Detection of metabolic syndrome burden in healthy young adults may enable timely introduction of disease prevention.

INTRODUCTION: Metabolic syndrome and associated diseases are a global health problem. Detection of early metabolic modifications that may lead to metabolic syndrome would enable timely introduction of preventive lifestyle modifications. MATERIAL AND METHODS: In total 103 young, healthy adults were assessed for indicators of metabolic alterations. Anthropometric, lifestyle, genetic and biochemical parameters were assessed. Individuals who fulfilled at least one criterion for diagnosis of metabolic syndrome were assigned to the group with the higher metabolic syndrome burden (B-MeS). RESULTS: The 34 young healthy individuals who were assigned to the B-MeS group had lower fat-free mass, higher body mass index, waist-to-hip ratio, fat mass, and blood pressure, more visceral fat, they were less physically active, had higher C-reactive protein values and higher catalase activity. Their phenotype was more similar to that of patients diagnosed with metabolic syndrome than the rest of the population. CONCLUSIONS: Simple anthropometric measurements, lifestyle assessment and basic biochemical measurements can be used to identify young healthy individuals with increased risk for metabolic syndrome. These assessments can be performed at periodic check-ups of the healthy population so that timely diagnosis of B-MeS can be made. As lifestyle factors have a big influence on development or improvement of the MeS, the timely diagnosis for B-MeS would enable an early opportunity for intervention for lifestyle modification in the still healthy population, saving costs and reducing disability adjusted life years.

ADORA2A Polymorphisms Influence Methotrexate Adverse Events in Rheumatoid Arthritis.

BACKGROUND: Methotrexate is the most frequently administered first-line treatment for rheumatoid arthritis (RA). The disease-modifying effects of methotrexate are mainly associated with enhanced release of free adenosine. The downstream anti-inflammatory effects of adenosine are mediated via its binding to adenosine receptor 2A (ADORA2A) and 3 (ADORA3). Many clinically important single nucleotide polymorphisms (SNPs) were reported in ADORA2A and ADORA3 genes. OBJECTIVES: To investigate whether tagging ADORA2A and ADORA3 polymorphisms influences methotrexate treatment in RA. METHODS: In total, 212 RA patients treated with methotrexate were genotyped for tagging ADORA2A (rs2298383, rs8141793, rs2236624, rs5751876, rs35320474, and rs17004921) and ADORA3 SNPs (rs2298191, rs1544223, rs78594984, rs35511654, rs2229155, rs3393, and rs3394). RESULTS: RA patients who carried ADORA3 rs35511654 G allele showed a tendency toward better response to methotrexate treatment (P = 0.054). Carriers of ADORA2A polymorphic allele rs2298383 (P = 0.011), rs2236624 (P = 0.027), rs5751876 (P = 0.018), and rs35320474 (P = 0.026) were less likely to experience methotrexate induced adverse events. All associations remained significant after adjustment for clinical factors. The effects of these polymorphisms were also significant in haplotype analyses. CONCLUSIONS: Polymorphisms in the ADORA2A gene may influence methotrexate treatment response and may be considered as a potential biomarker for methotrexate treatment in rheumatoid arthritis.

Clinical Pharmacogenetic Models of Treatment Response to Methotrexate Monotherapy in Slovenian and Serbian Rheumatoid Arthritis Patients: Differences in Patient's Management May Preclude Generalization of the Models.

Objectives: Methotrexate (MTX) is the first line treatment for rheumatoid arthritis (RA), but nevertheless 30% of patients experience MTX inefficacy. Our aim was to develop a clinical pharmacogenetic model to predict which RA patients will not respond to MTX monotherapy. We also assessed whether this model can be generalized to other populations by validating it on a group of Serbian RA patients. Methods: In 110 RA Slovenian patients, data on clinical factors and 34 polymorphisms in MTX pathway were analyzed by Least Absolute Shrinkage and Selection Operator (LASSO) penalized regression to select variables associated with the disease activity as measured by Disease Activity Score (DAS28) score after 6 months of MTX monotherapy. A clinical pharmacogenetic index was constructed from penalized regression coefficients with absolute value above 0.05. This index was cross-validated and also independently validated on 133 Serbian RA patients. Results: A clinical pharmacogenetic index for prediction of DAS28 after 6 months of MTX monotherapy in Slovenian RA patients consisted of DAS28 score at diagnosis, presence of erosions, MTX dose, Solute Carrier Family 19 Member 1 (SLC19A1) rs1051266, Solute Carrier Organic Anion Transporter Family Member 1B1 (SLCO1B1) rs2306283, Thymidylate Synthase (TYMS), and Adenosine Monophosphate Deaminase 1 (AMPD1) rs17602729. It correctly classified 69% of Slovenian patients as responders or nonresponders and explained 30% of variability in DAS28 after 6 months of MTX monotherapy. Testing for validity in another population showed that it classified correctly only 22.5% of Serbian RA patients. Conclusions: We developed a clinical pharmacogenetic model for DAS28 after 6 months of MTX monotherapy in Slovenian RA patients by combining clinical and genetic variables. The clinical pharmacogenetic index developed for Slovenian patients did not perform well on Serbian patients, presumably due to the differences in patients' characteristics and clinical management between the two groups.

NLRP3 and CARD8 Polymorphisms Influence Higher Disease Activity in Rheumatoid Arthritis.

BACKGROUND: The activation of NLRP3-inflammasome may contribute to inflammatory processes in rheumatoid arthritis (RA). Functional polymorphisms in the genes coding for its components NLRP3 and CARD8 were associated with a proinflammatory phenotype. Our aim was to investigate the influence of these polymorphisms on RA susceptibility and disease activity at the time of diagnosis and after six months of treatment. METHODS: A group of 128 RA patients treated with methotrexate and 122 healthy controls were genotyped for NLRP3 rs35829419 (p. Q705K) and CARD8 rs2043211 (p. C10X) polymorphisms. RESULTS: RA susceptibility was not influenced by the investigated polymorphisms or their interaction. The investigated polymorphisms explained 8% of variability in DAS28 at the time of diagnosis. Carriers of NLRP3 rs35829419 or CARD8 rs2043211 polymorphisms had significantly higher DAS28 at the time of diagnosis (p=0.003; p=0.022; respectively). Polymorphic CARD8 rs2043211 TT genotype was also associated with higher DAS28 after six months of treatment (p=0.033). CONCLUSIONS: Genetic variability of inflammasome components may contribute to higher disease activity at the time of diagnosis and after 6 months of methotrexate treatment in RA patients. Better understanding of the immunological mechanisms behind a more active course of RA may suggest novel treatment approaches in a subset of patients with a proinflammatory phenotype.

Survivin polymorphism is associated with disease activity in rheumatoid arthritis patients.

AIM: Survivin expression was associated with unfavorable and erosive course of rheumatoid arthritis (RA). This is the first study investigating association between BIRC5 polymorphisms, survivin plasma levels and disease activity in RA. PATIENTS & METHODS: A testing group of 123 and validation group of 150 RA patients initially treated with methotrexate monotherapy were genotyped for three BIRC5 promoter polymorphisms. Survivin plasma levels were determined in testing group. RESULTS: BIRC5 c.-31G>C was marginally associated with treatment response after 6 months of methotrexate treatment (p = 0.046) and with DAS28 at the time of inclusion in testing (p = 0.052) and in validation group (p = 0.057). Survivin plasma levels were not associated with BIRC5 polymorphisms or DAS28. CONCLUSION: BIRC5 -31C>G polymorphism could be useful pharmacogenetic marker for methotrexate treatment response in RA.