ABCB1-Gen-Polymorphismus in einer polnischen Kohorte ist mit Risiko für bullöses Pemphigoid assoziiert.

HINTERGRUND UND ZIELE: Polymorphismen im ABCB1-Gen, das für das P-Glykoprotein kodiert, können die intrazelluläre Konzentration von Xenobiotika beeinflussen und so zur Entwicklung von Autoimmunerkrankungen, einschließlich des bullösen Pemphigoids (BP), beitragen. In der vorliegenden Studie sollte untersucht werden, ob in einer polnischen Kohorte die C3435T- und G2677T/A-Polymorphismen im ABCB1-Gen mit dem Risiko für ein BP assoziiert sind. PATIENTEN UND METHODIK: Die Studie umfasste 71 Patienten mit BP und 156 gesunde Probanden. Der C3435T-Polymorphismus wurde mittels PCR-RFLP bestimmt und der G2677T/A-Polymorphismus mittels Allel-spezifischer PCR. ERGEBNISSE: Es gab zwar keine Korrelation zwischen dem C3435-Polymorphismus und dem BP-Risiko, aber wir konnten eine derartige Assoziation hinsichtlich des G2677T/A-Polymorphismus nachweisen. Das relative Risiko eines BP war bei Personen mit dem 2677TA-Genotyp um mehr als den Faktor fünf erhöht (OR = 5,52; p = 0,0063) und bei Trägern des 2677TT-Genotyps mehr als verdoppelt (OR = 2,40; p = 0,0076). Mit 2,40 (p = 0,000018) war die OR bei Trägern des 2677T-Allels ebenfalls erhöht. Die höhere Prävalenz des 2677GG-Genotyps und des 2677G-Allels bei der Kontrollgruppe sowie eine OR < 1,0 (0,22 beziehungsweise 0,33) legen eine Schutzfunktion des 2677G-Allels hinsichtlich der Ausbildung eines BP nahe. SCHLUSSFOLGERUNGEN: Die Ergebnisse der vorliegenden Studie zeigen, dass der G2677T/A-Polymorphismus im ABCB1-Gen das Risiko für die Entstehung eines BP beeinflussen könnte.

ABCB1 gene is associated with the risk of bullous pemphigoid in a polish population.

BACKGROUND AND OBJECTIVES: Polymorphisms in the P-glycoprotein-encoding ABCB1 gene may affect the intracellular concentration of xenobiotics, and thus contribute to the development of autoimmune diseases, including bullous pemphigoid (BP). The objective of the present study was to investigate whether there is an association between the C3435T and G2677T/A polymorphisms in the ABCB1 gene and the risk of BP in a Polish population. PATIENTS AND METHODS: The study included 71 patients with BP and 156 healthy volunteers. Determination of the C3435T polymorphism was carried out using PCR-RFLP; the G2677T/A polymorphism, using allele-specific PCR. RESULTS: While there was no correlation between the C3435T polymorphism and the risk of BP, we did find such an association with respect to the G2677T/A polymorphism. The relative risk of BP was more than five times greater in individuals with the 2677TA genotype (OR = 5.52, p = 0.0063), and more than twice as high in carriers of the 2677TT genotype (OR = 2.40, p = 0.0076). At 2.40 (0.000018), the OR in carriers of the 2677T allele was also increased. The greater prevalence of the 2677GG genotype and the 2677G allele in the control group, as well as the OR < 1.0 (0.22 and 0.33, respectively), suggest a protective role of the 2677G allele with respect to the development of BP. CONCLUSIONS: The results of the present study indicate that the G2677T/A polymorphism in the ABCB1 gene may affect the risk of developing BP.

[Hypersensitivity to acetylsalicylic acid]. / Nadwrazliwosc na kwas acetylosalicylowy.

Hypersensitivity to acetylsalicylic acid (ASA) is characterized by the co-occurrence of symptoms so-called aspirin triad, which include bronchial asthma, chronic rhinitis and sinusitis and the nasal mucosa polyps. The disease affects about 1% of the general population and in patients with bronchial asthma incidence may be as high as 10%. Hypersensitivity to aspirin is a difficult diagnostic problem, so the increased knowledge on this subject is a very important for the physicians of many specialties.

[Clinical significance of pharmacogenetics in psychiatry]. / Kliniczne znaczenie farmakogenetyki w psychiatrii.

One of the problems in the pharmacotherapy of mental disorders is among others a lack of appropriate response to treatment, which may be associated with ineffective therapy, adverse drug reactions and self medication. Participation of cytochrome P-450 isoenzymes (including CYP1A2, CYP2C19, CYP2D6, CYP3A4) in the metabolism of psychotropic drugs contributes to risk of adverse interactions, both in pharmacokinetic and pharmacodynamic phase. Pharmacogenetic studies may have an increasing importance in the field of improving both therapeutic effectiveness and safety of psychotropic drugs in treatment of mental disorders.

Genetic polymorphisms of CYP2D6 oxidation in patients with autoimmune bullous diseases.

INTRODUCTION: Bullous skin diseases, which include, among others pemphigoid, pemphigus, and dermatitis herpetiformis are classified as severe autoimmune dermatoses. It has been shown that a pattern of xenobiotic metabolism may play a role in the pathogenesis of autoimmune diseases. AIM: To estimate whether the CYP2D6 genotype may be considered a predisposing factor in autoimmune bullous diseases induction. MATERIAL AND METHODS: The study included 72 patients with autoimmune bullous diseases: 37 with pemphigoid, 21 with pemphigus, and 14 with dermatitis herpetiformis (DH). The CYP2D6 genotypes were analyzed by the polymerase chain reaction fragment length polymorphism (PCR-RFLP) method. RESULTS: Relative risk of DH development for particular genotype carriers expressed by odds ratio (OR) was statistically significantly higher for subjects with CYP2D6*1/CYP2D6*4 (OR = 4.2; p = 0.0104) and 2-fold higher for subjects with CYP2D6*4 (OR = 2.3; p = 0.0351). CONCLUSIONS: The results of the present study show that the CYP2D6 oxidation polymorphism cannot be considered a risk factor for development of pemphigoid and pemphigus, however it might have an impact on dermatitis herpetiformis.

Genetic polymorphisms of CYP2D6 oxidation in patients with systemic sclerosis.

BACKGROUND: Involvement of genetic and environmental factors in the pathogenesis of scleroderma has contributed to a number of studies whose aim is to elucidate the way in which xenobiotics exert effects on the occurrence of autoimmune processes resulting in development of systemic sclerosis (SSc). OBJECTIVE: The study dealt with the evaluation of the genetically determined polymorphism of CYP2D6, one of the phase I drug metabolizing isoenzymes, in patients suffering from SSc. Usefulness of the CYP2D6 genotype examination and prevalence of CYP2D6 gene mutation in light of susceptibility to SSc development were assessed. METHODS: Forty-three patients with SSc and 129 healthy volunteers were included in the study. Of the 43 patients with SSc, 17 fulfilled the criteria of diffuse SSc (dSSc) and 26 of limited SSc (lSSc). The determination of the CYP2D6 oxidative polymorphism was performed with the PCR-RFLP method. RESULTS: Relative risk of SSc development for particular genotype carriers expressed by the odds ratio (OR) was statistically significantly higher for subjects with CYP2D6*1/CYP2D6*4 (OR = 4.8; P < 0.001). A statistically significant correlation between the CYP2D6*4 allele prevalence and the risk for developing SSc was found (OR = 2.6; P = 0.0002). CONCLUSION: Higher prevalence of the CYP2D6*4 mutated alleles in patients with SSc and the obtained OR values suggest that this mutation has the effect of increasing SSc morbidity rate.

[Clinical significance of some genetic polymorphisms of cytochrome P-450 subfamilies CYP2D, CYP2E and CYP3A--part II]. / Kliniczne znaczenie polimorfizmu wybranych genów cytochromu P-450 podrodzin CYP2D, CYP2E i CYP3A--czesc II.

Polymorphism of drugs biotransformation is clinically significant from the point of view of the effectiveness and safety of pharmacotherapy and an increased risk of some illnesses. The paper presents molecular mechanisms and clinical implication of several genetic polymorphisms of cytochrome P-450 (CYP) xenobiotics metabolizing enzymes and genetic predisposition to the occurrence of some diseases.

[Genetic polymorphisms of oxidation and acetylation in cancers of digestive system]. / Genetycznie uwarunkowany polimorfizm utleniania i acetylacji w nowotworach przewodu pokarmowego.

Cancer diseases are the second most common cause of mortality in Poland. The cancers of digestive system: colorectal cancer, gastric cancer, pancreatic cancer and liver cancer are the first common malignant tumour. Pathogenesis of cancer diseases is connected with influence of environmental factors with individual dependent among others on detoxification enzymes. Genetic differences in the regulation, expression and activity of genes coding for phase I and phase II drug-metabolizing enzymes can be crucial factors in defining cancer of digestive system susceptibility. In this review our current knowledge about polymorphism in several of these genes is summarized.

[Clinical significance of some genetic polymorphisms of cytochrome P-450: family CYP1 and subfamilies CYP2A, CYP2B and CYP2C]. / Kliniczne znaczenie polimorfizmu wybranych genów cytochromu P-450: rodziny CYP1, podrodziny CYP2A, CYP2B oraz CYP2C.

The essence of pharmacogenetic studies is to provide a scientific explanation for personal differences in the process of drugs metabolism. Polymorphism of drugs biotransformation is clinically significant from the point of view of the effectiveness and safety of pharmacotherapy and an increased risk of some illnesses. The paper presents molecular mechanisms and clinical implication of several genetic polymorphisms of cytochrome P-450 (CYP) xenobiotics metabolizing enzymes and genetic predisposition to the occurrence of some diseases.

Analysis of genetic polymorphisms of glutathione S-transferase (GSTP1, GSTM1, and GSTT1) in Polish patients with systemic sclerosis.

AIM: It is commonly assumed that a genetically determined polymorphism of xenobiotic biotransformation plays a particular role in the development of such disease entities in which chemical compounds and environmental pollutants are relevant etiologic factors. Systemic sclerosis (SSc, scleroderma) belongs to diseases of connective tissue, characterized by chronic inflammation developing on an autoimmune background. The current state of knowledge on the etiopathogenesis of autoimmune diseases indicates the existence of many factors affecting the development of the disease, including factors of the external environment. Considering all the above, a study on a role of genetic polymorphisms of glutathione S-transferase has been undertaken in which predisposition to SSc in a Polish population was assessed. METHODS: The study was carried out in 161 subjects: 61 patients with SSc and 100 healthy volunteers. A determination of the polymorphism of GSTM1 and GSTT1 was performed with a multiplex PCR (polymerase chain reaction). The GSTP1 polymorphism was determined by using the PCR restriction fragment length polymorphism. RESULTS: The risk of developing SSc was 3-fold higher for persons with the null GSTM1 and GSTT1 genotypes (odds ratio [OR] = 3.3; P = .0051). The risk for SSc was also demonstrated to be over 2.5-fold greater in the GSTP1 Ile/Val genotype individuals (OR = 2.62; P = .0037). Carriers of the GSTP1 Val variant allele had a greater than 2-fold increase in SSc risk (OR = 2.41; P = .0006). CONCLUSION: The genetic polymorphism of glutathione S-transferase may affect the risk of SSc in a Polish population.

Genetic determinants in ischemic heart disease.

The present paper is a review of current knowledge about the relations between gene polymorphism and predisposition for ischemic heart disease. Many studies investigate polymorphic variants of genes whose protein products contribute to the genesis and development of atherosclerosis of coronary arteries, thrombogenesis and fibrinolysis and other processes significant for the progression of ischemic heart disease. In ischemic heart disease the most often analyzed genes are those connected with metabolism of lipids, the coagulation and fibrinolytic system and the renin-angiotensin-aldosterone system. Factors of inflammation (cytokines, TNF), proliferation of smooth muscles cells and vasoactivation are also important. Manifestation of the illness is connected with accumulation of several genetic determinants, while the clinical picture is additionally modified by environmental factors. Studies of genetic etiopathogenesis of ischemic heart disease may result in effective prevention and treatment in particular patients.

Polymorphism of dextromethorphan oxidation in Polish population.

Determination of oxidation phenotype is used to obtain the best results of pharmacotherapy and to explain a lower efficiency of some drugs in particular patients. The purpose of the present study was to determine the distribution of CYP2D6 metabolizer status in subjects from central Poland, using dextromethorphan as the probe drug. The study included 104 healthy Polish volunteers. All subjects received a single oral dose of 40 mg of dextromethorphan and the complete urine output was collected over a period of 10 h. DM and the metabolite dextrorphan (DT) were analyzed by HPLC method. The results of a Polish population study revealed a bimodal distribution of the dextromethorphan metabolic ratio and showed the existence of two oxidation phenotypes as extensive (EM) and poor (PM) metabolizers. In our population, the frequency of the PM phenotype was 9.6%. The results obtained (9.6% of PM phenotype) were in accordance with other results obtained in Poland and other Caucasian populations.

Oxidative phenotype status in related subjects.

Human population varies with regard to the rate of drug metabolism. Differences in pharmacological activity of a drug in patients who belong to the same population result from a different enzymatic activity and different genotypes of those subjects. The aim of the study was to assess the incidence of extensive (EM) and poor (PM) oxidative phenotypes in related persons and to establish whether any associations exist between an individual, genetically conditioned drug oxidation capacity and a family relationship. The study comprised 61 healthy subjects including 39 females and 22 males aged between 18 and 77 years (mean age 39.02 +/- 16.55 years). The persons belonged to 20 families and were first degree relatives. The oxidative phenotype status was established based on the metabolic ratio (MR); the amounts of urinary output of dextromethorphan and dextrorphan in the 10 h urine were determined using the HPLC method. Prevalence of poor metabolizers in the group of relatives reached 16.4%. The percentage of poor metabolizers was higher in the group of relatives than in the control group (9.6%), however, the difference was not statistically significant. Inheritance of the oxidative phenotype among relatives is mainly associated with mothers and their daughters.

Haplotypes of ABCB1 1236C >T (rs1128503), 2677G >T/A (rs2032582), and 3435C >T (rs1045642) in patients with bullous pemphigoid.

Bullous pemphigoid (BP) constitutes the most prevalent disease in the group of bullous dermatoses with the autoimmune background. Some authors suggest that certain cytokines (IL-2, IFN-γ) may be transported by P-glycoprotein (P-gp), the product of the ABCB1 gene. ABCB1 polymorphism might affect not only the effectiveness of treatment with drugs that are P-gp substrates but also contribute to the development of diseases, including BP. In the present work, we resolved to conduct a haplotype analysis of ABCB1 in patients with BP and to answer the question of whether any of the haplotypes are able to affect the incidence of this entity. The study involved 71 patients with BP and 100 healthy volunteers. Determination of polymorphisms 1236C > T and 3435C > T in ABCB1 was carried out with the PCR-RFLP (Polymerase Chain Reaction-Restriction Fragment Length Polymorphism) method. The 2677G > T/A ABCB1 polymorphism was analyzed with the allele-specific PCR method. It was observed that the 1236T-2677G-3435T haplotype occurred with a statistically significantly lower frequency in patients with BP than in controls (1.4 vs. 10.0%). Carriers of this haplotype were also shown to have had a low relative risk for BP (OR = 0.13, p = 0.003). Haplotype analysis of ABCB1 conducted in patients with BP demonstrated that the 1236T-2677G-3435T haplotype may protect against development of this entity.

CYP2D6 phenotyping with dextromethorphan.

Genetically determined individual differences in the ability to oxidize certain drugs have raised recently a considerable interest because of clinical importance of this problem. Determination of CYP2D6 oxidation phenotype is used to obtain more efficient pharmacotherapy and to explain lower efficacy of some drugs and presentation of adverse effects in particular patients. The aim of this study was to identify the CYP2D6 oxidation phenotype with dextromethorphan (DM) as a probe drug. The study included 85 healthy volunteers of Polish origin. DM (40 mg) was given orally to healthy adults and 10-h urine samples were collected. DM and the metabolite dextrorphan (DX) were analyzed by the HPLC method. Phenotyping was performed using the metabolic ratio (MR) calculated as the urinary DM/DX output. Based on the metabolic ratio, we can distinguish extensive (EM) and poor (PM) metabolizers in human population. Individuals with a dextromethorphan MR greater than 0.3 (log > -0.5) were classified as PMs. In our study, the frequency of the PM phenotype was 9.4%, which is in the range found in other Caucasian populations (3-10%).

[Genetics in ischaemic heart disease]. / Genetyczne uwarunkowanie choroby niedokrwiennej serca.

The role of genetic factors in the pathogenesis of ischaemic heart disease has recently raised a considerable interest among researchers. Numerous investigations aim at finding variants of genes which might be responsible for increasing the risk of this illness. Many studies investigate polymorphic variants of genes whose protein products contribute to the genesis and development of atherosclerosis of coronary arteries, thrombogenesis and fibrinolysis and other processes significant for the progression of ischaemic heart disease. Genes whose polymorphisms are potentially connected with a given illness are called genes candidates. In ischaemic heart disease the most often analyzed genes are those connected with metabolism of lipids, the coagulation and fibrinolytic system and the renin-angiotensin-aldosterone system. Factors of inflammation (cytokines, TNF), proliferation of smooth muscles cells and vasoactivation are also important. The analysis of genetic multifunctional basis of the disease is rather difficult. Manifestation of the illness is connected with accumulation of several genetic determinants, while the clinical picture is additionally modified by environmental factors. Studies of genetic etiopathogenesis of ischaemic heart disease may result in effective prevention and treatment in particular patients.

[Prospects of gene therapy]. / Perspektywy terapii genowej.

In recent years extensive development of gene therapy strategies has been observed. The studies on gene therapy focus on two different research methods. The first one concerns replacement of damaged genes in somatic cells of the organism by correcting genes. Application of modem methods of gene therapy permits to treat a disease already at the molecular level. Therefore, the second method deals with modification of gene expression or obstruction of pathogenic biosynthesis of proteins. Correct genes are introduced to cells by special vectors. The retroviral and adenoviral vectors are most frequently used clinically but very often the plasmid DNA is also useful. The number of clinical trials has been rapidly increasing. Cancer, monogenic diseases and cardiovascular diseases are the main targets of clinical gene therapy. Many hopes are linked with the gene therapy of autoimmune diseases in particular by blocking expression of inflammatory cytokines or neutralising cytokine's receptors. Recently discovered phenomenon of interference of RNA (RNAi) has initiated research on inhibition of selected gene expression by using small interfering RNA (siRNA). Despite the significant methodological progress, allowing safe gene therapy still represents a challenge and requires further intensive research.

Genotype and haplotype analysis of ABCB1 at 1236, 2677 and 3435 among systemic sclerosis patients.

Systemic sclerosis (SSc) belongs to the group of systemic diseases of the connective tissue, which are characterized by a chronic autoimmune inflammatory process. P-glycoprotein, initially associated with the drug resistance in patients with cancer, becomes more and more often a subject of considerations in terms of its significance in the development of illnesses, including autoimmune diseases. The aim of the study was an attempt to answer the question whether there was a relationship between ABCB1 polymorphisms and morbidity of systemic sclerosis in a Polish population. The study was carried out in 61 patients with SSc and 100 healthy volunteers. Determination of polymorphisms C1236T and C3435T in ABCB1 was carried out with the PCR-RFLP (polymerase chain reaction - restriction fragment length polymorphism) method. The G2677T/A ABCB1 polymorphism was analysed with the allele-specific PCR method. No statistically significant differences were observed in the frequencies of ABCB1 genotypes and alleles between SSc patients and the control group. It was observed that haplotype 1236 C-2677 G-3435 T occurred in the group of patients with SSc statistically more frequently than in the group of healthy volunteers (25% vs. 15%; p = .032). Carriers of the haplotype demonstrated almost a twofold greater risk of SSc (OR = 1.85; p = .032). No statistically significant correlations for the other nine haplotypes were found. Presented results concerning the relationship of ABCB1 polymorphisms with susceptibility to systemic sclerosis are the first ones that were obtained in a Polish population. They imply that single nucleotide polymorphisms do not affect the risk for SSc, but the 1236 C-2677 G-3435 T haplotype might increase this risk.

Acetylation genotype and phenotype in patients with systemic lupus erythematosus.

UNLABELLED: Systemic lupus erythematosus (SLE) is a chronic autoimmune disease affecting various tissues and organs. In the studies on SLE etiopathogenesis, a potential role of genetically determined impairment of xenobiotic metabolism has been emphasized. N-acetyltransferase 2 enzyme (NAT2) exhibits gene polymorphism and the acetylation rate with NAT2 involvement varies from person to person. The study on acetylation phenotype was carried out using isonicotinic acid hydrazide (isoniazid) as a model drug, while NAT2 alleles were determined by the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) assays. Among patients with SLE, NAT2*4/NAT2*6 and NAT2*5/NAT2*5 genotypes occurred most frequently, while NAT2*4/NAT2*6 and NAT2*5/NAT2*6 prevailed in the control group. The concordance of 96.8% was achieved between acetylation phenotype and NAT2 genotype in the group of SLE patients studied. CONCLUSION: Acetylation polymorphism appears not to be an important risk factor in SLE.

[Genetics in rheumatoid arthritis (RA)]. / Uwarunkowania genetyczne w patogenezie reumatoidalnego zapalenia stawów (RZS).

Rheumatoid arthritis (RA) is a chronic autoimmune disease. Genetic and environmental factors are implicated in the pathogenesis of RA. In this study we describe numerous genetic phenomena that may be implicated in the etiopathogenesis of RA i.e. antigens of major histocompatibility complex, genetic linkage analysis results of whole genome scan and polymorphism of several genes coding receptors, adhesion molecules and cytokines. Genetic background plays an important role in this disorder and is connected with multiple genes.