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Results for “intronic polymorphism”

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PubMed1998

Detection of the low density lipoprotein receptor gene PvuII intron 15 polymorphism using the polymerase chain reaction: association with plasma lipid traits in healthy men and women.

We have used anchored PCR to amplify and sequence 1400 bp of the 15th intron of the Low Density Lipoprotein (LDL) receptor gene, and have determined oligonucleotides and conditions for the genotyping of the previously reported PvuII polymorphism. The cutting site (CAGCTG) is created by the transition of a CpG to a TpG within the sequence CAGCCG at a position roughly 600 bp 5' from the splice acceptor site of exon 16. Genotype was determined in three population-based samples of healthy individuals. In a group of 318 men and women from Iceland the frequencies of the Intron-15 T (cutting) allele was 0.23 (95% CI, 0.19-0.28) and was similar in men and women. In two groups of men from England (n = 385) and Scotland (n = 320), the frequency was similar, being 0.23 (0.19-0.27) and 0.25 (0.22-0.28) respectively. Individuals who were homozygous for the T allele had lower levels of total-cholesterol triglycerides and apolipoprotein B, than those with other genotypes, and in the combined group of UK men this effect reached statistical significance; compared to the C/C group, the T/T group had 6% lower cholesterol (p = 0.02) and 15% lower triglycerides (p = 0.03). The lowering effect associated with the T/T genotype was greater in men who were in the lowest tertile of body mass index (< 25 kg/m2) and for the trait of apoB levels, this genotype x obesity interaction was statistically significant (p = 0.01). We thus confirm the association between this allele and lower levels of plasma lipid levels previously reported. The availability of a PCR-based method to detect this polymorphism will facilitate further investigation of the impact of LDL-receptor gene variation in determining lipid levels.

Alleles↗
PubMed2003

The 4830C>A polymorphism within intron 5 affects the pattern of alternative splicing occurring within exon 6 of the thrombopoietin gene.

OBJECTIVE: A common variant in intron 5 of the thrombopoietin (TPO) gene (4830C>A) has been associated with risk of myocardial infarction (MI). To explore the molecular mechanism of this association, the ability of the intron to act as a transcription enhancer and to influence mRNA splicing was tested. METHOD AND RESULTS: In HepG2 cells the presence of intron 5 upstream of the TPO promoter decreased promoter activity to between 60% and 30%. This effect was orientation dependent; in the reverse orientation, intron 5 caused a twofold greater decrease in promoter activity compared to the forward orientation. However, the effects were similar with either the C or the 4830A allele. An in vitro exon trapping system was used to study the effect of the polymorphism on splicing events in exon 6. The full-length (TPO-1) and three previously reported splice variants (TPO-2, TPO-3, and TPO-5) were identified. The 4830A allele resulted in a small but statistically significant increase in production of the TPO-3 splice variant relative to the full-length transcript (10.6%+/-0.6%) compared to the 4830C allele (8.3%+/-0.6%) (p=0.02). Generation of TPO-5 was also slightly increased, but this did not reach significance. CONCLUSION: The identification of a potential "silencer" sequence in intron 5 of the TPO gene demonstrates the complexity of control of expression of the gene. Although the precise role of the different splice variants is not known, the finding that the 4830C>A sequence change alters their relative amounts, suggests a possible molecular mechanism whereby TPO genotype may influence the risk of MI.

Alternative Splicing↗
PubMed2003

Relevance of interleukin-1 receptor antagonist intron-2 polymorphism in ischemic stroke.

Evidence of inflammatory phenomena associated with atherosclerotic plaques is extensive. Interleukin-1 (IL-1) is one of the key modulators of the inflammatory response, and its activity is critically regulated by its receptor antagonist (IL-1Ra). A variable number of tandem repeats (VNTR) in intron 2 of the human IL-1Ra shows a common polymorphism that has been related to different production of IL-1Ra and IL-1 proteins. In monocytes, the less common allele 2 has been associated with an increased production of IL-1Ra and a decreased production of IL-1. Moreover, a cooperative effect with a C to T polymorphism in the promoter of IL-1beta gene (C(-511)-->T) has been described. In the present study, we investigated the frequency of these polymorphisms in 110 subjects who survived an ischemic stroke, in 101 healthy age-matched individuals, and in a population-based sample of 1,303 healthy Italians. The frequency of the IL- 1Ra 1/1 genotype was significantly higher in stroke survivors with respect to age-matched controls (77.2 and 45.5%, respectively; p < 0.001), and to the wide group of healthy Italians (77.2 and 51.9%, respectively; p < 0.001). As expected, the estimated frequency of the IL-1Ra allele 1 (Ra*1 allele) in stroke survivors was higher than in age-matched controls (0.851 and 0.664, respectively; p < 0.001) and in healthy Italians (0.851 and 0.717, respectively; p < 0.001). Thus, ischemic stroke survivors that carry the Ra*1 allele showed a strong association with the disease with respect to age-matched controls [odds ratio (OR) = 3.905; 95% confidence interval (CI), 2.110-7.229] and healthy Italians [OR = 3.256 (95% CI, 1.971-5.379)]. No significant association was seen for the IL-1beta (C(-511)-->T) polymorphism. However, in stroke survivors, an association between the Ra*1 allele and the C allele of the IL-1beta (-511) polymorphism was found (p < 0.001). Our results implicate the IL-1Ra gene in the susceptibility to ischemic stroke, and suggest that IL-1Ra genotyping may be useful in the identification of patient subgroups for pharmacological intervention in IL-1 production or actions.

Adult↗
PubMed2004

A microsatellite polymorphism in intron 2 of human Toll-like receptor 2 gene: functional implications and racial differences.

The human Toll-like receptor 2 (TLR2) mediates responses of both innate and adaptive immunity to Gram-positive bacteria, including mycobacteria. We sought functional polymorphisms in the 5'-untranslated region (UTR) of TLR2. We found a highly polymorphic (GT)n dinucleotide repeat 100 bp upstream of the TLR2 translational start site in intron 2. The numbers of GT repeats varied from 12 to 28. There were significant differences in allele distribution between African Americans and Caucasians (P=0.008) and between African Americans and Koreans (P=0.0003). The promoter activities of recombinant promoter-intron2/reporter constructs including the shortest [GT)n=12] or longest [(GT)n=28] alleles were significantly more stimulated when exposed to 200 IU ml(-1) of interferon-gamma than when exposed to 100 IU ml(-1) of GM-CSF (P<==0.03). Since TLR2 plays a critical role in the human innate immune response, this functional microsatellite polymorphism may be important in the pathogenesis of infectious and inflammatory diseases.

Alleles↗
PubMed2000

CA-Repeat polymorphism in intron 1 of HSD11B2 : effects on gene expression and salt sensitivity.

Mutations in the HSD11B2 gene encoding the kidney (11-HSD2) isozyme of 11beta-hydroxysteroid dehydrogenase cause apparent mineralocorticoid excess, a form of familial hypertension. Because the hypertension associated with AME is of the salt-sensitive type, it seemed possible that decreases in 11-HSD2 activity might be associated with salt sensitivity. To examine this, Italians with mild hypertension underwent a protocol consisting of a rapid intravenous saline infusion and subsequent furosemide diuresis. To determine whether there were genetic associations between HSD11B2 and salt sensitivity, 198 Italians were genotyped for a CA repeat polymorphism (11 alleles) in the first intron. Increased differences in mean arterial pressure between the sodium loaded and depleted states were correlated with shorter CA repeat length (R=0.214, P=0. 0025). The effect behaved as a recessive trait. This suggested that decreased HSD11B2 expression was associated with shorter CA repeat length. Furthermore, activity of renal 11-HSD2 as measured by an increase in the ratio of urinary-free cortisol/urinary-free cortisone was lower in 33 salt-sensitive subjects (urinary-free cortisol/urinary-free cortisone 0.89+/-0.04 [mean+/-SE]) compared with 34 salt-resistant subjects (0.71+/-0.04, P<0.001). However, when minigenes containing either 14 or 23 CA repeats were transfected into rabbit or human kidney cortical collecting duct cells, the construct with 14 repeats was instead expressed at levels 50% higher than those of the construct with 23 repeats, as determined by reverse transcription-polymerase chain reaction. We conclude that polymorphisms in HSD11B2 and decreased 11-HSD2 activity are associated with sensitivity to sodium loading, but a functional explanation for these associations remains to be elucidated.

11-beta-Hydroxysteroid Dehydrogenases↗
PubMed2006

Microsatellite polymorphism in intron 1 of the bovine myostatin gene.

Microsatellites within genes have become important because of their association with genetic diseases in humans. A novel microsatellite was identified in the first intron of the bovine myostatin gene. It is characterized by a mononucleotide core motif that exhibits polymorphic sequence variants (from 12 to 21 repeats) within and between some bovine breeds. Structural analysis of the microsatellite region in bovines as well as in closely related species permitted to trace the possible mechanisms for its structural evolution across the order Artiodactyla.

Animals↗
PubMed1994

Structure of Brassica napus phosphoenolpyruvate carboxylase genes: missing introns causing polymorphisms among gene family members.

The Brassica napus genome contains more than four phosphoenolpyruvate carboxylase (PEPCase) genes. Although the nucleotide sequences of these genes highly resemble each other, an intron corresponding to the 7th intron in the maize gene is present in PE15- and PE105-PEPCase genes but absent in PE3-PEPCase. The intron corresponding to the maize 3rd intron is absent in PE15- and PE105-PEPCase genes. Deletion of these introns occurred precisely such that the coding sequence is faithfully preserved with respect to the maize gene. The PE19-PEPCase gene contains a deletion in the 8th exon instead of the presence of those introns.

Base Sequence↗
PubMed2005

Serotonin transporter intron 2 polymorphism associated with rigid-compulsive behaviors in Dutch individuals with pervasive developmental disorder.

Two putatively functional polymorphisms of the serotonin transporter gene (HTT, SLC6A4) were examined for associations with risk for pervasive developmental disorders (PDDs) and specific autism phenotypes. Dutch patients diagnosed with PDD (N = 125, age range 5-20 years, DSM-IV-TR based criteria, ADI-R and ADOS behavioral assessments) and their parents (N = 230) were genotyped for promoter ins/del (5-HTTLPR) and intron 2 variable number of tandem repeats (VNTR) alleles. Using the transmission disequilibrium test (TDT), no disorder-specific preferential transmission of promoter (long and short) or intron 2 (10- and 12-repeat) alleles was observed. However, multivariate analysis of continuous autism-related behavioral measures revealed that subjects with intron 2 12/12 genotype were significantly more impaired in the rigid-compulsive domain (P = 0.008). Quantitative TDT (QTDT) analysis also showed significant association of the intron 2 VNTR 12-repeat allele with rigid-compulsive behavior (P = 0.015). These results suggest that intron 2 VNTR alleles or nearby polymorphisms in linkage disequilibrium may play a role in specific aspects of the behavioral phenotype of autism.

Adolescent↗
PubMed1996

Human CFTR gene sequences in regions flanking exon 10: a simple repeat sequence polymorphism in intron 9.

A 2,908-bp segment of genomic DNA containing exon 10 and flanking intron regions of the human cystic fibrosis transmembrane conductance regulator gene was sequenced. A 30-bp sequence discrepancy and three missing nucleotides were detected when compared to a previously published 831-bp sequence. In the 30-bp region of sequence discrepancy, only a primer based on the new sequence information presented in this study gave products from polymerase chain reaction amplification of cellular DNA and a plasmid DNA encompassing the exon 10 region of CFTR. A 4-bp (TAAA) simple repeat sequence was also identified in intron 9 region. This repeat is dimorphic with nine (TAAA)9 or eleven (TAAA)11 copies on different chromosomes. Eleven repeats were exclusively associated with chromosomes carrying the delta508 mutation. Both 9 and 11 repeats were detected in non-delta508 chromosomes.

Base Sequence↗
PubMed1998

The human FE65 gene: genomic structure and an intronic biallelic polymorphism associated with sporadic dementia of the Alzheimer type.

The FE65 protein binds to the intracellular domain of the beta-amyloid precursor protein (betaPP) and may modulate the internalization of betaPP. This gene is highly expressed in regions of the brain specifically affected in dementia of the Alzheimer type (DAT). As a prelude to further investigations of the role of FE65 in the metabolism of betaPP and in the pathogenesis of DAT, we have determined the entire genomic structure and sequence of human FE65 and have discovered several polymorphisms in this gene. Human FE65 contains 14 exons ranging in size from 6 to 735 bp. All splice sites conform to consensus sequences except for the donor site of intron 10. The 5' end of FE65 mRNA was identified by rapid amplification of the cDNA 5' end and is 31 bp longer than the previously published cDNA sequence. The 5'-flanking region of this gene is TATA-less and is very GC-rich with at least five putative Sp1 binding sites. In comparison to the genomic rat FE65 sequence, the human FE65 5'-untranslated region is 134 bp longer and has an extra exon (exon 1, 86 bp). To identify mutations/polymorphisms of the coding regions of this gene, we performed blinded analysis of 457 Caucasian case-control samples from a large epidemiological study of sporadic DAT. Screening was conducted by single-strand conformation polymorphism. Four minor variants were found within the coding region, with frequencies between 0.002 and 0.015; two of the four result in amino acid substitutions. The more informative biallelic polymorphism (a trinucleotide deletion and a single base substitution) was found within intron 13 (84 bp), which interrupts two exons encoding the betaPP binding site. The frequency of the minor allele in this intron was 0.097 in DAT cases and 0.161 in controls (chi2=7.78, P=0.0054). Having at least one copy of the minor allele was associated with a decreased risk for DAT (chi2=9.20, P<0.005, odds ratio=0.49, 95% CI 0.31-0.77). Multivariate analysis showed that this association was independent of the APOE genotype. These results suggest that either FE65 itself or a closely linked gene influences the pathogenesis of sporadic DAT. The interaction of FE65 with betaPP and the association of a FE65 polymorphism with DAT lend credence to the hypothesis that the metabolism of betaPP is central to the pathogenesis of common sporadic forms of DAT.

Aged↗
PubMed2003

A risk for early-onset Alzheimer's disease associated with the APBB1 gene (FE65) intron 13 polymorphism.

Alzheimer's disease (AD) is a genetically complex neurodegenerative disorder and the leading cause of dementia of the elderly. Recently, Hu et al. suggested that a trinucleotide deletion in intron 13 of the APBB1 gene was a factor protecting against late-onset AD. We report here the results of a case/control study aimed at replicating this association. Our study included 461 AD patients and 397 matched controls. We compared the allele and genotype frequencies of the polymorphism between the two groups but did not find any statistically significant difference (P=0.08 and P=0.09, respectively). By contrast, adjusting for age and sex, we found a slight risk associated with the deletion (odds ratio=1.47, 95% confidence interval=1.05-2.04). Stratification by age showed that the risk effect associated with the deletion concerned subjects aged less than 65 years.

Age Factors↗