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PubMed2000

Alpha-1-antitrypsin phenotypes in patients with renal arterial fibromuscular dysplasia.

Fibromuscular dysplasia (FMD) is a significant cause of renal artery stenosis, especially in young females. A rare association between FMD and alpha 1-antitrypsin (alpha 1-AT) deficiency has been reported. We compared the alpha 1-AT phenotype distribution in 83 patients with renal arterial FMD with those published for Australian populations. alpha 1-AT phenotyping was performed by isoelectric focusing between pH 4.2 and pH 4.9 on polyacrylamide gels with PiM1M2, PiFM (non-deficiency alleles), PiMS and PiMZ (deficiency alleles) markers. Following phenotyping, alpha 1-AT genotyping was performed in 10 patients to confirm the presence of S and/or Z alleles. The phenotype distribution and allele frequencies were similar to those reported for normal subjects from two Australian populations (72 (86.7%) PiMM phenotype, one (1.2%) PiFM, seven (8.4%) PiMS, two (2.4%) PiMZ and one (1.2%) PiSZ), suggesting that alpha 1-AT deficiency is not a common aetiological factor in renal arterial FMD. However, despite FMD being three times less common in males than females, and carotid artery dissection being a rare occurrence, a male with PiMS deficiency phenotype presented with internal carotid artery dissection and had bilateral renal artery FMD. Further, a patient with PiSZ deficiency phenotype was one of two sisters with FMD and was more severely affected than her PiMM normal phenotype sibling. These two patients from the present series together with nine culled from the literature with alpha 1-AT deficiency phenotype and FMD suggest that the chance combination of alpha 1-AT deficiency and FMD may predispose to severe manifestations of FMD.

Female↗

PubMed2004

Genetic polymorphism of cytochrome P450 2C19 in healthy Malaysian subjects.

AIMS: Impaired S-mephenytoin 4'-hydroxylation is a well-described genetic polymorphism affecting drug metabolism in humans. Although ethnic differences in its distribution of polymorphism has been described, it is not known whether there is an ethnic heterogeneity of the structure and expression of the CYP2C19 enzyme in the Malaysian population. METHODS: Study subjects were 142 healthy, unrelated Malaysians aged 18-29 years. Baseline omeprazole and 2-h postingestion omeprazole and 5'-hydroxyomeprazole concentrations were measured for CYP2C19 phenotype determination. Identification of CYP2C19 genotypes was performed with the use of polymerase chain reaction. RESULTS: Phenotyping of CYP2C19 revealed that the prevalence of poor metabolizers (PMs) in the Malaysian population was 14.1%, whereas prevalence of PMs in genotyping was 12.6%. The PM genotypic prevalence rate was 5.6% in Malays, 19.1% in Chinese and 10.0% in Indian subjects. There were significant differences in PM genotypic prevalence rates among the three primary ethnic groups (P < or = 0.05). CONCLUSIONS: Phenotyping and genotyping revealed significant differences in the prevalence rates among the three ethnic groups in Malaysia, with Chinese recording highest prevalence.

2-Pyridinylmethylsulfinylbenzimidazoles↗

PubMed2005

Results of a case-detection programme for alpha1-antitrypsin deficiency in COPD patients.

Alpha1-antitrypsin (alpha1-AT) deficiency is an underdiagnosed condition in patients with chronic obstructive pulmonary disease (COPD). The present authors have conducted a nationwide case detection programme of alpha1-AT deficiency in unselected patients with COPD using dried blood spots. The first phase analysed samples from 971 patients by determining alpha1-AT concentrations and identifying the deficient Z allele by genotyping using rapid real-time PCR. The second phase analysed 1,166 samples with alpha1-AT concentrations and identified both the S and the Z allele, but only in samples with low alpha1-AT concentrations. A total of eight (0.37%) individuals with the severe deficiency PiZZ were detected. In addition, three patients were identified with the PiSZ genotype in the second phase (0.3%). The global cost of the programme was 41,512, which represents 19.42 per sample and 5,189 per PiZZ detected. A sensitivity analysis demonstrated that performing Z genotype to all samples would have resulted in increased costs of 28 per sample and 7,479.5 per PiZZ case identified. In conclusion, a case detection programme of alpha1-antitrypsin deficiency in patients with chronic obstructive pulmonary disease using dried blood spots is feasible and at a reasonable cost per case detected. Diagnostic yield and costs depend largely on inclusion criteria and the protocol for processing of samples.

Adult↗

PubMed2003

Genome-wide scan for quantitative trait loci influencing LDL size and plasma triglyceride in familial hypertriglyceridemia.

Small, dense LDLs and hypertriglyceridemia, two highly correlated and genetically influenced risk factors, are known to predict for risk of coronary heart disease. The objective of this study was to perform a whole-genome scan for linkage to LDL size and triglyceride (TG) levels in 26 kindreds with familial hypertriglyceridemia (FHTG). LDL size was estimated using gradient gel electrophoresis, and genotyping was performed for 355 autosomal markers with an average heterozygosity of 76% and an average spacing of 10.2 centimorgans (cMs). Using variance components linkage analysis, one possible linkage was found for LDL size [logarithm of odds (LOD) = 2.1] on chromosome 6, peak at 140 cM distal to marker F13A1 (closest marker D6S2436). With adjustment for TG and/or HDL cholesterol, the LOD scores were reduced, but remained in exactly the same location. For TG, LOD scores of 2.56 and 2.44 were observed at two locations on chromosome 15, with peaks at 29 and 61 cM distal to marker D15S822 (closest markers D15S643 and D15S211, respectively). These peaks were retained with adjustment for LDL size and/or HDL cholesterol. These findings, if confirmed, suggest that LDL particle size and plasma TG levels could be caused by two different genetic loci in FHTG.

Apolipoproteins↗

PubMed2001

Candidate gene markers for litter size in different German pig lines.

Three diallelic RFLP markers at candidate gene loci for litter size, the estrogen receptor (ESR) gene, the prolactin receptor (PRLR) gene, and the retinol-binding protein 4 (RBP4) gene, were evaluated for their association with the number of piglets born alive in different German pig lines. Genotyping was performed on boars and sows belonging to three different genetic groups from a single farm. Information on 8,336 litter records from 2,159 sows (German Landrace, n = 1,672; Duroc, n = 214; and a synthetic line, n = 273) was used in the analyses with respect to litter size. Growth performance traits were only analyzed for the synthetic line. The ESR locus showed no polymorphism in the tested boars of the German Landrace and Duroc lines. In the synthetic line, the frequency for the A allele was 0.90 and no homozygous BB animal was detected. No significant associations of ESR alleles with number of piglets born alive, backfat thickness, or average daily gain were observed. A new PCR-RFLP was developed for testing the PRLR polymorphism. The frequencies of PRLR allele A were 0.40 in the German Landrace, 0.49 in the synthetic, and 0.82 in the Duroc line. In the Duroc line, a small additive effect of the allele B on litter size was observed. The allelic substitution effect was 0.71 piglets born alive across all parities (P = 0.05). No significant associations of the PRLR locus with litter and growth performance traits were detected. The frequencies of RBP4 allele A ranged from 0.62 in the synthetic line to 0.67 in the German Landrace to 0.85 in the Duroc line. For the genotyped sows of the synthetic line, there was no indication of a favorable effect of the A allele with respect to litter size. Results of this study demonstrate that allele effects differ between lines or populations. This may be due to possible different linkage phases between the marker alleles and the causal mutations in the different lines. The results may also be explained by many minor genes affecting litter size. A selection strategy should be designed for each line separately and should always consider possible pleiotropic effects.

Animals↗

PubMed2006

Association of RAGE gene polymorphisms with in-stent restenosis in non-diabetic Korean population.

BACKGROUND: Interaction between advanced glycosylation end products (AGEs) and receptor for AGEs (RAGE) in vessel wall may lead to inflammation, smooth muscle cell proliferation, and extracellular matrix production, culminating in exaggerated intimal hyperplasia and restenosis. We investigated the possibility that single nucleotide polymorphisms of the genes encoding RAGE are associated with in-stent restenosis after coronary stenting. METHODS: Our study included 334 consecutive non-diabetic male patients with symptomatic coronary artery disease who underwent bare metal stent implantation. Follow-up angiography was performed in 297 patients (88.9%), 6 months after intervention. We screened -1106T-->C, -443T-->C, -388T-->A, -257G-->A, +557G-->A and +1704G-->T RAGE polymorphisms in these patients. Genotyping was performed by single base extension with amplifying primers and probes for TaqMan. RESULTS: A total of 355 target lesions were evaluated, in 297 patients. There was no significant association of the -1106T-->C, -443T-->C, -388T-->A, -257G-->A, +557G-->A or +1704G-->T polymorphisms with in-stent restenosis after coronary artery stenting. We did not observe a significant difference between the genotype distributions and the rates of angiographic restenosis between the polymorphisms. In a multivariate analysis of angiographic restenosis, we examined the possible influence of the baseline, lesion-related, and procedural variables. After adjustment for these potentially confounding factors, the multivariate analysis did not reveal an association of polymorphism with angiographic restenosis. CONCLUSION: Our observation suggests that the RAGE gene polymorphism is not associated with in-stent restenosis after coronary artery stenting in non-diabetic patients in the Korean population.

Angioplasty, Balloon, Coronary↗

PubMed2006

Improved technique that allows the performance of large-scale SNP genotyping on DNA immobilized by FTA technology.

FTA technology is a novel method designed to simplify the collection, shipment, archiving and purification of nucleic acids from a wide variety of biological sources. The number of punches that can normally be obtained from a single specimen card are often however, insufficient for the testing of the large numbers of loci required to identify genetic factors that control human susceptibility or resistance to multifactorial diseases. In this study, we propose an improved technique to perform large-scale SNP genotyping. We applied a whole genome amplification method to amplify DNA from buccal cell samples stabilized using FTA technology. The results show that using the improved technique it is possible to perform up to 15,000 genotypes from one buccal cell sample. Furthermore, the procedure is simple. We consider this improved technique to be a promising methods for performing large-scale SNP genotyping because the FTA technology simplifies the collection, shipment, archiving and purification of DNA, while whole genome amplification of FTA card bound DNA produces sufficient material for the determination of thousands of SNP genotypes.

DNA Fingerprinting↗

PubMed2006

Pharmacokinetics of codeine and its metabolite morphine in ultra-rapid metabolizers due to CYP2D6 duplication.

Codeine is an analgesic drug acting on mu-opiate receptors predominantly via its metabolite morphine, which is formed almost exclusively by the genetically polymorphic enzyme cytochrome P450 2D6 (CYP2D6). Whereas it is known that individuals lacking CYP2D6 activity (poor metabolizers, PM) suffer from poor analgesia from codeine, ultra-fast metabolizers (UM) due to the CYP2D6 gene duplication may experience exaggerated and even potentially dangerous opioidergic effects and no systematical study has been performed so far on this question. A single dose of 30 mg codeine was administered to 12 UM of CYP2D6 substrates carrying a CYP2D6 gene duplication, 11 extensive metabolizers (EM) and three PM. Genotyping was performed using polymerase chain reaction-restriction fragment length polymorphism methods and a single-base primer extension method for characterization of the gene-duplication alleles. Pharmacokinetics was measured over 24 h after drug intake and codeine and its metabolites in plasma and urine were analyzed by liquid chromatography with tandem mass spectrometry. Significant differences between the EM and UM groups were detected in areas under the plasma concentration versus time curves (AUCs) of morphine with a median (range) AUC of 11 (5-17) microg h l(-1) in EMs and 16 (10-24) microg h l(-1) in UM (P=0.02). In urine collected over 12 h, the metabolic ratios of the codeine+codeine-6-glucuronide divided by the sum of morphine+its glucuronides metabolites were 11 (6-17) in EMs and 9 (6-16) in UM (P=0.05). Ten of the 11 CYP2D6 UMs felt sedation (91%) compared to six (50%) of the 12 EMs (P=0.03). CYP2D6 genotypes predicting ultrarapid metabolism resulted in about 50% higher plasma concentrations of morphine and its glucuronides compared with the EM. No severe adverse effects were seen in the UMs in our study most likely because we used for safety reasons a low dose of only 30 mg. It might be good if physicians would know about the CYP2D6 duplication genotype of their patients before administering codeine.

Administration, Oral↗

PubMed2006

Novel genes identified in a high-density genome wide association study for nicotine dependence.

Tobacco use is a leading contributor to disability and death worldwide, and genetic factors contribute in part to the development of nicotine dependence. To identify novel genes for which natural variation contributes to the development of nicotine dependence, we performed a comprehensive genome wide association study using nicotine dependent smokers as cases and non-dependent smokers as controls. To allow the efficient, rapid, and cost effective screen of the genome, the study was carried out using a two-stage design. In the first stage, genotyping of over 2.4 million single nucleotide polymorphisms (SNPs) was completed in case and control pools. In the second stage, we selected SNPs for individual genotyping based on the most significant allele frequency differences between cases and controls from the pooled results. Individual genotyping was performed in 1050 cases and 879 controls using 31 960 selected SNPs. The primary analysis, a logistic regression model with covariates of age, gender, genotype and gender by genotype interaction, identified 35 SNPs with P-values less than 10(-4) (minimum P-value 1.53 x 10(-6)). Although none of the individual findings is statistically significant after correcting for multiple tests, additional statistical analyses support the existence of true findings in this group. Our study nominates several novel genes, such as Neurexin 1 (NRXN1), in the development of nicotine dependence while also identifying a known candidate gene, the beta3 nicotinic cholinergic receptor. This work anticipates the future directions of large-scale genome wide association studies with state-of-the-art methodological approaches and sharing of data with the scientific community.

Case-Control Studies↗

PubMed2004

Influence of interleukin 12B (IL12B) polymorphisms on spontaneous and treatment-induced recovery from hepatitis C virus infection.

BACKGROUND/AIMS: Interleukin-12 (IL-12) governs the Th1-type immune response, affecting the spontaneous and treatment-induced recovery from HCV-infection. We investigated whether the IL12B polymorphisms within the promoter region (4 bp insertion/deletion) and the 3'-UTR (1188-A/C), which have been reported to influence IL-12 synthesis, are associated with the outcome of HCV infection. METHODS: We analyzed 186 individuals with spontaneous HCV clearance, 501 chronically HCV infected patients, and 217 healthy controls. IL12B 3'-UTR and promoter genotyping was performed by Taqman-based assays with allele-specific oligonucleotide probes and PCR-based allele-specific DNA-amplification, respectively. RESULTS: The proportion of IL12B promoter and 3'-UTR genotypes did not differ significantly between the different cohorts. However, HCV genotype 1-infected patients with high baseline viremia carrying the IL12B 3'-UTR 1188-C-allele showed significantly higher sustained virologic response (SVR) rates (25.3% vs. 46% vs. 54.5% for A/A, A/C and C/C) due to reduced relapse rates (24.2% vs. 12% vs. zero % for A/A, A/C and C/C). CONCLUSIONS: IL12B 3'-UTR 1188-C-allele carriers appear to be capable of responding more efficiently to antiviral combination therapy as a consequence of a reduced relapse rate. No association of IL12B polymorphisms and self-limited HCV infection could be demonstrated.

3' Untranslated Regions↗

PubMed2026

Prevalence of POMC allele associated with obesity in feline population in Vietnam.

Feline obesity is an increasingly important health problem influenced by both genetic predisposition and husbandry practices. This study investigated the prevalence and phenotypic relevance of the feline proopiomelanocortin (POMC) c.28G > C (p.Gly10Arg) variant in a Vietnamese cat population and evaluated environmental factors associated with obesity. A total of 63 clinically healthy cats were classified as normal weight (body condition score [BCS] 5-6/9; n = 40) or obese (BCS ≥7/9; n = 23). Genotyping was performed using a newly developed PCR-restriction fragment length polymorphism assay and validated by Sanger sequencing. Ventral subcutaneous adipose tissue (VSAT) thickness was measured ultrasonographically as an objective indicator of adiposity. Genotyping revealed a high prevalence of the risk-associated C allele, with 45/63 cats (71.4%) carrying the GC genotype and 18/63 (28.6%) carrying the CC genotype, whereas the GG genotype was not detected, giving a Callele frequency of 64.3%. Obese cats had significantly greater body weight and VSAT thickness than normal-weight cats. Neuter status and ad libitum feeding were significantly associated with obesity, whereas diet type, housing, exercise frequency, and begging behavior were not. Although genotype distribution did not differ significantly between normal and obese cohorts, obese CC cats showed significantly greater VSAT thickness than obese GC cats, indicating an allele-dosage effect on adiposity. These findings suggest that the POMC c.28G > C variant is a useful risk-informative marker and that combining genetic screening with objective fat assessment may support earlier identification and prevention of feline obesity in Vietnam under routine laboratory conditions and guide personalized management strategies in practice.

Animals↗

PubMed1999

609 C --> T polymorphism in NAD(P)H:quinone oxidoreductase gene in patients with prostatic adenocarcinoma or benign prostatic hyperplasia.

Allelic variations at the NQO1 locus encoding for NAD(P)H:quinone oxidoreductase have recently been implicated in carcinogenesis, cancer chemoprevention and chemotherapy. Two naturally occurring alleles differ at nucleotide position 609 with the variant allele leading to diminished or absent enzyme activity. Using polymerase chain reaction-restriction fragment length polymorphic analysis, NQO1 genotyping was performed in DNA from blood cells from 54 patients with prostatic adenocarcinoma, 49 patients with benign prostatic hyperplasia and 100 healthy control subjects. Prostatic adenocarcinoma patients and healthy controls demonstrated almost identical genotype distribution and frequencies of the variant allele (17.6 versus 17.5%). The variant allele was slightly more frequent in benign prostatic hyperplasia patients (23.5%). Established prostate cancer-derived cell lines LnCAP, DU-145, and PC-3 demonstrated NQO1 wild-type genotype. Our study does not support the hypothesis that the variant NQO1 allele is a risk modifier for prostatic adenocarcinoma and/or benign prostatic hyperplasia in the Caucasian population.

Adenocarcinoma↗

PubMed2003

The T-786C endothelial nitric oxide synthase genotype is a novel risk factor for coronary artery disease in Caucasian patients of the GENICA study.

OBJECTIVES: We investigated the association of polymorphisms in the promoter region and exon 7 endothelial nitric oxide synthase (eNOS) gene with coronary artery disease (CAD). BACKGROUND: Endothelial dysfunction foretells cardiovascular events and can be genetically determined. METHODS: We genotyped for the promoter (T(-786)C) and exon 7 (Glu298Asp, G(894)T) polymorphisms in 1,225 subjects; 1,106 were consecutive patients undergoing coronary angiography and 119 control subjects without any cardiovascular risk factors. Genotyping was performed with melting curve analysis of polymerase chain reaction products from allele-specific acceptor and donor probes that were 5'- and 3'-end labeled with LCRed640 and fluorescein, respectively; CAD was assessed by quantitative coronary angiography. We performed multiple logistic regression analysis for the effect of the T(-786)C, the missense Glu298Asp variant, and other coronary risk factors on two- and three-vessel CAD. RESULTS: The overall genotype distribution of T(-786)C (CC = 17.7%, CT = 40.4%, and TT = 41.9%) and Glu298Asp (GG = 43.3%, GT = 37.0%, and TT = 19.7%) was consistent with the Hardy-Weinberg equilibrium. The regression analysis showed that the T(-786)C, but not the missense Glu298Asp variant, significantly predicted CAD, independent of other risk factors. Compared with TT homozygous, subjects carrying the C allele had a significant (p = 0.002) increase in the odds ratio of harboring two- or three-vessel CAD of 1.672 (95% confidence interval, 1.062 to 2.527). A subgroup analysis confirmed this effect of the T(-786)C polymorphism in men (p = 0.007), cigarette smokers (p = 0.001), subjects older than 60 years of age (p = 0.007), with hypercholesterolemia (p = 0.011), low high-density lipoprotein cholesterol (p = 0.006), and overweight or with obesity (p = 0.041). CONCLUSIONS: The C allele at the T(-786)C endothelial nitric oxide synthase polymorphism is associated with a higher risk of multivessel CAD in Caucasians.

Adult↗

PubMed2003

Single-nucleotide polymorphisms of the interleukin-18 gene promoter region in rheumatoid arthritis patients: protective effect of AA genotype.

Rheumatoid arthritis (RA) is a chronic arthritic condition that can lead to deformities and disabilities. Although numerous studies reported the association of human leukocyte antigen (HLA)-DRB1*04 and RA, other genes, e.g. cytokines genes, may contribute towards disease susceptibility. Interleukin-18 (IL-18) is a proinflammatory cytokine postulated to play a role in the acute and chronic inflammatory phases of RA. The IL-18 protein expression seems to be regulated by two single-nucleotide polymorphisms (SNPs) located at positions -607 and -137 in the promoter region of the gene. It is postulated that specific alleles may be associated with susceptibility to the development of RA. In the present study, we described the IL-18 gene promoter region genotypes and combined genotypes (-607/-137) in 106 RA patients and 273 unrelated healthy controls to evaluate the contributions of these alleles to RA predisposition in Chinese, Malays, and Indians. The genotyping were performed using sequence-specific polymerase chain reactions. Rheumatoid factors were assayed by enzyme-linked immunosorbent assay. Biodata were obtained through chart review. The controls had significantly higher frequency of AA genotype at position -607 when compared to RA patients. No significant differences were observed in the distribution of either allelic or genotypic frequencies at position -137. There was no association between the genotypes and the presence of rheumatoid factors. This study did not find evidence of a genetic susceptibility factor but demonstrated the novel finding that the AA genotype at position -607 is associated with a protective effect against development of RA in Chinese individuals. This protection may be mediated through inhibition of cyclic (Adenosine 3', 5'-cyclic monophosphate) AMP-responsive element (CRE)-binding protein by the disruption of the CRE consensus sequence.

Adult↗

PubMed2026

Sex- and age-specific associations of VEGFA polymorphisms with multiple sclerosis susceptibility.

AIM: To evaluate six VEGFA polymorphisms (rs1570360, rs699947, rs3025033, rs2146323, rs1413711 and rs833061) and serum VEGFA concentrations in 270 Lithuanian patients with multiple sclerosis (MS) and 270 matched healthy controls. METHODS: Genotyping was performed using real-time PCR, and serum VEGFA levels were measured by enzyme-linked immunosorbent assay. Statistical analyses were conducted using IBM SPSS version 31.0. RESULTS: Nominal differences in VEGFA genotype and allele distributions were observed in sex- and age-stratified analyses. Among females, the rs1413711 C allele was more frequent (p = 0.005), whereas the rs833061 C allele was less frequent (p = 0.006), in MS patients than controls. In participants aged >38 years, the rs1413711 C allele was also more frequent in MS cases (57.5% vs. 46.0%, p = 0.008). Logistic regression identified nominal associations, particularly for rs1413711, rs699947 and rs833061, but none remained significant after correction for multiple testing. Serum VEGFA levels were higher in MS patients than controls (p = 0.004). Nominal genotype-related differences in serum VEGFA levels and haplotype associations with reduced MS odds were also observed, but did not remain significant after multiple-testing correction. No consistent associations were found between VEGFA variants and clinical parameters. CONCLUSION: VEGFA genetic variation and elevated serum VEGFA may be associated with MS, but the genetic findings require confirmation in larger independent cohorts.

Humans↗

PubMed2000

A new MALDI-TOF based mini-sequencing assay for genotyping of SNPS.

A new MALDI-TOF based mini-sequencing assay termed VSET was developed for genotyping of SNPs. In this assay, specific fragments of genomic DNA containing the SNP site(s) are first amplified, followed by mini-sequencing in the presence of three ddNTPs and the fourth nucleotide in the deoxy form. In this way, the primer is extended by only one base from one allele, while it is typically extended by two bases from another allele. The products are then analyzed using MALDI-TOF mass spectrometry. The genotype of the SNP site is identified based on the number of nucleotides added. This assay has been examined using both synthetic and genomic DNA samples. In addition, multiplexed assays were successfully performed to genotype four SNP sites in a single tube. The main aspect of this assay is that it can overcome the key problems associated with the currently used mini-sequencing methods. First, it significantly reduces the stringent high-resolution and extensive desalting requirements that are essential to the pinpoint assay. Second, it avoids the long extension problem associated with the PROBE assay.

DNA Mutational Analysis↗

PubMed2006

Analysis of case-only studies accounting for genotyping error.

The case-only design provides one approach to assess possible interactions between genetic and environmental factors. It has been shown that if these factors are conditionally independent, then a case-only analysis is not only valid but also very efficient. However, a drawback of the case-only approach is that its conclusions may be biased by genotyping errors. In this paper, our main aim is to propose a method for analysis of case-only studies when these errors occur. We show that the bias can be adjusted through the use of internal validation data, which are obtained by genotyping some sampled individuals twice. Our analysis is based on a simple and yet highly efficient conditional likelihood approach. Simulation studies considered in this paper confirm that the new method has acceptable performance under genotyping errors.

Bias↗

PubMed2004

Thymidylate synthase gene polymorphism predicts toxicity in colorectal cancer patients receiving 5-fluorouracil-based chemotherapy.

PURPOSE: The target enzyme for 5-fluorouracil (5-FU) is thymidylate synthase (TS). The TYMS gene encoding this enzyme is polymorphic, having either double (2R) or tri-tandem (3R) repeats of a 28-bp sequence in the promoter region and a 6-bp variation in the 3'-untranslated region (3'-UTR). TS expression predicts response to 5-FU-based chemotherapy, and the expression seems to be determined by the TYMS gene promoter. The aim of this study was to investigate the utility of determining these two TYMS gene polymorphisms to predict the toxicity and efficacy of 5-FU treatment in patients with colorectal cancer. EXPERIMENTAL DESIGN: The determination of TYMS genotypes was performed in tumor and normal tissues by PCR amplification from 90 patients with colorectal cancer who were treated with adjuvant or palliative 5-FU-based chemotherapy. Associations between polymorphisms in the TYMS promoter and in the 3'-UTR gene and clinical outcome of these 90 patients treated with 5-FU based chemotherapy were evaluated individually. The linkage between TYMS promoter and TYMS 3'-UTR region polymorphisms was evaluated and a haplotype analysis was performed. RESULTS: Individuals who were homozygous for the double repeat in the TYMS promoter region had more severe side effects to 5-FU. Patients with a 2R/2R, a 2R/3R, or a 3R/3R genotype had a grade 3 or 4 toxicity rate of 43, 18, and 3% respectively (P < 0.01). The TYMS promoter and TYMS 3'-UTR polymorphisms were in linkage disequilibrium, and the haplotype 2R/ins 6-bp was significantly associated with a high risk of severe side effects to 5-FU. The TYMS promoter and TYMS 3'-UTR polymorphisms were not associated with a response to 5-FU and survival of patients who received palliative 5-FU-based chemotherapy. CONCLUSIONS: This study demonstrated that TYMS genotyping could be of help in predicting toxicity to 5-FU-based chemotherapy. TYMS genotyping might make it possible to individualize treatment for patients with colorectal cancer.

3' Untranslated Regions↗