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PubMed1997

Presenilin-1 intron 8 polymorphism is not associated with autopsy-confirmed late-onset Alzheimer's disease.

Mutations in the presenilin-1 (PS-1) gene may account for the majority of familial early-onset Alzheimer's disease (EOAD) cases. However, there is controversy as to whether the bi-allelic intron 8 PS-1 polymorphism plays a role in late-onset AD (LOAD). As previous association studies with this polymorphism have all investigated clinically diagnosed LOAD cases, we have analysed the frequency of the PS-1 intronic polymorphism in a series of autopsy-confirmed early- (n = 54) and late-onset (n = 199) cases and a large control population of non-demented, aged individuals (n = 215). Our sample size should have had the power to reveal effects of the size previously reported for the PS-1 polymorphism, but we detected no significant increase in the 1/1 risk genotype distribution in EOAD or LOAD cases. Thus, we have been unable to find an association between the PS-1 intronic polymorphism and early- or late-onset AD within this autopsy-confirmed population.

Age of Onset↗
PubMed2000

No association between an intronic biallelic polymorphism of the FE65 gene and Alzheimer's disease.

The cleavage of the amyloid precursor protein (APP) into amyloidogenic components (Abeta) is a central event in the pathogenesis of Alzheimer's disease (AD). FE65 is a protein that is involved in APP metabolism and may facilitate the production of Abeta. Recently, an intronic polymorphism of the gene encoding FE65 (FE65) was associated with altered risk for the development of sporadic AD. In our sample of 102 AD patients and 351 non-demented controls we did not replicate the association between FE65 and AD. Moreover, we observed no risk-modifying interaction and no linkage disequilibrium between FE65 and the gene encoding the acid protease cathepsin D (catD), which - like FE65 - is involved in APP metabolism and is also located on chromosome 11p15. We conclude that, whereas FE65 is implicated in AD pathology, the gene encoding FE65 does not appear to confer a substantial risk for AD.

Aged↗
PubMed1998

Effect of promoter and intron 2 polymorphisms on murine lung K-ras gene expression.

Differences in tumor formation among inbred mouse strains with high (A/J) and low (C3H) susceptibility for lung cancer have been linked to a repetitive element within the second intron of the K-ras gene. The purpose of this investigation was to determine whether differences within the K-ras gene promoter region or the intron 2 polymorphism affect K-ras gene expression in lung tumors and target alveolar type II cells isolated from A/J and C3H mice. Ribonuclease protection assays were performed using RNA isolated from 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK)-induced lung tumors from each mouse strain and alveolar type II cells isolated from A/J and C3H mice. An 838 bp fragment of the murine K-ras gene promoter region was amplified by PCR, cloned and sequenced from both mouse strains. Promoter regions from both mouse strains were inserted into a luciferase reporter gene vector, with and without the second intron polymorphism, and transfected into sensitive, intermediate and resistant lung tumor cell lines. No significant differences in K-ras gene promoter activity was found between the two strains using these specific reporter gene constructs. Consistent with these results, levels of K-ras expression did not differ between alveolar type II cells, whole lung or tumors induced by NNK in A/J or C3H mice. Moreover, in lung tumor cell lines derived from mice with differing susceptibility for lung cancer, K-ras expression did not correlate with the growth rate of tumors induced in nude mice from these cell lines. These results indicate that factors involved in modulating the rapid clonal expansion of the mutated K-ras allele from A/J mice are not directly linked to expression of this gene. Other genetic changes or losses in conjunction with hypothesized modifier loci, such as the Par1 locus, must play a significant role in establishing the phenotypic strain differences for lung tumor formation.

3T3 Cells↗
PubMed2000

Genetic polymorphism of dopamine D2 receptors in Parkinson's disease and interactions with cigarette smoking and MAO-B intron 13 polymorphism.

Genetic polymorphisms of dopamine D2 receptors (DRD2) may be susceptibility factors for Parkinson's disease due to their influence on dopamine response and association with cigarette smoking, which is inversely related to risk of Parkinson's disease. Relations of TaqIA and TaqIB DRD2 genotypes with Parkinson's disease were investigated and tested for interactive effects with smoking and the monoamine oxidase B (MAO-B) intron 13 polymorphism previously found to be related to smoking. Study subjects were 152 cases of idiopathic Parkinson's disease and 231 controls. The smoking history of all genotyped subjects was known. Subjects of genotype B12 were more frequent among cases than controls (27% and 23.8%, respectively), and were more frequent among "ever smokers" than "never smokers", among controls (27.8% and 17.2%, respectively), although these associations were not statistically significant. Neither TaqIA or TaqIB genotypes modified the inverse relation of smoking and Parkinson's disease. When genotypes for DRD2 were considered in combination with genotypes for intron 13 of MAO-B, genotype combinations with high risk of Parkinson's disease were found; although the MAO-B/DRD2 interaction did not reach statistical significance after Bonferroni correction for multiple comparisons, these results are suggestive of a possible synergism between MAOB and DRD2 genes with respect to Parkinson's disease.

Adult↗
PubMed2003

Association of a 27-bp repeat polymorphism in intron 4 of endothelial constitutive nitric oxide synthase gene with serum uric acid levels in Chinese subjects with type 2 diabetes.

Nitric oxide (NO) was found to modulate uric acid production through its influence on xanthine oxidase activity, and a close circadian relationship of serum uric acid (SUA) and NO was reported. Studies also revealed that serum NO activity could be determined by endothelial constitutive nitric oxide synthase gene (ecNOS) polymorphism. This study was designed to investigate whether SUA could be influenced by a 27-bp repeat polymorphism in intron 4 of ecNOS gene. A total of 398 nondiabetic subjects and 800 patients with type 2 diabetes were studied. The ecNOS gene intron 4 polymorphism was determined by polymerase chain reaction (PCR). The mean SUA level of patients having type 2 diabetes was significantly lower than that of control subjects (6.1 +/- 1.8 mg/dL v 6.6 +/- 1.8 mg/dL, P<.001); and the mean SUA level of diabetic patients with ecNOS ab/aa genotypes was lower than that of patients with bb genotype (5.7 +/- 1.6 mg/dL v 6.2 +/- 1.8 mg/dL, P=.008). When subgrouped by gender, the SUA of female diabetic subjects was found to be significantly associated with ecNOS genotype. Using Pearson's correlation analysis and multiple linear regression analysis, ecNOS genotype was noticed to be an independent factor in contributing to SUA variability in female diabetic patients. Our results suggest that SUA levels may be associated with NO activity and can be genetically predetermined.

Aged↗
PubMed1999

Endothelial nitric oxide synthase gene polymorphism in intron 4 affects the progression of renal failure in non-diabetic renal diseases.

BACKGROUND: Nitric oxide is a very potent regulator of intrarenal haemodynamics and is thought to be an important factor in the deterioration of renal function. Our study sought to verify the hypothesis that endothelial nitric oxide synthase (ecNOS) gene polymorphism in intron 4 might have some relevance to progression in chronic renal failure. METHODS: We studied the frequencies of gene polymorphism of ecNOS intron 4 in patients with end-stage renal disease (302 cases) and compared it with that of healthy subjects (248 cases). ecNOS genotypes were determined by the polymerase chain reaction, followed by agarose gel electrophoresis. RESULTS: Two alleles of ecNOS intron 4, labelled a and b could be detected; a has four and b has five tandem 27-bp repeats. The frequencies of ecNOS4b/b, ecNOS4b/a, ecNOS4a/a genotypes were 81.0% (201/248), 19. 0% (47/248), 0.0% (0/248) in the control group, and 74.8% (226/302), 23.5% (71/302), l.7% (5/302) in all the patients, 72.7% (168/231), 25.1% (58/231), 2.2% (5/231) in the group with end-stage renal diseases, excluding diabetic nephropathy (non-DM group), and 81.7% (58/71), 18.3% (13/71), 0.0% (0/71) in diabetic nephropathy (DM group) respectively. The frequency of the ecNOS4a (ecNOSb/a, and ecNOSa/a) in all the patients and in the non-DM group were significantly higher than that in the control group (P=0.021; P=0. 0096 respectively). In contrast, there was no significant difference in the frequencies of ecNOS genotypes between the DM group and the control group (P=0.81). CONCLUSION: Among the frequencies of ecNOS intron 4 gene polymorphism, a allele displayed a significantly higher frequency in cases with end-stage renal failure (ESRF) not caused by diabetic nephropathy. ecNOS gene polymorphism in intron 4 appears, therefore, to affect the progression of renal failure in non- diabetic renal diseases, but the same conclusion could not be drawn in diabetic nephropathy.

Adult↗
PubMedDate not supplied

Neutral polymorphisms in the deletion-prone regions of the dystrophin gene.

The single-strand conformational polymorphism technique was used to search for neutral polymorphisms in 18 PCR-amplified dystrophin gene fragments. Out of the seven polymorphisms (six intronic and one exonic) detected in Caucasians, one was absent from the Oriental population. Significant differences in allele frequencies between the two populations were observed for three of the intronic polymorphisms. In Caucasians, one variant position occurred per 728 bp of the total DNA or one per 483 bp of the intronic sequence; the corresponding average heterozygosities were 0.04 and 0.06%, respectively.

Alleles↗
PubMed2005

A study of lipoprotein lipase gene intron 8 polymorphisms in Chinese Han race essential hypertension patients.

OBJECTIVE: To investigate the association of lipoprotein lipase gene intron 8 polymorphisms and Essential Hypertension in Han race Chinese. METHODS AND RESULTS: 116 patients with Essential Hypertension were enrolled and another 116 normal people were served as controls. All cases were examined for the genotypes of intron 8 in lipoprotein lipase gene by the methods of polymerase chain reaction restriction fragment length polymorphism, and the serum lipoprotein levels were also observed. Results showed that body mass index blood pressure and the serum triglyceride level were obviously increased in the Essential Hypertension group. The genotype and allele frequency of intron 8 in lipoprotein lipase in the Essential Hypertension group showed obvious differences compared with the control group. Serum triglyceride levels were higher in the patients with H+H+ genotype than in those in non H+H+ genotype of intron 8 in lipoprotein lipase by HindIII digestion. The systolic blood pressure showed a decreasing tendency among the H+H+ genotype, the H+H- genotype and the H-H- genotype individuals. CONCLUSION: The results suggest that lipoprotein lipase may be an important genetic factor associated with the Chinese Han race Essential Hypertension patients. The polymorphisms of intron 8 in lipoprotein lipase influence the blood-lipid metabolism, induce blood vessel rebuilding and play an important role in the invasion and development of Essential Hypertension.

Asian People↗
PubMed2006

Genome-wide investigation of intron length polymorphisms and their potential as molecular markers in rice (Oryza sativa L.).

Intron length polymorphisms (ILPs) have been used as genetic markers in some studies. However, a systematic investigation and large-scale exploitation of ILP markers has not been reported. In this study, we performed a genome-wide search of ILPs between two subspecies (indica and japonica) in rice using the draft genomic sequences of cultivars 93-11 (indica) and Nipponbare (japonica) and 32,127 full-length cDNA sequences of Nipponbare obtained from public databases. We identified 13,308 putative ILPs. Based on these putative ILPs, we developed 5811 candidate ILP markers via electronic-PCR with primers designed in flanking exons. We further conducted experiment to verify the candidate ILP markers. Out of 215 candidate ILP markers tested on 93-11, Nipponbare and their hybrid, we successfully exploited 173 codominant ILP markers. Further analyses on 10 rice accessions showed that these ILP markers were widely applicable and most (71.1%) exhibited subspecies specificity. This feature suggests that ILPs would be useful for the studies of genome evolution and inter-subspecies heterosis and for cross-subspecies marker-assisted selection in rice. In addition, by testing 51 pairs of the ILP primers on five Gramineae plants and three dicot plants, we found another desirable characteristic of rice ILP markers that they have high transferability to other plants.

Base Sequence↗
PubMed2005

Polymorphisms in the 5-lipoxygenase activating protein (ALOX5AP) gene are not associated with asthma in an Australian population.

BACKGROUND: The cysteinyl-leukotrienes (cys-LTs) are important pro-inflammatory mediators in asthma, and have been shown to have a role in specific disease subtypes, including asthma severity. Few studies have investigated the role of polymorphisms in the ALOX5AP gene, encoding 5-lipoxygenase activating protein (FLAP), and asthma. We hypothesized that polymorphisms in this gene are associated with asthma and in particular, with asthma severity, in an Australian population. OBJECTIVE: To screen the coding region of the ALOX5AP gene for polymorphisms and to determine the association between previously described polymorphisms and asthma and asthma severity in an Australian population. METHODS: We used PCR-SSCP and PCR-RFLP analysis to examine a previously described promoter polyA variable repeat polymorphism and two intronic polymorphisms (IVS2+12C>A, IVS2+105T>C), and to screen all five exons of the gene for new polymorphisms, in a large Australian population of randomly selected, non-asthmatic controls (n=457), mild asthmatics (n=274), moderate asthmatics (n=231) and severe asthmatics (n=79). RESULTS: We confirmed the presence of two polymorphisms in intron 2 and found no association between these polymorphisms and asthma or asthma severity, nor between a promoter polymorphism in the ALOX5AP gene and asthma or asthma severity. Gene fragment analysis of the promoter polymorphism revealed novel, conserved repeat numbers in our population, and no new polymorphisms were found in the coding region of the gene. CONCLUSION: These findings in a large, well characterized asthma population, reveal that, while FLAP is an important enzyme in cys-LTs biosynthesis, polymorphisms in the ALOX5AP gene are not likely to be functionally associated with the asthma phenotype.

5-Lipoxygenase-Activating Proteins↗
PubMed2004

Differential genetic effects of ESR1 gene polymorphisms on osteoporosis outcomes.

CONTEXT: Both bone mineral density (BMD) and fracture risk have a strong genetic component. Estrogen receptor alpha (ESR1) is a candidate gene for osteoporosis, but previous studies of ESR1 polymorphisms in this field were hampered by small sample size, lack of standardization, and inconclusive results. OBJECTIVE: To generate large-scale evidence on whether 3 common ESR1 polymorphisms (intron 1 polymorphisms XbaI [dbSNP: rs9340799] and PvuII [dbSNP: rs2234693] and promoter TA repeats microsatellite) and haplotypes thereof are associated with BMD and fractures. DESIGN AND SETTING: Meta-analysis of individual-level data involving standardized genotyping of 18 917 individuals in 8 European centers. MAIN OUTCOME MEASURES: BMD of femoral neck and lumbar spine; all fractures and vertebral fractures by genotype. RESULTS: No between-center heterogeneity was observed for any outcome in any genetic contrast. None of the 3 polymorphisms or haplotypes had any statistically significant effect on BMD in adjusted or unadjusted analyses, and estimated differences between genetic contrasts were 0.01 g/cm2 or less. Conversely, we found significant reductions in fracture risk. In women homozygous for the absence of an XbaI recognition site, the adjusted odds of all fractures were reduced by 19% (odds ratio, 0.81 [95% CI, 0.71-0.93]; P = .002) and vertebral fractures by 35% (odds ratio, 0.65 [95% CI, 0.49-0.87]; P = .003). Effects on fractures were independent of BMD and unaltered in adjusted analyses. No significant effects on fracture risk were seen for PvuII and TA repeats. CONCLUSIONS: ESR1 is a susceptibility gene for fractures, and XbaI determines fracture risk by mechanisms independent of BMD. Our study demonstrates the value of adequately powered studies with standardized genotyping and clinical outcomes in defining effects of common genetic variants on complex diseases.

Aged↗
PubMed1997

Genetic polymorphism in intron 6 of the LMP7 gene in Japanese and its association with sarcoidosis.

Genetic polymorphism in intron 6 of the LMP7 gene was investigated using polymerase chain reaction-restriction fragment length polymorphism in 90 unrelated healthy Japanese controls and 66 Japanese patients with sarcoidosis. Four alleles, including two new ones recently identified in Koreans, LMP7*C and LMP7*D, were found in the Japanese population. The frequency of LMP7*C in the sarcoidosis patients was higher than in the healthy controls. However, this difference might be explained by a secondary association with HLA-DRB1*08 in the HLA-DRB1 gene, which is thought to be the gene primarily responsible for susceptibility to sarcoidosis.

Alleles↗
PubMed2002

Common single nucleotide polymorphisms in intron 3 of the calpain-10 gene influence hirsutism.

OBJECTIVE: To study three common polymorphisms in intron 3 of the calpain-10 gene (CAPN10) in hyperandrogenic patients. DESIGN: Case-control study. SETTING: Academic hospital. PATIENT(S): Ninety-seven hyperandrogenic patients and 37 healthy controls. INTERVENTION(S): Basal and adrenocorticotropin-stimulated serum samples and genomic DNA samples were obtained during the follicular phase of the menstrual cycle. MAIN OUTCOME MEASURE(S): Genotyping of the UCSNP43, UCSNP44, and UCSNP45 polymorphisms in CAPN10 and serum androgen levels. RESULT(S): Sixteen patients had idiopathic hirsutism, defined as normal serum androgen levels and regular menstrual cycles. Eighty-one hyperandrogenic patients (those presenting with hyperandrogenemic hirsutism or the polycystic ovary syndrome) were analyzed further. UCSNP45 alleles were distributed differently among the study groups. Heterozygosity for the uncommon C allele was increased in patients with idiopathic hirsutism (31.3%) and reduced in hyperandrogenic patients (7.4%) compared with controls (16.2%). The UCSNP44 and UCSNP43 alleles were in linkage disequilibrium, and were distributed equally among patients with idiopathic hirsutism, hyperandrogenism, and controls. However, the uncommon A allele at UCSNP43 was associated with higher hirsutism score (mean [+/- SD], 9.9 +/- 6.8, 12.7 +/- 7.7, and 14.6 +/- 8.2 in GG, GA, and AA participants, respectively). No other differences were observed in clinical and biochemical characteristics, including insulin sensitivity, by CAPN10 variant. CONCLUSION(S): The C allele at the UCSNP45 locus in CAPN10 is associated with idiopathic hirsutism, and UCSNP43 influences the hirsutism score.

17-alpha-Hydroxyprogesterone↗
PubMed1997

Association of presenilin-1 polymorphism with cerebral amyloid angiopathy in the elderly.

BACKGROUND AND PURPOSE: An intronic polymorphism of presenilin-1 (PS-1), a gene responsible for early-onset familial Alzheimer's disease, has been reported to be associated with late-onset sporadic Alzheimer's disease. In a search for a genetic risk factor of sporadic cerebral amyloid angiopathy (CAA), we investigated the association of the polymorphism of PS-1 with CAA. METHODS: The association between the severity of CAA and genotypes of a polymorphism in intron 8 of PS-1 was investigated in 137 autopsy cases of the elderly. RESULTS: A significant decrease of PS-1 2/2 genotype frequency was associated with severe or moderate CAA. CONCLUSIONS: Our results suggest that PS-1 intronic polymorphism may be associated with the severity of CAA in the elderly.

Aged↗
PubMed1995

Absence of correlation between IL-1 alpha intron 6 polymorphism and rheumatoid arthritis.

Several studies have implicated interleukin 1 alpha (IL-1 alpha) in the pathogenesis of rheumatoid arthritis (RA). We analysed IL-1 alpha intron 6 polymorphism in relation to RA (50 patients with RA and 50 healthy controls). The study of a healthy control population confirmed the existence of the different alleles with a frequency similar to that in the Caucasian populations of northern England. Allele and genotype distributions did not differ significantly between the normal and RA populations, although the allele corresponding to 8 repeats was over-represented in the RA population (8 and 14% in the healthy and RA populations respectively). This suggests that IL-1 alpha intron 6 polymorphism could be part of a complex process involving other unidentified genetic factors in the pathogenesis of RA.

Alleles↗
PubMed2001

Microsatellite polymorphism in intron 14 of the canine BRCA1 gene.

Microsatellite polymorphism due to differences in CT dinucleotide repeats was demonstrated in intron 14 of the canine BRCA1 gene. Genotype analysis of 103 unrelated dogs from 30 different breeds detected the presence of five alleles, including 10 of the expected 15 genotypes. Gene frequencies were biased and all alleles with the exception of one were below 0.1. This polymorphism, which occurs at the intron of canine BRCA1 should prove to be a useful marker for detecting the loss of heterozygosity (LOH). One of the more notable findings of the present study was the detection of homozygotes of rare alleles. This finding identified an accumulation of rare alleles in specific canine breeds and demonstrated the usefulness of this characteristic for the biological study of dog evolution.

Animals↗
PubMed2004

Polymorphism in intron 2 of the interleukin-1 receptor antagonist gene, local midtrimester cytokine response to vaginal flora, and subsequent preterm birth.

OBJECTIVE: This study investigated the association between polymorphism in intron 2 of the interleukin-1 receptor antagonist gene, midtrimester vaginal microflora, vaginal interleukin receptor antagonist and interleukin-1beta levels and subsequent spontaneous preterm birth. STUDY DESIGN: Vaginal samples from 212 women, collected at 18-22 weeks' gestation, were analyzed for the polymorphism in intron 2 of the interleukin-1 receptor antagonist gene by polymerase chain reaction, qualitative and quantitative vaginal microflora, and interleukin-1beta and interleukin-1ra concentrations by enzyme-linked immunosorbent assay. Pregnancy outcome data were subsequently obtained. RESULTS: Carriage of intron 2 of the interleukin-1 receptor antagonist allele 2 (IL1RN * 2) was associated with an elevated vaginal pH in black ( P < .001) and white ( P = .005) women, a reduced interleukin-1beta response to anaerobic Gram-negative rods and/or Gardnerella vaginalis ( P < .01), and a decreased rate of spontaneous preterm deliveries (6% versus 18%, P = .02). In black women, IL1RN * 2 carriage was associated with increased anaerobic Gram-negative rods, Mycoplasma, and Peptostreptococci and decreased Lactobacilli colonization. CONCLUSION: IL1RN * 2 carriage was associated with a blunted proinflammatory interleukin-1beta response to abnormal vaginal flora. This property may decrease susceptibility to infection-related preterm birth.

Adult↗