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Autoimmune polyendocrinopathy–candidiasis–ectodermal dystrophy (APECED) is an autosomal-recessive autoimmune disease caused by autoimmune regulator gene mutations. The aim of this study was to examine the mutation profile of Polish APECED patients, determine the carrier rate of the most frequent mutation(s) and estimate disease prevalence. While studying 14 unrelated patients, we identified three novel mutations (c.1A>T, affecting the start codon; [IVS1 + 1G>C; IVS1 + 5delG], a complex mutation affecting splice site; c. 908G>C, p.R303P, a missense mutation in plant homeodomain (PHD) and three previously reported mutations (c.769C>T, p.R257X; c.967_979del13bp, C322fsX372; c.931delT, p.C311fsX376). Eleven patients had mutations on both chromosomes, whereas in three patients only a single alteration with proven or likely pathogenic effect was detected. The most frequent was the p.R257X mutation (71% of chromosomes); its carriage rate was assessed in the background population. Analysis of 2008 samples showed eight heterozygotes, indicating the frequency of 0.40% (1:250) and the disease prevalence – 1:129,000 (95% confidence interval: 1:555,000 to 1:30,000). Comparison with an epidemiological estimate (1:619,000, derived for women) suggested that in Poland, APECED is underdiagnosed. Among the patients, no genotype/phenotype correlations were found, but we noted that women had earlier onset of hypoparathyroidism ( p < 0.02) and were younger at diagnosis ( p < 0.05) than men. [ABSTRACT FROM AUTHOR]

Background: Say-Barber-Biesecker-Young-Simpson (SBBYSS) variant of Ohdo syndrome is a rare, autosomal dominant and clinically heterogenous disorder, caused by pathogenic variants in the KAT6B gene located on chromosome 10q22.2. KAT6B encodes a highly conserved histone acetyltransferase belonging to the MYST family. Currently, diseases caused by pathogenic variants in KAT6B (KAT6B-related disorders) comprise two allelic entities: SBBYSS variant of Ohdo syndrome and genitopatellar syndrome (GPS). Increase in the number of cases with overlapping GPS/SBBYSS phenotype which makes it necessary to redefine this group of phenotypes as KAT6B-related disorders or KAT6B spectrum disorders. Individuals with SBBYSS usually present with facial abnormalities, hypotonia, joint laxity, feeding problems, and long thumbs/great toes. This syndrome also typically involves skeletal problems including patellar hypoplasia/agenesis., Methods: Here we report six SBBYS syndrome patients with the same dysmorphic features but a different course of the disease. One known and five novel KATB6 pathogenic variants were identified by molecular diagnostics using Next Generation Sequencing (NGS)., Results: We present a detailed phenotypic analysis of six individuals with KAT6B-related disorders, in whom a heterozygous pathogenic variant in KAT6B gene was found. In all of our patients facial dysmorphism as well as developmental and speech delay were present. Additionally, all but one patients presented with hypotonia, ocular abnormalities and long thumbs. Most of our probands showed blepharophimosis and skeletal (mainly knee) defects. Contrary to previously reported severe patellar defects (hypoplasia/agenesis) anomalies presented by our patients were less severe (dysplasia, habitual dislocation, subluxation) referring to KAT6B-related disorders., Conclusion: While most of the anomalies found in our patients comply with SBBYSS criteria, phenotypic differences in our probands support a broader spectrum of the disease phenotype. To establish the range of this spectrum, a detailed analysis of clinical variability among patients with SBBYSS requires further investigation., (© 2023 The Authors. Molecular Genetics & Genomic Medicine published by Wiley Periodicals LLC.)

Genetic factors play an important role in the origin of obesity. We investigated the association between the FTO rs9939609 genotype and overweight and obesity, along with additional anthropometric variables in the representative sample of adult Polish population. We genotyped a random sample of 3369 adult individuals examined in a cross-sectional population survey (WOBASZ 2003-2005). More than 40% of men and women had at least one A allele. The AA genotype was found in approximately one fifth of both men and women. The frequency of the AA genotype increased with higher BMI in both sexes and was associated with higher anthropometric obesity indicators in both men and women. The FTO rs9939609 AA genotype was significantly related to abnormal BMI [OR=1.55 (1.14-2.11)] and overweight [OR=1.55 (1.11-2.16)] or obesity [OR=1.56 (1.04-235)] in men regardless of age, tobacco smoking, physical activity, diet and diabetes, while in women it was related to abnormal BMI [OR=1.45 (1.05-2.01)] and overweight [OR=1.59 (1.11-2.29)] after adjustment in addition for menopause. The frequency of the A allele in the Polish population was the same as in other European countries. About one fifth of both men and women have the FTO rs9939609 AA variant. A significant relationship was found between the FTO genotype and anthropometric obesity indicators. The AA genotype was significantly associated with abnormal BMI and overweight in both sexes, but the relation to the obesity phenotype was observed only in men.

Interleukin-6 signal transducer (IL6ST) encodes the GP130 protein which transduces the proinflammatory signaling of the IL6 cytokine family through Janus kinase signal transducers and activators of transcription pathway (JAK/STAT) activation. Biallelic loss-of-function IL6ST variants cause autosomal recessive hyper-IgE syndrome or a variant of the Stuve-Wiedemann syndrome. Somatic gain-of-function IL6ST mutations, in particular, small monoallelic in-frame deletions of which the most prevalent is the IL6ST Ser187&#95;Tyr190del, are an established cause of inflammatory hepatocellular tumors, but so far, no disease caused by such mutations present constitutively has been described. Herein, we report a pediatric proband with a novel syndrome of neonatal onset immunodeficiency with autoinflammation and dysmorphy associated with the IL6ST Tyr186&#95;Tyr190del variant present constitutively. Tyr186&#95;Tyr190del was found by exome sequencing and was shown to be de novo (absent in proband's parents and siblings) and mosaic (present in approximately 15-40% of cells depending on the tissue studied-blood, urine sediment, hair bulbs and buccal swab). Functional studies were performed in the Epstein-Barr virus-immortalized patient's B cell lymphoblastoid cell line, which carried the variant in approximately 95% of the cells. Western blot showed that the patient's cells exhibited constitutive hyperphosphorylation of Tyr705 in STAT3, which is indicative of IL6-independent activation of GP130. Interestingly, the STAT3 phosphorylation could be inhibited with ruxolitinib as well as tofacitinib, which are clinically approved JAK1 and JAK3 (to lesser extent JAK2 and JAK1) inhibitors, respectively. Given our results and the recent reports of ruxolitinib and tofacitinib use for the treatment of diseases caused by direct activation of STAT3 or STAT1, we speculate that these drugs may be effective in the treatment of our patient's condition., (© The Author(s) 2021. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Genetic factors are known to influence sport performance. The aim of the present study was to assess genetic variants in genes coding for proteins potentially modulating activity of brain emotion centres in a group of 621 elite athletes (212 endurance, 183 power and 226 combat athletes) and 672 sedentary controls. Ten statistically significant variants were identified in genes encoding elements of serotoninergic, catecholaminergic and hypothalamic-pituitary-adrenal systems in different sport groups. Of those the rs860573 variant in the FEV gene coding for transcription factor exclusively expressed in neurons of the central serotonin system is the only one whose frequency significantly differentiates all the groups of athletes studied, regardless of discipline, from the controls (p = 0.000026). Our results support the hypothesis that genetic variants potentially affecting mental processes and emotions, particularly in the serotonergic pathway, also influence the predispositions to athletic performance.

The Neurofascins (NFASCs) are a family of proteins encoded by alternative transcripts of NFASC that cooperate in the assembly of the node of Ranvier in myelinated nerves. Differential expression of NFASC in neurons and glia presents a remarkable example of cell-type specific expression of protein isoforms with a common overall function. In mice there are three NFASC isoforms: Nfasc186 and Nfasc140, located in the axonal membrane at the node of Ranvier, and Nfasc155, a glial component of the paranodal axoglial junction. Nfasc186 and Nfasc155 are the major isoforms at mature nodes and paranodes, respectively. Conditional deletion of the glial isoform Nfasc155 in mice causes severe motor coordination defects and death at 16-17 days after birth. We describe a proband with severe congenital hypotonia, contractures of fingers and toes, and no reaction to touch or pain. Whole exome sequencing revealed a homozygous NFASC variant chr1:204953187-C>T (rs755160624). The variant creates a premature stop codon in 3 out of four NFASC human transcripts and is predicted to specifically eliminate Nfasc155 leaving neuronal Neurofascin intact. The selective absence of Nfasc155 and disruption of the paranodal junction was confirmed by an immunofluorescent study of skin biopsies from the patient versus control. We propose that the disease in our proband is the first reported example of genetic deficiency of glial Neurofascin isoforms in humans and that the severity of the condition reflects the importance of the Nfasc155 in forming paranodal axoglial junctions and in determining the structure and function of the node of Ranvier.

Purpose: The aim of this study was to identify the molecular genetic basis of cone-rod dystrophy in 18 unrelated families of Polish origin. Cone-rod dystrophy is one of the inherited retinal dystrophies, which constitute a highly heterogeneous group of disorders characterized by progressive dysfunction of photoreceptors and retinal pigment epithelium (RPE) cells., Methods: The study group was composed of four groups of patients representing different Mendelian inheritance of the disease: autosomal dominant (AD), autosomal recessive (AR), X-linked recessive (XL), and autosomal recessive or X-linked recessive (AR/XL). The combined molecular strategy included Sanger sequencing of the RPGR-ORF15 gene (three families with XL and three families with the AR/XL mode of inheritance), mutation-specific microarray analysis of the ABCA4 gene (five families with the AR mode of inheritance and two families with the AR/XL mode of inheritance), targeted next-generation sequencing (NGS) of inherited retinal disease-associated (IRD) genes (seven families with the AD mode of inheritance and five families with the AR mode of inheritance), and whole exome sequencing, performed in select families who had been mutation-negative in the analysis with the targeted NGS panel (one family with the AD mode of inheritance, one family with the AR mode of inheritance, and two families with the AR/XL mode of inheritance)., Results: Based on this combined strategy, we managed to identify potentially causative variants in seven out of 18 families with CRD. Five of these variants are novel: c.3142&#95;3143dupAA, p.(Glu1049Argfs*41) in the RPGR-ORF15 gene, two variants: c.1612delT, p.(Trp538Glyfs*15) and c.2389dupG, p.(Ile798Hisfs*20) in the PROM1 gene in one family, c.592A>C, p.(Ser198Arg) in the PRPH2 gene and the variant c.1691A>G, p.(Asp564Gly) in the ATF6 gene that we have already reported to be pathogenic. NGS on the IRD panel allowed the molecular basis of CRD to be identified in four out of 14 families with a total detection rate of 38%. WES allowed identification of the molecular genetic basis of CRD in one family., Conclusions: This is the first report on the spectrum of disease genes and pathogenic variants causing CRD in the Polish population. The study presents five novel variants identified in four genes and therefore, broadens the spectrum of probable pathogenic variants associated with CRD.

Autosomal recessive diseases (ARD) are typically caused by a limited number of mutations whose identification is challenged by their low prevalence. Our purpose was to develop a novel approach allowing an efficient search for mutations causing ARD and evaluation of their pathogenicity without a control group. We developed Iterative Sequencing and Variant Screening (ISVS) approach based on iterative cycles of gene sequencing and mutation screening, and ISVS Simulator software ( http://zsibio.ii.pw.edu.pl/shiny/isvs/ ) for assessment of detected variants' significance. As shown by simulations, ISVS efficiently identifies and correctly classifies pathogenic mutations except for cases where the gene of interest has extremely high number of low frequency nonpathogenic variants. By applying ISVS, we found 4 known and 9 novel (p.C73Y, p.S124L, p.C194Mfs*17, c.782 + 2 T > A, c.953-5 A > G, p.L325Q, p.D334Mfs*24, p.R436G, p.M448T) TMPRSS3 variants among deaf patients. For 3 known and 5 novel variants the disease association was supported by ISVS Simulator odds >90:1. Pathogenicity of 6 novel mutations has been supported by in-silico predictions of variants' deleteriousness. By directly comparing variant prevalence in patients and controls, disease association was demonstrated only for two variants and it was relatively weak (P < 0.05). Summarizing, ISVS strategy and ISVS Simulator are useful for detection of genetic variants causing AR diseases.

Introduction: Andersen-Tawil syndrome (ATS) is a potassium channelopathy affecting cardiac and skeletal muscle. Periodic paralysis is a presenting symptom in some patients, whereas, in others, symptomatic arrhythmias or prolongation of QT in echocardiographic recordings will lead to diagnosis of ATS. Striking intrafamilial variability of expression of KCNJ2 mutations and rarity of the syndrome may lead to misdiagnosis., Methods: We report 15 patients from 8 Polish families with ATS, including 3 with novel KCNJ2 mutations., Results: All patients had dysmorphic features; periodic paralysis affected males more frequently than females (80% vs. 20%), and most attacks were normokalemic. Two patients (with T75M and T309I mutations) had aborted sudden cardiac death. An implantable cardioverter-defibrillator was utilized in 40% of cases., Conclusions: KCNJ2 mutations cause a variable phenotype, with dysmorphic features seen in all patients studied, a high penetrance of periodic paralysis in males and ventricular arrhythmia with a risk of sudden cardiac death., (© 2014 Wiley Periodicals, Inc.)

Introduction:  rs9982601 (C>T) is a polymorphism of the noncoding region between the SLC5A3/MRPS6 and KCNE2 genes. It has been shown to be associated with early-onset myocardial infarction (MI) with T as a risk allele., Objectives:  The aim of our study was to investigate the association of the rs9982601 polymorphism with long-term overall mortality from MI and prevalence of MI in a Polish population., Patients and Methods:  The study involved patients with MI treated invasively. Individuals who underwent paternity testing served as a population group. Genotyping was performed by the TaqMan method. The analyzed endpoint was the overall long-term mortality., Results:  The study group comprised 981 patients (mean age, 62.8 ±12.1 years; 259 women [26.4%]). The percentages of TT, CT, and CC genotypes were 3.1%, 25.6%, and 71.3%, respectively, in the whole group, and 2.4%, 16.8%, and 80.8% (P = 0.01) in the population group (n = 167). During follow-up (median, 1826 days), 157 patients died (16%). No significant differences were observed between the genotypes either in clinical characteristics or in mortality. However, in a subgroup of high-risk patients (GRACE risk score of 155 points or higher, n = 428), low-risk CC homozygotes had a significantly better survival rate compared with the other genotypes (hazard ratio, 0.64; 95% confidence interval, 0.43-0.96; P = 0.03)., Conclusions:  We showed that the rs9982601 polymorphism of the region between SLC5A3/MRPS6 and KCNE2 genes is associated with long-term mortality in high-risk patients after MI. Additionally, our study supports the previous reports on the correlation of this polymorphism with the prevalence of MI.

Background: BAG3 gene mutations have been recently implicated as a novel cause of dilated cardiomyopathy (DCM). Our aim was to evaluate the prevalence of BAG3 mutations in Polish patients with DCM and to search for genotype-phenotype correlations., Methods: We studied 90 unrelated probands by direct sequencing of BAG3 exons and splice sites. Large deletions/insertions were screened for by quantitative real time polymerase chain reaction (qPCR)., Results: We found 5 different mutations in 6 probands and a total of 21 mutations among their relatives: the known p.Glu455Lys mutation (2 families), 4 novel mutations: p.Gln353ArgfsX10 (c.1055delC), p.Gly379AlafsX45 (c.1135delG), p.Tyr451X (c.1353C>A) and a large deletion of 17,990 bp removing BAG3 exons 3-4. Analysis of mutation positive relatives of the probands from this study pooled with those previously reported showed higher DCM prevalence among those with missense vs. truncating mutations (OR = 8.33, P = 0.0058) as well as a difference in age at disease onset between the former and the latter in Kaplan-Meier survival analysis (P = 0.006). Clinical data from our study suggested that in BAG3 mutation carriers acute onset DCM with hemodynamic compromise may be triggered by infection., Conclusions: BAG3 point mutations and large deletions are relatively frequent cause of DCM. Delayed DCM onset associated with truncating vs. non-truncating mutations may be important for genetic counseling.

The objective of the research was to provide a comprehensive database of autosomal microsatellite loci included in AmpFlSTR NGM PCR kit for a population of Poland considering possible genetic differentiation of a forensic interest. Fifteen STR markers were analyzed in 2041 unrelated individuals residing in eight geographically different regions. All the loci were found to be in Hardy-Weinberg equilibrium. The combined probability of match is 3.52 × 10(-19) and the combined Power of Exclusion is 0.9999998. The F(ST) estimate over all 15 STRs is 0.0051 for the Polish population. We established that a combined NGM database may be employed for a Polish population., (Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.)

Background: LMNA mutations are most frequently involved in the pathogenesis of dilated cardiomyopathy with conduction disease. The goal of this study was to identify LMNA mutations, estimate their frequency among Polish dilated cardiomyopathy patients and characterize their effect both in vivo and in vitro., Methods: Between January, 2008 and June, 2012 two patient populations were screened for the presence of LMNA mutations by direct sequencing: 66 dilated cardiomyopathy patients including 27 heart transplant recipients and 39 dilated cardiomyopathy patients with heart failure referred for heart transplantation evaluation, and 44 consecutive dilated cardiomyopathy patients, referred for a family evaluation and mutation screening., Results: We detected nine non-synonymous mutations including three novel mutations: p.Ser431*, p.Val256Gly and p.Gly400Argfs*11 deletion. There were 25 carriers altogether in nine families. The carriers were mostly characterized by dilated cardiomyopathy and heart failure with conduction system disease and/or complex ventricular arrhythmia, although five were asymptomatic. Among the LMNA mutation carriers, six underwent heart transplantation, fourteen ICD implantation and eight had pacemaker. In addition, we obtained ultrastructural images of cardiomyocytes from the patient carrying p.Thr510Tyrfs*42. Furthermore, because the novel p.Val256Gly mutation was found in a sporadic case, we verified its pathogenicity by expressing the mutation in a cellular model., Conclusions: In conclusion, in the two referral centre populations, the screening revealed five mutations among 66 heart transplant recipients or patients referred for heart transplantation (7.6%) and four mutations among 44 consecutive dilated cardiomyopathy patients referred for familial evaluation (9.1%). Dilated cardiomyopathy patients with LMNA mutations have poor prognosis, however considerable clinical variability is present among family members.

Background: Papillary thyroid carcinoma (PTC) shows high heritability, yet efforts to find predisposing genes have been largely negative., Objectives: The objective of this study was to identify susceptibility genes for PTC., Methods: A genome-wide linkage analysis was performed in 38 families. Targeted association study and screening were performed in 2 large cohorts of PTC patients and controls. Candidate DNA variants were tested in functional studies., Results: Linkage analysis and association studies identified the Slit-Robo Rho GTPase activating protein 1 gene (SRGAP1) in the linkage peak as a candidate gene. Two missense variants, Q149H and A275T, localized in the Fes/CIP4 homology domain segregated with the disease in 1 family each. One missense variant, R617C, located in the RhoGAP domain occurred in 1 family. Biochemical assays demonstrated that the ability to inactivate CDC42, a key function of SRGAP1, was severely impaired by the Q149H and R617C variants., Conclusions: Our findings suggest that SRGAP1 is a candidate gene in PTC susceptibility. SRGAP1 is likely a low-penetrant gene, possibly of a modifier type.

Background: Despite improved understanding of atherothrombosis pathophysiology, risk factors associated with premature coronary artery disease (CAD) in women are poorly recognized., Design and Methods: A single-centre, case-control study comprised 323 women (less than 55 years) with established CAD, enrolled between April 2005 and January 2008, and 347 age-matched healthy women selected from the Multi-Center All-Polish Health Survey. We aimed to assess the relationship of menopause and premature CAD., Results: In multivariate analysis smoking, parental history of premature CVD, diabetes, menopause and hypertension were the strongest risk markers for premature CAD with ORs (95% CI): 3.83 (2.52-5.82); 3.08 (1.85-5.14); 2.89 (1.59-5.23); 2.82 (1.91-4.19); 2.39 (1.16-3.54). The most significant association was found for early postmenopause in a model including the early and late stage of postmenopause (≤ and >3 years of its onset), with OR 4.55 (95% CI 2.82-7.35), higher than other risk factors. The receiver operating characteristic (ROC) curves area revealed a significant increase from 0.81 in that model that included traditional risk factors and parental premature CVD to 0.85 after addition of the early and late stage of postmenopause., Conclusions: We have shown that smoking and early postmenopausal stage (≤3 years) are the most important determinants of premature CAD followed by parental CVD, diabetes and hypertension.

Background: Genome-wide studies have shown that polymorphisms on chromosome 4q25, 16q22 and 1q21 correlate with atrial fibrillation (AF). However, the distribution of these polymorphisms differs significantly among populations., Objective: To test the polymorphisms on chromosome 4q25, 16q22 and 1q21 in a group of patients (pts) that underwent catheter ablation of AF., Methods: Four hundred and ten patients with AF that underwent pulmonary vein isolation were included in the study. Control group (n = 550) was taken from healthy population, matched for age, sex and presence of hypertension. All participants were genotyped for the presence of the rs2200733, rs10033464, rs17570669, rs3853445, rs6838973 (4q25), rs7193343 (16q22) and rs13376333 (1q21) polymorphisms., Results: All the polymorphisms tested (except rs17570669) correlated significantly with AF in univariate analysis (p values between 0.039 for rs7193343 and 2.7e-27 for rs2200733), with the odds ratio (OR) 0.572 and 0.617 for rs3853445 and rs6838973, respectively (protective role) and OR 1.268 to 3.52 for the other polymorphisms. All 4q25 SNPs tested but rs3853445 were independently linked with AF in multivariate logistic regression analysis. In haplotype analysis six out of nine 4q25 haplotypes were significantly linked with AF. The T allele of rs2200733 favoured increased number of episodes of AF per month (p = 0.045) and larger pulmonary vein diameter (recessive model, p = 0.032)., Conclusions: Patients qualified for catheter ablation of AF have a significantly higher frequency of 4q25, 16q22 and 1q21 variants than the control group. The T allele of rs2200733 favours larger pulmonary veins and increased number of episodes of AF.

Aims: Despite the large number of suicides that occur with intoxication, little is known about the unique predictors of suicide after alcohol consumption. The goal of this study was to examine clinical and genetic risk factors for alcohol-related suicide., Methods: Data on 162 suicide victims were obtained from post-mortem examinations, police and prosecution inquiries, autopsy protocols and available medical records. Four single nucleotide polymorphisms in the central serotonin system and the renin-angiotensin system related genes previously found to be associated with suicide, alcohol dependence or depression were genotyped., Results: The strongest predictor of suicide under the influence of alcohol was alcohol dependence (OR = 4.63). Those who did not drink alcohol before suicide were more likely to have a diagnosis of major depressive disorder in their medical record and more often had the TT genotype of the tryptophan hydroxylase 2 gene., Conclusions: Suicide under the influence of alcohol is strongly connected with alcohol dependence. The TPH2 gene may play an important role in suicide vulnerability especially in individuals who did not drink alcohol before suicide.

The purpose of this study was to evaluate the homogeneity of Polish populations with respect to STRs chosen as core markers of the Polish Forensic National DNA Intelligence Database, and to provide reference allele frequencies and to explore the genetic interrelationship between Poland and neighboring countries. The allele frequency distribution of 10 STRs included in the SGMplus kit was analyzed among 2176 unrelated individuals from 6 regional Polish populations and among 4321 individuals from Germany (three samples), Austria, The Netherlands, Sweden, Czech Republic, Slovakia, Belarus, Ukraine and the Russian Federation (six samples). The statistical approach consisted of AMOVA, calculation of pairwise Rst values and analysis by multidimensional scaling. We found homogeneity of present day Poland and consistent differences between Polish and German populations which contrasted with relative similarities between Russian and German populations. These discrepancies between genetic and geographic distances were confirmed by analysis of an independent data set on Y chromosome STRs. Migrations of Goths, Viking influences, German settlements in the region of Volga river and/or forced population resettlements and other events related to World War II are the historic events which might have caused these finding.

Recently, a functional polymorphism in the NFKB1 gene promoter (-94ins/del ATTG) has been identified and associated with chronic inflammatory diseases. The aim of this study was to analyze the association of NFKB1 polymorphism with susceptibility to and phenotype of Graves' disease (GD). The initial case-control association study, performed in a Polish-Warsaw cohort (388 GD patients and 688 controls), was followed by the two replication studies performed in Polish-Gliwice and Japanese-Kurume cohorts (198 GD patients and 194 controls, and 424 GD patients and 222 controls, respectively). The frequency of the -94del ATTG (D) allele was increased in GD compared to controls in Warsaw cohort. This finding was replicated in Gliwice cohort. Combining both Polish-Caucasian cohorts showed that the NFKB1 polymorphism was significantly associated with susceptibility to GD with a codominant mode of inheritance (P=0.00005; OR=1.37 (1.18-1.60)). No association with GD was found in Japanese cohort. However, subgroup analysis in Japanese GD patients revealed a correlation between the NFKB1genotype and the development of ophthalmopathy (P=0.009; OR=1.49 (1.10-2.01)), and the age of disease onset (P=0.009; OR=1.45 (1.09-1.91)). Our results suggest that NFKB1 -94ins/del ATTG polymorphism may be associated with susceptibility to and/or phenotype of GD.

The D7S1517, D3S1744, D12S391, D2S1360, D6S474, D8S1132, D5S2500, D10S2325 and D4S236613 are STR loci potentially useful for forensic purposes whose analysis has recently become facilitated by availability of a commercial kit. The purpose of the study was to evaluate the usefulness of these loci for forensic identification in a population of Central Poland. The distribution of alleles of the nine STRs was determined in sample of 353 unrelated individuals born in Central Poland and indices of forensic informativeness were calculated. The studied loci were highly informative and did not show departures from Hardy-Weinberg equilibrium. For the loci located on the same chromosomes (D2S1360, D3S1744 D4S2366, D5S2500, D7S1517, D8S1132, D12S391) as other loci commonly used for identification purposes (TPOX, D2S1338, D3S1358, FGA, D5S818, D7S820, D8S1179 and D12S391) appropriate pairwise analysis of linkage disequilibrium was performed. In all cases no statistically significant deviation from independence was found. We conclude that the studied STRs are informative and, when necessary, can be used to extend the results obtained with other STRs commonly analyzed for identification purposes, in particular the CODIS set.

To test for human population substructure and to investigate human population history we have analysed Y-chromosome diversity using seven microsatellites (Y-STRs) and ten binary markers (Y-SNPs) in samples from eight regionally distributed populations from Poland (n = 913) and 11 from Germany (n = 1,215). Based on data from both Y-chromosome marker systems, which we found to be highly correlated (r = 0.96), and using spatial analysis of the molecular variance (SAMOVA), we revealed statistically significant support for two groups of populations: (1) all Polish populations and (2) all German populations. By means of analysis of the molecular variance (AMOVA) we observed a large and statistically significant proportion of 14% (for Y-SNPs) and 15% (for Y-STRs) of the respective total genetic variation being explained between both countries. The same population differentiation was detected using Monmonier's algorithm, with a resulting genetic border between Poland and Germany that closely resembles the course of the political border between both countries. The observed genetic differentiation was mainly, but not exclusively, due to the frequency distribution of two Y-SNP haplogroups and their associated Y-STR haplotypes: R1a1*, most frequent in Poland, and R1*(xR1a1), most frequent in Germany. We suggest here that the pronounced population differentiation between the two geographically neighbouring countries, Poland and Germany, is the consequence of very recent events in human population history, namely the forced human resettlement of many millions of Germans and Poles during and, especially, shortly after World War II. In addition, our findings have consequences for the forensic application of Y-chromosome markers, strongly supporting the implementation of population substructure into forensic Y chromosome databases, and also for genetic association studies.

Objective: Susceptibility to Graves' disease (GD) is to a significant extent determined by genetic factors of which the best known are those associated with the HLA and the CTLA4 locus. Recently, two studies on British Caucasians reported that a single nucleotide polymorphism, 1858 C > T in PTPN22, encoding Arg620Trp in the lymphoid protein tyrosine phosphatase (LYP), which is a negative regulator of T-cell activation, increases the risk of GD. The purpose of our study was to investigate whether the PTPN22 'T' allele is associated with GD and/or its subsets, defined by clinical or genetic parameters, in a Polish population., Subjects and Design: A cohort of 290 patients and 310 controls was genotyped using a PCR-RFLP method. The distribution of PTPN22 alleles and genotypes among patients and controls was compared, and correlation was sought between PTPN22 'T' and sex, tobacco smoking status, family history of GD, age of disease onset, presence (and severity) of ophthalmopathy, and presence of the CTLA4 A49G or DRB1*03 alleles., Results: Association between GD and the PTPN22 'T' allele was confirmed (OR 1.7, P < 0.0008). Furthermore, a significant correlation between the PTPN22 genotype and the age of GD onset was demonstrated (r = -0.18, P = 0.0019). The PTPN22 'TT' and 'CC' genotypes defined groups characterized by more than twofold difference in median age of disease onset (20.8 years vs. 42 years, P < 0.003) whereas the 'CT' genotype was associated with an intermediate value (35 years). There were no statistically significant correlations with other analysed clinical or genetic parameters., Conclusions: We replicated the association between Graves' disease and PTPN22 'T' reported in British Caucasians. We also found a gene dose-dependent effect of PTPN22 'T' on the age of onset of Graves' disease.

Background: Endometriosis is associated with inflammatory autoimmune reactions; however, aetiopathogenesis of the disease is still poorly understood. While autoimmune disorders are often associated with particular HLA alleles, the possible involvement of HLA in the aetiopathogenesis of endometriosis is still a subject of controversy. The aim of the study was to examine the distribution of HLA-DRB1 alleles in women with endometriosis. To ensure homogeneity of the studied group, only women with ovarian endometrial cysts were included., Methods: The study included 65 Polish patients of Caucasian origin in whom ovarian endometriosis had been confirmed by laparoscopic and histopathological examinations. HLA-DRB1 alleles were typed using a reverse slot blot method. A frequency of particular HLA-DRB1 alleles in patients was compared with that of a control group of 700 unrelated ethnically matched individuals as well as 193 age-matched women without endometriosis., Results: No statistically significant differences were found in the distribution of HLA-DRB1 alleles in patients with ovarian endometriosis as compared with control populations., Conclusions: The results of the present study show that ovarian endometriosis is not associated with particular HLA-DRB1 allele(s). This may suggest that aetiology of this form of endometriosis may be not primarily associated with class II HLA-mediated autoimmune reactions.

The allele frequencies for the 13 CODIS core loci and two recently developed but not extensively validated in Central European populations pentanucleotide STRs (Penta E and D) were determined using the Power Plex-16 (Promega) kit in a sample of 430 unrelated individuals born in Central Poland. The calculated parameters of polymorphism showed Penta E to be the most valuable marker from the studied set. The obtained distribution of Penta E and D alleles was statistically significantly different from that previously reported for a population of Southern Poland. Analysis of Hardy-Weinberg equilibrium revealed a deviation for the D5S818 locus which may reflect presence of a null allele.

Allele frequencies for the 10 short tandem repeats (STRs) included in AmpFlSTR SGM Plus amplification kit (D3S1358, vWA, D16S539, D2S1338, D8S1179, D21S11, D18S51, D19S433, TH01, FGA) were estimated from a sample of 500 unrelated individuals born in Central Poland.

Different regional populations from Poland were studied in order to assess the genetic heterogeneity within Poland, investigate the genetic relationships with other European populations and provide a population-specific reference database for anthropological and forensic studies. Nine Y-chromosomal microsatellites were analysed in a total of 919 unrelated males from six regions of Poland and in 1,273 male individuals from nine other European populations. AMOVA revealed that all of the molecular variation in the Polish dataset is due to variation within populations, and no variation was detected among populations of different regions of Poland. However, in the non-Polish European dataset 9.3% ( P<0.0001) of the total variation was due to differences among populations. Consequently, differences in R(ST)-values between all possible pairs of Polish populations were not statistically significant, whereas significant differences were observed in nearly all comparisons of Polish and non-Polish European populations. Phylogenetic analyses demonstrated tight clustering of Polish populations separated from non-Polish groups. Population clustering based on Y-STR haplotypes generally correlates well with the geography and history of the region. Thus, our data are consistent with the assumption of homogeneity of present-day paternal lineages within Poland and their distinctiveness from other parts of Europe, at least in respect to their Y-STR haplotypes. Electronic supplementary material to this paper can be obtained by using the Springer LINK server located at http://dx.doi.org/10.1007/s00439-002-0728-0.