Assessment of clinical outcomes in breast cancer patients treated with taxanes: multi-analytical approach

Polymorphisms in genes encoding CYPs (Phase I) and ABCB1 (Phase III) enzymes may attribute to variability of efficacy of taxanes. The present study aims to find the influence of CYP and ABCB1 gene polymorphisms on taxanes based clinical outcomes. 132 breast cancer patients treated with taxanes based chemotherapy were genotyped for CYP3A4*1B, CYP3A5*3, CYP1B1*3, CYP2C8*3, ABCB1 1236C>T, 2677G>T/A and 3435C>T polymorphisms using PCR-RFLP. Associations of genetic variants with clinical outcomes in terms of response in 58 patients receiving neo-adjuvant chemotherapy (NACT), and chemo-toxicity in 132 patients were studied. Multifactor dimensionality reduction (MDR) analysis was performed to evaluate higher order gene–gene interactions with clinical outcomes. Pathological response to taxane based NACT was associated with GA genotype as well as A allele of CYP3A5*3 polymorphism (P_corr = 0.0465, P_corr = 0.0465). Similarly, association was found in dominant model of CYP3A5*3 polymorphism with responders (P_corr = 0.0465). Haplotype analysis further revealed A_CYP3A4–A_CYP3A5 haplotype to be significantly associated with responders (P_corr = 0.048). In assessing toxicity, significant association of variant (TT) genotype and T allele of ABCB1 2677G>T/A polymorphism, was found with ‘grade 1 or no leucopenia’ (P_corr = 0.0465, P_corr = 0.048). On evaluating higher order gene–gene interaction models by MDR analysis, CYP3A5*3; ABCB11236C>T and ABCB1 2677G>T/A; ABCB1 3435C>T and CYP1B1*3 showed significant association with treatment response, grade 2–4 anemia and dose delay/reduction due to neutropenia (P = 0.024, P = 0.004, P = 0.026), respectively. Multi-analytical approaches may provide a better assessment of pharmacogenetic based treatment outcomes in breast cancer patients treated with taxanes.     

Relation between 3435C>T multidrug resistance 1 gene polymorphism with high dose methylprednisolone treatment of childhood acute idiopathic thrombocytopenic purpura

The current study was conducted to assess 3435C>T multidrug resistance 1 gene polymorphism and the efficacy of high dose methylprednisolone (HDMP) in childhood acute idiopathic thrombocytopenic purpura patients.

Methods

A total of 31 childhood acute Idiopathic thrombocytopenic purpura patients (17 females, 14 males) between the ages of 2 and 16 years of age were included in the study. High-dose methylprednisolone was given at a dose of 30 mg/kg/day for 3 days and 20 mg/kg/day for 4 days, consecutively and intravenously. Polymerase chain reaction-restriction fragment length polymorphism was used for the detection of C3435T single nucleotide polymorphism. Fragments obtained were 238 bp to T/T genotype, 172 bp and 60 bp fragments to the C/C genotype, and 238 bp, 172 bp and 60 bp to the C/T genotype.

Results

The distribution of CC, CT, and TT genotypes were 19.0%, 61.3%, and 19.4%, respectively. Both allele frequencies of C and T were the same — 50%. There was no significant difference in genotype and allele distribution between the patients with ITP and the control group (χ² = 0.84 p = 0.65, χ² = 0.2 p = 0.63, respectively). There were no significant differences in age, gender, and pre- and post-treatment platelet counts between CC, CT, and TT genotypes of the MDR gene. Response to treatment shows no significant difference between genotype and allele groups.

Conclusion

In our study, there was no difference in the HDMP treatment response between MDR1 gene genotypes. However, it should be noted that this study includes a small group of patients. Our data should therefore be considered preliminary, awaiting further confirmatory studies on an expanded patient base.     

Multi-drug resistance-1 gene polymorphisms in nephrotic syndrome: Impact on susceptibility and response to steroids

Background

Role of multidrug resistance-1 (MDR-1) gene polymorphisms has not been clarified in nephrotic syndrome (NS). Additionally, researchers studied several genetic polymorphisms to explain their influence on different patients' responses to steroid; however the data were inconsistent. Therefore, we aimed to investigate the association of MDR-1 gene polymorphisms [C1236T, G2677T/A, C3435T] and haplotypes with susceptibility to childhood nephrotic syndrome, and whether they influence steroid response.

Methods

We detected MDR-1 gene polymorphisms using polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP) in 138 NS patients and 140 age and sex matched healthy children.

Results

The frequencies of MDR1 G2677T/A GT, GA, TT + AA genotypes or T allele, MDR1 C3435T TT genotype, and T allele genotype frequencies were significantly increased in NS group. While no significant differences were observed in distributions of C1236T genotypes or allele between NS patients and healthy children. Moreover, steroid non-responder NS patients had significantly higher frequencies of MDR1 G2677T/A GT, GA, and TT + AA genotypes than steroid responsive NS patients. We observed also that NS patients with age less than 6 years old had increased frequencies of MDR1 G2677T/A GT, GA, TT + AA genotypes or T allele MDR1 C3435T CT, TT genotypes and T allele. Interestingly the frequency of the TGC haplotype of MDR1 was lower in the initial steroid responders than in non-responders NS patients. On the contrary, there were no any association between the MDR1 haplotypes with NS susceptibility and they did not influence renal pathological findings.

Conclusion

Our data suggested that MDR1 C3435T or G2677T/A gene polymorphisms are risk factors of increased susceptibility, earlier onset of NS, and steroid resistance.     

The effect of ABCB1 C3435T polymorphism on pharmacokinetics of tacrolimus in liver transplantation: A meta-analysis

Objectives

The effect of ABCB1 C3435T SNP on the pharmacokinetics of immunosuppressive drug tacrolimus in different studies was conflicting. So a meta-analysis was employed to study the correlation of ABCB1 C3435T SNP and the pharmacokinetics of tacrolimus at different post-transplantation times.

Method

Several studies about ABCB1 C3435T polymorphism and the pharmacokinetics of tacrolimus were collected through the search on PubMed and the Cochrane Library. After the extraction of pharmacokinetic parameters from these studies, a meta-analysis was performed on the software STATA version11.0.

Results

A total of 9 studies were adopted including 558 liver transplant recipients. For the dose of tacrolimus, the subjects with wild-type CC had a significantly higher tacrolimus dose than homozygous mutated genotype TT within 1 week (WMD = 0.01 (0.00, 0.02), P = 0.014) and the similar result in recipients with heterozygous CT compared with TT after transplantation for 1 month (WMD = 0.01 (0.00, 0.02), P = 0.002). For the tacrolimus concentration/dose ratio, subjects with CT had higher C/D ratio than those with CC and TT at different post-transplantation times. A subgroup analysis based on different ethnic populations was also carried out. Donors' genotypes were also considered in this meta-analysis.

Conclusion

Through this meta-analysis for the including studies about the pharmacokinetics of tacrolimus and ABCB1 C3435T SNP, several significant associations were obtained. Particularly, the Caucasians showed more significant associations between the C/D ratio and ABCB1 C3435T polymorphism; however, the correlations were not steady at different post-transplantation times.     

Influence of MDR1 C1236T polymorphism on lopinavir plasma concentration and virological response in HIV-1-infected children

Background

Variability in MDR1 and PXR has been associated with differences in drug plasma levels and response to antiretroviral therapy. We investigated whether polymorphisms in MDR1 (T-129C, C1236T and C3435T) and PXR (C63396T) affect lopinavir plasma concentration and the virological or immunological response to HAART in HIV-1-infected children.

Methods

Genotypes were identified in 100 blood donors and 38 HIV-1-infected children. All children received HAART with lopinavir boosted with ritonavir (LPV/r) at the time of LPV plasma level quantification, before (C_trough) and between 1 and 2 h after (C_post-dose) the administration of the next dose of drug. CD4⁺ T-cell counts and plasma viral load were analyzed before and after the initiation of LPV/r.

Results

MDR1 1236T, MDR1 3435T and PXR 63396T alleles showed a frequency of ~ 50% while the MDR1 -129C allele only reached 5%. Children heterozygotes 1236CT showed a significantly lower LPV C_post-dose than homozygotes 1236TT (median C_post-dose = 3.04 μg/ml and 6.50 μg/ml, respectively; p = 0.016). Children heterozygotes 1236CT also had a lower decrease of viral load after 36 weeks of LPV/r exposure compared with homozygotes 1236CC (median viral load changes = − 0.50 log₁₀ copies/ml and − 2.08 log₁₀ copies/ml, respectively; p = 0.047). No effect on the immunological response was observed for polymorphisms of MDR1 or PXR.

Conclusions

Our results suggest that the MDR1 C1236T SNP significantly reduces LPV plasma concentration affecting the virological response to HAART. Heterozygotes 1236CT might have an altered level of P-gp expression/activity in enterocytes and CD4⁺ T lymphocytes that limits the absorption of LPV leading to an impaired virological suppression.     

Methylenetetrahydrofolate reductase C677T mutation in patients with alopecia areata in Turkish population

Objective

Methylene-tetrahydrofolate reductase (MTHFR) is a key enzyme regulating folate metabolism and it is thought to influence DNA methylation and nucleic acid synthesis. Mutations in the MTHFR gene have been associated with several autoimmune disorders in previous studies. Alopecia areata (AA) is considered to be a tissue-specific autoimmune disease as the hair follicle has been targeted and antibodies to their own hair follicle structures have been developed. Since there is a common shared pathway between AA and other autoimmune disorders, we aimed to investigate a possible association between the MTHFR gene C677T mutation and AA susceptibility in the Turkish population.

Methods

The study included 136 patients affected by AA and 130 healthy controls. Genomic DNA was isolated and genotyped using a polymerase chain reaction (PCR)-based restriction fragment length polymorphism (RFLP) assay for the MTHFR gene C677T mutation.

Results

The distributions of genotype and allele frequencies of MTHFR gene C677T mutation were statistically different between AA patients and the control group (p = 0.036 and p = 0.011, respectively). High differences were also observed when the patients and controls were compared according to CC versus CT + TT (p = 0.012). CT + TT genotypes and T allele of MTHFR gene C677T mutation were found to be a susceptibility factor for AA in the Turkish population.

Conclusion

The results suggest that MTHFR gene C677T mutation may have an effect on the risk of alopecia areata in the Turkish population. This is the first study reporting the association between the MTHFR (C677T) genotype and AA.     

Association between fibromyalgia syndrome and polymorphism of the IL-4 gene in a Turkish population

Purpose

Fibromyalgia (FM) syndrome is a form of non-articular rheumatism characterized by long term and widespread musculoskeletal pain, morning stiffness, sleep disturbance, paresthesia, and pressure hyperalgesia at characteristic sites, called soft tissue tender points. The etiology of FM is still obscure. Genetic factors may predispose individuals to FM. Cytokines may play a role in the pathophysiology of FM. The aim of this study was to investigate the interleukin-4 (IL-4) 70 bp VNTR variations in Turkish patients with FM and evaluate if there was an association with clinical features, especially between these polymorphisms.

Methods

The study included 300 patients with FM and 270 healthy controls. Genomic DNA was isolated and genotyped using polymerase chain reaction (PCR) for the IL-4 gene 70 bp VNTR polymorphisms.

Results

There was statistically significant difference between the groups with respect to IL-4 genotype distribution and allele frequencies (p < 0.0001). The homozygous P₁P₁ genotype and P₁ allele were significantly higher in FM patients than in healthy controls (p = 0.04; OR: 3.25, 95% CI: 1–10, p < 0.0001; OR:4.84, 95% CI:3–7.7). There was not any difference between the groups respect to IL-4 genotype distribution and allele frequencies (p > 0.05) and clinical characteristics.

Conclusion

Our findings suggest that there is an association of IL-4 gene 70 bp VNTR polymorphism with susceptibility of a person for development of FM. As a result, further studies are necessary to determine whether IL-4 may be a genetic marker for FM in the Turkish population.     

MDR1 gene polymorphisms may be associated with Behçet's disease and its colchicum treatment response

Behçet's disease (BD) is a chronic multisystem disorder. Infectious agents, immune system mechanisms, and genetic factors are implicated in the etiopathogenesis of BD, which remains to be explained. The human MDR1 (ABCB1) gene encoder P-glycoprotein (P-gp) plays a key role in drug disposition, serves as a protective mechanism against xenobiotics, and provides additional protection for the brain, testis, and fetus. We investigated the genotype and haplotype distributions of three MDR1 gene polymorphisms (C1236T, G2677T/A, and C3435T) in 104 BD patients and 130 control subjects. The genotyping analysis was performed by using PCR–RFLP methods.     

Association between interleukin 4 gene intron 3 VNTR polymorphism and recurrent aphthous stomatitis in a cohort of Turkish patients

Objective

Recurrent aphthous stomatitis (RAS) is one of the most common oral mucosal diseases, with a multifactorial etiopathogenesis, an interaction between predisposing factors and/or systemic conditions and immunological components in genetically predisposed subjects. Although there is no clear genetic mode of inheritance, there is evidence that inheritance of specific gene polymorphisms may predispose individuals to RAS. The purpose of the present study was to investigate a possible association between the functional interleukin 4 (IL4) VNTR genetic polymorphism and RAS in a sample of Turkish patients.

Methods

The study included 145 unrelated patients with a clinical diagnosis of RAS and 150 unrelated healthy controls. Genomic DNA was isolated and IL4 gene 70 bp VNTR polymorphism determined by using polymerase chain reaction (PCR) with specific primers.

Results

The distribution of genotype and allele frequencies of IL4 gene intron 3 VNTR polymorphism was statistically different between RAS patients and control group (p < 0.0001 and p < 0.0001, respectively) P2P2 genotype and P2 allele were also found to be protective with a lower risk for susceptibility to RAS (p < 0.0001).

Conclusion

The results of this study suggest that intron 3 VNTR polymorphism in the IL4 gene is associated with RAS susceptibility in Turkish population.     

ABCB1 genotypes and haplotypes in patients with dementia and age-matched non-demented control patients

Amyloid β is an in vitro substrate for P-glycoprotein (P-gp), an efflux pump at the blood brain barrier (BBB). The Multi Drug Resistance (ABCB1) gene, encoding for P-gp, is highly polymorphic and this may result in a changed function of P-gp and may possibly interfere with the pathogenesis of Alzheimer's disease. This study investigates to what extent ABCB1 Single Nucleotide Polymorphisms (SNPs; C1236T in exon 12, G2677T/A in exon 21 and C3435T in exon 26) and inferred haplotypes exist in an elderly population and if these SNPs and haplotypes differ between patients with dementia and age-matched non-demented control patients. ABCB1 genotype, allele and haplotype frequencies were neither significantly different between patients with dementia and age-matched controls, nor between subgroups of different types of dementia nor age-matched controls. This study shows ABCB1 genotype frequencies to be comparable with described younger populations. To our knowledge this is the first study on ABCB1 genotypes in dementia. ABCB1 genotypes are presently not useful as a biomarker for dementia, as they were not significantly different between demented patients and age-matched control subjects.     

Association of angiotensin converting enzyme (ACE) gene I/D polymorphism and rheumatoid arthritis

We sought to determine the frequency of I/D polymorphism genotypes of angiotensin converting enzyme gene in Turkish patients with rheumatoid arthritis. Genomic DNA obtained from 256 individuals (110 patients with rheumatoid arthritis and 146 healthy controls) was used in the study. ACE gene I/D polymorphism genotypes were determined using polymerase chain reaction using I and D allele-specific primers. There was a statistically significant difference between the groups with respect to genotype distribution (p = 0.001). A significant difference was found in frequencies of ACE I/D alleles between patients and controls, with RA patients having a higher representation of D and lower representation of I alleles compared to controls (p < 0.001). As a result of our study, angiotensin converting enzyme gene I/D polymorphism DD genotype could be a genetic marker in rheumatoid arthritis in the Turkish study population.     

Association between MDR1 C3435T polymorphism and risk of breast cancer

The C3435T (rs1045642) polymorphism, located in multi-drug resistance gene 1 (MDR1), has demonstrated its role in decreasing the P-gp activity level which is related to the carcinogenesis. Many published studies have evaluated the association between the MDR1 C3435T polymorphism and breast cancer risk. However, the results remain conflicting rather than conclusive. To derive a more precise estimation of the association between MDR1 C3435T polymorphism and risk of breast cancer, we performed a meta-analysis comprised of 10 case–control studies, including 5282 breast cancer cases and 7703 controls. Odds ratios (ORs) and 95% confidence intervals (CIs) were used to evaluate the strength of the association. The overall results indicated that the variant genotypes were associated with a significantly increased risk of breast cancer (TT versus CC: OR = 1.45, 95% CI = 1.14–1.30, TT versus CT/CC: OR = 1.13, 95% CI = 1.04–1.23, TT/CT versus CC: OR = 1.22, 95% CI = 1.02–1.46). Our results suggest that the MDR1 C3435T polymorphism may contribute to individual susceptibility to breast cancer.     

AT2R − 1332 G:A polymorphism and its interaction with AT1R 1166 A:C,ACE I/D and MMP-9 − 1562 C:T polymorphisms: Risk factors for susceptibility to preeclampsia

The possible association of angiotensin type 2 receptor (AT2R) − 1332 G:A polymorphism with susceptibility to preeclampsia was studied in 252 women consisted of 155 women with preeclampsia and 97 healthy pregnant women. Also, the interaction of this polymorphism with angiotensin type 1 receptor (AT1R) 1166 A:C, angiotensin converting enzyme insertion/deletion (ACE I/D) and also with matrix metalloproteinase-9 (MMP-9) − 1562 C:T polymorphism was investigated. The AT2R − 1332 G:A polymorphism was detected using PCR–RFLP method. Significantly higher frequencies of GG+GA genotype and G allele of AT2R were observed in mild (80.2%, p = 0.003 and 47.5%, p = 0.012, respectively) and severe (77.8%, p = 0.034 and 48.1%, p = 0.026, respectively) preeclampsia compared to controls (60.8% and 35.1%, respectively). The presence of G allele was associated with 1.69-fold increased risk of preeclampsia (p = 0.005). In severe preeclamptic women, systolic and diastolic blood pressures in the presence of GG+GA genotype were significantly higher compared to those in the presence of AA genotype. The concomitant presence of both alleles of AT2R G and AT1R C was associated with 1.3 times increased risk of mild preeclampsia (p = 0.03). There was an interaction between AT2R G and ACE D alleles that significantly increased the risk of mild and severe preeclampsia by 1.38- and 1.3-fold, respectively. Also, interaction between MMP-9 T and AT2R G alleles increased the risk of severe preeclampsia 1.39-fold (p = 0.028). Our study demonstrated that the G allele of AT2R − 1332 G:A polymorphism is associated with an increased risk of preeclampsia. Also, epistatic interaction of G allele and each allele of the AT1R C, ACE D and MMP-9 T was associated with the risk of preeclampsia. Our findings suggest that the renin–angiotensin system (RAS) variants and gene–gene interactions affect the risk of preeclampsia.     

The association of MDR1 C3435T and G2677T/A polymorphisms with plasma platelet-activating factor levels and coronary artery disease risk in Turkish population

Increased levels of peripheral proinflammatory mediators can contribute to the development of coronary artery disease (CAD). Platelet activating factor (PAF) is an important proinflammatory mediator and plasma levels of PAF correlate with transmembrane transporter multidrug resistant 1 P-glycoprotein (MDR1 Pgp) expression and activity. MDR1 polymorphisms can affect the expression and activity of Pgp and plasma PAF levels. Therefore, we investigated the possible relationship between MDR1 C3435T and G2677T/A polymorphisms and plasma PAF levels and the risk of CAD. The study population consisted of 198 patients angiographically documented CAD, including 113 cases with at least 1 coronary artery with ≥ 50% luminal diameter stenosis and 85 control subjects with strictly normal coronary angiograms. Genotypes of the MDR1 C3435T and G2677T/A polymorphisms were determined by polymerase chain reaction (PCR) followed by restriction fragment length polymorphism (RFLP). Plasma PAF levels were detected by enzyme-linked immunosorbent assay (ELISA). There were no significant differences among plasma PAF levels in regard to MDR1 C3435T and G2677T polymorphisms in CAD patients and controls. No statistically significant difference was found for the genotypic and allelic distributions of the polymorphisms in the MDR1 gene between the patients and the control subjects. Furthermore, analysis of MDR1 haplotypes did not show any associations with increased plasma PAF levels and risk of CAD. Our results suggest that plasma PAF levels are not associated with MDR1 gene polymorphisms. There is no association between MDR1 C3435T and G2677T/A polymorphisms and the risk of CAD in Turkish patients.     

Is Sp1 binding site polymorphism within COL1A1 gene associated with tennis elbow?

Tennis elbow defines a condition of pain and tenderness over the lateral epicondyle of the humerus. The exact aetiology of the injury is not yet fully understood. The major constituent of tendons is type 1 collagen which is encoded by COL1A1 gene. The aim of the study was to determine whether Sp1 binding site polymorphism (SNP rs1800012; 1546G/T) within the intronic region of COL1A1 gene is associated with tennis elbow. One hundred and three tennis elbow patients and one hundred and three healthy subjects without any history of previous ligament or tendon injuries were recruited for this genetic association study. All participants were genotyped for the COL1A1 Sp1 binding site polymorphism by using PCR–RFLP method. There were no observed statistical differences in the genotype (p = 0.17) or allele (p = 0.11) distributions between the groups. G allele frequency in patients and controls was 82.5% and 76.21%, and T allele frequency was 17.5% and 23.79% respectively. This study has shown that there is no association between this polymorphism and tennis elbow within the population studied.     

Association between 1603C>T polymorphism of DBH gene and bipolar disorder in a Turkish population

Objectives

Dopamine-β-hydroxylase (DBH) is the enzyme responsible for the conversion of dopamine (DA) to norepinephrine (NE, noradrenaline) which is a key neurotransmitter in the central and peripheral nervous systems. Bipolar disorder is a major psychiatric disorder. The present study was designed to explore the associations of polymorphisms of DBH gene in Turkish patients with bipolar disorder.

Methods

− 1021C>T (rs1611115) polymorphism in promoter region, 444G>A (rs1108580) polymorphism in exon 2 and 1603C>T (rs6271; C535R) polymorphism in exon11 of DBH gene were analyzed in 106 patients with bipolar disorder and 106 healthy subjects by using polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP) analysis.

Results

The results showed statistically significant associations for genotypic and allelic distribution between the 1603C>T polymorphism and bipolar disease (p = 0.0012 and p = 0.034, respectively). There was no association observed between the genotype and allelic frequencies for − 1021C>T and 444G>A polymorphisms and bipolar disorder.

Conclusions

Our data suggests that the 1603C>T polymorphism of the DBH gene is associated with susceptibility to bipolar disorder in a Turkish population.     

Genotype and allele frequency of human multidrug resistance (MDR1) gene C3435T polymorphism in Denizli province of Turkey

Human p-glycoprotein encoded by human multidrug resistance (MDR1) gene, is a transmembrane protein that serves as efflux pump for a wide variety of lipophilic compounds possessing a physiological role in protecting cells against the DNA damaging of certain xenobiotics. According to the published data, the frequency of C3435T polymorphism differs depending on the different ethnical populations such as Asian, African, and Caucasians populations. In our study, we identified the MDR1 C3435T polymorphism in 150 healthy volunteers in Denizli province of Turkey. DNA was extracted from peripheral blood samples by standard phenol/chloroform extraction method. Polymerase chain reaction–restriction fragment length polymorphism was used for the detection of C3435T single nucleotide polymorphism. We obtained CC, CT and TT genotype frequencies as 20, 53 and 27%, respectively. According to our results, the C allele in Turkish population (Denizli province, west of Turkey) is found 47% and this data shows similarity with Caucasian (UK and German) populations and significantly lower than African populations (p < 0.001). Our study is the first data on the genotype and allele frequency of the human multidrug resistance (MDR1) Gene C3435T Polymorphism in Denizli Province at regional basis in Turkey. Our results could serve as a basis for large-scale correlation studies on the relevance of C3435T genotype in cancer therapy and other diseases in Turkish population. Investigation of genotype frequencies related with p-glycoprotein substrates should be investigated in large scale at regional bases in Turkish population. The scaled-up data might help either to the use of p-glycoprotein substrates to be used for therapeutic applications and population genetics considering the genotype frequencies possibly occurring throughout the history in Anatolian basin.     

Association between osteoporosis and polymorphisms of the bone Gla protein, estrogen receptor 1, collagen 1-A1 and calcitonin receptor genes in Turkish postmenopausal women

In this study, we have investigated the association between osteoporosis and osteocalcin (BGLAP) − 298 C>T, estrogen receptor 1 (ER1) 397 T>C, collagen type1 alpha 1 (Col1A1) 2046 G>T and calcitonin receptor (CALCR) 1340 T>C polymorphisms. Genomic DNA was obtained from 266 persons (158 osteoporotic and 108 healthy controls). Genomic DNA was extracted from EDTA-preserved peripheral venous blood of patients and controls by a salting-out method and analyzed by PCR-RFLP. As a result, there was no statistically significant difference in the genotype and allele frequencies of patients and controls for BGLAP − 298 C>T, Col1A1 2046 G>T, ER1 397 T>C and CALCR 1340 T>C polymorphisms. However, ER1 CC genotype compared with TT + TC genotypes was found to increase the two fold the risk of osteoporosis [p = 0.039, OR = 2.156, 95% CI (1.083–4.293)] and CALCR CC genotype compared with TT + TC genotypes was found to have protective effect against osteoporosis [p = 0.045, OR = 0.471, 95% CI (0.237–0.9372)]. In the combined genotype analysis, ER1/CALCR TCCC combined genotype was estimated to have protective effect against osteoporosis [p = 0.0125, OR = 0.323, 95% CI (0.1383–0.755)] whereas BGLAP/Col1A1 CCTT and ER1/CALCR CCTT combined genotypes were estimated as risk factors for osteoporosis in Turkish population (p = 0.027, p = 0.009 respectively).     

The role of Multidrug Resistance-1 (MDR1) variants in response to atorvastatin among Jordanians

The MDR1 gene encodes for P-glycoprotein (P-gp), which is an efflux transporter at the cell membrane. The P-gp has wide substrate specificity for multiple medications including the lipid lowering drug, atorvastatin. In this study, we investigated the possible association between three common MDR1 gene polymorphisms (G2677T, C3435T, and C1236T), and the lipid lowering effect of atorvastatin among Jordanians. Lipid and lipoproteins were measured in blood samples collected from patients (n = 201) at baseline and during atorvastatin treatment. MDR1 polymorphisms were genotyped using polymerase chain reaction–restriction fragment length polymorphism. Both the TT genotype of G2677T and the TT genotype of the C3435T polymorphisms were associated with lower levels of low-density lipoproteins after atorvastatin treatment. However, the effects of atorvastatin on the levels of total cholesterol, triglycerides, and high-density lipoprotein, were not correlated with any of the genotypes in both polymorphisms. Finally, the C1236T polymorphism was not associated with the lipid lowering effect of atorvastatin. In conclusion, the MDR1 gene polymorphisms G2677T, and C3435T, but not C1236T were associated with the lipid lowering effect of atorvastatin among Jordanians.     

Characterization of pharmacogenetically relevant CYP2D6 and ABCB1 gene polymorphisms in a Portuguese population sample

Differences in metabolism of drugs can lead to severe toxicity or therapeutic failure. In addition to cytochrome P450 2D6, which plays a critical role in drug metabolism, ABCB1 encoded P‐glycoprotein (PGP) is also an important determinant in drug bioavailability. The genes encoding these molecules are highly variable among populations and, given their clinical importance in drug therapy, determining CYP2D6 and ABCB1 allele frequencies in specific populations is very important for useful application in clinical settings. In this study the frequency of the pharmacologically relevant CYP2D6*3, *4, *5, *6 allelic variants and gene duplication, and ABCB1 C1236T and C3435T gene polymorphisms and their haplotypes was determined in a population sample of 100 Portuguese healthy subjects. CYP2D6 allele frequencies were 1.4% (*3), 13.3% (*4), 2.8% (*5), 1.8% (*6) and 6.1% (gene duplication), with 5% of the individuals classified as PM and 8.4% as UM. The frequencies obtained for the non‐functional alleles and for the CYP2D6 gene duplication are in agreement with other South European populations, and reinforce the previously suggested south/north gradient of CYP2D6 duplications. Allelic frequencies for the ABCB1 polymorphisms were 52% (3435C) and 54% (1236C) and the most common haplotype (1236C‐3435C) occurred with a frequency of 45.5%. Although allele and haplotype frequency data for ABCB1 in Southern Europe is limited, some discrepancies were found with other European populations, with possible therapeutic implications for PGP substrate drugs. Copyright © 2009 John Wiley & Sons, Ltd.