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Introduction: Cleft lip with or without cleft palate (CL/P) is congenital deformity associated with hyperdontia. Objective: To determine the prevalence and characteristics of supernumerary teeth in patients with CL/P. Design: Retrospective descriptive and correlation clinical study. Patients: One hundred thirteen children with cleft (age ranged 9.3-19.2; 67 males and 46 females) treated in Clinic of Congenital Facial Deformities Medical University of Lublin were included in the study. Methods: Records evaluation was conducted regarding age, gender, cleft type (Q36, Q37— International Classification of Diseases 10th revision), cleft side, and incidence of supernumeraries. In all supernumerary teeth, size, shape, and developmental degree were analyzed and correlation between the incidence of hyperdontia with different variables was checked. Correlations were detected using chi-square and the Yates correction. Results: The majority of the examined group were males—59.29% with Q37 (67.26%) and the cleft on the left side (62.83%). Hyperdontia was noted in 26.55%. Only upper lateral incisors were affected. They usually had atypical shape (56.67%), reduced size (83.33%), and delayed development (56.67%). Conclusions: The prevalence of supernumerary permanent teeth in patients with cleft was higher than in the general population. Anomaly was more frequent in male patients and occurred mainly on the cleft side. The severity of the cleft did not influenced the frequency of supernumerary teeth, their shape, size, and developmental degree. Supernumerary teeth were characterized by reduced crown size, abnormal structure, incorrect inclination, and delayed development phase.

Paraoxonase 1 (PON1) is known for preventing atherosclerosis through lipid-modifying features, antioxidant activity, anti-inflammatory, anti-apoptosis, anti-thrombosis, and anti-adhesion properties. Uremic patients requiring haemodialysis (HD) are especially prone to atherosclerosis and its complications. We analysed the PON1 gene (PON1) polymorphisms and serum PON1 (paraoxonase) activity concerning dyslipidaemia and related cardiovascular diseases and mortality to show how they associate under uremic conditions modified by maintenance HD treatment. The rs662 AA + AG (OR 1.76, 95%CI 1.10–2.80, P = 0.018), rs854560 TT (OR 1.48, 95%CI 1.04–2.11, P = 0.031), and rs854560 AT + TT (OR 1.28, 95%CI 1.01–1.63, P = 0.040) contributed to the prevalence of atherogenic dyslipidaemia diagnosed by the triglyceride (TG)/HDL-cholesterol ratio ≥ 3.8. The normalized serum PON1 activity positively correlated with atherogenic dyslipidaemia (ẞ 0.67 ± 0.25, P = 0.008). The PON1 rs854560 allele T was involved in the higher prevalence of ischemic cerebral stroke (OR 1.38, 1.02–1.85, P = 0.034). The PON1 rs705379 TT genotype contributed to cardiovascular (HR 1.27, 95% CI 1.03–1.57, P = 0.025) and cardiac (HR 1.34, 95% CI 1.05–1.71, P = 0.018) mortality. All P-values were obtained in multiple regression analyses, including clinical variables. Multifaceted associations of PON1 with dyslipidaemia, ischemic cerebral stroke, and cardiovascular mortality in HD patients provide arguments for the consideration of PON1 and its protein product as therapeutic targets in the prevention of atherosclerosis and its complications in uremic patients.

Background: The rs368234815 polymorphism of interferon-λ4 (IFN-λ4) gene (IFNL4) is involved in HBV surface antigen (HBsAg) clearance in non-uremic subjects. The rs368234815 ΔG/ΔG genotype can expre...

Background There is scarce data on CASR associations with dyslipidemia. We investigated in hemodialysis (HD) patients whether CASR single nucleotide polymorphisms (SNPs) rs7652589 and rs1801725 have associations with dyslipidemia and show epistatic interactions with SNPs of the energy homeostasis-associated gene (ENHO), retinoid X receptor α gene (RXRA), and liver X receptor α gene (LXRA). Methods The study included 1208 HD subjects. For diagnosis of dyslipidemia, both K/DOQI criteria and atherogenic index ≥3.8 were used. CASR rs1801725 was genotyped by TaqMan SNP Genotyping Assay, other SNPs – by high-resolution melting curve analysis or polymerase chain reaction-restriction fragment length polymorphism, as appropriate. Relative transcript levels of CASR, ENHO, RXRA, and LXRA were measured in peripheral blood mononuclear cells. The occurrence of dyslipidemic phenotypes concerning tested polymorphisms was compared using models of inheritance. Haplotypes were estimated using the Haploview 4.2 software. Epistatic interactions between tested SNPs were analyzed using the logistic regression and epistasis option in the PLINK software. Results Rs7652589 indicated a greater probability of atherogenic dyslipidemia in the dominant inheritance model (OR 1.4, 95%CI 1.0–2.0, P = 0.026), principally because of increased triglyceride (TG) levels. The rs1801725 variant allele was associated with a decreased probability of dyslipidemia characterized by non-HDL-cholesterol ≥130 mg/dL and TG ≥200 mg/dL (OR 0.6, 0.4–0.9, P = 0.012). There were no epistatic interactions between CASR and RXRA, LXRA, and ENHO regarding dyslipidemia. Both rs7652589 and rs1801725 SNPs were not in linkage disequilibrium (D’ = 0.091, r2 = 0.003 for the entire HD group) and their haplotypes did not correlate with dyslipidemia. Relative CASR transcript was lower at a borderline significance level in patients harboring the rs1801725 variant allele compared with homozygotes of the major allele (0.20, 0.06–7.80 vs. 0.43, 0.04–5.06, P = 0.058). CASR transcript correlated positively with RXRA transcript (adjusted P = 0.001), LXRA transcript (adjusted P = 0.0009), ENHO transcript (borderline significance, adjusted P = 0.055), dry body weight (adjusted P = 0.035), and renal replacement therapy duration (adjusted P = 0.013). Conclusions CASR polymorphisms (rs7652589, rs1801725) are associated with dyslipidemia in HD patients. CASR correlates with RXRA, LXRA, and ENHO at the transcript level. Further investigations may elucidate whether other CASR SNPs contribute to associations shown in this study.

BackgroundIn non-uremic subjects,IFNL4rs368234815 predicts HCV clearance. We investigated whether rs368234815 is associated with spontaneous HCV clearance in haemodialysis patients and whether it is a stronger predictor of HCV resolution than theIFNLpolymorphisms already associated with HCV clearance in dialysis subjects. We also evaluated an association of rs368234815 with patients` survival and alterations in transcription factor binding sites (TFBS) caused byIFNLpolymorphisms.MethodsAmong 161 haemodialysis patients with positive anti-HCV antibodies, 68 (42.2%) spontaneously resolved HCV infection, whereas 93 remained HCV RNA positive. Patients were tested for nearIFNL3rs12980275,IFNL3rs4803217,IFNL4rs12979860,IFNL4rs368234815, and nearIFNL4rs8099917.IFNL4rs368234815 polymorphism (TT/TT, ΔG/TT, ΔG/ΔG) was genotyped by restriction fragment length polymorphism analysis; otherIFNLpolymorphisms - by high resolution melting curve analysis. We used the Kaplan-Meier method with the log-rank test for survival analysis. In silico analysis included the use of ENCODE TFBS ChIP-seq data, HOCOMOCO, JASPAR CORE, and CIS-BP databases, and FIMO software.ResultsThe probability (OR, 95%CI, P) of spontaneous HCV clearance for rs368234815 TT/TT patients was higher than for the ΔG allele carriers (2.63, 1.38–5.04, 0.003). This probability for other major homozygotes varied between 2.80, 1.45–5.43, 0.002 for rs12980275 and 2.44, 1.27–4.69, 0.007 for rs12979860. In the additive model, rs368234815 TT/TT was the strongest predictor of HCV clearance (6.38, 1.69–24.2, 0.003). Survival analysis suggested an association of the ΔG allele with mortality due to neoplasms (log-rankP = 0.005). The rs368234815 ∆G allele caused TFBS removal for PLAGL1.ConclusionsIn haemodialysis patients, the association of rs368234815 with the spontaneous HCV clearance is better than that documented for otherIFNL3/IFNL4polymorphisms only in the additive mode of inheritance. However, identifying the homozygosity in the variant ∆G allele of rs368234815 means a more potent prediction of persistent HCV infection in haemodialysis subjects that we observe in the case of the variant homozygosity of other testedIFNL3/IFNL4polymorphisms. Removal of PLAGL1 TFBS in subjects harbouring the rs368234815 ∆G allele may contribute to cancer susceptibility. The association of rs368234815 with cancer-related mortality needs further studies in HCV-exposed subjects.

Background Indoleamine 2,3-dioxygenase (IDO) contributes to maintaining immune homeostasis. Polymorphisms (SNPs) of the IDO encoding gene ( IDO1 ) influence the IDO activity. Interferon (IFN)-λ3 induces IDO expression. We aimed to investigate whether IDO1 variants are associated with anti-HBs production in response to HBV vaccination or infection, interact with IFN-λ3 associated variants of IFNL4 , and influence survival of hemodialysis (HD) patients. We also tested circulating IDO concerning IDO1 SNPs and plasma IFN-λ3 and anti-HBs levels. Methods The study included HD patients who had established status concerning responsiveness to HBV vaccination (n = 1022) or were exposed to HBV (n = 315). Ability to generate anti-HBs was diagnosed if anti-HBs after vaccination or infection exceeded 10 IU/L. Genotyping of IDO1 (rs3739319 A IFNL4 rs8099917 G IFNL4 rs12979860 C > T polymorphisms was carried out by high-resolution melting curve analysis. Circulating IDO and IFN-λ3 were measured with ELISA in 57 subjects. Survival probability was analyzed using the Kaplan-Meier method. Results IDO1 SNPs did not correlate with the ability to produce anti-HBs after vaccination or infection. Anti-HBs titers, including a frequency of anti-HBs ≥ 1000 IU/l, also did not associate with IDO1 SNPs, but there was an epistatic interaction between rs9657182, rs8099917, and rs12979860 concerning anti-HBs titers (P = 0.028). Significant associations between IDO1 SNPs and circulating IDO were not demonstrated. Anti-HBs titers negatively correlated with plasma IDO (r = −0.358, P = 0.006), and positively with circulating IFN-λ3 (r = 0.498, P = 0.00008). IDO and IFN-λ3 did not correlate. Patients possessing the rs9657182 TT genotype showed higher infection-related mortality, also in multivariate analysis (HR 2.073, 1.221–3.518, P = 0.007). Conclusions IDO1 rs9657182, IFNL4 rs8099917, and IFNL4 rs12979860 show epistatic interaction concerning anti-HBs titers. Overreacting immune responses to HBsAg occur in patients with lower IDO but simultaneously higher IFN-λ3 levels. The rs9657182 TT genotype associates with infection-related mortality of HD patients.

Objectives: Genome-wide association studies in patients with endometriosis revealed ten significant single nucleo­tide polymorphisms (SNPs) in the Caucasian population, which include rs12700667 near NFE2L3 , rs12037376 in WNT4 , rs7521902 near WNT4 , rs13394619 in GREB1 , rs10859871 near VEZT , rs1537377 near CDKN2B-AS1 , rs4141819 near ETAA1 , rs7739264 near ID4 , rs1519761 near RND3 and rs6542095 near IL1A . Material and methods: We replicated ten polymorphisms among infertile women with endometriosis (n = 315) and healthy fertile women (n = 406) in the Polish Caucasian population. Genotyping was conducted either by high-resolution melting curve analysis or by a pre-designed TaqMan probe. Results: For all infertile women with endometriosis, the p values of the Cochran-Armitage trend test for the rs12700667 SNP was ptrend = 0.038 and the odds ratio (OR) for the risk allele frequency (RAF) of rs12700667 was 1.304 (95% CI = 1.009–1.685; p = 0.042). In patients with endometriosis with severity stages III/IV, ptrend for rs12700667 SNP was 0.036 and OR for the RAF was 1.394 (95% CI = 1.010–1.923; p = 0.043). In infertile women with endometriosis with severity stages III/IV for rs4141819 SNP, we observed ptrend = 0.026 and for RAF the OR = 1.350 (95% CI = 1.032–1.766; p = 0.029). Conclusions: Our results demonstrate association of RAF of rs12700667 and rs4141819 SNPs with infertility in Polish women with advanced endometriosis.

Background/Aims: The calcium-sensing receptor gene (CASR) rs1801725 variant is responsible for a non-conservative amino-acid change (A986S) in the calcium-sensing receptor cytoplasmic tail. We hypothesized that rs1801725 polymorphism might be helpful in understanding Ca-related abnormalities in HD patients. Methods: In 1215 subjects (245 on cinacalcet), we determined the associations of rs1801725 with secondary hyperparathyroidism (sHPT)-related laboratory parameters, PTH-decreasing effect of cinacalcet hydrochloride, coronary artery disease (CAD), myocardial infarction (MI), nephrolithiasis-related ESRD, and mortality. CASR rs7652589(AT) haplotypes and rs1801725 epistatic interactions with vitamin D signaling pathway genes were examined for associations with selected phenotypes. Results: The rs1801725 variant allele showed an increasing independent effect on plasma PTH (Pcorrected = 0.009). CASR rs7652589_rs1801725 AT haplotype was associated with 1.7-fold higher frequency of PTH levels over 437 pg/mL than the reference haplotype GG (P = 0.001). CASR rs7652589_rs1801725 AG haplotype was 1.5-fold more frequent in nephrolithiasis-related ESRD than the GG haplotype (P = 0.004). There were no significant associations between rs1801725, CAD, MI, and response to cinacalcet. Variant homozygosity of rs1801725 correlated independently with higher infection-related mortality compared with heterozygosity (HR 7.95, 95%CI 2.15 – 29.37, P = 0.003) and major homozygosity (HR 5.89, 95%CI 1.69 – 20.55, P = 0.040). CASR rs1801725 did not show epistatic interactions with vitamin D signaling pathway genes concerning tested associations. Conclusion: The variant allele of CASR rs1801725 solely and together with the variant allele of rs7652589 increases risk of more advanced sHPT. Homozygosity of the rs1801725 variant allele contributes to infection-related mortality in HD patients.

Objective The etiology of tooth agenesis is multifactorial and still not fully understood. The aim of the study was to test whether variants of GREM2, encoding a BMP antagonist, are associated with the risk of this common dental anomaly in a Polish population. Subjects and Methods Direct sequencing of the GREM2 coding sequence including exon/intron boundaries was performed in 95 patients with both hypodontia and oligodontia. All identified GREM2 variants were then further tested in an independent group of patients (n=163) and controls (n=184). Results The previously described, functional GREM2 mutation (c.226C>G, p.Gln76Glu) was identified in two patients with hypodontia and associated dental anomalies, including taurodontism and microdontia. This mutation generating an allele with increased inhibitory activity was not detected in the control group. The second identified GREM2 variant, c.-1-21C>T (rs11806449), was not associated with the risk tooth agenesis. The polymorphism allele frequency in both patients and controls was 0.21 (OR=1.0, 95%CI: 0.76–1.46). The rs11806449 did not correlate either with the overall TA phenotype or hypodontia/oligodontia phenotypes. Conclusion Our study confirmed that GREM2 is a candidate gene for tooth agenesis, which mutations can explain, however, only a small fraction of the genetic contribution to the pathogenesis of this anomaly. This article is protected by copyright. All rights reserved.

Purpose Endometriosis is considered to be an estrogen-related chronic inflammatory disease. The 17β-hydroxysteroid dehydrogenase 1 (HSD17B1) converts estrone to 17β estradiol. The role of HSD17B1 937 A>G (rs605059) single nucleotide polymorphism (SNP) in development of endometriosis is still disputable. This study evaluated the association of the HSD17B1 937 A>G (rs605059) SNP with infertile women affected by endometriosis from Polish Caucasian population. Methods The genotyping of cases (n = 290) and fertile women (n = 410) was conducted by high-resolution melting curve analysis. Results Statistical analysis demonstrated that the HSD17B1 937 A>G SNP is associated with endometriosis in stages I and II. The p trend and p allelic values calculated for the HSD17B1 937 A>G polymorphism were statistically significant and were equal to 0.001 and 0.0009, respectively. There was a significant association for the dominant model: (AG + GG vs AA) OR = 1.973 (95% CI = 1.178–3.304), p = 0.009, and for the recessive model: (GG vs AG + AA) OR = 1.806 (95% CI = 1.178–2.770), p = 0.006. However, we did not find statistical association of HSD17B1 937 A>G polymorphism with all infertile women with endometriosis or infertile women with endometriosis in stages III and IV. Conclusion Our genetic study demonstrated HSD17B1 937 G variant as a risk factor for infertility in women with stage I and II endometriosis in Polish Caucasian patients. Electronic supplementary material The online version of this article (doi:10.1007/s10815-017-0911-9) contains supplementary material, which is available to authorized users.

Background The energy homeostasis-associated gene (ENHO), retinoid X receptor alpha gene (RXRA), and liver X receptor alpha gene (LXRA) are involved in adipogenic/lipogenic regulation. We investigated whether single-nucleotide polymorphisms in these genes (ENHO rs2281997, rs72735260; RXRA rs749759, rs10776909, rs10881578; LXRA rs2279238, rs7120118, rs11039155) are associated with dyslipidaemia, related comorbidities and survival of haemodialysis (HD) patients also tested for T-helper (Th) cell interleukin genes (IL). Methods The study was carried out in 873 HD patients. Dyslipidaemia was diagnosed by the recommendations of the Kidney Disease Outcomes Quality Initiative (K/DOQI) guidelines (2003); atherogenic dyslipidaemia was referred to if the TG/HDL cholesterol ratio was equal to or higher than 3.8. Genotyping of ENHO SNPs, LXRA SNPs, and IL12A rs568408 was carried out using HRM analysis. RXRA SNPs, IL12B rs3212227, and IL18 rs360719 were genotyped using PCR-RFLP analysis. The circulating adropin concentration was determined in 126 patients by enzyme-linked immunosorbent assay. Survival probability was analysed using the Kaplan-Meier method in 440 patients followed through 7.5 years. Results Dyslipidaemia by K/DOQI was diagnosed in 459 patients (91% revealed hyper-LDL- cholesterolaemia), atherogenic dyslipidaemia was diagnosed in 454 patients, and 231 patients were free of dyslipidaemia by both criteria. The variant allele (T) of ENHO rs2281997 was associated with the hyper-LDL cholesterolaemic pattern of dyslipidaemia by K/DOQI. The frequency of atherogenic dyslipidaemia was lower in T-allele bearers than in CC-genotype patients. The rs2281997 T allele was associated with lower cardiovascular mortality in HD patients showing atherogenic dyslipidaemia. ENHO, RXRA, and LXRA showed epistatic interactions in dyslipidaemia. Circulating adropin was lower in atherogenic dyslipidaemia than in non-atherogenic conditions. RXRA rs10776909 was associated with myocardial infarction. Bearers of LXRA rs2279238, rs7120118 or rs11039155 minor alleles showed higher mortality. ENHO SNP positions fell within the same DNase 1 hypersensitivity site expressed in the Th1 cell line. Epistatic interactions occurred between rs2281997 and Th1 IL SNPs (rs360719, rs568408). Conclusions Atherogenic dyslipidaemia occurs in HD patients in whom ENHO encodes less adropin. ENHO, RXRA, and LXRA SNPs, separately or jointly, are associated with dyslipidaemia, myocardial infarction, and survival in HD patients. Differences in the availability of transcription binding sites may contribute to these associations. Electronic supplementary material The online version of this article (10.1186/s12881-018-0708-4) contains supplementary material, which is available to authorized users.

INTRODUCTION The higher prevalence and risk of hepatitis B virus (HBV) or hepatitis C virus (HCV) infections are still observed in hemodialysis (HD) patients compared with healthy people. Interferons (IFNs) are known for their involvement in immune response. The addition of IFN-λ3 to immunization in animal models was shown to increase the immune response of T helper-1 cells. OBJECTIVES We studied whether polymorphisms of the IFN-λ3 gene (IFNL3) might be associated with the development of antibodies to HBV surface antigen [anti-HBs] in response to the HBV vaccination or HBV infection as well as spontaneous resolution of HCV infection in HD patients. PATIENTS AND METHODS The HD group consisted of 806 individuals without a history of HBV or HCV infection (of whom 672 developed anti-HBs in response to the HBV vaccination), 241 HBV-infected patients (of whom 186 developed anti-HBs), and 63 HCV-infected patients (including 39 HCV RNA-positive subjects). All patients were genotyped for IFNL3 rs8099917 and rs12979860 polymorphisms using a high-resolution melting curve analysis. RESULTS The comparison of responders and nonresponders to HBV vaccination revealed no significant differences in the IFNL3 genotype distribution. In HBV-infected patients, the differences in the distribution of IFNL3 variants between anti-HBs-negative and anti-HBs-positive patients were also nonsignificant. Spontaneous HCV clearance was significantly less common in the carriers of the rs8099917 allele G or rs12979860 allele T, while the CT rs12979860_rs8099917 haplotype was more frequent (P = 0.02) in patients showing spontaneous HCV clearance. CONCLUSIONS In HD patients, the IFNL3 polymorphisms do not affect anti-HBs development in response to HBV infection or vaccination, but might be involved in the resolution of HCV infection.

BACKGROUND Vitamin D (VD), VD binding protein, VD receptor (VDR), and retinoids are involved in pathogenesis of chronic glomerulonephritis (ChGN). We aimed to compare distribution of VD pathway gene polymorphisms in ChGN patients showing glomerular filtration rate (GFR) category 1-3, GFR category 5D, and healthy controls in order to elucidate the role of VD-related polymorphisms in the course of ChGN. MATERIAL AND METHODS GFR category 1-3 ChGN patients (n=195), GFR category 5D ChGN patients (n=178), and controls (n=751) underwent testing for polymorphisms of genes encoding VD binding protein (GC, rs2298849, rs7041, rs1155563), VDR (VDR, rs2228570, rs1544410), and retinoid X receptor alpha (RXRA, rs10776909, rs10881578, rs749759). RESULTS Among GFR 1-3 subjects possessing TT genotype of RXRA rs10776909, 75% of patients had nephrotic syndrome, and 37.5% had glomerular hyperfiltration defined as GFR >140 ml/min/1.73 m2, and, consequently, serum creatinine was lower in these patients compared to the remaining subjects (0.67±0.26 vs. 0.94±0.34, P=0.014). In GFR category 5D ChGN patients, frequencies of RXRA rs10776909 allele T (25% vs. 19%) and CT+TT (46% vs. 34%) were higher compared to frequencies of respective variants in controls (Ptrend=0.004, Pgenotype=0.008). CONCLUSIONS RXRA rs10776909 allele T is specifically involved in the pathogenesis of ChGN. This risk allele may be also associated with worse clinical course of ChGN.

Introduction Factors associated with hepatitis E virus (HEV) infection are rarely recognized in patients on renal replacement therapy (RRT), and the results of studies are inconsistent. Objectives We aimed to search for determinants of HEV seroprevalence among polymorphisms of the interferon‑λ4 gene (IFNL4) associated with seroclearance of hepatotropic viruses (IFNL4 rs12979860, rs8099917 near IFNL4), circulating interferon λ3 (IFN‑λ3), and clinical variables of patients treated with hemodialysis (HD) in a HEV‑endemic region. Patients and methods The study was carried out in 90 HD patients. HEV open reading frame 2 antigen (HEV Ag), immunoglobulin M and G antibodies to HEV (anti‑HEV IgM and anti‑HEV IgG, respectively) and IFN‑λ3 were tested, and IFNL4 polymorphic variants (rs8099917, rs12979860) were genotyped. Survival analysis was conducted concerning anti‑HEV IgG positivity. Results In the study group, there were 37.8% anti‑HEV IgG‑positive subjects. None was HEV Ag or anti‑HEV IgM positive. HD modalities utilizing high‑flux dialyzers (adjusted odds ratio [OR], 3.586; 95% confidence interval [CI], 1.142-11.263; P = 0.03) as well as major homozygosity in rs8099917 (adjusted OR, 4.933; 95% CI, 1.516-16.054; P = 0.008) and rs12979860 (adjusted OR, 3.537; 95% CI, 1.136-11.014, P = 0.03), but not circulating IFN‑λ3 levels, were positive determinants of anti‑HEV IgG positivity. Liver enzyme activities and C‑reactive protein levels tested as response variables to HEV exposure, as well as survival probability, were not different between patients stratified by anti‑HEV IgG positivity. Conclusions Among HD patients, IFNL4 polymorphisms and treatment with high‑flux HD are explanatory variables for isolated anti‑HEV IgG positivity indicating spontaneous HEV resolution.

It has recently been reported that vitamin D blood plasma levels are associated with reduced risk of endometriosis. The present study aimed to investigate whether the vitamin D binding protein (GC), vitamin D receptor (VDR), and retinoid X receptor (RXR) gene variants may be genetic risk factors for endometriosis‑associated infertility. The subjects consisted of 154 women with endometriosis‑associated infertility and 347 controls. Using polymerase chain reaction restriction fragment length polymorphism and high resolution melt techniques, the GC rs1155563, rs2298849 and rs7041; RXRA rs10881578, rs10776909 and rs749759; VDR BsmI rs1544410; and FokI rs2228570 single nucleotide polymorphisms (SNPs) were investigated in the patients with endometriosis and the healthy controls. The results indicated that no significant differences were observed between the genotype and allele frequencies of all experimental SNPs in the vitamin D signaling pathway genes in women with endometriosis-associated infertility and controls. However, a significant association was present between the A‑T haplotype, consisting of VDR rs1544410 and rs222857 minor alleles, and endometriosis-associated infertility [OR=1.659 (1.122‑2.453), P=0.011]. The results of the present study suggested that VDR gene variants act as genetic risk factors for endometriosis‑associated infertility.

Congenital maxillary lateral incisor agenesis (MLIA) is one of the most common subtypes of dental agenesis. Because little is known with regard to the aetiology of this anomaly, the aim of the study was to determine the contribution of nucleotide variants in wingless-type MMTV integration site family, member 10A (WNT10A), msh homeobox 1 (MSX1), and paired box 9 (PAX9) to the risk of MLIA in a Polish population. Coding regions of the selected genes were analysed by direct sequencing in a group of 20 individuals with unilateral and bilateral MLIA, associated or not with other dental anomalies. The frequencies of the identified nucleotide variants were assessed in an additional cohort of patients with isolated dental agenesis (n = 147) and in 178 controls. Mutation screening showed four non-synonymous substitutions located in the highly conserved coding sequence of WNT10A in five (25%) of the 20 patients. Analysis of genotyping results revealed that three of these variants – p.Arg113Cys, p.Phe228Ile, and the newly identified p.Arg171Leu – may represent aetiological mutations underlying MLIA with associated dental anomalies. No mutations that were potentially aetiologic were identified in MSX1 and PAX9. In conclusion, this is the first report implicating coding variants in the WNT10A gene in the aetiology of MLIA. These results will require further confirmation using larger-scale studies.

Although the aetiology of non-syndromic cleft lip with or without cleft palate (nsCL/P) has been studied extensively, knowledge regarding the role of genetic factors in the pathogenesis of this common craniofacial anomaly is still limited. We conducted a follow-up association study to confirm that CDKAL1 nucleotide variants identified in our genome-wide association study (GWAS) for nsCL/P are associated with the risk of this anomaly. In addition, we performed a sequence analysis of the selected CDKAL1 exons. A mega-analysis of the pooled individual data from the GWAS and a replication study revealed that six out of thirteen CDKAL1 variants were positively replicated and reached the threshold of statistical significance (Ptrend

Background Circulating pro-inflammatory cytokines were associated with increased relative mortality risk, while immune parameters reflecting improved T-cell function were predictors of survival in hemodialysis (HD) patients. We evaluated in the prospective study whether variants in T helper cell cytokine-associated genes are determinants of mortality in HD patients. Methods The study was carried out in 532 prevalent HD subjects who were followed-up for 7 years. HRM analysis was used for IFNL3, IL12A, IL13, and IL4R genotyping. CCL2, IL12B, and IL18 were genotyped using PCR–RFLP analysis. Survival analyses were conducted using the Kaplan-Meier method and the Cox proportional hazard model. Results In univariate analyses, IFNL3 rs8099917 was associated with all-cause mortality in recessive model of inheritance (log-rank test P = 0.044), IL12A rs568408 - in dominant model (log-rank test P = 0.029). Minor homozygotes (the genotype GG) in IFNL3 rs8099917 showed shorter survival during the study (3.6, 1.0–7.0 years vs 4.7, 0.1–7.0 years, P = 0.009) than the major allele (T) bearers. The rs8099917 GG patients demonstrated higher risk of death than the remaining patients (GT + TT) (OR 1.94, 95%CI 1.11–3.40, P = 0.020). Major homozygosity (the genotype GG) in IL12A rs568408 was associated with higher mortality than that shown in bearers of the minor allele (AA + AG) (HR 1.31, 95%CI 1.02–1.69, P = 0.035). In multivariate analyses, however, the mentioned polymorphisms were not independent predictors of survival. Conclusions Polymorphisms of IFNL3 rs8099917 and IL12A rs568408 contribute to survival of HD patients, but not as independent factors. Electronic supplementary material The online version of this article (doi:10.1186/s12882-017-0582-x) contains supplementary material, which is available to authorized users.

The IFN-λ3 gene (IFNL3) plays a role in HCV clearance. We investigated circulating IFN-λ3 and IFNL3 SNPs in haemodialysis patients who differed in their response to HBV vaccination and their HBV/HCV infection status. In 201 patients, plasma IFN-λ3 was determined using ELISA. IFNL3 SNPs (rs12979860, rs8099917) were genotyped using HRM analysis. Differences in IFN-λ3 levels were shown between responders and nonresponders to HBV vaccination and between HBsAg-positive patients and those who developed anti-HBs after infection and became HBsAg negative. HBV vaccine responders without HCV resolution revealed lower IFN-λ3 than noninfected responders. HBsAg/HCV RNA-positive subjects showed lower IFN-λ3 than patients positive only for HCV RNA or subjects who resolved both infections. Circulating IFN-λ3 correlated positively with anti-HBs and negatively with positive HCV RNA testing in the adjusted regression analyses. HBV vaccine nonresponders, HBsAg-positive patients, and subjects with replicating HCV composed a group with unfavourable outcomes. Responders to HBV vaccination, subjects who became HBsAg negative, and those who cleared HCV were analysed as having favourable outcomes. The latter showed higher IFN-λ3 but did not differ in distribution of IFNL3 SNPs compared with subjects with unfavourable outcomes. Higher IFN-λ3 concentrations are associated with response to HBV vaccination, self-limited HBV infection, and HCV resolution.

Aim: Vitamin D (VD) was recently associated with response to hepatitis B vaccination in chronic kidney disease. We investigated whether polymorphisms in VD binding protein (GC), VD receptor (VDR) and retinoid X receptor α (RXRA) genes were associated with response to hepatitis B vaccination in renal replacement therapy (RRT) patients. Method: The study was carried out on 692 responders and 223 non-responders. Results: After adjustment for gender, age at the RRT onset, RRT vintage, chronic glomerulonephritis as a cause of renal failure and mean serum parathyroid hormone level, VDR rs1544410 polymorphism was the only one significantly associated with response to hepatitis B vaccination: homozygotes AA (adjusted OR 1.50, 95% CI: 1.17–1.94, p = 0.002) had higher risk to be non-responders than GG homozygotes. Discussion: The VDR rs1544410 AA genotype may play a negative role (but not as an independent factor) in determining response to hepatitis B vaccination in RRT patients.

We investigated the previously-demonstrated association of seven genome-wide association studies (GWAS) single nucleotide polymorphisms (SNPs), including rs2072590 (HOXD-AS1), rs2665390 (TIPARP), rs10088218 and rs10098821 (8q24), rs3814113 (9p22), rs9303542 (SKAP1) and rs2363956 (ANKLE1), as risk factors of epithelial ovarian tumors (EOTs). These SNPs were genotyped in two hundred seventy three patients with EOTs and four hundred sixty four unrelated healthy females from the Polish population. We observed the lowest p values of the trend test for the 9p22 rs3814113 and 8q24 rs10098821 SNPs in patients with all subtypes of ovarian cancer (ptrend = 0.010 and ptrend = 0.014, respectively). There were also significant p values for the trend of the 9p22 rs3814113 and the 8q24 rs10098821 SNPs for serous histological subtypes of ovarian cancer (ptrend = 0.006, ptrend = 0.033, respectively). Moreover, stratification of the patients based on their histological type of cancer demonstrated, in the dominant hereditary model, a significant association of the 9p22 rs3814113 SNP with serous ovarian carcinoma OR = 0.532 (95 % CI = 0.342 - 0.827, p = 0.005, pcorr = 0.035). Despite the relatively small sample size of cases and controls, our studies confirmed some of the previously-demonstrated GWAS SNPs as genetic risk factors for EOTs. Electronic supplementary material The online version of this article (doi:10.1007/s12253-014-9822-6) contains supplementary material, which is available to authorized users.

a b s t r a c t Objective: Tooth agenesis is the most common dental anomaly, whose aetiology still remains to be fully elucidated. The aim of this study was to investigate the genetic cause of non-syndromic hypodontia with clinical variability in an Egyptian family. Design: The entire coding regions including exon-intron boundaries of the MSX1, PAX9 and WNT10A genes were investigated by direct sequencing in all affected family members. Results: Novel heterozygous mutation inherited in an autosomal dominant manner was identified in the WNT10A gene. This 21-bp deletion combined with 1-bp insertion, c.14_7delinsC, eliminates the translation initiation codon leading to either no protein production or translation of alternative open reading frames. None of the control subjects (400 chromosomes) were carriers of this novel WNT10A mutation. No pathogenic mutations were found in the MSX1 and PAX9 genes. Conclusions: The novel c.-14_7delinsC mutation might be the etiological variant of the WNT10A gene responsible for the permanent tooth agenesis in the Egyptian family. WNT10A is a major candidate gene for non-syndromic hypodontia.

The CDH1 gene plays an important role during carcinogenesis and craniofacial morphogenesis. Germline mutations in this gene have been described in families presenting syndromic diffuse gastric cancer and orofacial clefts. The aim of this study was to evaluate the association between nucleotide variants of CDH1 and the risk of non-syndromic cleft lip with or without cleft palate (NSCL/P). Six single nucleotide polymorphisms (SNPs) of the CDH1 gene (rs16260, rs9929218, rs7186053, rs4783573, rs16958383, and rs1801552) were genotyped using the TaqMan SNP genotyping assays in 250 patients with NSCL/P and 540 controls from the Polish population. Comparison between patient and control groups showed that the CDH1 rs1801552 variant, under the assumption of recessive model, was associated with a two-fold decrease in the risk of NSCL/P (ORTT vs CT + CC = 0.481, 95 % CI 0.281–0.824, p = 0.007). This association remained statistically significant even after the multiple testing correction. No significant associations with NSCL/P risk were found for the other five tested SNPs. We found a strong association between the cancer predisposing gene CDH1 and the risk of NSCL/P in the Polish population. This result, together with previous observations of co-occurrence of orofacial clefts and a variety of cancer types, suggests the need for replication studies testing rs1801552 in NSCL/P cohorts with a known cancer history.

Background and Objective The Wnt/β-catenin signaling pathway has been considered to be a factor in the development and progression of ovarian cancer. Methods All patients with ovarian cancer and controls were tested for BRCA1 mutations (5382incC, C61G, 4153delA) with HybProbe assays and for BRCA2 mutation (5946delT) using high-resolution melting curve analysis (HRM). Mutation carriers were excluded from the association analysis. We studied nine single nucleotide polymorphisms (SNPs) located in CTNNB1 (β-catenin) [rs4533622, rs2953], APC (rs11954856, rs351771, rs459552), and AXIN2 (rs4074947, rs7224837, rs3923087, rs2240308) in women with ovarian cancer without BRCA1/BRCA2 mutations (n = 228) and controls (n = 282). Genotyping of CTNNB1 rs4533622, rs2953, APC rs351771, AXIN2 rs4074947, rs3923087, and rs2240308 was performed by HRM, while that of APC rs11954856, rs459552 and AXIN2 rs7224837 was conducted by PCR followed by the appropriate restriction enzyme digestion [PCR–restriction fragment length polymorphism (PCR-RFLP)]. Results The most common BRCA1/BRCA2 mutations were identified in 30 patients with ovarian cancer. These mutations were not found in controls. The lowest p values of the trend test (ptrend) were observed for the APC rs351771 and rs11954856 SNPs in patients with ovarian cancer (ptrend = 0.006 and ptrend = 0.007, respectively). Using a dominant inheritance model, we found that the APC rs11954856 SNP is associated with an increased risk of ovarian cancer development [odds ratio = 2.034 (95 % CI 1.302–3.178); p = 0.002]. We also observed significant allelic differences for the APC rs351771 SNP between patients and controls (p = 0.006). Conclusion Our study demonstrated significantly increased APC rs11954856 and rs351771 SNP frequencies in Polish women with ovarian cancer. Electronic supplementary material The online version of this article (doi:10.1007/s40291-013-0059-y) contains supplementary material, which is available to authorized users.

Studies have demonstrated that changes in DNA methylation of cancer related genes can be an elementary process accounting for ovarian tumorigenesis. Therefore, we evaluated the possible association of single nucleotide polymorphisms (SNPs) of DNA methyltransferases (DNMTs) genes, including DNMT1, DNMT3B, and DNMT3A, with ovarian cancer development in the Polish population. Using PCR–RFLP and HRM analyses, we studied the prevalence of the DNMT1 rs8101626, rs2228611 and rs759920, DNMT3A rs2289195, 7590760, rs13401241, rs749131 and rs1550117, and DNMT3B rs1569686, rs2424913 and rs2424932 SNPs in patients with ovarian cancer (n = 159) and controls (n = 180). The lowest p values of the trend test were observed for the DNMT1 rs2228611 and rs759920 SNPs in patients with ovarian cancer (ptrend = 0.0118 and ptrend = 0.0173, respectively). Moreover, we observed, in the recessive inheritance model, that the DNMT1 rs2228611 and rs759920 SNPs are associated with an increased risk of ovarian cancer development [OR 1.836 (1.143–2.949), p = 0.0114, pcorr = 0.0342, and OR 1.932 (1.185–3.152), p = 0.0078, pcor=0.0234, respectively]. However, none of other nine studied SNPs displayed significant contribution to the development of ovarian cancer. Furthermore, haplotype and multifactor dimensionality reduction analysis of the studied DNMT1, DNMT3B, and DNMT3A polymorphisms did not reveal either SNP combinations or gene interactions to be associated with the risk of ovarian cancer development. Our results may suggest that DNMT1 variants may be risk factors of ovarian cancer. Electronic supplementary material The online version of this article (doi:10.1007/s11033-013-2589-0) contains supplementary material, which is available to authorized users.

Objective Overexpression of DNA methyltransferase 3A (DNMT3A) and aberrant methylation of various genes in eutopic endometrium have been demonstrated in women with endometriosis. We aimed to study whether DNMT3A polymorphisms could be a genetic risk factor for endometriosis and endometriosis-related infertility. Study design We studied 5 SNPs (rs2289195, rs7590760, rs13401241, rs749131 and rs1550117) located in the DNMT3A gene in 357 women with endometriosis and 640 controls. Results We did not observe significant differences between genotype and allele frequencies of rs2289195, rs7590760, rs13401241, rs749131 and rs1550117 SNPs in women with endometriosis, endometriosis-related infertility, and controls. The lowest p values of the trend test were observed for DNMT3A rs1550117 in endometriosis and endometriosis-related infertility ( p trend =0.049 and p trend =0.055, respectively). Conclusions Our results did not supply evidence for the contribution of SNPs located in DNMT3A to either endometriosis or endometriosis-related infertility.

Recently, several studies have demonstrated the role of vitamin D receptor (VDR) polymorphisms in the development of systemic lupus erythematosus (SLE); however, these results are inconsistent between different cohorts. Therefore, we studied the prevalence of the VDR FokI (rs2228570), BsmI (rs1544410), ApaI (rs7975232) and TaqI (rs731236) genotypes and alleles in SLE patients (n = 258) and healthy individuals (n = 545) in a Polish population. We did not observe significant differences for either the VDR FokI, BsmI, ApaI and TaqI genotype and allele frequencies in patients with SLE and healthy individuals. However, the frequency of the VDR F/F and F/f genotypes of FokI was statistically different between patients with renal disease and patients without this symptom OR = 3.228 (1.534–6.792, p = 0.0014), pcorr = 0.0476)]. There was no association of the studied VDR BsmI, ApaI and TaqI polymorphisms with clinical manifestations and laboratory profiles in patients with SLE. Our study indicates that the studied VDR FokI variant might increase the risk of some clinical presentations in patients with SLE. Electronic supplementary material The online version of this article (doi:10.1007/s11033-012-2118-6) contains supplementary material, which is available to authorized users.

To investigate circulating IFN-λ3 and IFNL3 polymorphisms in hemodialysis (HD) patients differing in HBV surface antigen antibody (anti-HBs) production.The study included 106 HBV-vaccinated HD patients (88 developed anti-HBs) and 36 HBV-infected HD subjects (27 developed anti-HBs). Plasma IFN-λ3 (enzyme-linked immunosorbent assay) and rs12979860 (CT) and rs8099917 (TG) in IFNL3 (high-resolution melting curve analysis) were analyzed with regard to the association with anti-HBs production in response to HBV vaccination or infection. The results were adjusted for gender, age, cause of renal disease, dialysis vintage, dialysis modality, IFN-λ3, and 25(OH)D as appropriate.HBV vaccine responders had higher circulating IFN-λ3 (ng/L) than non-responders (120, 36-233 vs. 53, 33-109, P0.000001). Patients who generated anti-HBs after HBV infection also had higher circulating IFN-λ3 levels than those who did not (133, 35-215 vs. 71, 9-229, P=0.043). The IFN-λ3 concentration correlated with the anti-HBs titer in vaccinated (r=0.614, P0.000001) and infected patients (r=0.589, P=0.0002). Plasma IFN-λ3 was the only significant indicator of responsiveness to HBV vaccination (adjusted P=0.018) and remained the only significant associate for the development of post-infection anti-HBs (adjusted P=0.049). A plasmaIFN-λ3 level of 85.5ng/L was thecut-off value for theprognosis of an anti-HBs titer below vs. equal to or over 10IU/L in the entire group of HD patients (ROC sensitivity 68.7%, specificity 85.2%, and AUC 0.827). Significant associations were not found between IFN-λ3 and IFNL3 rs12979860. Subjects treated with low flux HD that harbored the TT genotype in rs8099917 showed higher IFN-λ3 levels than patients bearing the G allele in rs8099917 (139, 68-233 vs. 103, 9-208, P=0.049).In HD patients, circulating IFN-λ3 strongly correlates with anti-HBs production after HBV vaccination and infection. IFNL3 rs8099917 polymorphisms seem to be associated with IFN-λ3 plasma levels in HD subjects.

Aims We examined the involvement of plasma adropin and adropin-associated genes (ENHO and RXRA) in metabolic abnormalities of hemodialysis (HD) patients. Main methods Among 50 HD patients (27 males and 23 females, aged 65.2 ± 12.6 years, HD vintage 29.0, 3.9–157.0 months), there were 26 dyslipidemics and 25 type 2 diabetics. Age-matched healthy subjects (n = 26) served as controls. Adropin levels were determined using ELISA. Insulin resistance/sensitivity was assessed using the Homeostasis Model Assessment for Insulin Resistance and Quantitative Insulin Sensitivity Check Index. ENHO (rs2281997, rs72735260) and RXRA (rs10881578, rs10776909) were genotyped by HRM, RXRA rs749759 by PCR-RFLP. Circulating adropin, serum lipids, and insulin indices were compared between bearers of the minor allele of tested polymorphisms and major homozygotes (the dominant model of inheritance). Key findings HD patients showed lower circulating adropin concentration compared with controls. In dyslipidemic patients, plasma adropin was lower than that in non-dyslipidemics, but it was not significantly different in diabetics vs. non-diabetics or in patients with or without metabolic syndrome. Major homozygotes of ENHO rs2281997 seemed to have higher circulating adropin, whereas major homozygotes of RXRA (rs749759, rs10776909) showed lower levels. Major homozygotes of ENHO rs2281997 showed borderline lower insulin resistance compared with bearers of the minor allele. Significance In HD patients, lower plasma adropin concentration is associated with dyslipidemia. Major homozygosity of RXRA seems to have an opposite effect on plasma adropin compared with that of ENHO rs2281997.

It has been shown that DNA repair is reduced in patients with systemic lupus erythematosus (SLE) and that the X-ray repair cross-complementing (XRCC1) Arg399Gln (rs25487) polymorphism may contribute to DNA repair. We evaluated the frequency of the XRCC1 Arg399Gln substitution in patients with SLE (n=265) and controls (n=360) in a sample of the Polish population. The odds ratio (OR) for SLE patients with the Gln/Gln versus Gln/Arg or Arg/Arg genotypes was 1.553 (95% confidence interval [CI]=0.9573-2.520; p=0.0729). OR for the Gln/Gln or Gln/Arg versus Arg/Arg genotype was 1.551 (95% CI=1.122-2.144, p=0.0077). The OR for the 399 Gln allele in patients with SLE was 1.406 (95% CI=1.111-1.779, p=0.0045). There was also a statistically significant p-value of the χ(2) test for the trend observed in the XRCC1 Arg399Gln polymorphism (ptrend=0.0048). We also found a significant contribution of the Gln/Gln or Arg/Gln versus Arg/Arg genotype to the presence of either the malar rash or photosensitivity manifestations of SLE OR=2.241 (1.328-3.781, p=0.0023, pcorr=0.0414). Moreover, the meta-analysis of Taiwanese Han Chinese, Brazilian, and Polish populations showed that the Gln/Gln or Gln/Arg genotype and Gln allele were associated with SLE incidence. OR for the Gln/Gln or Gln/Arg versus Arg/Arg genotype was 1.440 (95% CI=1.15-1.80, p=0.0019) and OR for the Gln allele was 1.27 (95% CI=1.08-1.51, p=0.0051). Our studies may confirm that the XRCC1 Arg399Gln polymorphism may increase the risk of incidence of SLE and the occurrence of some SLE manifestations.

BACKGROUND Non-syndromic cleft lip and palate (CLP) is one of the most common birth defects. Recent genome-wide association studies (GWAS) have identified several novel risk loci associated with this craniofacial anomaly. Therefore, the objective of this report was to investigate the contribution of the top seven polymorphisms reaching genome-wide statistical significance in GWAS analyses in the Polish population. METHODS and RESULTS Nucleotide variants located at chromosomal regions 1p22.1, 10q25.3, 17q22, and 20q12 were tested in a group of 206 patients with nonsyndromic CLP and a properly matched control group. Significant results, which persisted even after Bonferroni correction (p < 0.0071), were observed for polymorphisms located at 10q25.3 (rs7078160 and rs4752028) and 17q22 (rs227731). Under a recessive model, both rs7078160 and rs4752028 were associated with a greater than fourfold increase in the risk of CLP (odds ratio [OR] = 4.536; 95% confidence interval [CI], 1.678–12.265; p = 0.0012 and OR = 4.573; 95% CI, 1.817–11.512; p = 0.0004, respectively). Polymorphism rs227731 increased the risk of CLP when analyzed under a dominant model (OR = 1.732; 95% CI, 0.184–2.253; p = 0.0044). Borderline association was alsoidentified for the 1p22.1 locus (rs481931). Moreover, 10q25.3 haplotypes were significantly associated with a susceptibility to CLP. CONCLUSION Our evaluation study confirmed a substantial association of polymorphisms located at chromosomal regions 10q25.3 and 17q22 with nonsyndromic CLP in the Polish population. Birth Defects Research (Part A), 2012. © 2011 Wiley Periodicals, Inc.

Objective Endometriosis has been considered an epigenetic disease. Single nucleotide polymorphisms (SNPs) located in genes encoding enzymes of the folate and choline metabolism may affect DNA methyltransferase activity. Study design We studied 16 SNPs in 12 folate and choline metabolism genes, including BHMT (rs7356530 and rs3733890), BHMT2 (rs625879), CBS (844ins68), CHDH (rs893363 and rs2289205), CHKA (rs7928739), MTHFD1 (rs2236225), MTHFR (rs1801133), MTR (rs1805087), MTRR (rs1801394), PCYT1A (rs712012 and rs7639752), PEMT (rs4244593 and rs4646406) and TCN (rs1801198) in one hundred and sixty-three infertile women with minimal endometriosis and one hundred and fifty fertile women. Results There were no significant differences between genotype and allele frequencies of these gene variants in infertile women with endometriosis ( n =163) and controls ( n =150). The lowest, but not statistically significant, p values of the trend test were observed for the CBS 844ins68 and MTR rs1805087 ( p trend =0.0527 and p trend =0.0771, respectively) polymorphisms. However, the exhaustive multifactor dimensionality reduction analysis revealed an epistatic interaction between rs1801133 of MTHFR and rs4244593 of PEMT in endometriosis-associated infertility ( p =0.0240). Conclusions Our results showed moderate evidence for the contribution of SNPs located in genes encoding folate and choline metabolism enzymes to infertility in women with endometriosis.

Maternal zinc deficiency seems to be a risk factor for orofacial clefts in offspring. This study was undertaken to investigate the involvement of polymorphic variants of genes for zinc transporters in the susceptibility of clefting. PCRRFLP analysis was used to analyze single nucleotide polymorphisms of SLC30A1 (rs7526700, rs2278651, rs611386), SLC30A4 (rs2453531, rs8029246), SLC30A5 (rs351444, rs164393, rs6886492), SLC39A1 (rs10127484, rs11264736), and SLC39A3 (rs759071, rs4806874, rs10415622) in mothers of children with non-syndromic cleft lip with or without cleft palate (CL/P) and control mothers. The allele, genotype, and haplotype distribution was found to be similar among case and control mothers. Also, the gene-by-gene interaction analysis conducted using the Multifactor Dimensionality Reduction approach revealed no significant interactive genetic effect on having a child with a cleft. In conclusion, our results demonstrated that the analyzed polymorphic variants of genes for zinc transporters are not implicated in abnormal palatogenesis in the investigated group of women from the Polish population.

Objective: The study focused on the correlation between maternal polymorphisms of genes encoding antioxidant enzymes and the risk of having a child with CL/P in the Polish population. Method: PCR–RFLP analysis was used to analyze polymorphisms of MnSOD 2 (c.47T>C), CAT (c.− 330C>T) and GPX1 (c.599C>T) in mothers of children with CL/P and control mothers. Results and Conclusion: Polymorphic variants of genes for main antioxidant enzymes were determined not to be a maternal risk factor for having a child with CL/P in the investigated group of women.

The locus on chromosome 15q13.3 containing GREM1 is correlated with the risk of nonsyndromic cleft lip with or without cleft palate (NSCL/P). The aim of the present study was to find the GREM1 functional variants implicated in the aetiology of this common developmental anomaly in the Polish population.Eight polymorphisms were genotyped in 334 NSCL/P patients and 955 controls. In addition, the GREM1 protein-coding region was sequenced in 96 NSCL/P patients.Significant association with a risk of oral clefts was found for 5 tested polymorphisms. The lowest p(trend) values were identified for rs16969681, rs16969816, and rs1258763 (p(trend) 4.09E-05, 3.35E-05, and 0.0002, respectively). The putative functional variant rs16969681, located in a region that has enhancer activity, was associated with a 2.6-fold lower risk for NSCL/P (odds ratio [OR] = 0.38; 95% confidence interval [CI], 0.24-0.61, p = 2.37E-05). The previously reported association of rs1258763 with NSCL/P was replicated (OR = 0.57; 95% CI, 0.44-0.73; p = 1.10E-05). For all tested GREM1 variants, no significant sex-by-genotype interaction effects were observed. The sequencing analysis did not detect any rare variants implicated in the development of oral clefts.Our results might suggest that variants influencing GREM1 expression levels, rather than variants affecting the function of the encoded protein, are significant factors in NSCL/P etiology.

Introduction Negative outcomes in patients on renal replacement therapy (RRT) may have a source in T helper (Th)-cell imbalance or vitamin D deficiency. Objectives We examined the association of genes encoding cytokines related to Th1 and Th2 cells and vitamin D pathway genes with survival probability of patients on RRT. Patients and methods The study included 1253 patients on hemodialysis. IL13, IL4R, IL18, IL12A, IL12B, IL28B, MCP1, GC, VDR, and RXRA gene polymorphisms were tested. The Kaplan-Meier method with the log‑rank test was used to estimate significance of survival probabilities. Results Patients carrying the IL13 minor T allele had an increased risk of death compared with CC subjects (log‑rank test, P = 0.005; hazard ratio [HR], 1.40; 95% confidence interval [CI], 1.11-1.76; P = 0.005). IL28B rs8099 917 GG patients had higher mortality rates compared with IL28B GT+TT carriers (log‑rank test, P = 0.04; HR, 1.82; 95% CI, 1.10-3.01; P =0.02). IL28B rs12979860 TT carriers had an increased risk of death compared with CC+CT carriers (log‑rank test, P = 0.02; HR, 1.62; 95% CI, 1.09-2.42; P = 0.02) only when they were negative for hepatitis B virus (HBV) or hepatitis C virus (HCV) infection. The prevalence of coronary artery disease differed significantly among patients with the IL28B rs12979860 TT genotype compared with CC+CT carriers (odds ratio, 1.87; 95% CI, 1.14-3.09; P = 0.01). There was no association between the GC, VDR, and RXRA nucleotide variants and survival. Conclusions The IL13 rs20541 T allele and IL28B rs8099917 GG genotype are negative predictors of survival in patients on RRT, while the IL28B rs12979860 TT genotype increases the risk of death only in patients negative for HBV or HCV infection.

Endometriosis is considered to be an epigenetic disease. It has previously been reported that the DNA methyltransferase 3-like (DNMT3L) rs8129776 single nucleotide polymorphism (SNP) contributes to endometrioma. In the present study, high‑resolution melting curve analysis was used to investigate the risks associated with the DNMT3L c.910‑635A/G (rs8129776), c.832C/T (rs7354779), c.812C/T (rs113593938) and c.344+62C/T (rs2276248) SNPs on stage I‑II endometriosis‑associated infertility. Included in the present study were patients presenting with stage I‑II endometriosis‑associated infertility (n=154) and a control cohort of healthy patients with confirmed fertility (n=383). No significant association between the above‑listed DNMT3L SNPs and the development of endometriosis‑associated infertility was identified. The lowest P‑values generated from trend analysis were observed in the DNMT3L c.832C/T (rs7354779) SNP (Ptrend=0.114). Furthermore, haplotype analyses of the DNMT3L SNPs failed to reveal any risk association between the development of endometriosis‑associated infertility and the above‑listed polymorphisms, even when the SNPs were present in combinations. Finally, a meta‑analysis was performed to examine the association between the DNMT3L rs8129776 SNP and the development of endometrioma, from which no association between the two was identified. On the basis of these results, the present study has demonstrated that variations in the DNMT3L gene do not contribute to stage I-II endometriosis-associated infertility.

Even though selective tooth agenesis is the most common developmental anomaly of human dentition, its genetic background still remains poorly understood. To date, familial as well as sporadic forms of both hypodontia and oligodontia have been associated with mutations or polymorphisms of MSX1, PAX9, AXIN2 and TGFa, whose protein products play a crucial role in odontogenesis. In the present report we described a novel mutation of MSX1, which might be responsible for the lack of 14 permanent teeth in our proband. However, this c.581CT transition, localized in a highly conserved homeobox sequence of MSX1, was identified also in 2 healthy individuals from the proband's family. Our finding suggests that this transition might be the first described mutation of MSX1 that might be responsible for oligodontia and showing incomplete penetrance. It may also support the view that this common anomaly of human dentition might be an oligogenic trait caused by simultaneous mutations of different genes.

Introduction: We evaluate whether angiotensinogen AGT M235T (rs699), angiotensin-converting enzyme ACE (I/D) (rs4646994) and aldosterone synthase CYP11B2 –344C/T (rs1799998) polymorphisms can be genetic risk factors of chronic glomerulonephritis (GN) in the Polish population. Materials and methods: The study was conducted in 140 patients with primary chronic GN: mesangial proliferative GN (MesPGN) ( n = 49), IgA nephropathy (IgAN) ( n = 31), membranous nephropathy (MN) ( n = 27), focal segmental glomerulosclerosis (FSGS) ( n = 25), membranoproliferative GN (MPGN) ( n = 4), and minimal change disease (MCD) ( n = 4), and controls ( n = 187). Genotypes were determined by HRM curve analysis for AGT M235T, by PCR and agarose gel separation for ACE (I/D), and by PCR-RFLP for CYP11B2 –344C/T. Results: We found a significant association of the CYP11B2 –344C/T polymorphism in the recessive model with all subtypes of GN (OR = 1.925 (95% CI = 1.152–3.219, p = 0.0118, p corr = 0.0354)). We also observed that the CYP11B2 –344C/T polymorphism in the recessive model may also be an independent significant risk factor of IgAN (OR = 2.743 (95% CI = 1.219–6.172, p = 0.0122, p corr = 0.0366)), FSGS (OR = 2.895 (95% CI = 1.200–6.985, p = 0.0145, p corr = 0.0435)), and all proliferative GNs (MesPGN, IgAN, MPGN) (OR = 2.171 (95% CI = 1.211–3.894, p = 0.0084, p corr = 0.0252)). Conclusion: Our results suggest that the CYP11B2 –344C/T polymorphism might be an independent risk factor of IgAN, FSGS and all proliferative chronic GNs.

Various studies have indicated that chemokines such as monocyte chemotactic protein-1 (MCP-1) play an important role in the pathogenesis of primary glomerulonephritis (GN) and other glomerular diseases. Moreover, patients with primary GN display aberrant galactosylation of the O-linked carbohydrate moieties of IgA. Therefore, we analysed the distribution of the functional MCP-1 −2518 A > G (rs 1024611) and 1 beta 1,3-galactosyltransferase (C1GalT1) 1365 A > G (rs1047763) polymorphic variants in patients with primary GN (n = 144) and controls (n = 437) in a sample of the Polish population. We did not find a significant difference in the prevalence of the MCP-1 −2518 A > G and C1GalT1 1365 A > G polymorphisms in patients with primary GN and healthy individuals. Odds Ratio (OR) for GN patients with the MCP-1 −2518 GG genotype was 0.869 (95% CI = 0.410–1.840, P = 0.7130), and OR of the −2518 GG and −2518AG genotypes was 1.004 (95% CI = 0.689–1.464, P = 0.9836). OR for C1GalT1 1365AA genotype was 0.484 (95% CI = 0.181–1.293, P = 0.1402) and OR of the 1365AA and 1365AG genotypes was 0.839 (95% CI = 0.573–1.228, P = 0.3651). We also did not observe a difference in the distribution of alleles between patients and controls. The MCP-1 −2518 G allelic OR was 0.976 (95% CI = 0.725–1.314, P = 0.8744). The OR for the C1GalT1 1365A allele was 0.816 (95% CI = 0.596–1.118, P = 0.205). Moreover, there was no significant association between the MCP-1 −2518 A > G and C1GalT1 1365 A > G genotypes with different morphological types of primary GN or clinical manifestations. Our observations indicate that the MCP-1 −2518 A > G and C1GalT1 1365 A > G polymorphisms might not be a risk factor in the incidence of primary GN in the Polish population.

Data suggests that dopamine receptor DRD2 gene variants may contribute to hyperprolactinemia and that they may be risk factors for endometriosis-related infertility. The purpose of the present study was to determine whether nucleotide variants of the DRD2 gene may be associated with infertility related to endometriosis. Five DRD2 SNPs, rs1800497, rs6277, rs2283265, rs4245146 and rs4648317, which are located in different blocks of linkage disequilibrium, were studied in 151 cases and 381 controls. No significant differences between DRD2 rs1800497, rs6277, rs2283265, rs4245146 and rs4648317 genotype, allele nor haplotype frequencies were observed in women with endometriosis-related infertility compared with the control group. The present results did not confirm DRD2 gene variants to be genetic risk factors for endometriosis-related infertility.

The etiology of nonsyndromic cleft lip with or without cleft palate (NSCL/P) is very complex and still not well elucidated. Given the critical role of DNA damage repair in the embryonic development, we decided to test the hypothesis that polymorphisms of selected DNA repair genes might contribute to the risk of NSCL/P in the Polish population.Analysis of 36 polymorphisms in 12 DNA damage repair genes (ATM, BLM, BRCA1, BRIP1, E2F1, MLH1, MRE11A, MSH2, MSH6, NBN, RAD50, and RAD51) was conducted using TaqMan assays in a group of 263 NSCL/P patients and matched control group (n = 526).Statistical analysis of genotyping results revealed that nucleotide variants in the BRIP1 (BACH1) gene were associated with the risk of NSCL/P. Under assumption of a dominant model, the calculated odds ratios (ORs) for BRIP1 rs8075370 and rs9897121 were 1.689 (95% confidence interval [CI], 1.249-2.282; p = 0.0006) and 1.621 (95% CI, 1.200-2.191; p = 0.0016), respectively. These results were statistically significant even after applying multiple testing correction. Additional evidence for a causative role of BRIP1 in NSCL/P etiology was provided by haplotype analysis. Borderline association with a decreased risk of this anomaly was also observed for BLM rs401549 (ORrecessive = 0.406; 95% CI, 0.223-1.739; p = 0.002) and E2F1 rs2071054 (ORdominant = 0.632; 95% CI, 0.469-0.852; p = 0.003).Our study suggests that polymorphic variants of DNA damage repair genes play a role in the susceptibility to NSCL/P. BRIP1 might be novel candidate gene for this common developmental anomaly.

Background. T-cell cytokine gene polymorphisms and vitamin D pathway gene polymorphisms were evaluated as possibly associated with end-stage renal disease (ESRD) resulting from type 2 diabetes mellitus (DM) nephropathy.Methods. Studies were conducted among hemodialysis (HD) patients with ESRD due to type 2 DM nephropathy, chronic glomerulonephritis, chronic infective tubulointerstitial nephritis, and hypertensive nephropathy as well as in healthy subjects. A frequency distribution of T-cell-related interleukin (IL) genes (IL18rs360719,IL12Ars568408,IL12Brs3212227,IL4Rrs1805015,IL13rs20541,IL28Brs8099917,IL28B, and rs12979860) and vitamin D pathway genes (GC genes: rs2298849, rs7041, and rs1155563; VDR genes: rs2228570, rs1544410; and RXRA genes: rs10776909, rs10881578, and rs749759) was compared between groups.Results. No significant differences in a frequency distribution of tested polymorphisms were shown between type 2 DM nephropathy patients and controls. A difference was found inIL18rs360719 polymorphic distribution between the former group and chronic infective tubulointerstitial nephritic patients (Ptrend=0.033), which also differed in this polymorphism from controls (Ptrend=0.005).Conclusion. T-cell cytokine and vitamin D pathway gene polymorphisms are not associated with ESRD due to type 2 DM nephropathy in Polish HD patients.IL18rs360719 is probably associated with the pathogenesis of chronic infective tubulointerstitial nephritis.

Background Non-syndromic cleft lip with or without cleft palate (NSCL/P) is a common structural malformation with a complex and multifactorial aetiology. Associations of abnormalities in phenylalanine metabolism and orofacial clefts have been suggested. Methods Eight single nucleotide polymorphisms (SNPs) of genes encoding phenylalanine hydroxylase (PAH) and large neutral l -amino acid transporter type 1 (LAT1), as well as the PAH mutation that is most common in the Polish population (rs5030858; R408W), were investigated in 263 patients with NSCL/P and 270 matched controls using high resolution melting curve analysis (HRM). Results We found that two polymorphic variants of PAH appear to be risk factors for NSCL/P. The odds ratio (OR) for individuals with the rs7485331 A allele (AC or AA) compared to CC homozygotes was 0.616 (95% confidence interval [CI] = 0.437–0.868; p = 0.005) and this association remains statistically significant after multiple testing correction. The PAH rs12425434, previously associated with schizophrenia, was borderline associated with orofacial clefts. Moreover, haplotype analysis of polymorphisms in the PAH gene revealed a 4-marker combination that was significantly associated with NSCL/P. The global p -value for a haplotype comprised of SNPs rs74385331, rs12425434, rs1722392, and the mutation rs5030858 was 0.032, but this association did not survive multiple testing correction. Conclusion This study suggests the involvement of the PAH gene in the aetiology of NSCL/P in the tested population. Further replication will be required in separate cohorts to confirm the consistency of the observed association.

Tooth agenesis is the most common anomaly of dental development. The purpose of the present study was to identify the causative mutation(s) in a family with a syndromic form of hypodontia. The male proband lacked 19 permanent teeth and showed defects of hair, but lacked ectodermal symptoms of skin and nails. Direct sequencing of the coding regions, including exon/intron boundaries of the msh homeobox 1 (MSX1), paired box 9 (PAX9), ectodysplasin A (EDA), and wingless-type MMTV integration site family, member 10 (WNT10A) genes, was carried out in affected family members. All identified nucleotide variations were tested in 200 healthy individuals using high-resolution melting (HRM) curve analysis to exclude the possibility that they represent rare polymorphisms. A novel heterozygous c.59delC mutation, segregating in the autosomal-dominant model, was identified in the PAX9 gene of the proband and the family members studied. This one-nucleotide deletion, located in a highly conserved paired box sequence, resulted in a frameshift (p.Pro20Argfs65) and in premature termination of translation, yielding a truncated protein 258 amino acids shorter than the wildtype protein. No pathogenic mutations were found in the MSX1, EDA, and WNT10A genes. In conclusion, the novel PAX9 deletion might be responsible for tooth agenesis and trichodysplasia in the investigated family. This c.59delC mutation potentially leads to PAX9 transcription factor haploinsufficiency.

Orofacial clefts are among the most common birth defects and result in an improper formation of the mouth or the roof of the mouth. Monosomy of the distal aspect of human chromosome 6p has been recognized as causative in congenital malformations affecting the brain and cranial skeleton including orofacial clefts. Among the genes located in this region is PAK1IP1, which encodes a nucleolar factor involved in ribosomal stress response. Here, we report the identification of a novel mouse line that carries a point mutation in the Pak1ip1 gene. Homozygous mutants show severe developmental defects of the brain and craniofacial skeleton, including a median orofacial cleft. We recovered this line of mice in a forward genetic screen and named the allele manta-ray (mray). Our findings prompted us to examine human cases of orofacial clefting for mutations in the PAK1IP1 gene or association with the locus. No deleterious variants in the PAK1IP1 gene coding region were recognized, however, we identified a borderline association effect for SNP rs494723 suggesting a possible role for the PAK1IP1 gene in human orofacial clefting.

Cytokines, involved in the T-helper 1 system, play a role in the regulation of hepatitis B virus (HBV) clearance and the immune response to HBV antigens during natural infection or planned vaccination. Our aim was to examine whether the polymorphic variants of IL-12 are equally associated with development of antibodies to HBV surface antigen (anti-HBs) in hemodialysis (HD) patients in the case of HBV vaccination or HBV infection. The IL-12A rs568408 and IL-12B rs3212227 polymorphisms were analyzed in relation to anti-HBs development in 602 HD patients with negative antibodies to HBV core antigen (anti-HBc) who were hepatitis B vaccinated (group I) as well as in 237 anti-HBc positive HD patients who were infected with HBV in the past (group II). In group I, 199 patients did not develop an anti-HBs titre >10 IU/L (subgroup Ia), whereas in group II, 55 patients did not develop an anti-HBs titre >10 IU/L (subgroup IIa). Patients of groups I and II that developed an anti-HBs >10 IU/L were included into subgroups Ib and IIb, respectively. In hepatitis B vaccinated HD patients, development of a protective anti-HBs titre was positively associated with vintage of renal replacement therapy (RRT), chronic glomerulonephritis as a cause of RRT, and GA rs 568408 IL-12A (OR 1.6, 95 % CI 1.0–2.5, P = 0.035), but a frequency distribution of this genotype between responders and non-responders was not significant when the Bonferroni correction was applied. In HBV infected HD patients, anti-HBs development was positively associated with AC rs3212227 IL-12B (OR 8.0, 95 % CI 2.6–24.9, P

Tooth agenesis is one of the most common dental anomalies, with a complex and not yet fully elucidated aetiology. Given the crucial role of the Wnt signalling pathway during tooth development, the purpose of this study was to determine whether nucleotide variants of genes encoding components of this signalling pathway might be associated with hypodontia and oligodontia in the Polish population. A set of 34 single nucleotide polymorphism (SNPs) in 13 WNT and WNT-related genes were analyzed in a group of 157 patients with tooth agenesis and a properly matched control group (n = 430). In addition, direct sequencing was performed to detect mutations in the MSX1, PAX9 and WNT10A genes. Both single-marker and haplotype analyses showed highly significant association between SNPs in the WNT10A gene and the risk for tooth agenesis. Moreover, nine pathogenic mutations within the coding region of the WNT10A gene were identified in 26 out of 42 (62%) tested patients. One novel heterozygous mutation was identified in the PAX9 gene. Borderline association with the risk of non-syndromic tooth agenesis was also observed for the APC, CTNNB1, DVL2 and WNT11 polymorphisms. In conclusion, nucleotide variants of genes encoding important components of the Wnt signalling pathway might influence the risk of tooth agenesis.

Background The interleukin (IL)18 rs360719 CC genotype is associated with the development of antibodies to hepatitis B virus surface antigen (anti-HBs) in hemodialysis (HD) patients. IL18 shares biological properties with IL12 in promoting the T-hepler 1 (Th1) system. We studied whether polymorphisms in the IL12A 3` untranslated region (UTR) and IL12B 3`UTR may contribute to anti-HBs development (titre ≥ 10 IU/L) in HD patients either individually or jointly with the IL18 polymorphism. Methods In 518 HD patients and 240 controls the IL12A rs568408 3’UTR G > A polymorphism was genotyped by high-resolution melting curve analysis. Polymerase chain reaction restriction fragment length polymorphism was used to detect the IL12B rs3212227 3’UTR A > C and IL18 -1297 T > C rs360719 polymorphisms. The associations between the IL12A, IL12B and IL18 genotypes and the risk of impaired anti-HBs development were estimated by computing the odds ratios and their 95% confidence intervals using logistic regression analysis. Results In the logistic regression analysis, the higher frequency of rs360719 CC individually (2.9% in 207 patients without anti-HBs development vs 8.0% in 311 patients with anti-HBs development, p = 0.009) and of rs360719 CC combined with rs568408 GG (p = 0.048), rs568408 GA (p = 0.035), rs568408 GG/AA (p = 0.034) or rs3212227 AA (p = 0.046) was associated with an increased chance for the development of anti-HBs in HD patients. Patients bearing both rs568408 AA and rs360719 TT had a 10.9-fold or 8.9-fold lower chance, respectively, to develop anti-HBs compared with those carrying any other genotype (p = 0.005) or those who had both wild-type rs568408 GG and rs360719 TT (p = 0.011). Carriers of both rs3212227 CC and rs360719 TC had a 4.6-fold lower chance for anti-HBs development than carriers of any other genotype (p = 0.042). Conclusion Development of anti-HBs in HD patients is associated with gene polymorphisms of interleukins involved in the Th1 system.