References

Background SLE is a systemic autoimmune disorder with multiple organ manifestations. Despite of the innovations glucocorticoids (GC) have still remained the first-line therapy in SLE. Besides HSD11B enzymes, intracellular glucocorticoid receptors (GR) affect tissue-specific cortisol effect and the consequent signalisation pathway. SNPs of the glucocorticoid receptor gene (NR3C1) modulate individual sensitivity to glucocorticoids. Our aim was to determine the allele frequency of the three, clinically most important SNPs in a SLE patient population in comparison to healthy volunteers and to find association with particular manifestations of SLE. Methods We analysed results of 104 SLE patients compared to 160 healthy subjects. All patients were genotyped for the functional GR polymorphisms BclI, N363S, and A3669G. The GR gene polymorphisms were determined using allele-specific PCR and Taqman allelic discrimination assays. Results The BclI allele frequency was lower in the SLE group compared to the healthy control group. The central nervous system and especially psychiatric symptoms developed more frequently in the BclI carriers compared to none carriers. The prevalence of theA3669G polymorphism was the same in both groups, but showed a negative association with the psychiatric symptoms. Conclusion The increased and decreased sensitivity associated with GR BclI and A3669G polymorphisms could have a pathogenic significance in SLE especial with the central nervous system and psychiatric symptoms. Improving our knowledge on the importance of GR polymorphisms may reveal their pathophysiologic and therapeutic consequences.

Paget’s disease of bone (PDB) is characterized by focal or multifocal increase in bone turnover. One of the most well-established candidate genes for susceptibility to PDB is Sequestosome 1 (SQSTM1). Mutations in SQSTM1 have been documented among Western-European, British and American patients with PDB. However, there is no information on SQSTM1 mutation status in PDB patients from the Central- and Eastern-European regions. In this study, we conducted a mutation screening for SQSTM1 gene variants in 82 PDB patients and 100 control participants in Hungary. Mutations of SQSTM1 were detected in 18 PDB patients (21.95%); associations between genotype and clinical characteristics were also analyzed. Altogether, six different exonic alterations, including two types of UTR variants in the SQSTM1 gene, were observed in our PDB patients. Similarly, to previous genetic studies on Paget’s disease, our most commonly detected variant was the c.1175C > T (p.Pro392Leu) in nine cases (four in monostotic and five in polyostotic form). We have surveyed the germline SQSTM1 variant distribution among Hungarian patients with PDB. We also highlighted that the pattern of the analyzed disease-associated pathophysiological parameters could partially discriminate PDB patients with normal or mutant SQSTM1 genotype. However, our findings also underline and strengthen that not solely SQSTM1 stands in the background of the complex PDB etiology.

Gout is a common crystal induced disease of high personal and social burden, characterised by severe arthritis and comorbidity if untreated. Impaired function of ABCG2 transporter is causative in gout and may be responsible for renal-overload type hyperuricemia. Despite its importance, there is limited information on how clinical parameters correlate with protein expression and that with genetic changes. Urate and clinical parameters of 78 gouty patients and healthy controls were measured among standardised circumstances from a Hungarian population. ABCG2 membrane expression of red blood cells was determined by flow cytometry-based method and SNPs of this protein were analysed by TaqMan-based qPCR. The prevalence of ABCG2 functional polymorphisms in gouty and control patients were 32.1 and 13.7%, respectively. Most common SNP was Q141K while one sample with R236X, R383C and the lately described M71V were found in the gouty population. These polymorphisms showed strong linkage with decreased protein expression while the latter was also associated with higher fractional urate excretion (FUE) and urinary urate excretion (UUE). This study firstly evaluated ABCG2 protein expression in a clinically defined gouty population while also proving its associations between ABCG2 genetic changes and renal-overload hyperuricemia. The paper also highlighted relations between ABCG2 SNPs, gout susceptibility and disease severity characterised by an early onset disease with frequent flares and tophi formation.

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