Enikő Sáfrány

Variants of the IL23R Gene are Associated with Ankylosing Spondylitis but not with Sjögren Syndrome in Hungarian Population Samples

Recently, associations were found between several autoimmune diseases and functional variants of interleukin‐23 receptor (IL23R) gene; here, we studied the possible association of nine polymorphisms of IL23R with ankylosing spondylitis (AS) and with Sjögren syndrome (SS). In our study, we genotyped groups of patients with AS (n = 206), SS (n = 156) and healthy controls (n = 235) for rs11805303, rs10889677, rs1004819, rs2201841, rs11209032, rs11209026, rs10489629, rs7517847 and rs7530511 variants using PCR‐RFLP methods. We observed significant increase in the carriage of the T allele of rs11805303 and the A allele of rs1004189 in the AS group compared with the controls. For the rs10889677 variant, the prevalence of the AA genotype and for the rs2201841, the CC genotype showed a more than two‐fold increase in the AS group compared with the controls. By contrast, the GA heterozygous genotype of rs11209026 variant showed a significant decrease in AS patients compared with controls. Haplotype analysis revealed association of four IL23R haplotypes with AS. There was no difference in the distribution of any of the examined IL23R variants between controls and SS patients. In conclusion, we confirmed the susceptibility or protective associations of IL23R polymorphisms with AS in a Hungarian population and first demonstrated the involvement of the rs11805303 intronic single nucleotide polymorphisms, which was tested so far only for other autoimmune diseases.

Apolipoprotein A5 T-1131C Variant Confers Risk for Metabolic Syndrome

The −1131C is a naturally occurring variant of the apolipoprotein A5 (ApoA5) gene, which has been shown to associate with increased triglyceride levels. This variant has also been shown to confer risk for development of ischemic heart disease and stroke. The gene is in linkage disequilibrium with factors known to correlate with impaired glucose homeostasis. These observations prompted us to study the prevalence of the ApoA5 –1131C allele in patients with metabolic syndrome. A total of 201 metabolic syndrome patients and 210 controls were studied. In both groups the triglyceride levels of patients with −1131C allele were significantly increased compared to the subjects with −1131T allele (3.22 ±0.43 mmol/1 vs. 2.24 ±0.12 mmol/1, p<0.01 in the metabolic syndrome patients; 2.10 ±0.19 mmol/1 vs. 1.22 ±0.05 mmol/1, p<0.01 in the controls). In metabolic syndrome patients the prevalence of the ApoA5 –1131C variant was increased compared to the healthy controls (11% vs. 6.20%). Multiplex regression analysis model adjusted for age, gender, serum total cholesterol levels, acute myocardial infarction and stroke events revealed that the examined ApoA5 variant confers risk for the development of metabolic syndrome: the odds ratio at 95% confidence interval was 3.622 (1.200–10.936), p=0.02. Our findings strongly suggest that this variant is a risk factor for the development of hypertriglyceridemia and metabolic syndrome.

Functional Variants of Glucokinase Regulatory Protein and Apolipoprotein A5 Genes in Ischemic Stroke

Both the natural variants of the apolipoprotein A5 (APOA5) and the glucokinase regulatory protein gene (GCKR) have been shown to associate with increased fasting triglyceride levels. Here, we investigated the possible association of the functional variants of these two genes with non-fasting triglyceride levels and their susceptibility nature in ischemic stroke. A total of 513 stroke patients and 172 healthy controls were genotyped. All the APOA5 variants (T-1131C, IVS3 + G476A, C56G, and T1259C) were associated with increased triglyceride levels in all stroke patients and controls; except for T1259C, they all conferred risk for the disease. No such association was found for the examined GCKR rs1260326 (C1337T) variant. Furthermore, we examined the effects of specific combinations of the GCKR rs1260326 and APOA5 polymorphisms. Our findings confirmed the previous results regarding the association of APOA5 variants with triglyceride-level increase and stroke susceptibility of these alleles. By contrast, we could not detect any association of the studied GCKR allele with triglyceride levels or with the susceptibility of stroke in the same cohort of patients. In addition, the effect of APOA5 did not change significantly when specific combinations of the two genes were present.

GCKR gene functional variants in type 2 diabetes and metabolic syndrome: do the rare variants associate with increased carotid intima-media thickness?

BackgroundRecent studies revealed that glucokinase regulatory protein (GCKR) variants (rs780094 and rs1260326) are associated with serum triglycerides and plasma glucose levels. Here we analyzed primarily the association of these two variants with the lipid profile and plasma glucose levels in Hungarian subjects with type 2 diabetes mellitus and metabolic syndrome; and also correlated the genotypes with the carotid intima-media thickness records.MethodsA total of 321 type 2 diabetic patients, 455 metabolic syndrome patients, and 172 healthy controls were genotyped by PCR-RFLP.ResultsBoth GCKR variants were found to associate with serum triglycerides and with fasting plasma glucose. However, significant association with the development of type 2 diabetes mellitus and metabolic syndrome could not be observed. Analyzing the records of the patients, a positive association of prevalence the GCKR homozygous functional variants and carotid intima-media thickness was found in the metabolic syndrome patients.ConclusionsOur results support that rs780094 and rs1260326 functional variants of the GCKR gene are inversely associated with serum triglycerides and fasting plasma glucose levels, as it was already reported for diabetic and metabolic syndrome patients in some other populations. Besides this positive replication, as a novel feature, our preliminary findings also suggest a cardiovascular risk role of the GCKR minor allele carriage based on the carotid intima-media thickness association.

Triglyceride level modifying functional variants of GALTN2 and MLXIPL in patients with ischaemic stroke

Background:  Recent genome‐wide studies identified several genetic variants associated with blood lipid level alterations. Because affected lipid metabolism can confer risk to the development of ischaemic stroke, we studied three polymorphisms reportedly associated with triglyceride‐level changes, rs17145738 and rs3812316 of the MLXIPL locus, and rs4846914 variant of GALNT2 gene in biobanked samples of patients with stroke. This pool of samples was previously investigated for haplotype tagging minor alleles of apolipoprotein A5 gene (T‐1131C, T1259C, IVS3+G476A and C56G), and an association was found between the minor allele carriage and the triglyceride levels, and also these variants were found to confer risk to the development of stroke.

IGR2096a_1 T and IGR2198a_1 C alleles on IBD5 locus of chromosome 5q31 region confer risk for Crohn's disease in Hungarian patients.

Background and aimsWe investigated the possible association of IBD with C1672T of SLC22A4 and G-207C of SLC22A5 alleles, and with the novel IGR2096a_1 (rs12521868) and IGR2198a_1 (rs11739135) susceptibility loci, all located on IBD5 locus of chromosome 5q31.Materials and methodsDNA of 217 Crohn’s disease, 252 ulcerative colitis, and 290 control patients were analyzed by polymerase chain reaction/restriction fragment length polymorphism methods.ResultsNeither the C1672T and G-207C alleles, nor the TC haplotype were found to be risk factors. By contrast, the minor allele frequencies of IGR2096a_1 T (47.2%) and IGR2198a_1 C (45.9%) were increased in Crohn’s disease compared with the controls (38.2% and 37.7%, respectively; p < 0.05); multivariate regression analysis revealed a risk nature for Crohn’s disease (OR = 1.748, 95% CI 1.186–2.574; p = 0.007 for T allele, OR = 1.646, 95% CI 1.119–2.423, p = 0.011 for C allele of IGRs).ConclusionThe data suggest a special haplotype arrangement of susceptibility genes at the IBD5 locus in Hungarians, which nation differs historically from the surrounding Caucasian ethnicities in its origin.

Prevalence of SLC22A4 1672T and SLC22A5 −207C combination defined TC haplotype in Hungarian ulcerative colitis patients

Ulcerative colitis (UC) is a chronic inflammatory disease of the gastrointestinal tract. The aim of this study was to verify the prevalence rate of the haplotype called TC, determined by combination of two functional alleles of OCTN cation transporter genes (SLC22A4 1672T and SLC22A5 /t-207C combination variants) in ulcerative colitis patients and unrelated healthy controls. The “TC haplotype” has recently been suggested to confer risk for UC. A total of 121 unrelated Hungarian subjects with UC and 110 matched controls were genotyped for the two single nucleotide polymorphisms. The genotypes were determined by using PCR/RFLP assay and direct sequencing. The SLC22A4 1672T allele frequency was 46.7% in the patients with UC and 46.4% in the controls, whereas the SLC22A5 −207C allele occurred in 48.8% of the patients and 51.4% of the controls. The prevalence of the TC haplotype was 19% in the patient group and 22.7% in controls. Since there was no accumulation of the TC haplotype in the patient group, our observation suggests that carrying the TC haplotype is not associated with a higher risk for UC in the Hungarian population.

[Pseudo-Bartter syndrome in a case of cystic fibrosis caused by C1529G and G3978A compound heterozygosity].

The 8-month-old patient was hospitalized after a few days of apathy and feeding difficulty with moderate exsiccation. Severe hypokalemia, hyponatremia, hypochloremia associated with alkalosis were found, which were accompanied by the decreased urinary electrolytes and elevated serum renin and aldosterone, therefore the condition corresponded to a pseudo-Bartter syndrome. The diagnosis of cystic fibrosis was arisen, which was established by the elevated sweat chloride levels. Sequencing of the 27 exons of the cystic transmembrane regulator gene two rare mutations were detected in compound heterozygous form: in the exon 10 a C1529G transversion, whereas in the exon 20 a G3978A transition was verified, both of them result in development of premature stopcodons (S466X and W1282X, respectively). Carriage of first mutation could be found in the asymptomatic mother, while the other one was identified in the father. In the proband and in the mother a G3341A mutation was also detected in exon 17, which causes an R1070Q amino acid change. However, this likely cannot associate with pathology since the existing premature stopcodon on the same allele does not allow synthesis of protein. These mutations have been described in combination with delta F508 mutation, however, their simultaneous presence in the same subject has not been reported. During the one and half year follow-up the clinical picture appeared benign.

Interaction between CTLA4 gene and IBD5 locus in Hungarian Crohn’s disease patients

Backgrounds and aimsThe IGR2198a_1 and IGR2096a_1 variants of the IBD5 region were found to be associated with Crohn’s disease (CD) in the Hungarian population, while IGR2230a_1 does not seem to confer risk for the disease. In the present study, our aim was to investigate the statistical interaction of these three IBD5 polymorphisms with the +49 A/G substitution within the cytotoxic T lymphocyte antigen-4 (CTLA4) gene, detected previously as neutral gene variant in Hungarian IBD patients.MethodsA total of 305 unrelated subjects with CD and 310 healthy controls were genotyped with PCR-RFLP methods.ResultsIn contrast with single gene effects, after genotype stratification, the IGR2198a_1 C and IGR2096a_1 T variants were found to confer susceptibility only in subjects with CTLA4 +49 AA genotype (P = 0.008; OR = 1.86 and P = 0.016; OR = 1.74, respectively), for IGR2230a_1 no such effect on disease risk could be demonstrated.ConclusionAnalysis of specific genotype combinations unfolded a possible association between the CTLA4 +49 A/G substitution and two of the observed IBD5 variants with respect to disease risk.

[Possible role of selected IGR and SLC22A4/SLC22A5 loci in development of inflammatory bowel diseases].

Az idiopathias kronikus gyulladasos belbetegseg kialakulasaban kornyezeti tenyezők, immunologiai es genetikai faktorok egyarant szerepet jatszanak. Az utobbi evekben a CARD15 gen mellett egyre tobb adat tamasztja ala mas genek, tobbek kozott az 5q31-33 regioban elhelyezkedő IBD5 locus (MIM#606348) szerepet. Egyes tanulmanyok ezen regioban az SLC22A4 gen C1672T szubsz-tituciojanak, illetve az SLC22A5 gen G-207C transzverziojanak egyuttes szerepet hangsulyozzak, kulonosen Crohn-betegseg kiala-kulasaban, mig mas szerzők uj minor hajlamosito tenyezőket azonositottak az IBD5 kromoszomaregioban, ezek az IGR-variansok.UNLABELLED 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 Crohns 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 Crohns 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 Crohns 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 Crohns 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.