The plausible association of MTHFR and ADORA2A polymorphisms with nodules in rheumatoid arthritis patients treated with methotrexate

Objective: The treatment of rheumatoid arthritis (RA) patients with methotrexate (MTX) is linked to the development or progression of rheumatoid nodules. The aim of this study was to determine whether folate and adenosine pathways-related single nucleotide polymorphisms might be predictive of increased nodule formation in RA patients treated with oral MTX. Methods: A total of 185 Caucasian RA patients were enrolled in this cross-sectional study, all of whom fulfilled the 1987 RA criteria of the American College of Rheumatology; each patient had a history of MTX treatment. Results: A higher frequency of the MTHFR 1298AA genotype was found in 17 (70.8%) of 24 patients with general nodules [odds ratio (OR)=3.08, 95% confidence interval (CI): 1.20–7.69] and in 14 (73.7%) of 19 patients who developed nodules during MTX treatment (OR=3.55, 95% CI: 1.22–10.32). In contrast, a negative association with nodules during MTX treatment (OR=0.29, 95% CI: 0.08–1.10) was found for 19 (79.2%) patients with the TT genotype (rs2298383) in the adenosine A2a receptor gene (ADORA2A). However, the significance did not remain upon correction for multiple testing. The combination of MTHFR 1298AA along with ADORA2A rs2298383 CC or CT genotypes occurring in one-third of RA patients showed a higher frequency of general nodules 15/59 (25.4%) as well as developing nodules during MTX treatment 13/59 (22.0%) in comparison with the overall studied group: 24/185 (13.0%) and 19/185 (10.3%), respectively. Conclusion: This exploratory study indicates for the first time a plausible association of adenosine and folate pathways single nucleotide polymorphisms in nodules' etiopathogenesis.

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Nomenclature for alleles of the human carboxylesterase 1 gene

No abstract available

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A novel ABCC6 haplotype is associated with azathioprine drug response in myasthenia gravis

Objective: We investigated the association of single nucleotide polymorphisms (SNPs) in drug-metabolizing enzymes and transporters (DMETs) with the response to azathioprine (AZA) in patients affected by myasthenia gravis (MG) to determine possible genotype–phenotype correlations. Patients and methods: Genomic DNA from 180 AZA-treated MG patients was screened through the Affymetrix DMET platform, which characterizes 1931 SNPs in 225 genes. The significant SNPs, identified to be involved in AZA response, were subsequently validated by allelic discrimination and direct sequencing. SNP analysis was carried out using the SNPassoc R package and the haploblocks were determined using haploview software. Results: We studied 127 patients in the discovery phase and 53 patients in the validation phase. We showed that two SNPs (rs8058694 and rs8058696) found in ATP-binding cassette subfamily C member 6, a subfamily member of ATP-binding cassette genes, constituted a new haplotype associated with AZA response in MG patients in the discovery cohort (P=0.011; odds ratio: 0.40; 95% confidence interval: 0.20–0.83) and in the combined cohort (P=0.04; odds ratio: 1.58). Conclusion: These findings highlight the role that the ATP-binding cassette subfamily C member 6 haplotype may play in AZA drug response. In view of the significant effects and AZA intolerance, these novel SNPs should be taken into consideration in pharmacogenetic profiling for AZA.

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Rituximab response in follicular lymphoma is associated with the rs20575 polymorphism in TRAILR1 extrinsic apoptosis trigger

Objective: Rituximab in combination with chemotherapy has been proven to increase progression-free and overall survival in follicular lymphoma (FL), but there is considerable interindividual variability in the response. Extrinsic pathway apoptosis triggered by death receptors seems to be involved in the mechanism of action of monoclonal antibodies. This study aimed to assess the association between TRAILR1/TRAIL polymorphisms (rs20575, rs20576, rs2230229, rs12488654) and rituximab response and the relationship with FASL rs763110, previously found to be associated with rituximab response. Patients and methods: Polymorphisms were determined in a study cohort of 125 FL patients treated with rituximab as first-line treatment and correlated with response, which was scored according to the International Working Group Consensus Revised as complete response, partial response, stable disease, and progressive disease. Results: No significant association with response was found for rs20576, rs2230229, and rs12488654 polymorphisms. In contrast, rs20575 GC/GG carriers were more partial/nonresponders (88.2%) than complete responders (72.5%), showing a trend toward statistical significance (P=0.064). In a multivariable setting, we found that female sex [odds ratio=0.355, 95% confidence interval (CI): 0.137–0.922, P=0.033] and the TRAILR1 rs20575 CC genotype (odds ratio=0.162, 95% CI: 0.035–0.757, P=0.021) were independent positive predictive factors of complete clinical response to rituximab, constructing a parsimonious model with good calibration [χ2 of 5.719 (d.f.=6, P=0.455)] and discrimination (C-statistic=0.739, 95% CI: 0.636–0.842). Conclusion: After studying the pharmacogenetic role of TRAILR1/TRAIL polymorphisms in rituximab-treated FL patients, we found that the rs20575 CC genotype is an independent predictive factor of better rituximab response, indicating the possible involvement of death receptors in anti-CD20 mechanisms of action.

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A comprehensive contribution of genes for aryl hydrocarbon receptor signaling pathway to hypertension susceptibility

Objective: The present study was designed to investigate whether genetic polymorphisms of the aryl hydrocarbon receptor (AHR) signaling pathway are involved in the molecular basis of essential hypertension (EH). Methods: A total of 2160 unrelated Russian individuals comprising 1341 EH patients and 819 healthy controls were recruited into the study. Seven common AHR pathway single-nucleotide polymorphisms (SNPs) such as rs2066853, rs2292596, rs2228099, rs1048943, rs762551, rs1056836, and rs1800566 were genotyped by TaqMan-based allele discrimination assays. Results: We found that SNP rs2228099 of ARNT is associated with an increased risk of EH (odds ratio=1.20 95% confidence interval: 1.01–1.44, P=0.043) in a dominant genetic model, whereas polymorphism rs762551 of CYP1A2 showed an association with a decreased risk of disease in a recessive genetic model (odds ratio=0.68, 95% confidence interval: 0.52–0.89, P=0.006). A log-likelihood ratio test enabled identification of epistatic interaction effects on EH susceptibility for all SNPs. MB-MDR analysis showed that cigarette smoking, rs1048943, rs762551, rs1056836, and rs2228099 were significant contributing factors in 19, 18, 13, 13, and 11 interaction models, respectively. The best MDR model associated with EH risk included rs1048943, rs762551, rs1056836, and cigarette smoking (cross-validation consistency 100%, prediction error 45.7%, Ppermutation

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HLA-B*57

No abstract available

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Persistency of Prediction Accuracy and Genetic Gain in Synthetic Populations Under Recurrent Genomic Selection

Recurrent selection (RS) has been used in plant breeding to successively improve synthetic and other multiparental populations. Synthetics are generated from a limited number of parents (N_p), but little is known about how N_p affects genomic selection (GS) in RS, especially the persistency of prediction accuracy and genetic gain. Synthetics were simulated by intermating N_p= 2 to 32 parent lines from an ancestral population with short- or long-range linkage disequilibrium (LD_A) and subjected to multiple cycles of GS. We determined accuracy and genetic gain across 30 cycles for different training set (TS) sizes, marker densities, and generations of recombination before model training. Contributions to accuracy and genetic gain from pedigree relationships as well as from co-segregation and LD_A between QTL and markers were analyzed via four scenarios differing in (i) the relatedness between TS and selection candidates and (ii) whether selection was based on markers or pedigree records. Persistency of accuracy was high for small N_p, where predominantly co-segregation contributed to accuracy, but also for large N_p, where LD_A replaced co-segregation as dominant information source. Together with increasing genetic variance, this compensation resulted in relatively constant long- and short-term genetic gain for increasing N_p larger than 4, given long-range LD_A in the ancestral population. Although our scenarios suggest that information from pedigree relationships contributed only for very few generations to accuracy in GS, we expect a longer contribution than in pedigree BLUP, because capturing Mendelian sampling by markers reduces selective pressure on pedigree relationships. Larger TS and higher marker density improved persistency of accuracy and hence genetic gain, but additional recombinations could not increase genetic gain.

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