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PubMed2005

TaqMan assays for genotyping of single nucleotide polymorphisms present at a disease susceptibility locus on chromosome 6.

Multiple single-nucleotide polymorphisms in the BAT1-NFKBIL1-LTA region on the short arm of chromosome 6 have been found to be associated with susceptibility to myocardial infarction in a recent case-control study including individuals from Japan. Specifically, the association relates to homozygosity for the minor alleles of five individual polymorphisms (one each in BAT1 and NFKBIL1 and three in LTA) and a haplotype defined by a particular allele combination of 10 polymorphisms (three each in BAT1 and NFKBIL1 and four in LTA). In the Japanese study, genotype determinations were carried out using a multiplex PCR-Invader assay or DNA sequencing. As an alternative to these methods, we have established TaqMan assays for genotyping of nine of the 10 polymorphisms. Accuracy of the genotyping results obtained with the TaqMan reactions was demonstrated in experiments involving restriction enzyme analysis or DNA sequencing. Using the new TaqMan assays, we have genotyped the polymorphisms in a group of 1211 Caucasians who presented without symptoms or signs of acute or previous myocardial infarction. Genotype distributions of each of the five myocardial infarction-associated polymorphisms were significantly different between the present study group and two Japanese control groups (p < or = 0.01). High linkage disequilibrium measures between polymorphisms suggested that the nine polymorphisms reside in a single haplotype block. Based on the nine polymorphisms, eight different haplotypes with allele frequencies above 1% were identified, which together represented 98.4% of the total number of chromosome 6 in the 1211 individuals. This Caucasian study group and the Japanese sample showed strong linkage disequilibrium in the myocardial infarction-associated BAT1-NFKBIL1-LTA genomic region and related haplotype content, but significantly different genotype frequencies. The new TaqMan systems provide relatively simple and fast assays to test the clinical relevance of these polymorphisms.

Alleles↗

PubMed2004

Applications of polymorphisms and pharmacogenomics in obstetrics and gynecology.

The number of reports investigating disease susceptibility based on the carriage of low-penetrance, high-frequency polymorphisms has steadily increased over the last years. Evidence based on meta-analyses of individual case-control studies is accumulating, defining specific individual variations in disease susceptibility. For example, genetic variations of the estradiol metabolism have been described as significant contributors to disease susceptibility with variations depending on ethnic background. In the field of obstetrics and gynecology, the genetic contribution of polymorphic markers to a series of disorders has been characterized. These disorders include recurrent pregnancy loss, pre-eclampsia, endometriosis, breast cancer, and hormone replacement therapy (HRT)-related complications such as thrombosis. Among other genetic markers, thrombophilic genetic variants, such as the Factor V Leiden and prothrombin G20210A polymorphisms, as well as genetic variants of cytochrome P450 (CYP) enzymes, for example, CYP19 and CYP1B1, have been established as genetic risk markers and disease modifiers of recurrent and sporadic pregnancy loss and HRT-independent and -dependent breast cancer, respectively. In addition, meta-analyses of data in the literature established the TGFBR1*6A, GSTP I105V, and TP53 R72P polymorphisms, as well as the GSTM1 gene deletion as low-penetrance genetic risk factors of sporadic breast cancer. With respect to genetic modulation of therapeutic effects, beneficial effects of estrogen replacement therapy and HRT are modulated by the carriage of single nucleotide polymorphisms, for example, osteoprotection and blood lipid changes by the estrogen receptor-alpha (ER-a) PvuII polymorphism. Polymorphisms of the catechol-O-methyltransferase (COMT), ER-alpha, IL-1 receptor antagonist, and Factor V genes have been demonstrated to modulate the timing of natural menopause. Lastly, a strong genetic contribution of polymorphisms to the development and the clinical course of endometriosis has been established with data pointing to polymorphisms of the COMT, GST, NAT-2, and ER-alpha genes as susceptibility markers. In summary, the available evidence points to a number of polymorphisms of a wide variety of genes as strong hereditary determinants of the susceptibility to benign and malignant gynecologic and obstetric conditions.

Female↗

PubMed2006

Association of proinflammatory cytokine gene polymorphisms with susceptibility to otitis media.

OBJECTIVE: Susceptibility to otitis media results from complex interactions among genetic factors of the host, exposure to pathogens, and environmental influences. The objective of this study was to study the role of single-nucleotide polymorphisms of regulatory elements of proinflammatory cytokine genes tumor necrosis factor-alpha(-308), interleukin-1beta(+3953), and interleukin-6(-174), in susceptibility to recurrent otitis media in childhood. METHODS: A total of 505 children (296 otitis media susceptible, 209 nonsusceptible as control) were enrolled at 2 sites (Texas and Kentucky). DNA of the children was studied for specific single-nucleotide polymorphisms by restriction fragment length polymorphism assay and confirmed by gene sequencing. RESULTS: In the overall study group, tumor necrosis factor-alpha(-308) and interleukin-6(-174) heterozygous or homozygous polymorphisms (high cytokine-producing genotypes) were significantly associated with otitis media susceptibility. The same association was found in a match-paired subgroup of 384 subjects. In the overall study group, there was a significant step-wise increase in otitis media susceptibility with increasing number of concomitant polymorphic genotypes. Simultaneous combination of tumor necrosis factor-alpha(-308) and interleukin-6(-174) polymorphisms further increased the risk for otitis media susceptibility. These 2 polymorphic genotypes also were associated with the increased risk for tympanostomy tube placement. Children who had tumor necrosis factor-alpha(-308) polymorphism and were breastfed for <1 month or exposed to cigarette smoke were more likely to be otitis media susceptible. CONCLUSIONS: Our data suggest that tumor necrosis factor-alpha(-308) and interleukin-6(-174) polymorphisms are associated with increased risk for otitis media susceptibility and placement of tympanostomy tubes. Environmental factors such as breastfeeding may modify the risk for otitis media susceptibility in polymorphic individuals.

Child, Preschool↗

PubMed2005

Increased risk of obesity resulting from the interaction between high energy intake and the Trp64Arg polymorphism of the beta3-adrenergic receptor gene in healthy Japanese men.

BACKGROUND: Few studies have investigated the interaction between the Trp64Arg polymorphism of the beta3-adrenergic receptor gene (ADRB3) and environmental factors. This study aimed to investigate whether energy intake affects the relationship between this polymorphism and obesity. METHODS: Healthy Japanese men (n=295; age 46.1+/-11.5 years (mean +/-standard deviation); waist circumference 83.9+/-9.3 cm; body mass index (BMI) 23.3+/-3.3 kg/m2) recruited in a Japanese chemical industry firm were eligible for analysis. Daily energy intake, protein, fat, and carbohydrate (PFC) ratio and daily physical activity were assessed by self-reported questionnaires. Genotyping for the polymorphism was performed with written informed consent. RESULTS: When the subjects were classified into two groups according to presence of the polymorphism, the groups were not significantly different in waist circumference or BMI. Quartile classification of energy intake, however, demonstrated a significantly larger ratio of obese subjects to non-obese subjects in the group with the polymorphism in the highest 4th quartile alone. Multiple logistic regression analysis also revealed that the presence of the polymorphism increased the risk of obesity significantly in the 4th quartile alone (adjusted odds ratio=3.37, 95% confidence interval=1.12-10.2). CONCLUSION: Presence of the polymorphism alone does not significantly increase the risk of obesity. However, high energy intake interacts with the polymorphism and leads to a significant increase in risk of obesity. The Trp64Arg polymorphism of ADRB3 warrants consideration, along with other polymorphisms involved in the development of obesity, for tailor-made prevention of obesity.

Body Mass Index↗

PubMed1998

[Study on the relationship between tumour necrosis factor gene polymorphism and prognosis in the patients with renal cell carcinoma].

BACKGROUND: Clinical significance of polymorphism of tumour necrosis factor (TNF) genes encoded on the short arm of the 6th chromosome in the patients with renal cell carcinoma (RCC) has not been evaluated well so far. We studied on the TNF genes polymorphism of RCC focusing on the relationship between the genetic polymorphism and the prognosis. METHODS: The subjects were seventy-three patients with RCC treated at our hospitals during the past 20 years. The genomic DNA was examined by the methods of polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) from frozen peripheral blood of these patients. The items examined were the genetic polymorphisms of TNF-alpha (alpha 1, alpha 2) and TNF-beta (beta 1, beta 2), and we tried to study on the prognostic outcome of RCC based upon each zygote of TNF. RESULTS: 1) The proportion of TNF-alpha and TNF-beta polymorphisms: We observed TNF-alpha 1/1 homozygote in 71 patients (97.3%). As to TNF-beta polymorphism, we observed TNF-beta 2/2 homozygote in 33 patients (45.2%), TNF-beta 1/2 heterozygote in 31 (42.5%) and TNF-beta 1/1 homozygote in 9 (12.3%). The proportion of TNF-beta polymorphism was almost the same as that of healthy Japanese. 2) PROGNOSIS: Regarding the 17-year survival, all patients with TNF-beta 1/1 homozygote were alive, and we observed a significantly favourable prognosis in the patients with TNF-beta 1/1 homozygote compared with other zygotes of TNF-beta polymorphism. The reasons for these favourable prognosis were thought that the patients with TNF-beta 1/1 homozygote showed much lower stage and/or grade than those of other zygotes. CONCLUSION: We conclude that the TNF-beta gene polymorphism is a useful marker for understanding the prognosis of RCC and a part of cellular immunity related to the tumour and its host.

Adult↗

PubMed1999

Apolipoprotein J polymorphisms and serum HDL cholesterol levels in African blacks.

Apolipoprotein J (apoJ, protein; APOJ, gene) is found in serum associated with high-density lipoprotein (HDL) subfractions, which also contain apolipoprotein A-I (apoA1) and cholesteryl ester transfer protein. ApoJ has been shown to be involved in a variety of physiological functions, including lipid transport. In earlier studies we reported the existence of a common genetic polymorphism (APOJ*1 and APOJ*2 alleles) using isoelectric focusing (IEF) and immunoblotting. In this study we determined the molecular basis of this polymorphism and together with another polymorphism at codon 328 (G-->A) evaluated its relationship with serum HDL cholesterol and apoA1 levels in 767 African blacks stratified by staff level: junior (less affluent, n = 450) and senior (more affluent, n = 317). The molecular analysis of the cathodally shifted APOJ*2 allele on IEF gels revealed an amino acid substitution of asparagine by histidine resulting from a missense mutation (A-->C) at codon 317 in exon 7. The frequency of the APOJ*2 (C) allele of codon 317 in the total sample was 0.267, whereas that of the less common allele A of codon 328 was 0.04. Despite their close proximity, no linkage disequilibrium was observed between the 2 polymorphisms. The impact of the codon 317 polymorphic variation was significant on serum HDL cholesterol (p = 0.003) and HDL3 cholesterol (p = 0.001) in junior staff. The adjusted mean values of these traits were higher in the codon 317 APOJ*2/*2 genotype than in the *1/*1 and *1/*2 genotypes. Overall, the APOJ codon 317 polymorphism explained 10.2% and 8.3% of the phenotypic variation in HDL cholesterol and HDL3 cholesterol, respectively, in junior staff. The codon 328 polymorphism showed a significant effect on HDL2 cholesterol (p = 0.039) and apoA1 (p = 0.007) only in junior women and accounted for 2.5% and 4.2% of the phenotypic variation in HDL2 cholesterol and apoA1, respectively. We also analyzed the combined effects of these genotypes at the 2 polymorphic sites. Significant effects on HDL cholesterol (p = 0.004) and HDL3 cholesterol (p = 0.008) in junior men and on HDL2 cholesterol (p = 0.003) in junior women were observed in the combined genotype data. The 2-locus genotypes explained 6.0% and 5.3% of the residual phenotypic variation of HDL cholesterol and HDL3 cholesterol in junior men and 10.4% of HDL2 cholesterol in junior women. These data indicate that the effect of the APOJ polymorphism on HDL cholesterol levels is modulated by socioeconomic status, as measured by staff level. Given the association of HDL and its subfractions with cardiovascular disease, these polymorphisms may lead to a better understanding of interracial differences in the risk of cardiovascular disease.

Adult↗

PubMed2001

The cyclin D1 alternative transcripts [a] and [b] are expressed in normal and malignant lymphocytes and their relative levels are influenced by the polymorphism at codon 241.

BACKGROUND AND OBJECTIVES: The cyclin D1 gene, CCND1, is alternatively spliced to produce transcripts [a] and [b] in a manner apparently modulated by a polymorphism (A/G) at codon 241. Studies have indicated that the polymorphism can affect the prognosis of patients with different types of solid tumors. This study aimed to determine the relative levels of transcripts [a] and [b] in normal and malignant peripheral blood mononuclear cells (PBMNC), and to investigate whether these were influenced by the polymorphism. The impact of the polymorphism on the survival of a group of mantle cell lymphoma (MCL) patients was also to be studied. DESIGN AND METHODS: The polymorphism was genotyped, using restriction fragment length polymorphism analysis, in 74 patients (42 MCL, 19 chronic lymphocytic leukemia, 13 normal controls) and the relative level of transcripts [a] and [b] determined using a competitive reverse transcription polymerase chain reaction method. Kaplan-Meier survival curves and the log-rank test were used to analyze the survival data. RESULTS: Of the cases genotyped, 39 were heterozygous for the polymorphism, 24 homozygous G and 11 homozygous A. Both transcripts [a] and [b] were expressed in normal PBMNC and malignant lymphocytes, with the polymorphism affecting their relative levels. Neither the predominant transcript, nor genotype, significantly influenced survival of the MCL patients studied. INTERPRETATION AND CONCLUSIONS: Contrary to previous reports, patients who were homozygous A at the polymorphism produced more transcript [a] whilst homozygous G patients had more transcript [b]. In the small cohort studied, the polymorphism did not appear to affect the prognosis of the patients with MCL.

Adult↗

PubMed2002

Relationship between polymorphisms in the renin-angiotensin system and nephropathy in type 2 diabetic patients.

BACKGROUND: Renin Angiotensin system is involved in renal function and its polymorphisms may influence diabetic nephropathy. ID ACE polymorphism modulates ACE level whereas M235T AGT polymorphism is involved in arterial hypertension. The A1166C AT1R polymorphism is involved in arterial hypertension and in diabetic retinopathy. METHODS: Two hundred thirty five type 2 diabetic patients were enrolled in this transversal study. Data were documented for clinical characteristics of the population, HbA(1c), urinary albumin excretion, presence of retinopathy or antihypertensive treatment. Polymorphisms were analyzed by PCR techniques. The patients were divided into 3 groups: group 1, without nephropathy (n=118), group 2, microalbuminuria (n=78), group 3, macroalbuminuria (n=39). RESULTS: Diabetes duration was longer (p<0.001), retinopathy (p<0.001) and antihypertensive treatment (p<0.02) were more frequent in group 3 compared to group 1 and 2. The I/D ACE and M235T AGT polymorphisms were not differently distributed between the three groups. In contrast, the CC genotype of the AT1R polymorphism was overrepresented in group 2 (p=0.021). The presence of the CC AT1R genotype considerably increased the incidence of albuminuria after 10 years of diabetes (AA vs CC p=0.01), particurlarly in men. No effect was seen with I/D ACE and M235T AGT polymorphisms. CONCLUSION: In conclusion, we observed an interaction of A1166C AT1R polymorphism with diabetes in men but not of I/D ACE and M235T AGT polymorphisms.

Aged↗

PubMed2004

The renin-angiotensin system genetic polymorphisms and rheumatic mitral valve disease.

BACKGROUND AND AIM OF THE STUDY: Angiotensin-converting enzyme (ACE) gene insertion/deletion (I/D) polymorphism, angiotensinogen (AGT) gene polymorphism and angiotensin II type 1 receptor (AT1R) polymorphism in relation to rheumatic mitral valve disease were examined in a case-control study to investigate possible relationships between these gene polymorphisms and rheumatic mitral valve disease in patients undergoing mitral valve replacement (MVR). METHODS: A total of 50 patients with rheumatic mitral valve disease and undergoing MVR was compared with 50 normal, and age- and sex-matched control subjects. ACE I/D, AGT gene M235T and AT1R-adenine/cytosine 1166 (A1166C) genotype polymorphisms were identified by polymerase chain reaction (PCR) -based restriction analysis. RESULTS: ACE I/D polymorphism differed significantly between the groups. The control group mostly represented the heterozygote ID allele (74%), while the MVR group showed frequencies of 60% for the homozygote DD and II alleles. MM homozygote frequency was significantly greater in controls, but TT homozygote frequency was significantly greater in the MVR group. AT1R-A1166C genotype polymorphism also differed significantly between groups; the MVR group had 73.7% of the AC heterozygote allele, while controls had 64.4% of the AA and 66.7% of the CC homozygote alleles. CONCLUSION: These results provided evidence of an association between ACE I/D polymorphism, M235T polymorphism and AT1R-A1166C genotype polymorphism and rheumatic mitral valve disease.

Adult↗

PubMed2004

[Association of polymorphisms in the angiotensin system genes with obstructive sleep apnea-hypopnea syndrome].

OBJECTIVE: To investigate the association of polymorphisms in the angiotensin system gene with obstructive sleep apnea-hypopnea syndrome (OSAHS). METHODS: The genotypes and alleles of angiotensin-converting enzyme (ACE) and angiotensinogen (AGT) genes were identified by polymerase chain reaction-restricted fragment length polymorphism assay in 221 unrelated subjects of the north region "Han" population of China (including 121 OSAHS subjects and 100 non-OSAHS subjects). The genotypes and allele frequencies of the polymorphisms were compared between OSAHS group and non-OSAHS group. The effects of the polymorphisms in OSAHS group on body mass index (BMI), neck circumference (NC), waist/hip rate (WHR), apnea-hypopnea index (AHI), systolic blood pressure (SBP), and diastolic blood pressure (DBP) were analysed. RESULTS: There were significant differences in genotypes distribution in AGT polymorphism between the two groups (P = 0.009). Compared with the control group, OSAHS group had significantly higher T allele frequency in AGT polymorphism (P = 0.020). There were independent effects of AGT polymorphism on BMI, NC, WHR in OSAHS group, and carriers of the T allele of AGT polymorphism had greater BMI, NC, and WHR, while the carriers of the T allele had greater AHI, SBP, and DBP. CONCLUSIONS: ACE polymorphism may not be correlated with central obesity and OSAHS in the population. AGT polymorphism may be involved in the development of central obesity and may be related to OSAHS and hypertension in OSAHS patients by the central obesity in male OSAHS subjects of North region "Han" population of China.

Adult↗

PubMed1992

Detection of multiallele polymorphisms within gene sequences by GC-clamped denaturing gradient gel electrophoresis.

The ability to efficiently detect DNA polymorphisms is essential for the completion of a high-resolution polymorphic linkage map of the human genome. Currently the most informative polymorphisms are the multiallelic dinucleotide repeat polymorphisms. However, many gene sequences lack an associated dinucleotide repeat sequence. We used GC-clamped denaturing gradient gel electrophoresis to screen for DNA polymorphisms in the following six gene sequences: MCC, p53, prealbumin (transthyretin), rhodopsin, S-antigen, and TGF-alpha. A single-base sequence polymorphism was identified in each of these gene sequences. Some of these polymorphisms were multiallelic and highly informative. Our results demonstrate the value of denaturing gradient gel electrophoresis for both identifying and analyzing human DNA polymorphisms. The ability to detect highly informative polymorphisms within gene sequences will greatly contribute to a gene-based polymorphic linkage map.

Alleles↗

PubMed2005

Impact of gene polymorphisms on clinical outcome for stage IV melanoma patients treated with biochemotherapy: an exploratory study.

PURPOSE: Biochemotherapy can achieve high response rates in advanced melanoma, but the factors that influence regression and survival remain unknown. The present exploratory study tested the hypothesis that cytokine gene polymorphisms predict clinical outcome in stage IV melanoma patients treated with biochemotherapy. EXPERIMENTAL DESIGN: Ninety patients with stage IV melanoma were treated with biochemotherapy, including cisplatin, vinblastine, and dacarbazine combined with interleukin (IL)-2 and IFN-alpha either with or without tamoxifen. Cytokine gene polymorphisms for IFN-gamma (+874A-->T) and IL-10 (-1082G-->A) were assessed. X-ray repair cross-complementing gene 1 (XRCC1; Arg399Gln), xeroderma pigmentosum complementary group D (XPD; Lys751Gln), and excision repair cross-complementing gene 1 (ERCC1; codon 118) DNA repair polymorphisms were also determined. RESULTS: IFN-gamma (+874A-->T) gene polymorphism was statistically significantly associated with response (P = 0.001), progression-free survival (P = 0.0012), and overall survival (P < 0.001), whereas the IL-10 polymorphism was marginally associated with response (P = 0.03) and overall survival (P = 0.065). Multivariate analysis revealed that IFN-gamma (+874A-->T) independently predicted overall survival (P = 0.003). The ERCC1 polymorphism was weakly associated with overall survival (P = 0.045). Combining polymorphisms for IFN-gamma, IL-10, and ERCC1 stratified patients into four distinct groups with significantly different clinical outcome (P < 0.001), so that patients with more "favorable" polymorphisms had a better outcome. CONCLUSIONS: Cytokine gene polymorphisms predicted clinical outcome for advanced melanoma patients who received biochemotherapy. The combined effects of multiple genetic polymorphisms may provide more accurate prognostic information. Additional independent studies are needed to confirm these pilot findings.

Adolescent↗

PubMed2005

[Association of DNA polymorphisms of the growth hormone and prolactin genes with milk productivity in Yaroslavl and black-and-white cattle].

Polymorphisms of the prolactin (bPRL) and growth hormone (bGH) genes were studied comparatively in the Russian and German Black-and-White and Yaroslavl cattle breeds. Two polymorphisms were studied for each gene. In the case of the bPRL gene, the polymorphism of the 5'-untranslated region was examined by microsatellite analysis and the RsaI polymorphism of exon 3, by RFLP analysis. In the case of the bGH gene, the MspI polymorphism of intron III and the AluI polymorphism of exon 5 were assessed by RFLP analysis. Differences in allele and genotype frequencies were observed both between and within breeds. The heterozygosity at the RsaI marker was low (9.4%) in the Russian Black-and-White breed; that at the microsatellite of the bPRL gene was low (3.2-24%) in all breeds examined. Homozygotes BB at the bPRL gene, which had not been reported earlier for European cattle breeds, were detected in the German Black-and-White and Yaroslavl breeds (at frequencies 0.16 and 0.13, respectively). The frequency of allele MspI(-) of the bGH gene in the Yaroslavl breed was extremely low (0.02), comparable only with that of the Holstein cattle (0.02). The heterozygosity at the AluI polymorphism was higher than at the MspI polymorphism of the bGH gene and reached 55% in the Yaroslavl breed. Genotype BB of the RsaI polymorphism of the bPRL gene tended to show a negative association with the fat content in milk. The genotypes of the AluI polymorphism of the bGH gene were associated with the fat content in milk in the Yaroslavl (F = 4.56, P = 0.013) and German Black-and-White (F = 4.1, P = 0.014) breeds: the highest fat content in milk was observed in the subsample of cows with heterozygous genotype VL.

5' Untranslated Regions↗

PubMed2005

[Effect of polymorphism of transforming growth factor beta1 gene on HBV-induced liver cirrhosis].

OBJECTIVE: To explore the effects of transforming growth factor beta1 (TGFbeta1) gene polymorphism on liver cirrhosis induced by HBV infection and on plasma concentration of TGFbeta1. METHODS: Peripheral blood samples were collected from 134 patients with HBV-induced liver cirrhosis, which were further classified into three groups (A, B and C groups) according to Child-Pugh classification and 92 healthy blood donors. The polymorphisms at position -988, -800, -509 and codon10, codon25, and codon263 of TGFbeta1 gene were determined by PCR-ARMS- and Lightcycler respectively, combined with sequence analysis. The concentrations of TGFbeta1 and collagen type IV were measured by ELISA, and the plasma concentrations of hyaluronan and N-terminal type III procollagen peptide were measured by RIA. ARLEQUIN Ver 2.0 software was used to analyze the linkage disequilibrium between -509C > T and codon10T > C polymorphisms. RESULTS: No polymorphism was found at positions -800, -988, codon25 and codon263. No significant difference for -509C > T polymorphism between the diseased and control groups was found, however, the frequencies of genotype TT and allele T at codon10 in the diseased group were 0.313 and 0.537 respectively, both significantly higher than those of the control group (0.916 and 0.440 respectively, both P < 0.05). In Child-Pugh C grade group the frequency of C allele at position -509 was 0.631, significantly higher than that of T allele (0.325), but there was no significant difference for codon10T > C polymorphism. The TGFbeta1 plasma concentration did not show any difference between the genotypes -509CC and TT in the control group, however, the TGFbeta1 plasma concentration was statistically lower in the those with TT genotype than in those with CC genotype in the diseased group. Linkage disequilibrium was found between -509C > T and codon10T > C polymorphisms and the major haplotypes were C-T and T-C, of which C-T frequency was significantly higher in the patients than in the control group. The plasma concentration of TGFbeta1 was significantly higher in the populations of haplotype C-T than in those of other haplotypes. CONCLUSION: No relationship is found between -509C > T polymorphism of TGFbeta1 and liver cirrhosis in Chinese populations, but the presence of C allele at position -509 may play an important role in the progression of liver cirrhosis and may influence plasma concentration of TGFbeta1 in liver cirrhosis patients. Codon10T > C polymorphism may play a significant role in development of liver cirrhosis, but has no correlation with plasma concentration of TGFbeta1 and progression of liver cirrhosis. The -509C > T and codon10T > C polymorphisms are in tight linkage disequilibrium, and the major haplotypes are C-T and T-C. The haplotype C-T influences plasma concentration of TGFbeta1 and is closely related to liver cirrhosis.

Adult↗

PubMed1995

[New polymorphic variants of the gene for human blood coagulation factor IX].

The polymorphism of Alu-repeats, which are located in the introns of the human factor IX gene (copies 1-3), was studied. To identify polymorphic variants, direct sequencing of PCR products that contained appropriate repeats was used. In each case, 20 unrelated X chromosomes were studied. A polymorphic Dra I site was found near the 3'-end of Alu copy 3 within the region of the polyA tract. A PCR-based testing system with internal control of restriction hydrolysis was suggested. Testing 81 unrelated X chromosomes revealed that the frequency of the polymorphic Dra I site is 0.23. Taq I polymorphism, which was revealed in Alu copy 4 of factor IX gene in our previous work, was found to be closely linked to Dra I polymorphism. Studies in linkage between different types of polymorphisms of the factor IX gene revealed the presence of a rare polymorphism in intron A that was located within the same minisatellite region as the known polymorphic insertion 50bp/Dde I. However, the size of the insertion in our case was 26 bp. Only one polymorphic variant was found among over 150 unrelated X chromosomes derived from humans from Moscow and its vicinity.

Base Sequence↗

PubMed1993

Gene polymorphism of apolipoprotein AI, the major protein of high density lipoprotein in predicting stroke risk among white and black subjects.

BACKGROUND AND PURPOSE: Restriction fragment length polymorphism of the apolipoprotein AI gene, which encodes the most prominent apoproteins in high density lipoprotein (HDL), were investigated using the restriction enzymes Sac I and Pst I in white and black subjects to determine the potential role of genetic variations as stroke risks as determined by carotid stenosis and an atherogenic serum profile, such as elevated total cholesterol and low density lipoprotein (LDL) levels or reduced HDL levels. METHODS: Ninety-eight subjects, including normal control subjects with no carotid stenosis and subjects with carotid stenosis, who were believed to be at stroke risk, were the study subjects and included 70 white and 28 black subjects. RESULTS: Sac I polymorphic S2 allele frequency was higher in stroke-risk groups. Significantly higher levels of serum cholesterol, triglycerides, and LDL (P < .05) and significantly lower levels of HDL (P < .05) were present in the stroke-risk group with carotid stenosis. Our study showed the following: Sac I polymorphism frequency was significantly higher in black than white subjects (chi 2 = 3.92, P < .05). Triglyceride level was significantly higher in white subjects compared with black subjects (P < .05). In white subjects, carotid artery stenosis was associated with significantly elevated total cholesterol and LDL levels (P < .01) but not with Sac I polymorphism. In black subjects, the reverse was seen with the Sac I polymorphic S2 allele associated with carotid bifurcation stenosis but did not reach statistical significance because of the small number of subjects. In addition, Sac I polymorphism did not correlate with any lipid profile. Pst I polymorphism was not associated with an abnormal atherogenic lipid profile or carotid artery stenosis abnormalities. CONCLUSIONS: Our study shows that carotid artery stenosis in white subjects is associated with increased plasma total cholesterol and LDL levels and an atherogenic profile but not with Sac I polymorphism for apoprotein AI. In black subjects, Sac I polymorphism appears to identify individuals with significant carotid stenosis, a necessary precursor to atherothrombotic brain infarction, but not those with elevated total cholesterol or LDL and/or reduced HDL levels. These results suggest that Sac I polymorphism may identify black subjects at increased risk for atherothrombotic brain infarctions.

Aged↗

PubMed2004

Characterization of two polymorphisms in the leukotriene C4 synthase gene in an Australian population of subjects with mild, moderate, and severe asthma.

BACKGROUND: The cysteinyl-leukotrienes (cys-LTs) are proinflammatory mediators that are important in the pathophysiology of asthma. LTC(4) synthase is a key enzyme in the cys-LT biosynthetic pathway, and studies in small populations have suggested that a promoter polymorphism (A(-444)C) in the gene might be associated with asthma severity and aspirin intolerance. OBJECTIVE: We sought to screen the LTC(4) synthase gene for polymorphisms and to determine whether there is an association between these polymorphisms and asthma severity or aspirin sensitivity in a large, well-phenotyped population and to determine whether this polymorphism is functionally relevant. METHODS: The coding regions of the LTC(4) synthase gene were screened for polymorphisms and the A(-444)C polymorphism was analyzed in a large Australian white adult population of mild (n=282), moderate (n=236), and severe asthmatic subjects (n=86) and nonasthmatic subjects (n=458), as well as in aspirin-intolerant asthmatic subjects (n=67). The functional activity of the promoter polymorphism was investigated by transient transfection of HL-60 cells with a promoter construct. RESULTS: A new polymorphism was identified in intron 1 of the gene (IVS1-10c>a) but was not associated with asthma. Association studies showed that the A(-444)C polymorphism was weakly associated with asthma per se, but there was no association between the C(-444) allele and chronic asthma severity or aspirin intolerance. A meta-analysis of all the genetic studies conducted to date found significant between-study heterogeneity in C(-444) allele frequencies within different clinical subgroups. In vitro functional studies showed no significant differences in transcription efficiency between constructs containing the A(-444) allele or the C(-444) allele. CONCLUSIONS: Our data confirm that, independent of transcriptional activity, the C(-444) allele in the LTC(4) synthase gene is weakly associated with the asthma phenotype, but it is not related to disease severity or aspirin intolerance.

Adolescent↗

PubMed2005

Association of the osteoprotegerin gene polymorphisms with bone mineral density in postmenopausal women.

OBJECTIVES: Osteoprotegerin (OPG) is a recently discovered member of the tumour necrosis factor receptor superfamily. It plays a crucial role in the control of bone resorption and its gene could therefore be a good candidate gene for osteoporosis. The aim of our work was to find polymorphisms in the OPG gene and to investigate their possible contribution to the genetic susceptibility to osteoporosis by testing for their association with bone mineral density (BMD). METHODS: The whole OPG gene coding region was screened for the presence of polymorphisms in a group of 60 osteoporotic women by single-strand conformation polymorphism analysis (SSCP) approach. Association of the discovered polymorphisms with bone mineral density was investigated in 136 Slovenian postmenopausal women. RESULTS: We detected eight OPG gene polymorphisms that were confirmed by direct DNA sequencing, deletion 4752_4753delCT and nucleotide substitutions 1181G>C, 1217C>T, 1284G>A, 4501C>T, 6893A>G, 6950A>C and 8738T>A. Nucleotide substitutions 1284G>A and 8738T>A have not been previously described. Polymorphisms 4752_4753delCT, 6893A>G and 6950A>C were in complete linkage and the same was true for 1217C>T and 4501C>T. The association with BMD was found only for polymorphism 1181G>C. Subjects with genotype 1181GG had significantly lower lumbar spine BMD than subjects displaying 1181GC. CONCLUSIONS: By our approach we detected eight polymorphisms in the OPG gene. According to our analysis polymorphism 1181G>C is associated with BMD and could therefore be considered as an element of genetic susceptibility to osteoporosis.

Aged↗