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PubMed1997

Association of a polymorphism in intron 13 of the monoamine oxidase B gene with Parkinson disease.

Monoamine oxidase B (MAO-B) is an enzyme that has relevance for Parkinson disease (PD) because of its roles in catabolizing dopamine and potentially activating exogenous neurotoxicants. A polymorphism of the gene encoding MAO-B has been identified as a single base change (A or G) in intron 13 of the X chromosome. The A allele was previously associated with an approximately twofold risk of PD. The present study compared A and G allele frequencies between newly diagnosed idiopathic PD cases and a control group free of neurodegenerative diseases. All study subjects were Caucasian. Cases were 37 men and 25 women, age 37-80 years; controls were 50 men and 29 women, age 45-82 years. MAO-B genotype was determined by the allele-specific polymerase chain reaction on DNA extracted from peripheral lymphocytes. In complete contrast to previous studies, elevated risks were detected with the G allele. The age-adjusted odds ratio for the G allele in males was 1.87 ((95% confidence interval) 0.78-4.47). Among females the age-adjusted odds ratios were 5.00 ((95% confidence interval) 1.13-22.1) for the GA genotype and 5.60 ((95% confidence interval) 1.01-30.9) for the GG genotype. These findings, although of limited statistical precision, suggest that the G allele of this MAO-B polymorphism may relate to PD risk.

Adult↗
PubMed1997

Human renin binding protein: complete genomic sequence and association of an intronic T/C polymorphism with the prorenin level in males.

The role of renin binding protein (RnBP) in human (patho)physiology, despite its biochemical characterization, is as yet unclear. RnBP has been shown to bind and inactivate renin, a key player of the blood pressure regulating renin-angiotensin system. This renders the RnBP gene a promising candidate gene in human hypertension. Herein, a molecular genetic approach was employed to investigate if RnBP might affect renin, prorenin and/or blood pressure levels. Sequencing of the human Xq28 chromosomal region provided the precise chromosomal location and full genomic sequence of the RnBP gene. All 11 exons, adjacent intronic splice sites and the promoter region were sequenced in 20 patients with essential hypertension of early onset and possible X-linked inheritance and in four normotensive individuals. The only variant found was a single base exchange polymorphism 61 base pairs upstream of the intron 6/exon 7 boundary (T61C). Several cardiovascular parameters, the renin, and prorenin levels and the T61C allele status were determined in 505 Caucasian individuals. Male individuals without medication who were hemizygous for the C allele were characterized by lower prorenin levels (196 +/- 15 versus 256 +/- 12 mU/l, P = 0.05) and a significantly higher renin/prorenin ratio (10.7 +/- 1.5 versus 7.7 +/- 0.3%, P = 0.002), whereas no variations in circulating renin, blood pressure, heart rate and left ventricular mass index were associated with the C allele. No significant association was observed in women. The data do not exclude a role of RnBP in essential hypertension. The complete genomic structure of the RnBP gene, including the identified repetitive sequence elements, provides an essential tool for further studies of the RnBP gene in hypertensive patients with a different genetic background.

Base Sequence↗
PubMed2002

Polymorphism in intron 2 of islet amyloid polypeptide gene is associated with lower low-density lipoprotein cholesterol in nondiabetic subjects and in type 2 diabetic patients.

The aim of this study was to investigate the presence of mutations in the islet amyloid polypeptide (IAPP) gene in a Spanish population with type 2 diabetes and gestational diabetes mellitus (GDM). Using polymerase chain reaction single-stranded conformation polymorphism, we examined the coding region and the 5'-untranslated region (UTR) of the IAPP gene in 177 unrelated type 2 diabetic patients, 110 healthy control subjects, 38 women with GDM, and 38 gestational control subjects. Mutations were confirmed by DNA sequencing. A heterozygous C-to-A nucleotide substitution at +79 bp in intron 2 of the IAPP gene was detected. The frequencies of the +79-bp polymorphism (A allele) were 6.8% in type 2 diabetic patients, 7.7% in nondiabetic control subjects, 11.8% in women with GDM, and 9.2% in gestational control subjects. No AA genotypes were detected. Nondiabetic subjects and patients with type 2 diabetes bearing the CA genotype had lower low-density lipoprotein (LDL) cholesterol levels than subjects bearing wild genotype. Multivariate logistic regression analysis showed an independent association (p < 0.001; odds ratio: 0.33; 95% confidence interval: 0.17-0.63). We did not detect any sequence variant within exons 1 or 2. One diabetic patient was heterozygous for a silent mutation at codon 31 of exon 3 (Asn31 AAC --> AAT). Our findings indicate that the presence of the +79-bp polymorphism of the IAPP gene in nondiabetic subjects and in patients with type 2 diabetes is associated with lower levels of LDL cholesterol. Furthermore, abnormalities of the coding regions or the 5'-UTR of the IAPP gene are not associated with type 2 diabetes or GDM in the Spanish population.

Aged↗
PubMedDate not supplied

Role of intron 5 C/T polymorphism of the calcium sensing receptor gene in the regulation of the serum FSH and LH in post-menopausal women.

OBJECTIVE: High extracellular calcium concentration (Cao(2+)) acts to inhibit calcium sensing receptor (CaR) signalling on cellular surfaces in parathyroid glands. This receptor is, however, also expressed on the membranes of some non-calciotropic endocrine cells, including pituitary-derived cells. The aim of our study was to analyse relationships between the CaR gene and the circulating FSH and LH in normal post-menopausal women. METHODS: A total of 95 untreated euparathyroid post-menopausal women were investigated in the study. The serum FSH and LH levels were evaluated in relationship to allele combinations of the CaR gene (C/T polymorphism in the intron 5 and A986S polymorphism in exon 7), using an analysis of co-variance (ANCOVA) model. RESULTS: Distribution of TT, TC and CC allele combinations (intron 5 C/T polymorphism) was 51, 43 and 6 %, respectively. Higher serum FSH and LH levels were found in carriers of C allele than in women without this allele (p < 0.002 and p < 0.03, respectively). No correlations were found between A986S polymorphism and serum FSH and LH levels. CONCLUSIONS: Serum FSH and LH levels are associated with intron 5 C/T (but not A986S) polymorphism of the CaR gene in untreated post-menopausal women. The physiological role of the CaR gene in the regulation of the gonadotropic function needs to be further investigated.

Adult↗
PubMed1997

Polymorphisms and intron sequences flanking the alternatively spliced 8-amino-acid exon of gamma2 subunit gene for GABAA receptors.

Gamma-amminobutyric acid (GABA) is a major inhibitory neurotransmitter. Two alternatively spliced forms of the gamma2 subunit of GABAA receptor (gamma2L and gamma2S), which differ by an exon of eight amino acids, show different sensitivities to modulatory effects of ethanol on receptor activities. A 2.7 kb DNA fragment and an 1.7 kb DNA fragment covering respectively the introns upstream and downstream from the 8-amino-acid exon were obtained through PCR-amplification of human genomic DNA using primers derived from cDNA sequences. Total sequencing of these fragments showed a composite 4.2 kb segment containing the 8-amino-acid exon and consensus sequences for RNA splice junctions. Restriction fragment length polymorphisms (RFLP) based on NciI restriction digestion were found among Chinese in Taiwan. This RFLP provides a useful DNA marker for allelic association or linkage analyses of the role of GABAA receptors in predisposition to alcoholism or other neuropsychiatric disorders.

Alternative Splicing↗
PubMed2006

IL1RN intron 2 polymorphism caused by variable number tandem repeats is associated with 1-year outcome in patients with ischaemic stroke.

BACKGROUND: Results of experimental and clinical studies suggest that recombinant human interleukin 1 receptor antagonist (rhIL1ra) may be a good new therapeutic agent for acute stroke. In humans, IL1ra is encoded by the IL1RN gene located on chromosome 2. OBJECTIVES: To report on the association between different genotypes of the variable number tandem repeat (VNTR) polymorphism within IL1RN, and disease severity and 1-year outcome in patients with ischaemic stroke. METHODS: IL1RN genotypes were evaluated using polymerase chain reaction in 391 patients with ischaemic stroke diagnosed according to the World Health Organization definition. The effects of IL1RN genotypes on severity of stroke at maximum impairment, and on the survival status and neurological and functional condition of patients at 7 days, 1 month, 3 months and 1 year after the onset, were evaluated. RESULTS: No relationship was found between IL1RN genotypes and severity of symptoms at the time of maximum impairment. Homozygotes for the IL1RN*2 allele showed less severe neurological and functional impairments when assessed after the time period between 7 days and 1 year after stroke compared with carriers of the other two IL1RN genotypes. Patients with at least one copy of the IL1RN*2 allele had increased risk of death during the first week, and patients homozygotic for this allele had increased risk of death within the first month after stroke. CONCLUSION: IL1RN intron 2 variable number tandem repeats polymorphism influences the clinical outcome in patients with ischaemic stroke. It may possibly modify effects of treatment with rhIL1ra in patients with acute stroke.

Brain Ischemia↗
PubMed1998

Implications of a common polymorphism in intron 12 of the dystrophin gene for deletion detection by multiplex PCR.

The multiplex polymerase chain reaction (PCR) is a reliable and efficient method for detecting dystrophin gene deletions in about 65% of patients with Duchenne or Becker muscular dystrophy (DMD or BMD). The 9-plex PCR assay, which simultaneously amplifies the muscle-specific promoter and exons 3, 6, 13, 43, 47, 50, 52 and 60, is one of the multiplex PCR assays used routinely to test for DMD and BMD deletions. In this study, we describe a previously unrecognized A to G base variation in intron 12 (nt -110 from exon 13) of the dystrophin gene. This variant, located within the annealing site of the exon 13 forward primer, prevented amplification of exon 13 in the 9-plex PCR assay. Present in 56% (25 of 45) of normal Caucasian alleles and 23% (3 of 13) of normal black American alleles, it is likely encountered frequently during dystrophin deletion analysis by multiplex PCR, and may complicate test result interpretation. Therefore, we suggest two modifications for the multiplex PCR detection of dystrophin gene deletion.

Alleles↗
PubMed2004

Intronic CYP46 polymorphism along with ApoE genotype in sporadic Alzheimer Disease: from risk factors to disease modulators.

Increasing biological and clinical findings argue for a link between brain cholesterol turnover and Alzheimer Disease (AD), high cerebral levels of the former increasing Abeta load. Cerebral cholesterol elimination involves two mechanisms dependent on Apolipoprotein E (ApoE) and cholesterol 24-hydroxylase (CYP46). The aim of this study was to evaluate an intronic variation in CYP46 (intron 2, T --> C ) along with ApoE genotype as risk factors for AD and to establish the correlation between CYP46/ApoE polymorphism and disease progression. One-hundred and fifty-seven AD patients, who had been followed periodically through 1-year follow-up after enrollment, and 134 age- and gender-matched controls entered the study. The distribution of CYP46 genotypes was significantly different in AD compared to controls (P<0.004), being CYP*C allele higher in AD patients ( P<0.002). ApoE 4 genotype was more frequent in AD (41.4%) than in controls (15.9%, P<0.0001). The odds ratio (OR) for AD risk in CYP46*C carriers was 2.8, and in ApoE epsilon4 carriers was 4.05; the OR for having both CYP46*C and ApoE epsilon4 was 17.75, demonstrating the their synergic effect on AD risk. In AD patients, CYP46*C along with ApoE epsilon4 genotype were associated with a higher cognitive decline at 1-year follow-up (P<0.02). These findings provide direct evidence that CYP46 and ApoE polymorphisms synergically increase the risk for AD development, and influence on the rate of cognitive decline.

Aged↗
PubMed2006

Identification of a single nucleotide polymorphism at intron 16 of the caprine acyl-coenzyme A: diacylglycerol acyltransferase 1 (DGAT1) gene.

The DGAT1 gene encodes a microsomal enzyme that catalyses the only committed step in triacylglycerol synthesis by joining diacylglycerol and fatty acyl coenzyme A. In cattle, a K232A substitution in the DGAT1 molecule has a significant effect on enzyme activity and milk fat content. The prominent role of this gene in lipid metabolism led us to undertake the structural characterization of DGAT1 in goats. In this way, we have sequenced a 1552 bp fragment of the goat DGAT1 cDNA, which encompasses most of the coding sequence (from exon 1 to 17), and a genomic fragment covering exons 12 to 17. Multiple alignment of the goat DGAT1 sequences revealed the existence of a single nucleotide polymorphism (SNP) involving a T to C substitution at intron 16. We optimized a primer extension based genotyping method that allowed us to determine that the C variant is a minority allele with frequencies ranging from 0.062 (Murciano-Granadina) to 0.109 (Malagueña). This SNP, although not expected to have any functional effect, might be useful as a genetic marker in association studies to detect additional DGAT1 polymorphisms which might influence fat milk content and other traits of economic interest.

Amino Acid Sequence↗