Susceptibility Genetic Variants in Hungarian Morbus Crohn and Ulcerative Colitis Patients

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Cytotoxic T lymphocyte-Associated Antigen +49G Variant Confers Risk for Anti-CCP- and Rheumatoid Factor-Positive Type of Rheumatoid Arthritis Only in Combination with CT60∗G Allele

Controversial observations have been published on the association of the cytotoxic T lymphocyte associated antigen gene's variants with rheumatoid arthritis (RA). After genotyping 428 patients and 230 matched controls, the prevalence of the CT60∗G allele was more frequent in RF- and/or anti-CCP-seropositive RApatients, compared to the healthy controls (P < .001). Regression analysis revealed that the CT60∗G allele is a possible predisposing factor for RA in these subgroups. No accumulation of the +49∗G allele was found among patients, and this variant was not found to correlate with RA. Assaying the possible genotype variations, the +49∗G-CT60∗G allelic combination was accumulated in seropositive RA-subtypes, and was associated with the risk of RA (OR = 1.73, P = .001 for the whole RA-population). Although the +49∗G allele did not mean a predisposition to RA alone, in combination with CT60∗G it, also conferred risk, suggesting that the +49A/G variant is associated with the risk of RA only in certain haplotypes

Prevalence of SLC22A4, SLC22A% and CARD15 gene mutations in Hungarian pediatric patients with Crohn's disease

AIM: To investigate the frequency of the common NOD2/CARD15 susceptibility variants and two functional polymorphisms of OCTN cation transporter genes in Hungarian pediatric patients with Crohn’s disease (CD). METHODS: A cohort of 19 unrelated pediatric and 55 unrelated adult patients with Crohn’s disease and 49 healthy controls were studied. Genotyping of the three common CD-associated CARD15 variants (Arg702Trp, Gly908Arg and 1007finsC changes) with the SLC22A4 1672C→T, and SLC22A5 -207G→C mutations was performed by direct sequencing of the specific regions of these genes. RESULTS: At least one CARD15 mutation was present in 52.6% of the children and in 34.5% of the adults compared to 14.3% in controls. Surprisingly, strongly different mutation profile was detected in the pediatric versus adult patients. While the G908R and 1007finsC variants were 18.4% and 21.1% in the pediatric group, they were 1.82% and 11.8% in the adults, and were 1.02% and 3.06% in the controls, respectively. The R702W allele was increased approximately two-fold in the adult subjects, while in the pediatric group it was only approximately 64% of the controls (9.09% in the adults, 2.63% in pediatric patients, and 4.08% in the controls). No accumulation of the OCTN variants was observed in any patient group versus the controls. CONCLUSION: The frequency of the NOD2/CARD15 susceptibility variants in the Hungarian pediatric CD population is high and the profile differs from the adult CD patients, whereas the results for SLC22A4 and SLC22A5 mutation screening do not confirm the assumption that the carriage of these genotypes means an obligatory susceptibility to CD

No association of the cytotoxic T-lymphocyte associated gene CTLA4 +49A/G polymorphisms with Crohn’s disease and ulcerative colitis in Hungarian population samples

AIM: The goal of the current work was to analyse the prevalence of the +49A/G variant of the cytotoxic T-lymphocyte antigen 4 gene (CTLA4) in Hungarian patients with Crohnos disease (CD) and ulcerative colitis (UC). METHODS: A total of 130 unrelated subjects with CD and 150 with UC, and 170 matched controls were genotyped for the single nucleotide polymorphism (SNP). The genotypes were determined by using PCR/RFLP test. RESULTS: The G allele frequency and the prevalence of the GG genotype were 38.1% and 12.3% in the CD group, 40.6% and 18.6% in the UC patients, and 37.4% and 15.9% in the control group, respectively. CONCLUSION: The results of the current study show that carriage of the +49G SNP in heterozygous or in homozygous form does not confer risk either for CD or for UC in the Hungarian population

Az 5q31 IBD5-régióban található IGR és SLC22A4/SLC22A5 variánsok lehetséges szerepe a gyulladásos bélbetegség kialakulásában = Possible role of selected IGR and SLC22A4/SLC22A5 loci in development of inflammatory bowel diseases

Az idiopathiás krónikus gyulladásos bélbetegség kialakulásában környezeti tényezők, immunológiai és genetikai faktorok egyaránt szerepet játszanak. Az utóbbi években a CARD15 gén mellett egyre több adat támasztja alá más gének, többek között az 5q31-33 régióban elhelyezkedő IBD5 locus (MIM#606348) szerepét. Egyes tanulmányok ezen régióban az SLC22A4 gén C1672T szubsztitúciójának, illetve az SLC22A5 gén G-207C transzverziójának együttes szerepét hangsúlyozzák, különösen Crohn-betegség kialakulásában, míg más szerzők új minor hajlamosító tényezőket azonosítottak az IBD5 kromoszómarégióban, ezek az IGR-variánsok. Célkitűzés: Az SLC22A4 C1672T és SLC22A5 G-207C mutációk mellett az IGR2096a_1 (rs12521868) és az IGR2198a_1 (rs11739135) polimorfizmusok szerepének vizsgálata gyulladásos bélbetegség kialakulásában. Betegek és módszer: Vizsgálatunk során 440 gyulladásos bélbeteg (206 Crohn- és 234 colitis ulcerosás beteg), valamint 279 kontrollegyén perifériás vérmintájából PCR-RFLP technikával végeztünk DNS-analízist. Eredmények: Sem a C1672T, sem a G-207C allélek, sem a TC haplotípus nem bizonyult rizikófaktornak sem Crohn-betegség, sem colitis ulcerosa esetében. Ezzel ellentétben mindkét minor IGR allél frekvenciája: mind az IGR2096a_1 T (48,1%), mind az IGR2198a_1 C (46,1%) szignifikánsan magasabb volt Crohn-betegségben a kontrollokéhoz (38,5%, 38,4%) képest (p<0,05). Korra és nemre standardizált regressziós analízissel mindkét allélnél fokozott rizikót észleltünk Crohn-betegség vonatkozásában (T-allél: OR=1,694, 95%-os CI: 1,137–2,522, p=0,010, C-allél: OR=1,644, 95%-os CI=1,103–2,449, p=0,015). Colitis ulcerosa esetén nem találtunk összefüggést a két IGR-variáns és a betegség kialakulása között. Következtetés: az IGR minor alléleknek a környező kaukázusi népcsoportoktól eltérően magyarországi populációban szerepük lehet a Crohn-betegség kialakulásában. | The IBD5 locus (MIM#606348) on chromosome 5q31 has been demonstrated to confer increased risk for inflammatory bowel disease. Controversial reports have been published about the significance of individual loci located in this region. Here we investigated the possible genetic association of inflammatory bowel diseases with C1672T of SLC22A4 and G-207C SLC22A5 alleles, and with IGR2096a_1 (rs12521868) and IGR2198a_1 (rs11739135) susceptibility variants of the IBD5 region located on chromosome 5q31. Patients and methods: Total of 440 patients, 206 with Crohn’s disease, 234 with ulcerative colitis, and 279 controls were studied by PCR-RFLP methods. Results: Neither the C1672T, and G-207C alleles, nor the TC haplotype were found to confer risk for Crohn’s disease or ulcerative colitis. By contrast, both of the minor allele frequencies of IGR2096a_1 T (48.1%) and IGR2198a_1 C (46.1%) were increased in Crohn’s disease subjects as compared with the controls (38.5% and 38.4%, respectively; p<0.05). Using regression analysis adjusted to age and gender these alleles were found to confer risk for Crohn’s disease (OR=1.694, 95% CI: 1.137–2.522; p=0.010 for T allele, OR=1.644, 95% CI=1.103–2.449; p=0.015 for C allele of IGRs). In UC no such associations were found. Conclusions: Our results revealed the susceptibility nature of the examined IGR minor alleles in Hungarians, which nation differs historically from the surrounding Caucasian populations in origin of the founders of the state

Hajlamosító gének vizsgálata magyar morbus Crohn- és colitis ulcerosás betegpopulációban = Susceptibility genetic variants in Hungarian morbus Crohn and ulcerative colitis patients

Gyulladásos bélbetegségekre (Crohn-betegség, colitis ulcerosa) hajlamosító gének vizsgálatát végeztük magyar populációban, ezek a CARD15 gén R702W, G908R, 1007finsC variánsai, az SLC22A4 gén C1672T és az SLC22A5 G-207C variánsai, valamint az általuk meghatározott TC haplotípus, a CTLA4 gén A+49G eltérése és az IL23R gén rs10889677 C/A, rs2201841 T/C, rs1884444 G/T variánsai. Vizsgálataink során 201 felnőtt Crohn-beteg, 241 felnőtt colitis ulcerosás, valamint 19 gyermek Crohn-beteget analizáltunk. Kontrollnak 235 felnőttől és 49 gyermektől vettünk vért. A genotipizálás során PCR/RFLP módszert és direkt szekvenálást alkalmaztunk. Eredményeink alapján kijelenthetjük, hogy a CARD15 gén mutációi közül felnőttekben az 1007finsC, míg gyermekekben az 1007finsC és a G908R variáns is hajlamosít Crohn-betegség kialakulására. Az SLC22A4 és SLC22A5 gének által meghatározott TC haplotípus esetén nem találtunk szignifikáns különbséget a betegcsoportok kontrollokkal való összevetése során. A CTLA4 gén A+49G variánsa nem bizonyult hajlamosító tényezőnek gyulladásos bélbetegségekre. Az IL23R gén esetén az rs10889677 C/A és az rs2201841 T/C jelent kockázati tényezőt Crohn-betegség kialakulására. Megállapíthatjuk, hogy különböző populációktól függ, hogy az adott genetikai variánsok hajlamosítanak-e az adott populációban a gyulladásos bélbetegségek valamelyikének kialakulására. | We examined several susceptibility genetic variants to inflammatory bowel disease (Crohn’s disease, ulcerative colitis) in Hungarian population, such as the CARD15 R702W, G908R, 1007finsC genetic variants, the SLC22A4 C1672T and SLC22A5 G-207C variants and their determined TC haplotype, the CTLA4 gene A+49G genetic variant and the rs10889677 C/A, rs2201841 T/C, rs1884444 G/T variants of the IL23R gene. We examined 201 adult patients with Crohn’s disease, 241 adult patients with ulcerative colitis and 19 pediatric patients with Crohn’s disease. For control 235 adult and 49 pediatric subjects were used. The genotyping was carried out using PCR/RFLP methods and direct sequencing. From the CARD15 gene mutations in the adult Crohn’s disease population the 1007finsC, while in the pediatric population the 1007finsC and the G908R were significantly associated with an increased risk for Crohn’s disease. We found no significant differences comparing the results of the patients and the controls by the SLC22A4, SLC22A5 genetic variants and the TC haplotype. The A+49G variant of the CTLA4 gene was not an independent determinant to inflammatory bowel disease. We found that the IL23R gene variants, rs10889677 C/A and rs2201841 T/C appear to increase susceptibility to Crohn’s disease. It depends on the different populations whether this genetic variant means an obligatory risk factor to inflammatory bowel disease

Autologous Transplantation May Still Effectively Treat Relapsed Diffuse Large B-Cell Lymphoma in Selected Patients

Treating relapsed and refractory diffuse large B-cell lymphoma is still challenging for clinicians, but the available CAR-T and bispecific antibodies have revolutionized therapy. Autologous stem cell transplantation was the most effective treatment modality previously. The authors reported data from a single center over ten years. The retrospective study included 116 patients, with 53 relapsed cases, 39 primary refractory cases, 19 who had CNS involvement, and 5 who had received primary consolidation transplants. The median duration of follow-up was 46 months. The median event-free survival was 75 months, and the median overall survival was 105 months for all cases. Five-year overall survival was 59%, and event-free survival was 54%. Pretreatment prognostic factors at diagnosis had no effect on the outcome of transplantation. The authors found no difference between survival in relapsed or refractory cases, and the number of salvage lines or the germinal center/activated B-cell type also did not influence the results. Complete metabolic response before transplantation confirmed by 18FDG PET/CT strongly affected survival. The pre-transplant creatinine and CRP levels significantly influenced the long-term outcome. The number of stem cells infused did not affect survival, but engraftment within nine days did result in a longer survival. These data support the finding that the response to salvage therapy did facilitate the identification of a better prognostic group who may still benefit from autologous transplantation