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1.  Association Study of the 2-bp Deletion Polymorphism in Exon 6 of the CHRFAM7A Gene with Idiopathic Generalized Epilepsy 
DNA and Cell Biology  2013;32(11):640-647.
There is evidence of linkage between the 15q13–q14 locus, containing the gene encoding the α7 subunit (CHRNA7) of the neuronal nicotinic acetylcholine receptor (nAChR) and its partially duplicated isoform (CHRFAM7A), and epilepsy. Additionally, a 2-bp deletion polymorphism (c.497–498delTG; rs67158670) in CHRFAM7A, resulting in a frame shift and truncation of the protein product, is associated with some neurological diseases. This study was designed to explore the possibility of an association of the c.497–498delTG polymorphism of CHRFAM7A with idiopathic generalized epilepsies (IGEs) in Polish children and young patients. The study included 197 IGE patients and 258 unrelated healthy individuals. The frequency of the CHRFAM7A c.497–498delTG polymorphism was determined in each group using heteroduplex analysis. An association between the c.497–498delTG polymorphism of CHRFAM7A and IGE was evidenced. It was demonstrated that the frequency of the CHRFAM7A 2-bp deletion carriers was significantly lower in the IGE patients than in the control group. The observed frequency of 2-bp deletion carriers was high in IGE subjects (64%), but significantly higher in control subjects (76%). Carriers of at least one copy of the −2 bp allele had halved their risk of IGE susceptibility (delTG/delTG and delTG/wild-type versus wild-type/wild-type: odds ratio=0.55; 95% confidence intervals=0.365–0.827; p=0.004). Moreover, it has been demonstrated that this polymorphic variant is associated with the c.524-12_524-11insGTT variation (rs10649395) in intron 7 of CHRFAM7A. Our study substantiates the involvement of the α7 subunit of nAChR in the pathophysiology of IGEs and indicates that the CHRFAM7A c.497–498TG deletion or a nearby polymorphism may play a role in the pathogenesis of IGE. Further work should concentrate on ascertaining the exact mechanism of this polymorphism's effect and its relationship with IGE.
doi:10.1089/dna.2012.1880
PMCID: PMC3806399  PMID: 24024466
2.  Genetic Variants in Diseases of the Extrapyramidal System 
Current Genomics  2014;15(1):18-27.
Knowledge on the genetics of movement disorders has advanced significantly in recent years. It is now recognized that disorders of the basal ganglia have genetic basis and it is suggested that molecular genetic data will provide clues to the pathophysiology of normal and abnormal motor control. Progress in molecular genetic studies, leading to the detection of genetic mutations and loci, has contributed to the understanding of mechanisms of neurodegeneration and has helped clarify the pathogenesis of some neurodegenerative diseases. Molecular studies have also found application in the diagnosis of neurodegenerative diseases, increasing the range of genetic counseling and enabling a more accurate diagno-sis. It seems that understanding pathogenic processes and the significant role of genetics has led to many experiments that may in the future will result in more effective treatment of such diseases as Parkinson’s or Huntington’s. Currently used molecular diagnostics based on DNA analysis can identify 9 neurodegenerative diseases, including spinal cerebellar ataxia inherited in an autosomal dominant manner, dentate-rubro-pallido-luysian atrophy, Friedreich’s disease, ataxia with ocu-lomotorapraxia, Huntington's disease, dystonia type 1, Wilson’s disease, and some cases of Parkinson's disease.
doi:10.2174/1389202914666131210213327
PMCID: PMC3958955  PMID: 24653660
Ataxia; Dystonia; Huntington’s disease; Parkinson’s disease; Wilson s disease.
3.  Molecular Effects of L-dopa Therapy in Parkinson’s Disease 
Current Genomics  2014;15(1):11-17.
Parkinson’s disease (PD) is one of the most common neurological diseases in elderly people. The mean age of onset is 55 years of age, and the risk for developing PD increases 5-fold by the age of 70. In PD, there is impairment in both motor and nonmotor (NMS) functions. The strategy of PD motor dysfunction treatment is simple and generally based on the enhancement of dopaminergic transmission by means of the L-dihydroxyphenylalanine (L-dopa) and dopamine (DA) agonists. L-dopa was discovered in the early -60's of the last century by Hornykiewicz and used for the treatment of patients with PD. L-dopa treatment in PD is related to decreased levels of the neurotransmitter (DA) in striatum and ab-sence of DA transporters on the nerve terminals in the brain. L-dopa may also indirectly stimulate the receptors of the D1 and D2 families. Administration of L-dopa to PD patients, especially long-time therapy, may cause side effects in the form of increased toxicity and inflammatory response, as well as disturbances in biothiols metabolism. Therefore, in PD pa-tients treated with L-dopa, monitoring of oxidative stress markers (8-oxo-2’-deoxyguanosine, apoptotic proteins) and in-flammatory factors (high-sensitivity C-reactive protein, soluble intracellular adhesion molecule), as well as biothiol com-pounds (homocysteine, cysteine, glutathione) is recommended. Administration of vitamins B6, B12, and folates along with an effective therapy with antioxidants and/or anti-inflammatory drugs at an early stage of PD might contribute to improvement in the quality of the life of patients with PD and to slowing down or stopping the progression of the disease.
doi:10.2174/1389202914666131210213042
PMCID: PMC3958954  PMID: 24653659
Oxidative stress; Immune response; Biothiols; L-dopa; PD.
5.  Mutations in PRKN and SNCA Genes Important for the Progress of Parkinson’s Disease 
Current Genomics  2013;14(8):502-517.
Although Parkinson’s disease (PD) was first described almost 200 years ago, it remains an incurable disease with a cause that is not fully understood. Nowadays it is known that disturbances in the structure of pathological proteins in PD can be caused by more than environmental and genetic factors. Despite numerous debates and controversies in the literature about the role of mutations in the SNCA and PRKN genes in the pathogenesis of PD, it is evident that these genes play a key role in maintaining dopamine (DA) neuronal homeostasis and that the dysfunction of this homeostasis is relevant to both familial (FPD) and sporadic (SPD) PD with different onset. In recent years, the importance of alphasynuclein (ASN) in the process of neurodegeneration and neuroprotective function of the Parkin is becoming better understood. Moreover, there have been an increasing number of recent reports indicating the importance of the interaction between these proteins and their encoding genes. Among others interactions, it is suggested that even heterozygous substitution in the PRKN gene in the presence of the variants +2/+2 or +2/+3 of NACP-Rep1 in the SNCA promoter, may increase the risk of PD manifestation, which is probably due to ineffective elimination of over-expressed ASN by the mutated Parkin protein. Finally, it seems that genetic testing may be an important part of diagnostics in patients with PD and may improve the prognostic process in the course of PD. However, only full knowledge of the mechanism of the interaction between the genes associated with the pathogenesis of PD is likely to help explain the currently unknown pathways of selective damage to dopaminergic neurons in the course of PD.
doi:10.2174/1389202914666131210205839
PMCID: PMC3924246  PMID: 24532983
Alpha-synuclein; Parkin; Parkinson’s disease; PRKN; SNCA.
6.  Polymorphism of the COMT, MAO, DAT, NET and 5-HTT Genes, and Biogenic Amines in Parkinson’s Disease 
Current Genomics  2013;14(8):518-533.
Epinephrine (E) and sympathetic nerve stimulation were described by Thomas Renton Elliott in 1905 for the first time. Dopamine (DA), norepinephrine (NE), E, and serotonin (5-HT) belong to the classic biogenic amines (or monoamines). Parkinson’s disease (PD) is among the diseases in which it has been established that catecholamines may account for the neurodegeneration of central and peripheral catecholamine neural systems. PD is a chronic and progressive neurological disorder characterized by resting tremor, rigidity, and bradykinesia, affecting 2% of individuals above the age of 65 years. This disorder is a result of degeneration of DA-producing neurons of the substantia nigra and a significant loss of noradrenergic neurons in the locus coeruleus. In PD and other related neurodegerative diseases, catecholamines play the role of endogenous neurotoxins. Catechol-O-methyltransferase (COMT) and/or monoamine oxidase (MAO) catalyze the metabolism of monoamines. However, the monoamine transporters for DA, NE, and 5-HT namely DAT, NET, and SERT, respectively regulate the monoamine concentration. The metabolism of catecholamines and 5-HT involves common factors. Monoamine transporters represent targets for many pharmacological agents that affect brain function, including psychostimulators and antidepressants. In PD, polymorphisms of the COMT, MAO, DAT, NET, and 5- HTT genes may change the levels of biogenic amines and their metabolic products. The currently available therapies for PD improve the symptoms but do not halt the progression of the disease. The most effective treatment for PD patients is therapy with L-dopa. Combined therapy for PD involves a DA agonist and decarboxylase, MAOs and COMT inhibitors, and is the current optimal form of PD treatment maintaining monoamine balance.
doi:10.2174/1389202914666131210210241
PMCID: PMC3924247  PMID: 24532984
COMT; MAO; Monoamine transporters polymorphism; PD.
7.  Homocysteine Level and Mechanisms of Injury in Parkinson's Disease as Related to MTHFR, MTR, and MTHFD1 Genes Polymorphisms and L-Dopa Treatment 
Current Genomics  2013;14(8):534-542.
An elevated concentration of total homocysteine (tHcy) in plasma and cerebrospinal fluid is considered to be a risk factor for Alzheimer's disease (AD) and Parkinson's disease (PD). Homocysteine (Hcy) levels are influenced by folate concentrations and numerous genetic factors through the folate cycle, however, their role in the pathogenesis of PD remains controversial. Hcy exerts a neurotoxic action and may participate in the mechanisms of neurodegeneration, such as excitotoxicity, oxidative stress, calcium accumulation, and apoptosis. Elevated Hcy levels can lead to prooxidative activity, most probably through direct interaction with N-methyl-D-aspartate (NMDA) receptors and sensitization of dopaminergic neurons to age-related dysfunction and death. Several studies have shown that higher concentration of Hcy in PD is related to long-term administration of levodopa (L-dopa). An elevation of plasma tHcy levels can also reflect deficiencies of cofactors in remethylation of Hcy to methionine (Met) (folates and vitamin B12) and in its transsulfuration to cysteine (Cys) (vitamin B6). It is believed that the increase in the concentration of Hcy in PD can affect genetic polymorphisms of the folate metabolic pathway genes, such as MTHFR (C677T, A1298C and G1793A), MTR (A2756G), and MTHFD1 (G1958A), whose frequencies tend to increase in PD patients, as well as the reduced concentration of B vitamins. In PD, increased levels of Hcy may lead to dementia, depression and progression of the disease.
doi:10.2174/1389202914666131210210559
PMCID: PMC3924248  PMID: 24532985
MTHFR; MTR; MTHFD1 polymorphism; Biothiols, PD.
8.  CYP1A1 Ile462Val Polymorphism as a Risk Factor in Cervical Cancer Development in the Polish Population 
Molecular Diagnosis & Therapy  2014;18(4):445-450.
Background and objective
There are inconsistent data of the cytochrome P450 1A1 (CYP1A1) Ile462Val (rs1048943) single nuclear polymorphism (SNP) as a genetic susceptibility factor for cervical cancer in various populations. Moreover, little is known about the interaction of this SNP with other risk factors, including contraceptive use, postmenopausal status, parity, and tobacco smoking.
Methods
Polymerase chain reaction-restriction fragment length polymorphism was used to study the prevalence of the CYP1A1 Ile462Val SNP in women with cervical cancer (n = 456) and controls (n = 495).
Results
Logistic regression analysis adjusting for age, parity, oral contraceptive use, tobacco smoking, and menopausal status demonstrated that that the CYP1A1 Ile/Val polymorphism was not associated with an increased risk of cervical cancer in all patients. The adjusted odds ratio (OR) for patients with the Ile/Val genotype vs. Ile/Ile genotype was 1.539 (95 % confidence interval [CI] 0.932–2.541, p = 0.091). However, an increase in cervical cancer risk was seen among patients with a positive history of tobacco smoking and parity. The adjusted OR for positive history of tobacco smoking with the Ile/Val vs. Ile/Ile genotypes was 2.978 (95 % CI 1.382–6.418, p = 0.0052). The adjusted OR for parity with the Ile/Val vs. Ile/Ile genotype was 1.739 (95 % CI 1.006–3.009, p = 0.0472).
Conclusion
Our genetic study suggests that the CYP1A1 Ile462Val SNP may be a risk factor for cervical cancer among patients with a positive history of tobacco smoking and parity.
doi:10.1007/s40291-014-0095-2
PMCID: PMC4105588  PMID: 24626963
9.  Vitamin D Receptor Gene BsmI and FokI Polymorphisms in Relation to Ovarian Cancer Risk in the Polish Population 
Background: The role of vitamin D receptor (VDR) single-nucleotide polymorphisms (SNPs) in ovarian cancer has been studied in various populations; however, these results are discordant between different ethnicities. Method: Using the polymerase chain reaction–restriction fragment length polymorphism method, we studied the prevalence of the VDR FokI (rs2228570) and BsmI (rs1544410) SNPs in women with ovarian cancer (n=168) and controls (n=182) in a Polish population. Results: We found a significant contribution of the BsmI SNP Bb+BB-versus-bb dominant inheritance model to ovarian cancer development (p=0.0221, pcorr=0.0442, odds ratio [OR]=1.648 [95% confidence intervals, CI=1.073–2.532]). However, we did not observe an association of the BsmI SNP BB versus Bb+bb recessive inheritance model in patients (p=0.8059, OR=1.093 [95% CI=0.538–2.218]). Moreover, there was no association of FokI SNPs either in Ff+ff versus FF dominant or ff versus Ff+FF recessive inheritance models with ovarian cancer development (p=0.9924, OR=1.002 [95% CI=0.628–1.599] and p=0.1123, OR=1.542 [95% CI=0.901–2.638], respectively). The p-values of the trend test observed for the VDR BsmI and FokI SNPs in patients with ovarian cancer were ptrend=0.0613 and ptrend=0.3655, respectively. Conclusion: Our study indicates that the VDR B gene variant might be a moderate risk factor of ovarian cancer development in the Polish population.
doi:10.1089/gtmb.2012.0332
PMCID: PMC3582284  PMID: 23320576
10.  An Analysis of Polymorphisms Within the Wnt Signaling Pathway in Relation to Ovarian Cancer Risk in a Polish Population 
Molecular Diagnosis & Therapy  2013;18(1):85-91.
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.
doi:10.1007/s40291-013-0059-y
PMCID: PMC3899496  PMID: 24078348
11.  Prevalence of the NKG2D Thr72Ala Polymorphism in Patients with Cervical Carcinoma 
Background: The natural killer group 2, member D (NKG2D) receptor is mainly situated on the surface of NK and CD8+ αβ T cells that are involved in the defense against viral agents and in cancer immunosurveillance. The G>A transition (Thr72Ala) (rs2255336) located in the NKG2D region encoding the transmembrane part of this receptor has been associated with decreased functionality of NK and T cells. Methods: Using polymerase chain reaction–restriction fragment length polymorphisms, we examined the NKG2D Thr72Ala polymorphism in patients with cervical cancer (n=353) and controls (n=366) in a Polish population. Results: We observed an increased frequency of Thr/Thr or/and Thr/Ala genotypes in controls compared with all patients with cervical cancer; however, these differences were not significant. We found a significantly increased frequency of the NKG2D 72Thr allele in controls than in all patients (odds ratio [OR]=0.7410 [95% confidence intervals (CI)=0.5683–0.9662, p=0.0265]). Moreover, stratification of patients based on cancer stage showed a significant increase in the Thr/Thr genotype frequency (OR=0.3086 [95% CI=0.09097–1.047, p=0.0461]), as well as in the Thr/Thr and Thr/Ala genotype frequency (OR=0.4504 [95% CI=0.2891–0.7018, p=0.0003]), in controls compared with patients with cervical cancer in stages III and IV. The frequency of the NKG2D 72Thr allele was also significantly increased in controls as compared with patients in stage III and IV cancer (OR=0.4699 [95% CI=0.3170–0.6967, p=0.0001]). Conclusion: Our studies may suggest that the women with cervical cancer bearing the NKG2D 72Thr gene variant might be protected against progression to advanced stages of this cancer.
doi:10.1089/gtmb.2011.0308
PMCID: PMC3422554  PMID: 22480139
12.  DNMT1, DNMT3A and DNMT3B gene variants in relation to ovarian cancer risk in the Polish population 
Molecular Biology Reports  2013;40(8):4893-4899.
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.
doi:10.1007/s11033-013-2589-0
PMCID: PMC3723978  PMID: 23666104
Ovarian cancer; Polymorphism; DNMT1; DNMT3A; DNMT3B
13.  Involvement of PARP-1 Val762Ala Polymorphism in the Onset of Cervical Cancer in Caucasian Women 
Molecular Diagnosis & Therapy  2013;17(4):239-245.
Background and Objective
Data on the Val762Ala (rs1136410) polymorphism in the poly(adenosine diphosphate [ADP]-ribose) polymerase 1 (PARP-1) gene as a risk factor for various types of cancers in different ethnicities are inconsistent. We studied this association in a Caucasian population.
Methods
Using high-resolution melting curve analysis (HRM), we studied the distribution of the PARP-1 Val762Ala polymorphism in patients with cervical cancer (n = 446) and in controls (n = 491).
Results
Logistic regression analysis adjusting for age, pregnancy, oral contraceptive use, tobacco smoking, and menopausal status demonstrated that the PARP-1 Val762Ala polymorphism was associated with an increased risk of cervical cancer. The adjusted odds ratio (OR) for patients with the Ala/Val genotype versus the Val/Val genotype was 1.381 (95 % CI = 1.025–1.859, p = 0.033), and the adjusted OR for the Ala/Ala or Ala/Val genotype versus the Val/Val genotype was 1.403 (95 % CI = 1.057–1.863, p = 0.019). The p value from the chi-square test of the trend observed for the PARP-1 Val762Ala polymorphism was statistically significant (ptrend = 0.0123). Stratified analyses of the PARP-1 Val762Ala genotype distribution and cervical cancer risk showed that the age-adjusted OR of Ala/Ala or Ala/Val vs Val/Val for pregnancy was 1.388 (95 % CI = 1.027–1.877, p = 0.0328), 1.773 (95 % CI = 1.145–2.745, p = 0.0100) for contraceptive use, and 1.604 (95 % CI = 1.132–2.272, p = 0.0077) for postmenopausal women. The age-adjusted OR of Ala/Val vs Val/Val for contraceptive use was 1.769 (95 % CI = 1.114–2.809, p = 0.0154) and for postmenopausal women was 1.577 (95 % CI = 1.094–2.272, p = 0.0143).
Conclusion
Our studies suggest that the PARP-1 Val762Ala polymorphism may be a genetic risk factor for cervical cancer.
doi:10.1007/s40291-013-0036-5
PMCID: PMC3715681  PMID: 23633189
14.  XRCC1 Arg399Gln Gene Polymorphism and the Risk of Systemic Lupus Erythematosus in the Polish Population 
DNA and Cell Biology  2012;31(1):50-56.
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 χ2 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 phototosensitivity 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.
doi:10.1089/dna.2011.1246
PMCID: PMC3246417  PMID: 21682595
15.  Vitamin D receptor gene BsmI, FokI, ApaI and TaqI polymorphisms and the risk of systemic lupus erythematosus 
Molecular Biology Reports  2012;40(2):803-810.
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.
doi:10.1007/s11033-012-2118-6
PMCID: PMC3538008  PMID: 23065277
VDR polymorphism; SLE; PCR–RFLP
16.  Contribution of toll-like receptor 9 gene single-nucleotide polymorphism to systemic lupus erythematosus 
Rheumatology International  2012;33(5):1121-1125.
There are several studies on the association of TLR9 polymorphisms with systemic lupus erythematosus (SLE) in different ethnicities; however, the results are inconsistent. Therefore, we studied the distribution of the TLR9 C > T (rs352140) polymorphism in patients with SLE (n = 254) and controls (n = 521) in a Polish population. We did not observe significant differences in the prevalence of the TLR9 C > T genotype and alleles between patients with SLE and controls. However, we found a contribution of the T/T and T/C genotypes to renal [OR = 2.949 (95 % CI = 1.523–5.711, p = 0.001), (pcorr = 0.017)] and immunologic disorders [OR = 2.938 (95 % CI 1.500–5.755, p = 0.0012), (pcorr = 0.0204)] in SLE patients. Moreover, we observed a significant association between the TLR9 T/T and T/C genotypes and the presence of anti-dsDNA Ab [OR = 3.682 (1.647–8.230, p = 0.001), (pcorr = 0.017)]. Our studies suggest that the TLR9 C > T (rs352140) polymorphism might contribute to renal and immunologic disorders and to the presence of anti-dsDNA Ab.
doi:10.1007/s00296-012-2509-y
PMCID: PMC3632719  PMID: 22948541
TLR9; Polymorphisms; SLE
17.  Contribution of STAT4 gene single-nucleotide polymorphism to systemic lupus erythematosus in the Polish population 
Molecular Biology Reports  2012;39(9):8861-8866.
The STAT4 has been found to be a susceptible gene in the development of systemic lupus erythematosus (SLE) in various populations. There are evident population differences in the context of clinical manifestations of SLE, therefore we investigated the prevalence of the STAT4 G > C (rs7582694) polymorphism in patients with SLE (n = 253) and controls (n = 521) in a sample of the Polish population. We found that patients with the STAT4 C/G and CC genotypes exhibited a 1.583-fold increased risk of SLE incidence (95 % CI = 1.168–2.145, p = 0.003), with OR for the C/C versus C/G and G/G genotypes was 1.967 (95 % CI = 1.152–3.358, p = 0.0119). The OR for the STAT4 C allele frequency showed a 1.539-fold increased risk of SLE (95 % CI = 1.209–1.959, p = 0.0004). We also observed an increased frequency of STAT4 C/C and C/G genotypes in SLE patients with renal symptoms OR = 2.259 (1.365–3.738, p = 0.0014), (pcorr = 0.0238) and in SLE patients with neurologic manifestations OR = 2.867 (1.467–5.604, p = 0.0016), (pcorr = 0.0272). Moreover, we found a contribution of STAT4 C/C and C/G genotypes to the presence of the anti-snRNP Ab OR = 3.237 (1.667–6.288, p = 0.0003), (pcorr = 0.0051) and the presence of the anti-Scl-70 Ab OR = 2.665 (1.380–5.147, p = 0.0028), (pcorr = 0.0476). Our studies confirmed an association of the STAT4 C (rs7582694) variant with the development of SLE and occurrence of some clinical manifestations of the disease.
Electronic supplementary material
The online version of this article (doi:10.1007/s11033-012-1752-3) contains supplementary material, which is available to authorized users.
doi:10.1007/s11033-012-1752-3
PMCID: PMC3404285  PMID: 22729903
SLE; STAT4; Polymorphism
18.  Involvement of toll-like receptor 9 polymorphism in cervical cancer development 
Molecular Biology Reports  2012;39(8):8425-8430.
The role played by the polymorphism located in Toll-like Receptor 9 (TLR9) as a risk factor of cervical cancer remains elusive. Therefore, we studied the association of the TLR9 −1486 T/C (rs187084) and C2848T (rs352140) polymorphisms with cervical cancer. The TLR9 −1486 T/C and C2848T polymorphism was genotyped in 426 patients and 460 unrelated healthy females from the Polish population. Logistic regression analysis adjusting for age, pregnancy, oral contraceptive use, tobacco smoking, and menopausal status showed that both the TLR9 −1486 T/C and C2848T polymorphisms could be a genetic risk factor for cervical cancer. For the TLR9 −1486 T/C polymorphism, the adjusted OR for patients with the C/T genotype versus T/T genotype was 1.371 (95 % CI 1.021–1.842, p = 0.0361), the adjusted OR for the C/C genotype vs the T/T genotype was 1.300 (95 % CI 1.016–1.507, p = 0.0096), and the adjusted OR for the C/T or C/C genotype vs the T/T genotype was 1.448 (95 % CI 1.099–1.908, p = 0.0083). For the C2848T polymorphism, the adjusted OR for patients with the C/T genotype vs C/C genotype was 1.443 (95 % CI 1.019–2.043, p = 0.0380), the adjusted OR for the T/T genotype vs the C/C genotype was 1.237 (95 % CI 1.016–1.507, p = 0.0328), and the adjusted OR for the T/C or T/T genotype vs the C/C genotype was 1.345 (95 % CI 0.976–1.855, p = 0.0700). Our studies suggest that the TLR9 −1486 T/C and C2848T polymorphisms may be a genetic risk factor for cervical cancer.
doi:10.1007/s11033-012-1695-8
PMCID: PMC3383973  PMID: 22714906
Cervical carcinoma; TLR9; Polymorphisms
19.  Polymorphic variants of genes involved in homocysteine metabolism in celiac disease 
Molecular Biology Reports  2011;39(3):3123-3130.
Celiac disease (CD) is a polygenic chronic enteropathy conferring an increased risk for various nutrient deficiency states. Hyperhomocysteinemia is a frequent finding in CD and may be related to the development of venous thrombosis, cardiovascular disease, and stroke in untreated CD patients. Recently, a possible excess in the frequency of the MTHFR c.677C>T (rs1801133) gene variant in CD patients was reported. The purpose of this study was to determine if there exist differences in the distribution of polymorphic variants of genes involved in homocysteine/methyl group metabolism between CD patients and the general population. A set of 10 gene polymorphisms (MTHFR rs1801133, MTR rs1805087, MTHFD1 rs2236225, MTRR rs1801394, CBS 844ins68, BHMT1 rs7356530 and rs3733890, BHMT2 rs526264 and rs625879, and TCN2 rs1801198) was tested in 134 patients with CD and 160 matched healthy controls. The frequency of the MTR rs1805087 GG genotype in CD patients was lower than in controls (0.01 and 0.06, respectively), although statistical significance was not achieved (P = 0.06). For the other analyzed polymorphisms, there was no evidence of difference in both allelic and genotypic distribution between cases and controls. The exhaustive Multifactor Dimensionality Reduction analysis revealed no combination of interactive polymorphisms predicting the incidence of CD. In contrast to the well-documented clinical observations of increased risks of vascular disease in patients with longstanding untreated CD, in our group of patients no significant association with CD was found for all tested polymorphic variants of genes involved in homocysteine metabolism. These findings should be replicated in studies with a larger sample size.
Electronic supplementary material
The online version of this article (doi:10.1007/s11033-011-1077-7) contains supplementary material, which is available to authorized users.
doi:10.1007/s11033-011-1077-7
PMCID: PMC3271217  PMID: 21688148
MTHFR; MTR; Polymorphisms; Celiac disease; Homocysteine
20.  Monocyte Chemoattractant Protein-1− 2518 A/G Single Nucleotide Polymorphism Might Be Associated with Renal Disease and Thrombocytopenia of SLE 
There is conflicting evidence on the contribution of the MCP-1 −2518 A>G (rs 1024611) polymorphism to SLE incidence and clinical manifestations. We examined the prevalence of the MCP-1 −2518 A>G polymorphism in SLE patients (n = 199) and controls (n = 250) in Poland. We did not observe a significant difference in the distribution of MCP-1 −2518 A>G polymorphic variants in patients with SLE and healthy individuals. However, we found an association between the GG versus AG and AA genotypes as well as the AG and GG versus AA genotypes with renal manifestations of SLE OR = 3.614 (1.123–11.631, P = 0.0345) and OR = 2.297 (1.301–4.057, P = 0.0046), respectively. We also observed that the MCP-1 AG and GG -genotypes contribute to the occurrence of thrombocytopenia in SLE patients OR = 2.618 (1.280–5.352, P = 0.0089). Our observations indicate that either MCP-1 −2518 G variant can be associated with some clinical findings in patients with SLE.
doi:10.1155/2010/130265
PMCID: PMC2858281  PMID: 20414371

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