

Some well defined connectivity topological indices are Randic index, atom-bond connectivity index, geometric-arithmetic index and Shigehalli & Kanabur indices, brought into light by M. Randic, Estrada et al, Vukicevic et al and V. S. Shigehalli, in their respective research articles. Topological indices preserve the symmetry of molecular structures and provide a mathematical formulation to predict their properties like boiling points, viscosity and the radius of gyrations,1 mainly their study gets a cover under the category of physical chemistry. Due to its mathematical nature, this idea has caught the attention of many chemists. It has also been reported that these indices are useful in the study of anti- inflammatory activities of certain chemical instances. In this paper, we shall calculate these topological indices of an infinite class of octagonal tilling structures OT [m, n], which is a molecular graph of a semiconductor allotrope consisting of octagons and rectangles, for all possible values of the parameters m and n. We shall also calculate Shigehalli & Kanabur indices of infinite structure of the titania TiO2 nanotubes.

The relationship between ferritin and urate levels and risk of gout.

BACKGROUND: Ferritin positively associates with serum urate and an interventional study suggests that iron has a role in triggering gout flares. The objective of this study was to further explore the relationship between iron/ferritin and urate/gout. METHODS: European (100 cases, 60 controls) and Polynesian (100 cases, 60 controls) New Zealand (NZ) males and 189 US male cases and 60 male controls participated. The 10,727 participants without gout were from the Jackson Heart (JHS; African American = 1260) and NHANES III (European = 5112; African American = 4355) studies. Regression analyses were adjusted for age, sex, body mass index and C-reactive protein. To test for a causal relationship between ferritin and urate, bidirectional two-sample Mendelian randomization analysis was performed. RESULTS: Serum ferritin positively associated with gout in NZ Polynesian (OR (per 10 ng ml- 1 increase) = 1.03, p = 1.8E-03) and US (OR = 1.11, p = 7.4E-06) data sets but not in NZ European (OR = 1.00, p = 0.84) data sets. Ferritin positively associated with urate in NZ Polynesian (ß (mg dl- 1) = 0.014, p = 2.5E-04), JHS (ß = 0.009, p = 3.2E-05) and NHANES III (European ß = 0.007, p = 5.1E-11; African American ß = 0.011, p = 2.1E-16) data sets but not in NZ European (ß = 0.009, p = 0.31) or US (ß = 0.041, p = 0.15) gout data sets. Ferritin positively associated with the frequency of gout flares in two of the gout data sets. By Mendelian randomization analysis a one standard deviation unit increase in iron and ferritin was, respectively, associated with 0.11 (p = 8E-04) and 0.19 mg dl- 1 (p = 2E-04) increases in serum urate. There was no evidence for a causal effect of urate on iron/ferritin. CONCLUSIONS: These data replicate the association of ferritin with serum urate. Increased ferritin levels associated with gout and flare frequency. There was evidence of a causal effect of iron and ferritin on urate.

Mediation analysis to understand genetic relationships between habitual coffee intake and gout.

BACKGROUND: Increased coffee intake is associated with reduced serum urate concentrations and lower risk of gout. Specific alleles of the GCKR, ABCG2, MLXIPL, and CYP1A2 genes have been associated with both reduced coffee intake and increased serum urate in separate genome-wide association studies (GWAS). The aim of this study was to determine whether these single nucleotide polymorphisms (SNPs) influence the risk of gout through their effects on coffee consumption. METHODS: This research was conducted using the UK Biobank Resource. Data were available for 130,966 European participants aged 40-69 years. Gout status and coffee intake were tested for association with four urate-associated SNPs: GCKR (rs1260326), ABCG2 (rs2231142), MLXIPL (rs1178977), and CYP1A2 (rs2472297). Multiple regression and path analysis were used to examine whether coffee consumption mediated the effect of the SNPs on gout risk. RESULTS: Coffee consumption was inversely associated with gout (multivariate adjusted odds ratio (95% confidence interval (CI)) for any coffee consumption 0.75 (0.67-0.84, P = 9 × 10-7)). There was also evidence of a dose-effect with multivariate adjusted odds ratio (95% CI) per cup consumed per day of 0.85 (0.82-0.87, P = 9 × 10-32). The urate-increasing GCKR, ABCG2, MLXIPL, and CYP1A2 alleles were associated with reduced daily coffee consumption, with the strongest associations for CYP1A2 (beta -0.30, P = 8 × 10-40), and MLXIPL (beta -0.17, P = 3 × 10-8), and weaker associations for GCKR (beta -0.07, P = 3 × 10-10) and ABCG2 (beta -0.09, P = 2 × 10-9). The urate-increasing GCKR and ABCG2 alleles were associated with gout (multivariate adjusted p < 5 × 10-8 for both), but the urate-increasing MLXIPL and CYP1A2 alleles were not. In mediation analysis, the direct effects of GCKR and ABCG2 accounted for most of the total effect on gout risk, with much smaller indirect effects mediated by coffee consumption. CONCLUSION: Coffee consumption is inversely associated with risk of gout. Although alleles at several SNPs associate with both lower coffee consumption and higher risk of gout, these SNPs largely influence gout risk directly, rather than indirectly through effects on coffee consumption.

Association analysis of the beta-3 adrenergic receptor Trp64Arg (rs4994) polymorphism with urate and gout.

The Arg64 allele of variant rs4994 (Trp64Arg) in the ß3-adrenergic receptor gene has been associated with increased serum urate and risk of gout. Our objective was to investigate the relationship of rs4994 with serum urate and gout in New Zealand European, Maori and Pacific subjects. A total of 1730 clinically ascertained gout cases and 2145 controls were genotyped for rs4994 by Taqman(®). Maori and Pacific subjects were subdivided into Eastern Polynesian (EP) and Western Polynesian (WP) sample sets. Publicly available genotype data from the Atherosclerosis Risk in Communities Study and the Framingham Heart Study were utilized for serum urate association analysis. Multivariate logistic and linear regression adjusted for potential confounders was carried out using R version 2.15.2. No significant association of the minor Arg64 (G) allele of rs4994 with gout was found in the combined Polynesian cohorts (OR = 0.98, P = 0.88), although there was evidence, after adjustment for renal disease, for association in both the WP (OR = 0.53, P = 0.03) and the lower Polynesian ancestry EP sample sets (OR = 1.86, P = 0.05). There was no evidence for association with gout in the European sample set (OR = 1.11, P = 0.57). However, the Arg64 allele was positively associated with urate in the WP data set (ß = 0.036, P = 0.004, P Corrected = 0.032). Association of the Arg64 variant with increased urate in the WP sample set was consistent with the previous literature, although the protective effect of this variant with gout in WP was inconsistent. This association provides an etiological link between metabolic syndrome components and urate homeostasis.