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Results for “Polymorphism”

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PubMed2001

The gene polymorphism of tumor necrosis factor-beta, but not that of tumor necrosis factor-alpha, is associated with the prognosis of sarcoidosis.

OBJECTIVES: Few genetic markers for the prognosis of sarcoidosis have been found. Tumor necrosis factor (TNF)-alpha has been implicated in the pathogenesis of sarcoidosis. Induced TNF-alpha or TNF-beta levels have been shown to be associated with the polymorphisms of the TNF genes. We investigated the roles of such polymorphisms in the development and prolongation of sarcoidosis. SUBJECTS AND MEASUREMENTS: One hundred ten Japanese patients with sarcoidosis and 161 control subjects were genotyped for three biallelic polymorphisms in the promoter region of TNF-alpha gene by direct sequencing of polymerase chain reaction (PCR) products. A polymorphism of the TNF-beta gene (TNFB*1/TNFB*2) was detected by NCO: I restriction fragment length polymorphism analysis of PCR products spanning intron 1 and exon 2 of the TNF-beta gene. RESULTS: None of the polymorphisms conferred susceptibility to sarcoidosis. However, our study identified the allele TNFB*1, detected by the presence of a NCO: I restriction site, as a marker of prolonged clinical course, with the resolution of sarcoidosis being defined as the disappearance of all clinical symptoms, physical signs of active lesions, abnormal chest radiograph findings, and abnormal results of pulmonary function and biochemical tests. When the probability of remission in patients homozygous for TNFB*2 was defined as 1.00, it was 0.48 (95% confidence interval, 0.26 to 0.88; p < 0.05) in patients with TNFB*1 (genotypes TNFB*1/1 and TNFB*1/2). CONCLUSIONS: The TNFB*1 allele is a marker for prolonged clinical course in patients with sarcoidosis. Our study is the first to link a cytokine gene polymorphism to the prognosis of sarcoidosis.

Adult↗

PubMed2001

Polymorphism of the beta(2)-adrenoceptor in COPD in Chinese subjects.

STUDY OBJECTIVES: To assess the frequencies of three polymorphisms at amino acid positions 16, 27, and 164 of the beta(2)-adrenoceptor (beta(2)-AR) gene and their effects on COPD patients. DESIGN: Prospective, case-control study PATIENTS: Sixty-five patients with COPD and 41 healthy subjects were included. MEASUREMENTS: Polymorphisms of the beta(2)-AR coding block were delineated using an allele-specific polymerase chain reaction (PCR) approach. The allele-specific PCR technique was verified by direct dideoxy sequencing of PCR products. Pulmonary function tests were performed in all patients. RESULTS: The Arg16 beta(2)-AR polymorphism was less prevalent in COPD patients than in healthy populations (p = 0.01). A significant correlation (p < 0.018) between the Gln27 beta(2)-AR polymorphism and FEV(1) percent predicted value was found. Patients with the Gln27 polymorphism had a higher percentage of low FEV(1) percent predicted than did patients with the GlnGlu and GluGlu variants. CONCLUSIONS: The polymorphism of Gly16 may increase the patient's susceptibility to the development of COPD. The Gln27 beta(2)-AR polymorphism may be associated with the severity of COPD in a Chinese population.

Aged↗

PubMed2004

Polymorphisms of renin-angiotensin system genes with high-altitude pulmonary edema in Japanese subjects.

STUDY OBJECTIVES: The renin-angiotensin system (RAS), including angiotensin-converting enzyme (ACE) and angiotensin II type 1 receptor (AT(1)R), plays an important role in the pathogenesis of pulmonary hypertension, which is suggested to be critical in the development of high-altitude pulmonary edema (HAPE). Investigating the associations of the polymorphisms in the genes of RAS with HAPE is to elucidate the genetic background underlying this disease. DESIGN: A cross-sectional, case-control study. SETTING: Shinshu University Hospital, Matsumoto, Japan. PARTICIPANTS: Forty-nine HAPE-susceptible (HAPE-s) subjects with a history of HAPE, and 55 healthy climbers with HAPE resistance (HAPE-r). INTERVENTIONS: Twenty-one of 49 HAPE-s subjects underwent right cardiac catheterization. MEASUREMENTS AND RESULTS: The insertion/deletion polymorphism in the ACE gene (ACE-I/D) was investigated by polymerase chain reaction (PCR). There was no significant difference of the distribution of the ACE-I/D polymorphism between the HAPE-s and HAPE-r groups. The A(1166)C and G(1517)T single-nucleotide polymorphisms (SNPs) in AT(1)R gene were investigated by the PCR following digested by corresponding restricted endonuclease enzymes. The distribution of the G(1517)T SNP was significantly different between the two groups (p = 0.012). The pulmonary hemodynamics of the 21 HAPE-s subjects were retrospectively examined. The pulmonary artery pressure (PAP), pulmonary vascular resistance (PVR), and PVR index (PVRI) were all significantly increased on hospital admission. Moreover, the PVR and PVRI were significantly higher in the HAPE-s subjects with D positivity than in the HAPE-s subjects with I positivity (PVR, p = 0.015; PVRI, p = 0.028), while the PAP did not show any significant difference between the two subgroups. CONCLUSIONS: The ACE-I/D polymorphism is not associated with HAPE susceptibility in Japanese subjects. The AT(1)R gene polymorphisms may likely associate with HAPE susceptibility. The D allele of the ACE-I/D polymorphism probably contributes to the hyperresponsive PVR and PVRI to acute hypoxia.

Adult↗

PubMed2002

Pilot study examining the frequency of several gene polymorphisms in a morbidly obese population.

BACKGROUND: Obesity is a growing problem and is associated with numerous medical conditions. Several polymorphisms have been associated with lipid metabolism and obesity: PPAR-gamma2-Pro115Gln, PPARgamma2-Pro12Ala, beta3AR-Trp64Arg and SR-BI IVS5 C > T. We examined the frequency of these polymorphisms in patients with a BMI > 40 and compared them to individuals with a BMI < 30. Our hypothesis was that these polymorphisms would occur more frequently in the obese population. METHODS: This case-control study examined 126 individuals with a BMI > 40 in the McGill University Health Centre Bariatric Surgery Program and 102 individuals (controls) with a BMI < 30 attending a Lipid Clinic. DNA was extracted from whole blood by standard techniques. The polymorphisms were determined by polymerase chain reaction (PCR) and restriction genotyping. RESULTS: A significant difference between controls and the morbidly obese group was observed for 2 of 4 polymorphisms. The carrier frequency for PPARgamma2-Pro12Ala was 24.8% in the obese group and 12.9% in controls (odds ratio = 2.2; 95% CI = 1.1-4.4; P = 0.02). The carrier frequency for SR-BI IVS5 C > T was 22.8% in obese individuals versus 8.1% in controls (odds ratio = 3.5; 95% CI = 1.6-7.7; P = 0.002). There were no differences in frequency of diabetes in both obese (13/104) and control (9/126) groups (odds ratio = 1.86, 95% CI = 0.76 < O.R. < 4.54, P = 0.184). CONCLUSIONS: These results underscore the relationship between gene polymorphisms and obesity. Obese individuals may differ from non-obese individuals in the gene polymorphisms associated with metabolic control.

CD36 Antigens↗

PubMed2005

RET polymorphisms and sporadic medullary thyroid carcinoma in a Portuguese population.

The genetic basis of the sporadic form of medullary thyroid carcinoma, derived from "C" cells, is still poorly understood. Somatic mutations of RET proto-oncogene have been reported at a variable frequency ranging from 23% to 69%. The hypothesis that low penetrance factors, such as polymorphisms, might contribute to the phenotype of this neoplasm has been addressed in a few studies conducting to conflicting results. Herein, we studied 100 individuals (50 patients and 50 controls) aiming to compare the frequencies of G691S, L769L, S836S, and S904S RET polymorphisms observed in patients with respect to controls. Furthermore, meta-analysis of published studies including the present results was conducted. To test the contributory role of the above polymorphisms for the development of "C"-cell hyperplasia, we studied a group of 10 individuals selected for having a positive pentagastrin test despite the absence of a RET germline mutation. An over-representation of the G691S polymorphism, particularly in females, was observed in patients with respect to controls, although not reaching the level of significance. Allelic frequencies of the other three polymorphisms were not different in patients and controls. Results obtained in the admittedly small group of individuals with a positive pentagastrin test are unlikely to support a major influence of any polymorphism in the development of "C"-cell hyperplasia. The meta-analysis provided evidence for a significant association of the S691 allele with MTC (odds ratio 1.54, 95% confidence interval 1.12-2.12, p=0.008) and found no significant associations for the other polymorphisms.

Adult↗

PubMed2004

Lack of association between the brain-derived neurotrophin factor (C-270T) polymorphism and late-onset Alzheimer's disease (LOAD) in Brazilian patients.

After the identification of the apolipoprotein E gene isoform (APOE-epsilon4) as a risk factor for late-onset Alzheimer's disease (LOAD), the search for other polymorphisms associated with AD has been undertaken by many groups of investigators around the world. These studies have shown controversial results in many populations. More recently, a single nucleotide polymorphism in the promoter region of the brain-derived neurotrophin factor (BDNF) was found to be a risk factor for AD in two independent population studies. Here we report the analysis of this polymorphism in a group of 188 LOAD Brazilian patients compared to matched normal controls. A strong association between the APOE-epsilon4 polymorphism and LOAD was observed, but there was no significant association between this BNDF polymorphism and affected patients. The possibility that other polymorphisms or mutations in this gene play a role in the development of AD cannot be ruled out. However, the results of the present study suggest that in opposition to the two reported studies, this polymorphism does not seem to be implicated in LOAD Brazilian patients. It also shows the importance of replication studies in different populations, as susceptibility loci might differ in different ethnic groups; this will have important implications in future treatments with pharmacological agents.

Aged↗

PubMed2000

Apolipoprotein E polymorphisms and concentration in chronic diseases and drug responses.

Apolipoprotein (apo) E is an important circulating and tissue protein involved in cholesterol homeostasis and many other functions. The common polymorphism in the coding region of the gene, four polymorphisms in the promoter region, other additional single nucleotide polymorphisms, as well as several apo E variants have been identified. The common coding polymorphism strongly influences the lipid metabolism and the circulating concentration of apo E itself. This polymorphism is at the origin of the implication of apo E in cardiovascular and neurodegenerative diseases, but also of the relation of apo E with longevity. Probably due to its many metabolic and functional consequences, apo E polymorphism has been shown to influence the responses of patients to several drugs (fibrates, statins, hormone replacement therapy, anti-Alzheimer drugs) or environmental interventions (black tea, alcohol, diet). Apo E genotyping may be clinically helpful in defining the risk of patients and their responses to therapeutics. Finally, circulating apo E concentration appears to be altered in diseases and can be modulated by some of the drugs cited above. This parameter can thus also give interesting clinical information and could be a therapeutic target, providing it is validated. At the present time, we cannot exclude that apo E concentration may be the most prominent apo E parameter to be considered in health and disease, while apo E polymorphisms would represent only secondary parameters influencing apo E concentration.

Alleles↗

PubMed2002

Evidence that luteinising hormone receptor polymorphisms may contribute to male undermasculinisation.

BACKGROUND: The luteinising hormone receptor (LHR) is necessary for the stimulation of androgen production and male genital development. It contains three protein polymorphisms: a leucine and glutamine insertion between codons 8 and 9 (LQ+) and two amino acid substitutions (N291S, N312S). OBJECTIVES: To determine whether these LHR polymorphisms are associated with male genital undermasculinisation or the androgen receptor polyglutamine repeat polymorphism (AR(Q)n), which contributes in some cases to the cause of genital undermasculinisation. METHODS: The LHR polymorphisms were assessed by PCR amplification of genomic DNA, followed by restriction enzyme analysis. The frequency of the LHR polymorphisms were compared between an undermasculinised male group (n=75) and a control group (n=55). RESULTS: LQ+ was not independently associated with the undermasculinised group (P=0.09), but it was associated with increased AR(Q)n within the undermasculinised group (P=0.02), particularly for AR(Q)n lengths >or=26 (P=0.002). In the undermasculinised group, homozygosity for N291 (872A/A) was more frequent (P=0.05), whereas homozygosity for N312 (935A/A) was less frequent (P=0.05). The combination of the presence of 872A/A and the absence of 935A/A showed a stronger association with the undermasculinised group than either polymorphism independently (P=0.006). The odds ratio of this genotype compared with any other, between the undermasculinised and control groups was 3.28 (95% confidence interval (CI) 1.33 to 8.08). CONCLUSION: LHR polymorphisms may contribute to genital undermasculinisation.

Disorders of Sex Development↗

PubMed2004

A promoter polymorphism of the CYP27B1 gene is associated with Addison's disease, Hashimoto's thyroiditis, Graves' disease and type 1 diabetes mellitus in Germans.

BACKGROUND: CYP27B1 hydroxylase catalyzes the conversion of 25 hydroxyvitamin D(3) (25OHD(3)) to 1,25(OH)(2)D(3), the most active natural vitamin D metabolite, which plays a role in the regulation of immunity and cell proliferation. We therefore investigated two single nucleotide polymorphisms in the CYP27B1 hydroxylase gene for an association with Addison's disease, Hashimoto's thyroiditis, Graves' disease and type 1 diabetes mellitus. METHODS: Patients with Addison's disease (n=124), Hashimoto's thyroiditis (n=139), Graves' disease (n=334), type 1 diabetes mellitus (n=252) and healthy controls (n=320) were genotyped for the promoter (-1260) C/A polymorphism and for the intron 6 (+2838) C/T polymorphism of the CYP27B1 gene. Patients and controls were compared using genotype-wise and allele-wise X(2) testing. RESULTS: A significant association was found between allelic variation of the promoter (-1260) C/A polymorphism and Addison's disease, Hashimoto's thyroiditis, Graves' disease and type 1 diabetes mellitus (P=0.0062, P=0.0173, P=0.0094 and P=0.0028 respectively). Significant differences were also observed for the intron 6 (+2838) C/T polymorphism (P=0.0058) in Hashimoto's thyroiditis but not for the other autoimmune endocrine diseases. CONCLUSIONS: The CYP27B1 promoter (-1260) C/A polymorphism appears to be associated with endocrine autoimmune diseases but the CYP27B1 intron 6 (+2838) C/T polymorphism appears to be associated only with Hashimoto's thyroiditis. These results imply a regulatory difference of the CYP27B1 hydroxylase to predispose to endocrine autoimmunity.

25-Hydroxyvitamin D3 1-alpha-Hydroxylase↗

PubMed2002

The polymorphisms of codon 727 and 52 of thyroid-stimulating hormone receptor gene are not associated with mitral valve prolapse syndrome in Taiwan Chinese.

A germline mutation of the thyroid-stimulating hormone receptor (TSHR) gene has been reported to be associated with thyrotoxicosis and mitral valve prolapse syndrome (MVPS) in a Chinese family. The role of TSHR genetic variants in MVPS has not been well studied. This study investigated the possible relationship between the polymorphisms of codon 727 and 52 of the TSHR gene and MVPS among the Chinese population in Taiwan. We studied 100 patients with MVPS diagnosed by echocardiography and 100 ageand sex-matched normal control subjects. The polymorphisms of codon 727 and 52 of the TSHR gene were identified by polymerase chain reaction-based restriction analysis. There was no significant difference in either the genotype distribution or allelic frequencies between MVPS cases and controls for either TSHR gene D727E polymorphism ( = 0.51 and 0.45, respectively ) or P52T polymorphism (P = 0.60 and 0.31, respectively). The MVPS patients were divided into 2 subgroups: those with Graves' disease, and those without the thyroid disorder, and there were no statistical differences from the controls for both the TSHR gene D727E and P52T polymorphisms. Further categorization of the MVPS patients into mild and severe subgroups also revealed no statistical difference from controls for either the TSHR gene D727E or P52T polymorphisms. These findings suggest that the codon 727 and 52 polymorphisms of the TSHR gene are not the suitable genetic markers of MVPS in Taiwan Chinese.

Adolescent↗

PubMed2003

Association study of CD14 polymorphism with myocardial infarction in a Japanese population.

There have been many studies investigating the association between gene polymorphisms and coronary artery disease (CAD) including myocardial infarction (MI), and some studies have shown that certain gene polymorphisms are associated with CAD/MI. However, the results of the association have sometimes been controversial. The reason may be that the contribution of genetic risk factors to CAD/MI varies depending on the ethnic, environmental, and habitual backgrounds, and differs between males and females. In this study, we analyzed 17 polymorphisms in 12 candidate genes for MI in 136 patients and 200 to 235 controls, and found that there is a significant association of MI with the polymorphisms in the genes for E-selectin and CD14 receptor. To further explore the association, we investigated the C-260 T polymorphism in the promoter region of the CD14 gene in 502 MI patients and 527 control subjects. The genotype distributions of the CD14 polymorphism were as follows: patients; T/T 32.5%, C/T 48.2%, C/C 19.3%, and controls; T/T 25.4%, C/T 52.8%, C/C 21.8%. The frequencies of the T/T homozygotes were significantly higher in the patients (OR = 1.41, P = 0.013) than in the control group, confirming the association of CD14 polymorphism with MI in Japanese. Stratification analyses further demonstrated that the association was more prominent in females and in patients with a relatively low body mass index, suggesting that the contribution of the CD14-linked genetic risk to MI differs with respect to gender and habitual background.

Aged↗

PubMed2001

Analysis of single nucleotide polymorphisms in the 5'-flanking region of tumor necrosis factor-alpha gene in Japanese patients with early-onset periodontitis.

BACKGROUND: Early-onset periodontitis (EOP) is considered to have a genetic basis, which has not been clearly defined. The tumor necrosis factor-alpha (TNF-alpha) gene polymorphism as one of the genetic factors may influence the expression of several chronic inflammatory diseases. The aim of the present study was to evaluate whether the polymorphisms in the 5'-flanking region of the TNF-alpha gene are associated with Japanese EOP patients. METHODS: Forty-six Japanese, generalized EOP (G-EOP) patients and 104 Japanese healthy subjects were identified according to established clinical criteria. Twenty healthy subjects were analyzed by nucleotide sequence to screen polymorphisms of the 5'-flanking region of the TNF-alpha gene. Then, all subjects were analyzed by polymerase chain reaction and sequence-specific oligonucleotide probe (SSOP) methods. RESULTS: We determined 5 single nucleotide polymorphisms at positions -1031 (T/C), -863 (C/A), -857 (C/T), -308 (G/A), and -238 (G/A) in the 5'-flanking region of the TNF-alpha gene. There were no significant differences in the genotype and allele frequency when we compared G-EOP patients to healthy subjects. Because the frequency of polymorphic alleles at positions -308 and -238 was very low in this study population, we demonstrated the existence of 4 detected haplotypes and 6 detected genotypes concerning 3 single nucleotide polymorphisms (-1031, -863, and -857). The frequency of the H1/H3 (TCC/TCT)-detected genotype tended to decrease in G-EOP patients compared to healthy subjects, but was not statistically significant. CONCLUSION: These findings suggest there is no significant association between polymorphisms in the 5'-flanking region of the TNF-alpha gene and susceptibility to G-EOP in Japanese patients.

5' Flanking Region↗

PubMed2004

Functional evaluation of ABCB1 (P-glycoprotein) polymorphisms: high-speed screening and structure-activity relationship analyses.

Evidence is accumulating to strongly suggest that drug transporters are one of the determinant factors governing the pharmacokinetic profile of drugs. Effort has been made to identify genetic variation in drug transporter genes. In particular, genetic variations of the human ABCB1 (MDR1) gene have been most extensively studied. Hitherto more than fifty single nucleotide polymorphisms (SNPs) and insertion/deletion polymorphisms in the ABCB1 gene have been reported. However, at the present time, information is still limited with respect to the actual effect of those genetic polymorphisms on the function of ABCB1. In this context, we have undertaken functional analyses of ABCB1 polymorphisms. To quantify the impact of genetic polymorphisms on the substrate specificity of ABCB1, we have developed a high-speed screening system and a new structure-activity relationship (SAR) analysis method. This review addresses functional aspects of the genetic polymorphism of ABCB1 and provides the standard method to evaluate the effect of polymorphisms on the function.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed2001

Correlation between C677T MTHFR gene polymorphism, plasma homocysteine levels and the incidence of CAD.

The lesions of coronary atherosclerosis represent the result of a complex, multicellular, inflammatory-healing response in the coronary arterial wall. In vivo and in vitro cellular and molecular studies have suggested a role for tissue homocysteine in endothelial cell injury and adverse extra-cellular matrix remodeling. Gene polymorphisms in relation with numerous risk factors might increase the incidence of coronary artery disease (CAD). In this review we have focused on the correlations between plasma homocysteine levels, the incidence of cardiovascular disease and the cytosine-to-thymidine substitution at nucleotide 677 (C677T) of the 5,10-methylenetetrahydrofolate reductase (MTHFR) gene, coding for a key enzyme in methionine-homocysteine metabolism. The role of the C677T MTHFR gene polymorphism in the causation of CAD is controversial. We reviewed 12 recent case-control studies comprising 5370 genotyped patients with CAD and 4961 genotyped participants without CAD. There was no significant difference between those with and without CAD in the frequency of the C677T polymorphism (34.9 vs 33.6%). The frequency of homozygous C677T polymorphism in these groups was 10.9 versus 12.8%, respectively, although there were some ethnic differences in the C677T MTHFR polymorphism. In the analysis of the 12 studies, the odds ratio of CAD associated with the TT genotype (homozygous C677T polymorphism) was 1.18. Only slightly higher plasma homocysteine levels were observed in participants with the val/val (TT) genotype (14.4+/-2.9 micro mol/L in TT genotype vs 11.1+/-1.9 and 11.9+/-2 micro mol/L in CC and CT genotype, respectively). In addition, the relation between homocysteine increase after methionine loading and MTHFR genotypes is also controversial. However, hyperhomocysteinemia because of the C677T MTHFR allele may be corrected with oral folic acid therapy. Further investigations on the relationships between MTHFR genotypes and the incidence of CAD should be based on larger samples, paying attention to the differences between various ethnic populations. Individual therapeutic strategies based on single nucleotide polymorphism may become increasingly important for preventive treatment against polygenic CAD.

Clinical Trials as Topic↗

PubMed2002

MCP-1 and MIP-1A gene polymorphisms in Japanese patients with sarcoidosis.

OBJECTIVES: Monocyte chemoattractant protein (MCP)-1 and macrophage inflammatory protein (MIP)-1alpha exhibit chemotactic activity toward macrophages/monocytes and induce the production of inflammatory cytokines affecting granuloma formation. Recently, a single nucleotide polymorphism (SNP) in the MCP-1 distal regulatory region and a dinucleotide repeat in the MIP-1A gene promoter region were identified. We investigated the relationships between the polymorphisms and susceptibility to sarcoidosis, clinical manifestations, and BALF findings of sarcoidosis. METHODS: The polymorphisms of the MCP-1 and MIP-1A genes in 118 patients with sarcoidosis and 145 healthy control subjects were examined. The MCP-1 polymorphism was genotyped by a PCR-restriction fragment length polymorphism method and the MIP-1A genotype was determined using PCR. RESULTS: No significant difference in the genotype distribution or in the allele frequency between the patients and control subjects was observed. We found no relationship between the polymorphisms and the serum ACE level, organ involvement, roentgenographic stages, or deterioration in chest radiographs during the follow-up. A significant difference in the absolute counts of AMs in BALF of 51 patients among the genotypes of the MCP-1 gene was found (p = 0.048). The AM counts in BALF of the G/A and G/G genotypes were significantly increased compared with that of the A/A genotype (p < 0.05). CONCLUSION: The polymorphisms of the MCP-1 and MIP-1A genes do not play a substantial role in genetic predisposition for sarcoidosis or in clinical manifestations of sarcoidosis in this Japanese population. The MCP-1 SNP might be related to the recruitment of monocytes/macrophages to the alveolar spaces in sarcoidosis.

Adult↗

PubMed2002

The 4,752 C/T polymorphism in the presenilin 1 gene increases the risk of Alzheimer's disease in apolipoprotein E4 carriers.

OBJECTIVE: We sought to establish an association between sporadic Alzheimer's disease (AD) and presenilin 1 (PSEN1) gene polymorphisms in the Japanese population. METHODS: A 5 kb fragment containing the putative promoter of the PSEN1 gene for randomly selected control subjects was subcloned into plasmid and sequenced to screen novel polymorphisms in this region. Patients and controls were genotyped for five polymorphic markers in the PSEN1 region. We then constructed haplotypes using the computer program HAPLO and compared the frequencies between cases and controls. SUBJECTS: A total of 189 AD cases (NINCDS-ADRDA criteria) and 240 controls were studied. RESULTS: We discovered a novel polymorphism with high heterozygosity on -4,752 of the PSEN1 promoter region. A significant association was observed between the -4,752 C/T polymorphism and late-onset AD. The odds ratio for AD associated with the CC vs non-CC genotype was 1.59 (95% CI = 1.01-2.51), while that of epsilon 4 vs non-epsilon 4 in APOE gene was 4.41 (95% CI = 2.72-7.16). The C allele was associated with a further increase in the risk of AD in APOE epsilon 4 carriers. We found 12 major haplotypes using five polymorphisms. The distribution pattern was significantly different between cases and controls. CONCLUSION: The PSEN1 gene -4,752 C/T polymorphism modifies the risk for AD.

Alleles↗

PubMed2004

Cytochrome P450 gene polymorphism and cancer.

Human cytochrome P450 (CYP) enzymes play a key role in the metabolism of drugs and environmental chemicals. Several CYP enzymes metabolically activate procarcinogens to genotoxic intermediates. Phenotyping analyses revealed an association between CYP enzyme activity and the risk to develop several forms of cancer. Research carried out in the last decade demonstrated that several CYP enzymes are polymorphic due to single nucleotide polymorphisms, gene duplications and deletions. As genotyping procedures became available for most human CYP, an impressive number of association studies on CYP polymorphisms and cancer risk were conducted. Here we review the findings obtained in these studies regarding CYP1A1, CYP1A2, CYP1B1, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C18, CYP2C19, CYP2D6, CYP2E1, CYP3A4, CYP3A5, CYP3A7, CYP8A1 and CYP21 gene polymorphisms. Consistent evidences for association between CYP polymorphisms and lung, head and neck, and liver cancer were reported. Controversial findings suggest that colorectal and prostate cancers may be associated to CYP polymorphisms, whereas no evidences for a relevant association with breast or bladder cancers were reported. We summarize the available information related to the association of CYP polymorphisms with leukaemia, lymphomas and diverse types of cancer that were investigated only for some CYP genes, including brain, esophagus, stomach, pancreas, pituitary, cervical epithelium, melanoma, ovarian, kidney, anal and vulvar cancers. This review discusses on causes of heterogeneity in the proposed associations, controversial findings on cancer risk, and identifies topics that require further investigation. In addition, some recommendations on study design, in order to obtain more conclusive findings in further studies, are provided.

Clinical Trials as Topic↗

PubMed2005

Polymorphism of UDP-glucuronosyltransferase and drug metabolism.

UDP-glucuronosyltransferase is a group of catabolic enzymes involved in the detoxification and excretion of many xenobiotic and endogeneous substances in intrahepatic and extrahepatic tissues. The group consists of two subfamilies, UGT1 and UGT2. UGT1 consists of 5 exons and has a unique gene structure. There are thirteen exon 1s from UGT1A1 to UGT1A13P, and exon 2 to exon 5 are used in common for all mRNAs expressed from the gene. Each isoform of UGT1 results from differential splicing of exon1s to common exon 2-5, and has an unique spectrum of substrate specificity. In contrast, the genes of the UGT2 family consist of 6 exons, and all the enzymes have an individual set of exon 1 to exon 6. In UGT1 there are no reports of polymorphism in the common exons, although a number of polymorphisms have been reported for exon 1s. The mutations of UGT1A1 cause hereditary unconjugated hyperbilirubinemias: Crigler-Najjar syndrome type I, type II and Gilbert syndrome. UGT1A1 has two major polymorphisms--a missense mutation of G71R and an insertion mutation of TATA box. Prevalence of Gilbert syndrome is attributed to these polymorphisms. Since UGT1A1 metabolizes not only bilirubin but also hormones and drugs, the mutations could be involved in carcinogenesis and adverse drug reactions. Recent studies also revealed a widespread presence of diverse polymorphisms in other isoforms of UGT1 as well as the UGT2 family, including UGT1A6, UGTG1A7, UGT1A8, UGT1A10, UGT2B4, UGT2B7 and UGT2B15. The incidences and types of the polymorphisms for these enzymes are quite different in region and ethnic groups. Understanding of these polymorphisms is essential for the prevention of adverse effects of a considerable number of drugs and to predict cancer risks.

Animals↗