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PubMed2000

p53 and WAF1 polymorphisms in Jewish-Israeli women with epithelial ovarian cancer and its association with BRCA mutations.

OBJECTIVE: To investigate whether polymorphic p53 and WAF1 alleles are associated with clinical, demographic and histopathological features and BRCA mutation in women with ovarian cancer. DESIGN: A cross-sectional study. POPULATION: Two hundred and twenty-one nonselected Israeli women with epithelial ovarian cancer. METHODS: DNA was analysed for known polymorphisms in intron 3 (a 16 nucleotide single repeat) and intron 6 (a G to A change at nucleotide 13,494) of the p53 gene, the S31R polymorphism in the WAF1 gene, and for three predominant Jewish mutations in the BRCA genes (185delAG and 5382insC in BRCA1, and 6174delT in BRCA2). MAIN OUTCOME MEASURE: The rate of polymorphic p53 and WAF1 alleles and their association with BRCA mutation, ethnic origin, age and stage at diagnosis, and family history of cancer. RESULTS: Of the tested women, 72 (32.6%) were either BRCA1 (n = 57) or BRCA2 (n = 15) mutation carriers. Sixty-eight of 213 (31.9%) were heterozygous for intron 3 polymorphism, 67/193 (34.7%) for intron 6 polymorphism, and 22/154 (14.3%) for S31R of the WAF1 gene. The p53 and WAF1 polymorphism rate did not differ between BRCA mutation carriers and noncarriers. No significant association between specific p53 or WAF1 genotypes, and clinical, histopathological or demographic variables was observed. CONCLUSION: In Jewish-Israeli women with sporadic and familial ovarian cancer, p53 or WAF1 polymorphisms do not seem to affect the phenotype.

Adult↗
PubMed1994

A new restriction fragment length polymorphism in the first intron of the spontaneously hypertensive rat renin gene.

1. Amplification of the entire first intron of the renin gene of spontaneously hypertensive rat (SHR), Wistar-Kyoto (WKY) and Sprague-Dawley rats (SD) followed by Bgl II digestion uncovered a new deletion (approximately 50 bp) which exists upstream of the SHR renin gene first intron tandem repeat element. 2. The SHR tandem repeat element was 600 bp shorter than that in the WKY while the WKY tandem repeat element was 280 bp shorter than that in the SD. 3. Since elements regulating gene expression are known to exist in the first intron of other genes, this new restriction fragment length polymorphism (RFLP) might play a role in the reported overexpression of the SHR renin gene independent of changes in the length of the tandem repeat element.

Animals↗
PubMed1991

A cluster of highly polymorphic dinucleotide repeats in intron 17b of the cystic fibrosis transmembrane conductance regulator (CFTR) gene.

A cluster of highly polymorphic dinucleotide repeats has been detected in intron 17b of the CFTR gene, 200 bp downstream from the preceding exon. At least 24 alleles, with sizes ranging from 7 to 56 units of a TA repeat, have been identified in a panel of 92 unrelated carriers of cystic fibrosis (CF). The common ones are those with 7, 30, and 31 dinucleotide units, with frequencies of .22, .19, and .12, respectively, among the non-CF chromosomes. Mendelian, codominant segregation of the alleles has been demonstrated in family studies, as expected. A less polymorphic dinucleotide (CA repeat) cluster has also been detected in a region 167 bp downstream from the TA repeat. The length of the CA repeat cluster varies from 11 to 17 dinucleotide units, and it appears to have an inverse relationship to that of the TA repeats. These dinucleotide repeats should be useful in genetic linkage studies, in counseling for CF families with unknown mutations, and in tracing the origins of the various mutant CF alleles.

Adenine Nucleotides↗
PubMed2006

Endothelial nitric oxide synthase gene intron 4 a/b VNTR polymorphism in children with APSGN.

The role of endothelial nitric oxide synthase gene intron 4 a/b (eNOS4a/b) variable number of tandem repeats (VNTR) polymorphism in various renal diseases was investigated. We investigated whether the eNOS4a/b VNTR polymorphism is associated with susceptibility to acute poststreptococcal glomerulonephritis (APSGN) and its clinical features. Endothelial NOS4a/b VNTR polymorphism is determined by the polymerase chain reaction in 60 children with APSGN, and 66 healthy controls. The genotype distribution of eNOS4 does not differ between the patients and the controls (X(2)=5.1, p=0.079). However, the frequency of eNOS4a (eNOS4a/a and eNOS4a/b) genotype is higher in the patients than in the controls (X(2)=4.5, p=0.046). In the APSGN group we performed renal biopsy on eight patients because of nephrotic syndrome accompanies acute nephritic syndrome or glomerular filtration rate (GFR) is lower than 50% of normal, and found that to carry a/a and a/b genotypes were a significant risk factor for this type presentation (OR=17.3, 95% CI:1.95-152.67, p=0.03). Mean serum creatinine values are found statistically significantly higher in a/a and a/b genotypes when compared with b/b genotypes (p=0.022). Children carrying the "aa" and "ab" genotype or "a" allele of eNOS4 have a greater tendency to develop and clinical presentation of APSGN.

Acute Disease↗
PubMed1999

Intron variants of the p53 gene are associated with increased risk for ovarian cancer but not in carriers of BRCA1 or BRCA2 germline mutations.

Two biallelic polymorphisms in introns 3 and 6 of the p53 gene were analysed for a possible risk-modifying effect for ovarian cancer. Germline DNA was genotyped from 310 German Caucasian ovarian cancer patients and 364 healthy controls. We also typed 124 affected and 276 unaffected female carriers with known deleterious BRCA1 or BRCA2 germline mutation from high-risk breast-ovarian cancer families. Genotyping was based on PCR and high-resolution gel electrophoresis. German ovarian cancer patients who carried the rare allele of the MspI restriction fragment length polymorphism (RELP) in intron 6 were found to have an overall 1.93-fold increased risk (95% confidence internal (CI) 1.27-2.91) which further increased with the age at diagnosis of 41-60 years (odds ratio (OR) 2.71, 95% CI 1.10-6.71 for 41-50 and OR 2.44, 95% CI 1.12-5.28 for 51-60). The 16 bp duplication polymorphism in intron 3 was in a strong linkage to the MspI RFLP. In BRCA1 or BRCA2 mutation carriers, no difference in allele frequency was observed for carriers affected or unaffected with ovarian cancer. Our data suggest that intronic polymorphisms of the p53 gene modify the risk for ovarian cancer patients but not in carriers with BRCA1 or BRCA2 mutations.

Adolescent↗
PubMed1998

Dinucleotide repeat polymorphism in the first intron of the CSR gene.

The CSR (cellular stress response) gene encodes a protein that structurally resembles the macrophage scavenger receptor, and is a potent regulator of intracellular reactive oxygen intermediates. We found a polymorphic dinucleotide repeat in the first intron of the CSR gene. This polymorphism will be a useful genetic marker to study diseases associated with oxidative stress.

Dinucleotide Repeats↗
PubMed2004

[Deletional polymorphism of the 11th intron of the human c-fms gene: allele frequency in certain Russian populations and possible functional significance].

Analysis of deletion polymorphism of human c-fms gene intron 11 (approximately 425-bp deletion) is of particular interest because of the increased proportion of the deletion heterozygotes among the infants born from the parents, one of which lacks the deletion allele, and the other is heterozygous for the deletion. In this study, allele and haplotype frequencies of the polymorphism examined were assessed in a number of Caucasoid and Mongoloid populations of Russia. In all populations tested, relatively high prevalence of the deletion-bearing allele, ranging from 9.45% in ethnic Germans to 20.75% in Altaians, was detected. Russians and Kazakhs were characterized by intermediate frequencies of the rare allele, constituting in these populations 12.89 and 14.93%, respectively. Hardy-Weinberg expectations were met in all populations examined, pointing to a stable level of polymorphism at the c-fms intron 11. It was established by the context analysis of DNA of the deleted fragment along with the flanking sequences that this region contained a number of transcription factor motifs (Ets, SRF, and Myc), potentially capable of the regulation of the M-CFF-dependant c-fms transcription. The deletion breakpoint was localized within the CArG motif, which, together with the neighboring ets motif, form the potential CArG/ets composite element. It was suggested that allele lacking the fragment of intron 11 could be restricted in its ability to modulate the level of the c-fms transcription in response to the action of M-CSF. The data of molecular epidemiological survey serve as the indirect evidence favoring the suggestion on the possible functional value of this gene fragment. It was demonstrated that in the samples of acute bronchitis and trichomoniasis patients allelic and genotype frequencies were statistically significantly different from those in the population sample. In case of trichmoniasis, the frequency of rare allele was 2.4 times lower, and in case of acute bronchitis it was 2.1 times higher than in the control sample.

Base Sequence↗
PubMed1996

A highly polymorphic CA/GT repeat in intron 3 of the human urokinase receptor gene (PLAUR).

We describe the first highly polymorphic microsatellite marker for the human urokinase plasminogen activator receptor gene (PLAUR). The urokinase receptor (uPAR) has a central role in cancer invasion and metastasis, which may enable the development of new anti-metastatic therapies. Analysis of the marker genotypes in colorectal cancer cell lines revealed three alleles that were not detected in a series of healthy control individuals, which encourages further genetic study of the role of uPAR in cancer.

Alleles↗
PubMed2000

[Genetic polymorphism analysis of apoE intron 1 enhancer in patients with coronary heart disease and the association with serum lipid level].

OBJECTIVE: To investigate the association between the polymorphism of apolipoprotein E (apoE) intron 1 enhancer (IE1) and the level of serum lipid in patients with coronary heart disease (CHD). METHODS: ApoE IE1 genotypes of 81 patients with CHD and 108 healthy subjects were detected by polymerase chain reaction and restriction fragment length polymorphism. RESULTS: The frequency of G/G genotype in patients with CHD was significantly higher than that in control group (P < 0.05). The frequency of G allele was significantly higher in patients than in control group (P < 0.05). The gene polymorphism of apoE IE1 obviously influenced the serum lipid levels. The concentrations of TC, and LDL-C among different genotype groups were significantly different, and the level in G/G group was higher than that in C/C group (P < 0.05). CONCLUSION: ApoE IE1 gene polymorphism is closely related to serum lipid, and G/G genotype of apoE IE1 may be a risk factor of coronary heart disease in Han Chinese.

Aged↗
PubMed2006

Intron 2 (T/C) CYP46 polymorphism is associated with Alzheimer's disease in Chinese patients.

BACKGROUND: Cholesterol metabolism has been implicated in the pathophysiology of Alzheimer's disease (AD), and cholesterol-related genes are plausible candidate genes for AD. Genetic association of CYP46A1 polymorphisms with AD had been under extensive investigations; however, observations on intron 2 T-->C (rs754203) generated inconclusive results. OBJECTIVE: To analyse an independent data set in a Chinese population to see whether the polymorphic site rs754203 of the CYP46A1 gene is associated with AD. METHODS: We analysed 130 sporadic AD patients and 110 healthy controls of the Southern Chinese origin. RESULTS: An association between the genotype frequency and AD was suggested in the general population (p = 0.047, odds ratio, OR = 1. 61, 95% confidence interval, CI = 0.96-2.70), while the association was most significant in the apolipoprotein E (ApoE) epsilon4-negative group (p = 0.004, OR = 2.54, 95% CI =1.31-4.95). Linkage disequilibrium block prediction results also favoured this association. Consistent with previous reports, intron 3 C-->T (rs4900442) polymorphism did not show any evidence of association; in our data set ApoEepsilon4 was confirmed to be a genetic risk factor for AD (p = 0.0016, OR = 2.76, 95% CI = 1.50-5.11).

Aged↗
PubMed2001

Association of polymorphic alleles of the calcium-sensing receptor gene with the clinical severity of primary hyperparathyroidism.

OBJECTIVE: Primary hyperparathyroidism (pHPT) is a heterogeneous disease in its clinical course and severity. Previous studies have suggested an association between the clinical severity of pHPT and the genotypes of vitamin D receptor, oestrogen receptors and PTH molecules. The Ca-sensing receptor (CaR) is activated by an extracellular calcium ion and controls PTH secretion, and thus polymorphisms of CaR might be associated with the magnitude of PTH secretion and the clinical severity of pHPT. In this study, we examined the relationship between CaR polymorphisms and biochemical markers in pHPT patients. METHODS: We analysed 105 Japanese pHPT patients (85 females and 20 males; mean age 55.6 +/- 14.0 years). We determined the CaR genotypes of G990R and intron 5 polymorphisms with genomic DNA extracted from peripheral lymphocytes. The intron 5 polymorphism was defined as T/T, T/C and C/C. RESULTS: In the G990R polymorphism, serum levels of both intact PTH and alkaline phosphatase (ALP) were significantly higher and the serum level of phosphorus was significantly lower in the RR group than in the GG group. In the intron 5 polymorphism, the T/T group showed significantly lower serum levels of intact PTH and Ca. Furthermore, patients with both the codon 990 RR and the intron 5 C allele (the RRC(+) group) had significantly higher serum levels of intact PTH and ALP than did the other patients. CONCLUSIONS: The present study is the first to show that CaR polymorphisms of G990R and intron 5 were closely associated with the magnitude of PTH secretion and/or PTH degradation as well as the clinical severity in pHPT patients.

Adolescent↗
PubMed2001

Molecular genetic analysis of the von Hippel-Lindau and human peroxisome proliferator-activated receptor gamma tumor-suppressor genes in adenocarcinomas of the gastroesophageal junction.

We investigated whether 2 candidate tumor-suppressor genes, VHL at 3p25-26 and PPAR gamma at 3p24.2-25, are involved in GEJ adenocarcinogenesis. In 43 GEJ tumor samples from 40 patients, the entire coding sequence of the VHL gene and the 5' and part of the 3' UTR as well as exons 3 and 5 of the PPAR gamma gene were screened by PCR-SSCP analysis. LOH at 3p25-26 was analyzed with 2 polymorphic microsatellite markers and with the VHL exon 1 and intron 2 polymorphisms. The relationship between LOH and clinicopathologic parameters was assessed. Expression of VHL was investigated by immunohistochemistry with a VHL-specific antibody. PCR-SSCP analysis of VHL revealed 2 different aberrant patterns in 19 patients. Upon DNA sequencing, 1 pattern appeared to be a previously described exon 1 polymorphism. The other single aberrant pattern was an intron 2 polymorphism, not yet described. PCR-SSCP analysis of PPAR gamma showed no aberrant migration patterns. LOH analysis revealed 3p25-26 loss in 24/36 (67%) informative cases, but this was not significantly correlated with clinicopathologic parameters. By immunohistochemistry, all tumors showed expression of VHL protein. Despite the very frequent LOH of 3p in GEJ adenocarcinomas, mutations in VHL and PPAR gamma were not detected. Mutations outside the screened sequences, a gene dosage effect or involvement of another tumor-suppressor gene on 3p as the target of LOH should be considered.

Adenocarcinoma↗
PubMed2006

[Relationship between genetic polymorphisms of Interferon-gamma gene intron 1 +874 site and susceptibility of hepatitis B virus infection].

OBJECTIVE: To explore the possible relationship between the polymorphisms of interferon-gamma (IFN-gamma) gene intron 1 at position +874 and the susceptibility of hepatitis B virus infection. METHODS: IFN-gamma gene single nucleotide polymorphism (intron 1 at position +874) were detected in 531 subjects including 231 chronic carrier of hepatitis B virus (group CC), 165 individuals who spontaneously recovered from HBV infection (group SR) and 135 healthy controls, by polymerase chain reaction with sequence specific primers. RESULTS: Significant difference of IFN-gamma +874 AA genotype frequency was found between group CC (TT, TA and AA frequencies were 9.1%, 12.1% and 78.8%, respectively) and control group (TT, TA and AA frequencies were 12.6%, 23.0% and 64.4%, respectively) (chi(2) = 9.60, P = 0.008), but no significant difference found between group SR (TT, TA and AA frequencies were 13.9%, 23.7% and 62.4%, respectively) and control group (chi(2) = 0.16, P = 0.92). CONCLUSION: There was association between IFN-gamma gene polymorphism (intron 1 at position +874) and chronic HBV infection. This study suggested the possibility that IFN-gamma gene polymorphism (intron 1 at position +874) might be important in determining an individual's susceptibility in the development of chronic HBV infection.

Carrier State↗
PubMed2001

Serotonin transporter gene polymorphisms are associated with anxiety-related personality traits in women.

Several studies have reported an association between anxiety-related personality traits and a promoter polymorphism in the human serotonin transporter (5-HTT) gene (5-HTT gene-linked polymorphic region, 5-HTTLPR). In the present study, a population of 251 subjects was assessed with the Karolinska Scales of Personality (KSP) and genotyped both for the 5-HTTLPR and for a variable number of tandem repeats polymorphism in the second intron of the same gene. The interpretation of previous studies has to some extent been confounded by the studied subjects differing with respect to ethnicity, sex, and age. To circumvent this problem, all included subjects were Caucasians, women, and born in the same year (1956). Associations were found between the 5-HTTLPR and four of the five anxiety-related KSP scales (psychic anxiety, muscular tension, psychasthenia, and lack of assertiveness), subjects being homozygous for the short allele displaying higher anxiety scores than those of the long/long or long/short genotype. In addition, an association was found between the intron 2 polymorphism and one anxiety-related personality trait (somatic anxiety).

Alleles↗
PubMed1999

Sequence variants of the sarco(endo)plasmic reticulum Ca(2+)-transport ATPase 3 gene (SERCA3) in Caucasian type II diabetic patients (UK Prospective Diabetes Study 48).

AIMS/HYPOTHESIS: Type II (non-insulin-dependent) diabetes mellitus is a common heterogeneous metabolic disorder of largely unknown genetic aetiology. The sarco(endo)plasmic reticulum Ca(2+)-transport ATPase (SERCA) plays an important part in the glucose-activated beta-cell Ca(2+) signalling that regulates insulin secretion. Impaired function and expression of SERCA have been shown in islets of Langerhans from diabetic animal models and have also been associated with beta-cell apoptosis. Thus, the SERCA3 encoding gene is a plausible candidate for a primary pancreatic beta-cell defect. METHODS: In this study, the entire coding and the promoter regions of SERCA3 gene were screened by single-strand conformation polymorphism analysis in white Caucasian Type II diabetic patients. RESULTS: We found four rare missense mutations [Exon 4: Gln(108)-->His (CAG-->CAT), Exon 14: Val(648) -->Met (GTG-->ATG) and Arg(674)-->Cys (CGC--> TGC), and Exon 15: Ile(753)-->Leu (ATC-->CTC)]. The patients with Gln(108)-->His, Val(648)-->Met and Arg(674)-->Cys mutations, which may affect the E1P-E2P transition of SERCA3 during its enzyme cycle, had normal body weight with marked hyperglycaemia and beta-cell dysfunction. That is an unusual phenotype only found in 6 % of the Type II diabetic patients recruited for the UK Prospective Diabetes Study. In addition, five silent polymorphisms, six intron variants and two polymorphisms in the 3' untranslated region of exon 22 were found with similar frequency in diabetic and control subjects. CONCLUSION/INTERPRETATION: Our result suggests that in white Caucasians, the SERCA3 locus possibly contributes to the genetic susceptibility to Type II diabetes [Diabetologia (1999) 42: 1240-1243].

Calcium-Transporting ATPases↗
PubMed2006

An intronic variable number of tandem repeat polymorphisms of the cold-induced autoinflammatory syndrome 1 (CIAS1) gene modifies gene expression and is associated with essential hypertension.

Cold-induced autoinflammatory syndrome 1 (CIAS1) gene is a member of the NALP subfamily of the CATERPILLER protein family that is expressed predominantly in peripheral blood leukocytes, which is to regulate apoptosis or inflammation through the activation of NF-kappaB and caspase. Recent genetic analyses suggested an association between inflammation and oxidative stress-related genes in the development of hypertension. This is the first genetic study indicating an association between the CIAS1 gene and susceptibility to essential hypertension (EH). The frequency of subject with the homozygote of 12 repeat allele was significantly higher in patients with hypertension compared with control subjects (987 cases, 924 controls) (P=0.030; odds ratio=1.24) at a novel VNTR polymorphism of CIAS1 intron 4 loci. We also found that the mean of systolic blood pressure of homozygotes of 12 repeat allele was 6.4 mmHg higher than those of homozygotes of non-12 repeat allele in male random population (P=0.009). The frequency of six SNPs spanning of the CIAS1 gene was not significantly between patients and controls. The real-time PCR analysis showed that among healthy young adults, 12-12 subjects expressed CIAS1 mRNA in peripheral leukocytes significantly more abundantly than homozygote of non-12 repeat alleles subjects (P<0.05). Reporter gene assay of the CIAS1-VNTR in HL60 stimulated by lipopolysaccharides showed that the intronic sequence involving 12 repeat increased the expression of luciferase compared with 9, 7, and 6 repeats. Thus, we propose here the CIAS1 is associated with EH through the dominant expression of transcripts, which may depend on the CIAS1-VNTR genotype.

Alleles↗
PubMed2000

Neither IL-1beta, IL-1 receptor antagonist, nor TNF-alpha polymorphisms are associated with susceptibility to COPD.

The cytokines that contribute to airway inflammation, including interleukin-1beta (IL-1beta) and tumour necrosis factor alpha (TNFalpha), might have key roles in the development of chronic obstructive pulmonary disease (COPD). Interleukin-1 receptor antagonist (IL-1RN), the physiological antagonist of IL-1beta, is also known to play a crucial role in several chronic inflammatory diseases. In this study, we investigated the association of the polymorphisms of IL-1beta, IL-1RN and TNFalpha with susceptibility to COPD. To elucidate the genotype of the IL-1beta polymorphisms at position -511 base and at the amino acid residue 105, the IL-1RN polymorphism in intron 2, and TNFalpha polymorphism at position -308, polymerase chain reaction (PCR) and restriction enzyme fragment length polymorphism (RFLP) were performed on blood samples from both patients with COPD (n = 53) and control subjects (n = 65). There were no differences on the allele and genotype frequency of IL-1beta, IL-1RN, and TNFalpha between the two groups. We could not find a significant link between the polymorphism of TNFalpha, which was previously reported to be associated with chronic bronchitis, and COPD. Furthermore, no association between genetic polymorphisms of IL-1beta and IL-1RN and individual susceptibility to COPD was found.

Aged↗