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PubMed2001

Genetic repeat polymorphism in the regulating region of CYP2E1: frequency and relationship with enzymatic activity in alcoholics.

BACKGROUND: Differences in the regulatory region of the CYP2E1 gene could be responsible for the interindividual variation in the cytochrome P-450 2E1 (CYP2E1) involved in ethanol oxidation. Recently, a polymorphic repeat sequence in the human gene was described between -2178 and -1945 base pairs. Its frequency seemed to vary among different ethnic populations, and it was suspected to be related to an increased inducibility to further ethanol intake. In the study reported here, the frequency of this polymorphism was investigated in a white French population. Its relationship with the previously described PstI/RsaI or DraI CYP2E1 polymorphisms, alcoholism, alcoholic liver disease, and inducibility of CYP2E1 by ethanol was examined. METHODS: The polymorphic region was characterized by polymerase chain reaction in 103 controls, 148 alcoholic subjects without liver diseases, and 98 others with liver cirrhosis. By using in vivo chlorzoxazone (CHZ) metabolism, CYP2E1 phenotype was assessed in 36 non-ethanol-induced subjects (17 controls and 19 withdrawn alcoholics) and in 14 ethanol-induced subjects (10 controls after ingestion of 0.8 g/kg ethanol and four alcoholics with 100 g of daily intake). This phenotype was expressed as the 6-hydroxy CHZ/CHZ ratio. RESULTS: The rare allele frequency was found to be 1.58% in whites (n = 349). Neither significant association with alcoholism or alcoholic liver diseases, nor relationship with the PstI/RsaI polymorphism, was observed. But the DraI polymorphism was more frequent among the heterozygous subjects when compared with wild-type homozygous ones (p < 0.05). The CYP2E1 phenotype was similar in wild-type homozygotes and in heterozygotes at the constitutive level, as well as after induction with ethanol. CONCLUSIONS: Our data suggest that CYP2E1 repeat polymorphism does not seem to constitute a major factor for interindividual differences in CYP2E1 expression and susceptibility to alcohol-related disorders in whites.

Adult↗

PubMed2001

Role of genetic polymorphism of glutathione-S-transferase T1 and microsomal epoxide hydrolase in aflatoxin-associated hepatocellular carcinoma.

Exposure to aflatoxins is a risk factor for hepatocellular carcinoma (HCC). Aflatoxins occur in peanut butter and are metabolized by genetically polymorphic enzymes such as glutathione-S-transferases encoded by glutathione-S-transferase mu 1 gene (GSTM1) and glutathione-S-transferase theta 1 gene (GSTT1) and microsomal epoxide hydrolase encoded by epoxide hydrolase gene (EPHX). The rate at which aflatoxins become activated or detoxified may depend on polymorphisms in the encoding genes. GSTM1 homozygous deletion was indeed found to modify the association between peanut butter consumption and HCC. In this study, we investigate possible roles of GSTT1 and EPHX polymorphisms in this relationship. From a Sudanese case-control study on HCC, we analyzed data of 112 incident cases and 194 controls. All participants were interviewed using a standardized questionnaire inquiring about social and demographic factors, peanut butter consumption, and other known HCC risk factors. Univariate analysis showed that GSTT1 polymorphism was not associated with HCC, whereas EPHX 113HH and 139HH genotypes increased the risk of HCC (Odds ratio, 3.10; 95% Confidence interval, 1.18-8.12). Adjustment for age and region of origin slightly attenuated this association (Odds ratio, 2.56; 95% Confidence interval, 0.83-7.95). Interestingly, unlike GSTM1, both GSTT1 and EPHX polymorphism did not modify the association between peanut butter consumption and HCC. In conclusion, these epidemiological findings do not suggest significant roles of GSTT1 and EPHX in aflatoxin metabolism, although EPHX polymorphism is possibly related to the increased risk of HCC. Further studies are needed to investigate mechanisms by which the EPHX polymorphism potentially modifies cancer risk.

Adult↗

PubMed2001

Lack of association between intercellular adhesion molecule-1 gene polymorphisms and giant cell arteritis.

OBJECTIVE: Studies have shown an association between HLA-DRB1*04 and giant cell arteritis (GCA). Intercellular adhesion molecule-1 (ICAM-1) gene polymorphisms were reported to contribute susceptibility to GCA in Italian patients where susceptibility to GCA is not associated with HLA-DRB1*04 alleles. ICAM-1 is also highly expressed within inflammatory infiltrates of the blood vessels of GCA patients. To investigate the clinical implications of ICAM-1 polymorphisms in GCA, we examined their potential association and influence in the development of visual ischemic complications in a series of patients with GCA from Northwest Spain where GCA susceptibility is associated with HLA-DRB1*04. METHODS: Fifty-eight biopsy proven GCA and 129 ethnically matched controls were studied. Patients and controls were genotyped for ICAM-1 polymorphism at codons 241 and 469 by PCR-RFLP. RESULTS: The distribution of the alleles and genotypes for each ICAM- polymorphism did not show significant differences between GCA patients and controls. Although visual manifestations were significantly more likely to occur in men than women (OR 5.2, p = 0.018), allele and genotype frequencies of ICAM-1 polymorphisms in patients with GCA were not associated with development of visual complications or anemia. Visual complications in GCA were primarily associated with carriage of an HLA-DRB1*04 allele. No evidence was found for interaction between HLA-DRB1*04 and ICAM-1 polymorphism. CONCLUSION: ICAM-1 polymorphisms are not genetic risk factors for the susceptibility and severity of GCA in Northwest Spain.

Aged↗

PubMed2001

Examination of a CYP2E1 repeat polymorphism in a monkey model of alcohol abuse.

BACKGROUND: Cytochrome P-450 2E1 (CYP2E1) is involved in alcohol metabolism, and the expression of this enzyme displays wide phenotypic variability in humans. It has been proposed that some of this variability in expression may be a consequence of the size of a repeat polymorphism in the 5" regulatory region of the gene and that the polymorphism may segregate with alcoholism. This study examined whether the repeat polymorphism exists in macaque monkeys and whether it associates with excessive alcohol consumption in this animal model. METHODS: Ten outbred cynomolgus monkeys (Macaca fascicularis) that displayed a voluntary alcohol consumption ranging from 1.0 to 3.6 g/kg/day were genotyped for a CYP2E1 repeat polymorphism. This polymorphism has been documented in the region from -2519 base pair (bp) to -1953 bp of the human CYP2E1 gene 5" distal promoter. RESULTS: Individual polymerase chain reaction amplification of genomic DNA from each of the 10 monkey samples revealed a single band of approximately 400 bp in the region corresponding to the human CYP2E1 polymorphism. Polymerase chain reaction amplicons from the 10 individuals were sequenced, and each one generated a 370 bp sequence that is 90% identical to the human gene sequence. However, unlike human alleles that contain five to eight repeats, the cynomolgus monkey is homozygous for a single copy of the repeat most closely resembling repeat 8 (88% identical) in the human gene. CONCLUSIONS: These data demonstrate that the CYP2E1 distal promoter region in monkeys is very similar to the human sequence yet lacks the extensive repeated DNA found in humans. This includes the rare repeats 3 and 4, which have been postulated to play a role in transcription regulation and to associate with alcohol abuse liability in humans. These data suggest that the CYP2E1 polymorphism arose late in evolution and that the regulation of the gene by this genetic region is not associated with a heavy alcohol drinking phenotype in the cynomolgus monkey.

Alcoholism↗

PubMed2001

Fluorescence-based, nonradioactive method for efficient detection of the pentanucleotide repeat (TTTTA)(n) polymorphism in the apolipoprotein(a) gene.

BACKGROUND: The apolipoprotein(a) [apo(a)] gene is a major predictor of plasma lipoprotein(a) concentrations, an independent risk factor for cardiovascular disease. The apo(a) gene contains a pentanucleotide repeat (PNR) polymorphism, 1.4 kb upstream from the apo(a) gene reading frame. This polymorphism has been suggested to be important in control of apo(a) gene expression. METHODS: We developed a fluorescence-based, nonradioactive procedure to detect the PNR polymorphism. After amplification of the polymorphism by PCR, the respective PCR products were separated by denaturing polyacrylamide gel electrophoresis and detected using a 3'-end fluorescently labeled oligonucleotide as a probe. We used the method to characterize the PNR polymorphism pattern in 313 individuals, 195 Caucasians and 118 African Americans. The new method efficiently separated DNAs corresponding to the different PNR repeats. RESULTS: Among both ethnic groups, alleles containing eight PNRs were most common. Smaller PNRs were more common among African Americans, and larger PNRs were more common among Caucasians. CONCLUSIONS: We developed a nonradioactive technique that separates the PNR polymorphism in the apo(a) gene and can be used in other studies involving closely sized polymorphisms.

Apolipoproteins A↗

PubMed2001

[Association between the interleukin 1B (C-31T) polymorphism and Helicobacter pylori infection in health checkup examinees].

PURPOSE: Associations between Helicobacter pylori (HP) infection and lifestyle factors have been demonstrated by several studies, but there are very few reports on links with host factors, especially concerning genetic polymorphisms for inhabitants of large city. The present investigation was conducted to determine the HP infection rate with reference to the Interleukin-1 beta gene (IL-1B) polymorphism and assess the interactions with smoking reported for outpatients. METHOD: The subjects were 468 participants in a health-check-up program of law of health for aged conducted by Nagoya Nishi Health Center. The participants were asked to permit use of their residual blood drawn during a health-check-up program and written informed consent was obtained for gene polymorphism tests. Data on smoking habit were obtained by self-administered questionnaire. The IL-1B C-to-T polymorphism at -31 was genotyped by PCR-CTPP (polymerase chain reaction with confronting two-pair primers) and an anti-HP IgG antibody test was used for detecting HP infection. Differences in values were assessed by a chi 2 test. An unconditional logistic model was applied for estimating odds ratios with the computer program STATA Version 6. This study was approved by the Ethical Committee at Aichi Cancer Center in 2000 before it was commenced (Ethical Committee Approval Number 11-12) RESULTS: The HP infection rate was 52.6% (61/116) for the C/C genotype of IL-1B-31, 48.6% (89/183) for the C/T, and 63.2% (103/163) for T/T; the difference were not statistically significant. However, when non-current smokers were excluded, the rate were 47.8% (11/23), 52.9% (18/34), and 72.7% (16/22), respectively, indicating the T/T genotype to have a higher infection rate. The age-sex-smoking adjusted odds ratio (OR) relative to the C/C genotype were 0.97 (95% confidence interval, 0.59-1.57) for the T/C genotype and 1.73 (1.04-2.87) for the T/T genotype. Among current and former smokers the age-sex adjusted OR were 1.68 (0.50-5.71) for the T/C genotype and 5.29 (1.11-25.1) for the T/T genotype, suggesting a effect of this polymorphism prominent in smokers. CONCLUSION: An association between the IL-1B-31 polymorphism and persistent HP infection was observed for inhabitants with a smoking habit, indicating that this polymorphism is one genetic trait conferring an increased likelihood of persistent HP infection.

Adult↗

PubMed1999

[Association of polymorphisms of apolipoprotein B gene with cholesterol gallstone disease].

OBJECTIVE: To investigate the association between the apolipoprotein B (apoB) gene polymorphic sites Ins/Del and Xbal, and cholesterol gallstone disease. METHODS: The two polymorphic sites of apoB gene were examed in 101 cholesterol gallstone patients and 50 controls by polymerase chain reaction and restriction fragment length polymorphism methods. RESULTS: For Xbal polymorphic site, the frequency of the rare allele X+ and the distribution of X+X- genotype were significantly higher in the patient group than in the control group (P < 0.05). For Ins/Del polymorphic site, no significant difference was found in allele frequency and genotype distribution between the patient group and the control group. CONCLUSIONS: Xba1 polymorphism of apoB gene may be associated with cholesterol gallstone disease. The association, however, is not present for Ins/De1 polymorphism of apoB gene with cholesterol gallstone disease.

Adult↗

PubMed2001

[Introduction to Go! Poly, a human genome polymorphism database].

Databases play an important role in the study of genetic polymorphism. To meet the need for more studies of human genome polymorphism by Chinese medical and pharmaceutical community, a gene oriented human genome polymorphism database-Go! Poly was constructed. As a generalized polymorphism database, Go! Poly extracted human gene-linked sequence variations of all common types from various public resources including scientific journals and Web resources such as HGBASE (http://hgbase.cgr.ki.se) and dbSNP (http://www.ncbi.nlm.nih.gov/SNP/). The polymorphism data were then categorized into different gene loci, and the reference sequences given by LocusLink were used as positioning reference. To facilitate the use, a friendly web interface and a text based query strategy were implemented. Users can fetch specific polymorphism data in just three steps: find specific gene locus by simple search, display sequence variation information of a specific gene locus select, and view the final result of a specific variation site. Besides, a web-based submission tool is provided for direct submission, which can make the polymorphism information generated by the Chinese scientific community available from this resource.

China↗

PubMed2001

[Study on the correlation of estrogen receptor gene polymorphism to bone mineral density of radius in Chinese Han postmenopausal women in Beijing].

OBJECTIVE: To investigate the distribution of estrogen receptor (ER) gene polymorphism in postmenopausal Han women in Beijing as well as its correlation with bone mineral density (BMD) of radius. METHODS: Xba I, and Pvu II polymorphism of ER gene were studied by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) in 99 healthy postmenopausal Han women. BMD of distal (spongy bone) and proximal (compact bone) radius were determined by dual-energy X-ray absorptiometry (DEXA) as well. The relationship between BMD and polymorphism of ER gene was analyzed by variance analysis. RESULTS: Pvu II polymorphism of ER gene is not associated with BMD of both sites of radius (P > 0.05); while Xba I polymorphism of ER gene is significantly associated with BMD spongy and compact bone of radius (P < 0.05). Women with XX genotype have the lowest BMD T-score of -1.55 +/- 0.37 for the compact and -2.54 +/- 0.38 for the spongy, and those with xx genotype have the highest BMD T-score of -0.95 +/- 0.24 for compact and -1.74 +/- 0.16 for spongy. CONCLUSION: There is a significant correlation of Xba I polymorphism of ER gene with BMD of distal and proximal radius. It is indicated that the difference in ER genotypes among individuals might influence the development of osteoporosis.

Asian People↗

PubMed2001

Relationship between gene polymorphism of the PAI-1 promoter and myocardial infarction.

OBJECTIVE: To investigate the association between gene polymorphism of the plasminogen activator inhibitor-1 (PAI-1) and myocardial infarction (MI) in Chinese. METHODS: PAI-1 genotyping with polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) and allele specific polymerase chain reaction (ASPCR) was performed in 87 myocardial infarction patients and 92 unrelated healthy controls. All subjects' clinical features and PAI-1 activity were tested. RESULTS: There were two polymorphisms within the promoter, a G/A single base substitution polymorphism upstream at -844 bp, and a single guanosine deletion/insertion 4G/5G polymorphism -675 bp upstream from the start of transcription. Significant differences between the patients and the controls were observed neither for the frequencies of the GG, GA and AA genotypes nor for the PAI-1 activities of these three types. But for the 4G/5G polymorphism, there were significant differences between patients and controls for the frequencies of the 4G/4G, 4G/5G and 5G/5G genotypes (P < 0.05). In the MI group, the PAI-1 activity of the 4G/4G type was significantly higher than that of the 5G/5G type (P < 0.05). Further more, a positive correlation between the glucose level and PAI-1 activity was found (r = 0.34, P = 0.02). CONCLUSION: This study indicates that the 4G/5G gene polymorphism of PAI-1 is associated with myocardial infarction, that 4G/4G type is probably an important hereditary risk factor, and that glucose has functional importance in regulating PAI-1 activity.

Adult↗

PubMed2002

DMBT1 polymorphisms: relationship to malignant glioma tumorigenesis.

The deleted in malignant brain tumors 1 (DMBT1) gene on 10q25-26 is a candidate tumor suppressor gene in malignant gliomas, but its role is controversial, e.g., some DMBT1 homozygous deletions reflect unmasking of constitutional deletion polymorphisms by 10q loss. To clarify the role of DMBT1 in gliomagenesis, we investigated three reported deletion hot spots. Homozygous deletions at DMBT1 repeat 2-4 to 2-7 were found in 10 of 73 gliomas with 10q loss, but all 10 deletions reflected unmasking of constitutional hemizygous deletions. Alleles bearing deletion 2-4/2-7 were not selected significantly for by 10q loss, with retention of only 10 of 16 deleted alleles. No homozygous deletion was detected at locus 74k in the 5' upstream region of DMBT1, and four tightly linked polymorphisms were found around this region; chromosome 10q loss randomly affected alleles with or without the variant sequences around locus 74k. Moreover, no significant selection pressure was detected for the haplotype with both deletion 2-4/2-7 and 5' polymorphisms. There was no segregation of deletion 2-4/2-7 in glioma patients compared with unrelated individuals from reference families but a suggestion of a difference in the distribution of the 5' polymorphisms between the reference individuals and glioma patients. Constitutional polymorphisms at DMBT1 repeat 2-9/2-10 appeared common in patients with both benign brain tumors and gliomas. A homozygote for both the 2-4/2-7 deletion and the 5' polymorphisms had a glioma arise at a typical age and without an apparent family cancer predisposition. These data suggest that DMBT1 polymorphisms are not likely primary targets of 10q loss in malignant gliomas and do not support a major role for DMBT1 in gliomagenesis.

Agglutinins↗

PubMed2002

Frequent polymorphism of peroxisome proliferator activated receptor gamma gene in colorectal cancer containing wild-type K-ras gene.

We analyzed the K-ras gene mutation and the polymorphism of peroxisome proliferator activated receptor gamma (PPARgamma) gene, which is known as a master gene for adipocyte differentiation and a tumor suppressor gene, in patients with colorectal cancer by polymerase chain reaction-restriction fragment length polymorphism. We detected a mutation of K-ras gene at codon 12 in 8 of 39 colorectal cancers. We also detected a polymorphism of PPARgamma gene at codon 12 in 10 of 39 patients with colorectal cancer. Homozygous polymorphism (Ala12Ala) in PPARgamma gene was found only in one patient, but heterozygous polymorphism (Pro12Ala) was found in 9 of 29 patients. Surprisingly, all 10 colorectal cancers developed in the patients with polymorphism of PPARgamma gene carrying the wild-type K-ras gene. These findings suggest that PPARgamma gene polymorphism may be implicated with the development of colorectal cancers, in which K-ras gene is not mutated.

Adult↗

PubMed2002

Type I IgE receptor, interleukin 4 receptor and interleukin 13 polymorphisms in children with nephrotic syndrome.

Polymorphisms in the genes encoding the high-affinity IgE receptor, the interleukin 4 (IL4) receptor and IL13 can be associated with the development of asthma and allergy. Although several studies have described an association between atopy and idiopathic childhood nephrotic syndrome (NS), it is not clear whether this association is of a causal nature. Furthermore, it is not known whether these polymorphisms are associated with the clinical course of NS. A total of 84 children (52 male and 32 female; mean age 12.1 years) with NS were included in the present study. Of these, 78 could be classified as either atopic or non-atopic. Atopy was defined by elevated IgE levels (>100 k-units/l) and/or a positive history of atopy (33 of 78 patients). DNA was extracted from blood collected in EDTA tubes, and polymorphisms at positions 50 and 551 of the IL4 receptor, position 110 of IL13 and position 181 of the high-affinity IgE receptor were investigated by sequence-specific PCR or direct sequencing. Although we noted a strong tendency towards a higher allele frequency of polymorphisms in children with atopy and NS compared with children with NS but without atopy (IL4 50, 30% compared with 18%; IL4 551, 39% compared with 31%; IL13 110, 45% compared with 33%; IgE 181, 12% compared with 13%), these differences did not reach statistical significance. There were no differences in the frequency of polymorphisms between the different clinical courses of NS (frequent relapsers, steroid-dependent or steroid-resistant NS). We conclude that polymorphisms in the IL4 receptor, the high-affinity IgE receptor and IL13 do not seem to predict the clinical course of NS, despite the fact that serum IgE elevations are more frequent in patients with NS than in normal control subjects. The investigated polymorphisms may contribute to the IgE switch in patients with NS.

Adolescent↗

PubMed2002

[Polymorphism of the renin-angiotensin system and renal failure].

The renin-angiotenin-aldosterone system (RAAS) is not only involved in cardiovascular disease but also in renal pathophysiology and progression of renal disease. Several polymorphisms of genes coding for components of the RAAS have been identified. The I/D polymorphism of the ACE gene, a variant of the angiotensiogen gen, the M235T polymorphism, and the variant A1166 C polymorphism of the angiotensin II type 1 receptor gene are the most important. Several studies have suggested a potential role for I/D polymorphism of the ACE gen in the progression of renal diseases and in the cardiovascular death rate of patients with renal failure. Data on RAAS polymorphisms as determinants of the prevalence of renal diseases and the response to renoprotective therapies are conflicting. Given the polygenic nature of renal and cardiovascular disease and the growing number of candidate genes, large prospective and collaborative studies are required to assess the effect of RAAS polymorphisms on the progression of renal disease and on the response to renoprotective therapies.

Cardiovascular Diseases↗

PubMed2002

Gene polymorphisms of tissue plasminogen activator and plasminogen activator inhibitor-1 in patients with antiphospholipid antibodies.

OBJECTIVE: Impaired fibrinolytical outcomes may be one of the pathogenic factors for thrombotic events in patients with antiphospholipid antibodies (aPL). We investigated the consequences of the gene polymorphisms of tissue plasminogen activator (tPA) and plasminogen activator inhibitor-1 (PAI-1) in patients positive for aPL. METHODS: Seventy-seven Japanese and 82 British patients with aPL were examined for Alu-repeat insertion (I)/deletion (D) polymorphism of the tPA gene by polymerase chain reaction (PCR), and 4G/5G polymorphism in the PAI-1 promoter gene by site-directed mutagenesis-PCR and restriction fragment length polymorphism analysis. Correlations between these polymorphisms and clinical symptoms of antiphospholipid syndrome (APS) (arterial thrombosis, venous thrombosis, miscarriage) were analyzed. RESULTS: Significant differences in the allele frequencies of these genes did not exist between patients and controls. There was no significant correlation between these gene polymorphisms and clinical symptoms of APS in patients with aPL. CONCLUSION: Polymorphisms of the tPA or PAI-1 genes probably do not significantly influence the risk of anerial thrombosis, venous thrombosis, or pregnancy morbidity in patients with aPL.

Alleles↗

PubMed2002

Distribution of p53 codon 72 polymorphism in Indian primary open angle glaucoma patients.

PURPOSE: Glaucoma is a complex neurodegenerative disorder of the eye. Primary Open Angle Glaucoma (POAG) is the most common type, accounting for over half of the total cases. Recently, a significant difference in the distribution of the codon 72 polymorphism of the tumor suppressor gene p53 between control subjects and POAG patients of Chinese origin (p=0.00782) was demonstrated. The proline residue at codon 72 of the p53 gene was significantly over represented in the POAG patients relative to healthy controls. The purpose of this study was to investigate whether the reported association between the p53 polymorphism and POAG is a common phenomenon irrespective of geographical location or ethnicity of the population. METHODS: Sixty seven unrelated POAG patients, ranging from 10-65 years of age (mean+/-SD of 41.16+/-18.52 years), and 112 control subjects having a similar age range of 18-63 years (mean+/-SD of 36.64+/-14.65 years) were enrolled in this study. A region of the p53 gene encompassing two polymorphic sites, a 16 bp duplication in intron 3 and a BstU I RFLP in exon 4, were amplified by polymerase chain reaction from Indian POAG patients and normal healthy controls. A single base change (G to C) in codon 72 alters the amino acid residue from arginine to proline and removes the polymorphic BstU I site mentioned above. The amplified DNA fragments were digested with the restriction enzyme and the digestion patterns of the fragments were used to identify the alleles for both the polymorphic sites. RESULTS: No significant association between p53 alleles and Indian POAG patients were observed by analyzing either codon 72 polymorphism (p=0.5627) or the intronic 16 bp duplication polymorphism (p=0.059). Haplotype analysis, reported to be a better predictor of association of the p53 gene with different types of cancer, was also performed and no association of any haplotype was detected with POAG (p=0.1831). CONCLUSIONS: Association between the p53 gene encoding for proline at codon 72 and POAG presumably exists in some ethnic populations but cannot be used as a predictor for the role of the gene as a common regulator of cell death of retinal ganglions leading to POAG.

Adolescent↗

PubMed2002

[Genomic polymorphism within interleukin-1 family cytokines influences the outcome of septic patients].

OBJECTIVE: To determine the allele frequencies and genotype distribution of interleukin (IL)-1 alpha, IL-1 beta and IL-1 receptor antagonist (IL-1ra) gene polymorphism in septic patients. METHODS: A prospective, consecutive entry study was made among 60 patients with the diagnosis of sepsis who were admitted consecutively into the general intensive care unit (ICU), Peking Union Medical College Hospital between 1997 and 1999. APACHE II scoring and MODS scoring were made within 24 hours after admission. The genomic DNA of peripheral blood nucleated cells was extracted. The polymorphic regions within intron 6 of IL-1 alpha gene containing variable numbers of a tandem repeat (VNTR) of 46 bp, and intron 2 of IL-1ra gene containing VNTR of 86 bp were amplified by means of polymerase chain reaction (PCR). Alleles A1-4 and RN1-4 were identified according to the size of amplified DNA product. The region containing the AvaI polymorphic site at position -511 of IL-1 beta gene was amplified by PCR, and subsequently digested with AvaI restriction enzyme. RESULTS: The frequencies of allele IL-1ra RN2 and genotype RN2/2 in the 60 septic patients were significantly higher than those in normal controls (0.34 vs 0.23, P < 0.01, and 0.12 vs 0.05, P < 0.05, respectively). The allele frequencies or genotype distribution of IL-1 alpha VNTR gene polymorphism and IL-1 beta AvaI polymorphism did not differ between the septic patients and normal controls. In addition, genotypes A2/2, B2/2 and RN2/2 were associated with a significantly higher mortality (80%, 81% and 71%, respectively) in septic patients. Patients with any 2 of the three alleles, i.e. A2, B2 and RN2, suffered from a much more severe sepsis (as measured by APACHE II and MODS scores) and higher mortality rate ( 55-65%), while septic patients with genotypes A1/1, B1/1 or RN1/1 showed a much lower mortality (0-13%). CONCLUSION: Allele IL-1RN2 polymorphism, but not IL-1A or IL-1B gene polymorphism, is associated with susceptibility to sepsis. Alleles A2, B2 and RN2 might be important high-risk genetic markers for sepsis.

Adult↗

PubMed2002

A single nucleotide polymorphism in the matrix metalloproteinase-3 promoter enhances breast cancer susceptibility.

PURPOSE: Matrix metalloproteinases (MMPs) are likely to be involved in invasion and metastasis of several tumors by degrading the extracellular matrix. A single adenine insertion/deletion polymorphism (5A/6A) in the MMP-3 promoter region causes the elevation of transcriptional level and local expression of MMP-3. The aim of this pilot study was to evaluate the impact of this 5A/6A polymorphism on susceptibility and metastasis in breast cancer. EXPERIMENTAL DESIGN: Genotyping for 5A/6A polymorphism was performed in 86 Italian women operated on for breast cancer and followed for 6-30 months (median follow-up, 21 months). A control population of 110 Italian age-matched tumor-free women was also genotyped for the same polymorphism. The 1G/2G gene promoter polymorphism for MMP-1 was additionally tested. RESULTS: The frequency of 5A allele was higher in the breast cancer group than in controls (P = 0.035; odds ratio, 1.53; 95% confidence interval, 1.02-2.29). The breast cancer group was divided into a group without metastasis (M-) and a group that had developed metastasis (M+). At the time of diagnosis, the 5A allele was more prevalent in the M+ group than in controls (P = 0.010; odds ratio, 1.96; 95% confidence interval, 1.16-3.30). The difference between M- patients and controls did not reach statistical significance (P = 0.37). This study was not able to demonstrate any statistical differences with respect to 1G/2G polymorphism between controls and cases and between M+ and M- subgroups. CONCLUSIONS: Although this should be considered only as a pilot study, our results suggest that the presence of 5A polymorphism at the MMP-3 promoter region may represent an unfavorable prognostic feature in breast cancer patients associated with more invasive disease.

Adenocarcinoma↗