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PubMed2006

Genomic organization, localization and polymorphism of porcine PSMB10, a gene encoding the third beta-type proteasome subunit of 26S proteasome complex.

The proteasome subunit, beta type 10 (PSMB10) gene regulated by interferon-gamma is a core part of the 26S proteasome complex, which is an important protein degrading system. Isolation and characterization of swine PSMB10 revealed a conserved structure with other mammalian PSMB10 genes. An A/G nucleotide polymorphism in PSMB10 intron 2 and a C/T single nucleotide polymorphism in exon 5 were detected by polymerase chain reaction restriction fragment length polymorphism. The allele frequencies were significantly different among Tongcheng, Landrace, Large White and Duroc. The porcine PSMB10 was mapped by somatic cell hybrid panel and radiation hybrid mapping on SSC6p14-p15, which is in good agreement with human-pig comparative maps.

Animals↗

PubMed1996

Genetic bases of human complement C7 deficiency.

Complement C7 deficiency (C7D) is associated frequently with recurrent bacterial infections, especially meningitis caused by Neisseria meningitidis. We report in this work the molecular bases of C7D in two unrelated Japanese males. We used exon-specific PCR/single-strand conformation polymorphism analysis as a screening step for mutations. Subsequent direct sequencing of the target exons identified homozygous mutations in exon 16 of case 1 and in exon 15 of case 2. The mutation of case 1 was a homozygous T to A transversion at nucleotide 2250, the third nucleotide of the codon TGT for Cys728, leading to a stop codon TGA (C728X). In case 2, a homozygous 2-bp deletion (2137delTG/2138delGT/2139delTG) caused a frameshift, generating a premature termination codon 4 to 6 nucleotides downstream. Family study in case 1 confirmed the genetic nature of the defect. Moreover, we detected a novel polymorphism in intron 11 that presumably is linked to the mutation responsible for C7D in case 1. Our results indicate that the pathogenesis of C7D is heterogeneous like most of the other deficiencies of complement components.

Adult↗

PubMed1985

The Vi element. A transposon-like repeated DNA sequence interspersed in the vitellogenin locus of Xenopus laevis.

A repeated DNA element in Xenopus laevis is described that is present in about 7500 copies dispersed throughout the genome. It was first identified in the 5' flanking region of one vitellogenin gene and was therefore named the Vi element. Seven copies are present within the vitellogenin gene region, three of them within introns of the genes A1, A2 and B2, and the other four copies in the gene flanking regions. Four of these copies have been sequenced. The Vi element is bounded by a well-conserved 13 base-pair inverted repeat; in addition, it is flanked by a three base-pair direct repeat that appears to be site-specific. The length of these four copies varies from 112 to 469 base-pairs; however, sequence homology between the different copies is very high. Their structural characteristics suggest that length heterogeneity may have arisen by either unequal recombinations, deletions or tandem duplications. Altogether, the characteristics and properties of the Vi element indicate that it might represent a mobile genetic element. One of the four copies sequenced is inserted close (position -535) to the transcription initiation site of the vitellogenin gene B2 in a region otherwise showing considerable homology with the closely related gene B1. Nevertheless, the presence of the Vi element does not seem to influence significantly the estrogen-controlled expression of gene B2. In addition, three alleles of this gene created by length polymorphism in intron 3 and in the Vi element inserted near the transcription initiation site are described.

Animals↗

PubMed2001

Serum angiotensin I-converting enzyme is reduced in Crohn's disease and ulcerative colitis irrespective of genotype.

OBJECTIVES: Crohn's disease (CD) is recognized to be a vascular endothelial-associated disease. Angiotensin I-converting enzyme (ACE) exists mainly in endothelial cells. There are some reports on serum ACE levels in patients with CD, but the ACE level is still controversial. Recently, genetic control of serum ACE levels by ACE gene polymorphisms (classified as II, ID, and DD) has been suggested. Although we must consider such polymorphisms to elucidate ACE levels in patients with CD, there is no report about this. METHODS: We studied 341 healthy controls (male/female = 178/162), 39 patients with CD (31/8), 43 patients with ulcerative colitis (UC) (22/21) and 19 patients with infectious enterocolitis (8/11). The polymorphism in intron 16 of the ACE gene was examined by PCR. Serum ACE levels were measured by the method of Kasahara. RESULTS: Serum ACE levels in patients with CD and UC were significantly lower than in healthy controls, irrespective of the genotype of ACE (genotype II: CD 7.0+/-2.5 [mean +/- SD], UC 7.1+/-3.3, controls 11.8+/-2.9, genotype ID: CD 9.7+/-4.1, UC 11.4+/-4.6, controls 15.2+/-3.6, genotype DD: CD 13.9+/-5.8, UC 10.7+/-3.6, controls 19.3+/-3.9 IU/L, controls vs CD, UC; p < 0.01, 0.05). However, there was no significant difference in serum ACE levels between CD and UC. CONCLUSIONS: Considering ACE gene polymorphism, serum ACE levels in patients with inflammatory bowel disease are lower than in controls. Serum ACE levels reflect a part of the pathogenesis of inflammatory bowel disease.

Adult↗

PubMed1996

A rapid and cost effective method for analysis of dinucleotide repeat polymorphisms in the factor VIII gene.

A simple, rapid and cheap method for the analysis of variable dinucleotide tandem polymorphisms in introns 13 and 22 of the factor VIII gene has been established. The protocol uses blood spots stored on filter paper (Guthrie spots) and other DNA containing materials as sources of DNA. Following DNA amplification using a thermostable DNA polymerase, products are size fractionated on native polyacrylamide gels and visualized by silver staining. This simplified protocol obviates the use of DNA extraction, reducing time and costs and in addition, reduces the requirement for gel documentation equipment (i.e., photography), as silver staining can be visualized readily without additional equipment and the gels themselves can be stored. These alterations to the analysis enhance the universal applicability of these polymorphisms, as was demonstrated by a comparative study in Caucasian and Thai females.

Cost-Benefit Analysis↗

PubMed2004

DD genotype of ACE gene is a risk factor for intracerebral hemorrhage.

Genetic factors may play a role in susceptibility to stroke. The angiotensin converting enzyme (ACE) gene is a candidate gene for two phenotypically different types of stroke affecting small perforating arteries: spontaneous intracerebral hemorrhage (SIH) and ischemic stroke due to small vessel disease (SVD). The authors report evidence that ACE gene DD homozygosity of the I/D polymorphism in intron 16 is an independent risk factor for SIH, and not for SVD stroke, in a Polish population.

Adult↗

PubMed2002

Analysis of the coxsackievirus B-adenovirus receptor gene in patients with myocarditis or dilated cardiomyopathy.

Myocarditis and dilated cardiomyopathy (DCM) are common causes of morbidity and mortality in children and adults, most commonly due to infection with coxsackievirus B or adenovirus. Increased expression of the common human coxsackievirus B-adenovirus receptor (CAR) has been reported in patients with DCM. We investigated the CAR gene in patients with acquired or familial myocarditis/DCM for mutations/polymorphisms. Several polymorphisms or intronic substitutions, distant from the intron-exon boundaries, were identified but no mutations. Based upon these data it appears that CAR gene mutations are not a major host determinant in the development of myocarditis and DCM.

Adenoviridae↗

PubMed1994

Myotonic dystrophy CTG repeats and the associated insertion/deletion polymorphism in human and primate populations.

Myotonic dystrophy (DM) is associated with abnormal expansions of the CTG repeats in the 3' untranslated region of its gene. Previous studies in individuals of European origin demonstrated strong linkage disequilibrium between different CTG repeat length alleles and an Alu element insertion/deletion polymorphism in intron 8 of the DM gene: CTG11-13 chromosomes were almost exclusively associated with the deletion allele, while chromosomes with five or 19-30 repeats or disease chromosomes were only found on the insertion allele. One of the models suggested by these results proposed that the triplet repeats on insertion-associated chromosomes were particularly prone to mutation. Studies of other triplet repeat disorders have suggested that arrays of perfect repeats are more prone to instability than those that are interrupted. We have examined the evolution of this locus by typing a variety of primates and samples drawn from several different human populations for both CTG repeat length and the insertion/deletion polymorphism. DM gene sequences from different primates revealed inter- and intraspecies variability in the number of CTG repeats. Human chromosomes with five repeats or 11-13 repeats (the two major modes of the human CTG repeat distributions) showed no evidence of preferential stabilization of these repeat sizes by imperfect sequences. The insertion and deletion allele frequencies showed large interpopulation variation and the degree of association between these alleles and various CTG repeat lengths is not nearly as complete as was previously supposed. We have found deletion alleles carrying long normal (> 19) CTG repeats and insertion alleles associated with CTG11 - 13 in two african populations.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1995

The human TAX1 gene encoding the axon-associated cell adhesion molecule TAG-1/axonin-1: genomic structure and basic promoter.

The human TAX-1 gene (HGMW-approved symbol TAX1) is located on chromosome 1 (1q32.1) and encodes the neuronal cell adhesion molecule TAG-1/axonin-1. The gene product, termed TAG-1 in the rat and axonin-1 in the chicken, is composed of six immunoglobulin (Ig)-like and four fibronectin type III (FNIII)-like domains. It is found predominantly on the axons of particular nerve fiber tracts during neural development, and it has been demonstrated to function as a potent substratum for neurite outgrowth in vitro. Here we report the cloning and structural characterization of the TAX-1 gene. The transcribed region of the TAX-1 gene extends over about 40 kb. Like its chicken homologue, the human TAX-1 gene consists of 23 exons. Two GT/CA microsatellites were localized in the first intron; a polymorphism was found for one of them. Reporter gene analysis with serially truncated fragments of the 5'-flanking region indicated that a 164-bp fragment located immediately upstream of the putative transcription initiation site was sufficient to function as a basal promoter.

Animals↗

PubMed1999

Polymorphisms in PTEN in breast cancer families.

Germline mutations in PTEN are the underlying genetic defect in Cowden disease, which is associated with a lifetime risk of 25-50% of developing breast cancer. To investigate the role of PTEN in inherited breast cancer in the absence of manifestations of Cowden disease, we screened 177 unrelated subjects with breast cancer who also had a family history of breast cancer in at least one relative. We found no disease associated PTEN mutations in this cohort, supporting previous studies suggesting that PTEN mutations do not contribute to inherited susceptibility to breast cancer without associated manifestations of Cowden disease. We did identify an association between a common polymorphism in intron 4 and lower mean age of diagnosis of breast cancer. While preliminary, these findings suggest that further study is warranted to determine whether this allelic variant of PTEN could function as a low penetrance breast cancer susceptibility allele.

Age Factors↗

PubMed2006

Cholesteryl ester transfer protein gene polymorphisms and severity of coronary stenosis.

PURPOSE: Cholesteryl ester transfer protein (CETP) gene is involved in the reverse cholesterol transport in humans. Thus, it is a candidate for studying the susceptibility to coronary heart disease (CHD). The goal of the current investigation was to determine any association between CETP polymorphisms (I405V and TaqIB), and severity of coronary stenosis, since the extent of coronary artery narrowing has been considered as a primary determinant of survival in CHD patients. METHODS: The severity of coronary stenosis was estimated by Gensini (GS) and Duke Jeopardy (JS) scores in 130 men with documented CHD (mean age 61 +/- 10 yr). Genotyping was performed by polymerase chain reaction and restriction fragment length polymorphism analysis. RESULTS: The allele frequencies for both TaqIB and I405V were found in Hardy-Weinberg equilibrium. Homozygotes for I had lower GS compared with heterozygotes (IV) and homozygotes for V [72(95% CI 51-92) vs. 122(95% CI 88-157) and 136 (95% CI 74-198), P = 0.009, P = 0.010, respectively]. In addition, GS differed between carriers of I and carriers of V allele [86(95% CI 72-101) vs. 128(95% CI 102-154), P = 0.003]. A correlation was found between the GS and I405V polymorphism (r = 0.250, P = 0.005), but not with JS. CONCLUSION: Homozygosity for I405 favours less severe coronary stenosis. Our findings indicate that the I405V polymorphism may have potential importance in screening individuals at high risk for developing CHD, establishing efficient prevention measures, and searching for other risk factors for CHD. However, further prospective investigations in larger populations are required to confirm these findings.

Base Sequence↗

PubMed2003

Genetic polymorphisms in the Renin-Angiotensin system in high-altitude and low-altitude Native American populations.

Cardiovascular disease (CVD) is reportedly less common in high-altitude native populations than in lowlanders. To some extent, this is due to cultural and demographic factors; however, increased cardiovascular efficiency contributing to hypoxia adaptation may also be involved. Numerous genetic variants have been associated with cardiovascular health. If the decreased incidence of CVD in modern high-altitude populations reflects selective pressures having favoured the transmission of these alleles in their antecedents, it would be expected that these alleles would be more common in highlanders than in lowlanders. We tested this hypothesis by determining the allele frequencies of five polymorphic loci in genes encoding components of the renin-angiotensin system (RAS) that have alleles associated with hypertension and cardiovascular disease in a high-altitude native Andean population, Quechua from the Peruvian altiplano, and in a lowland Amerindian population, Maya from the Yucatan peninsula. The polymorphisms examined were 1) the insertion/deletion polymorphism in intron 16 of the angiotensin converting enzyme (ACE) gene; 2) the A/G2350 transition (ACE-8) in intron 17 of the ACE gene; 3) the A/C1166 transversion in the 3' untranslated region of the angiotensin II receptor (type 1) gene (AGTR1); 4) the G/AI9-83 transition in intron 8 of the renin gene (REN); and 5) the T/C704 (Met235Thr) transition mutation in angiotensinogen (AGT). There was no evidence for an over-representation of the RAS alleles associated with cardiovascular fitness in the high-altitude Amerindian population when compared to the lowland Amerindian population.

Altitude↗

PubMed2003

Tissue plasminogen activator and plasminogen activator inhibitor type 1 gene polymorphism in patients with gastric ulcer complicated with bleeding.

Tissue plasminogen activator (t-PA) and plasminogen activator inhibitor type 1 (PAI-1) may be involved in the pathogenesis of peptic ulcers through suppression of fibrinolysis. This study was designed to investigate associations of t-PA and PAI-1 genes with clinical features of the patients with bleeding gastric ulcers. Eighty-four patients with peptic ulcers and 100 controls were studied between January 1998 and April 2000. We used polymerase chain reaction and endonuclease digestion to genotype for 4G/5G polymorphism in the promoter region of the PAI-1 gene and the Alurepeat insertion/deletion (I/D) polymorphism in intron h of the t-PA gene. Various clinical features, including lesion site, bleeding event, recurrence of ulcer, and rebleeding, were assessed using a multiple logistic regression model. The genotype distributions of both the t-PA and PAI-1 genes did not differ between the patient and control groups. The occurrence of the I/D or D/D genotype of t-PA was significantly higher in cases of duodenal ulcer (adjusted OR=4.39, 95% CI=1.12-17.21). When a dominant effect (i.e., 4G/4G or 4G/5G versus 5G/5G) of the 4G allele was assumed, the PAI-1 4G/4G genotype was independently associated with rebleeding after hemostasis (adjusted OR=5.07, 95% CI=1.03-24.87). Our data suggest that t-PA gene polymorphism is associated with duodenal ulcers, and that the PAI-1 gene may be a risk factor leading to recurrent bleeding after initial hemostasis.

Adult↗

PubMed1998

Polymorphisms in angiotensin-converting enzyme gene and severity of renal disease in Henoch-Schoenlein patients. Italian Group of Renal Immunopathology.

BACKGROUND: The influence of angiotensin converting enzyme (ACE) gene polymorphism on the progression of primary IgA nephropathy (pIgAN) is still debated. Even though the allele frequency was reported to be similar to controls, in some studies D/D patients had a faster decline of renal function and need of dialysis. Since Henoch-Schoenlein purpura (HSP) nephritis is considered a systemic vasculitis with renal lesions indistinguishable from pIgAN, we investigated the effect of the ACE polymorphism on presentation and progression of HSP IgAN. METHODS: We examined the insertion (I) and deletion (D) polymorphism in intron 16 of ACE gene by PCR amplification of genomic DNA of 82 patients (37 children), with biopsy-proven IgAN associated with HSP enrolled in a collaborative study. RESULTS: No significant association with clinical presentation at onset or with final outcome was found (functional impairment at outcome in 31.8%, D/D, 27.4%, I/D and 44% I/I, heavy proteinuria in 36.3% D/D, 21.6% I/D, and 11.1% I/I). Patients homozygous for the D allele had a greater number of extrarenal relapses (P=0.0028). No association was found between the ACE genotype and the presence of hypertension at onset and at the end of the follow-up. No difference was found between adults and children. CONCLUSIONS: In this cohort of HSP IgAN, no ACE I/D polymorphisms were found to be associated with progressive deterioration of renal function. Different genes possibly involved in vasculitis might more strictly modulate expression and evolution of HSP IgAN.

Adolescent↗

PubMed2002

PAX6 mutation as a genetic factor common to aniridia and glucose intolerance.

A paired homeodomain transcription factor, PAX6, is a well-known regulator of eye development, and its heterozygous mutations in humans cause congenital eye anomalies such as aniridia. Because it was recently shown that PAX6 also plays an indispensable role in islet cell development, a PAX6 gene mutation in humans may lead to a defect of the endocrine pancreas. Whereas heterozygous mutations in islet-cell transcription factors such as IPF1/IDX-1/STF-1/PDX-1 and NEUROD1/BETA2 serve as a genetic cause of diabetes or glucose intolerance, we investigated the possibility of PAX6 gene mutations being a genetic factor common to aniridia and diabetes. In five aniridia and one Peters' anomaly patients, all of the coding exons and their flanking exon-intron junctions of the PAX6 gene were surveyed for mutations. The results of direct DNA sequencing revealed three different mutations in four aniridia patients: one previously reported type of mutation and two unreported types. In agreement with polypeptide truncation and a lack of the carboxyl-terminal transactivation domain in all of the mutated PAX6 proteins, no transcriptional activity was found in the reporter gene analyses. Oral glucose tolerance tests revealed that all of the patients with a PAX6 gene mutation had glucose intolerance characterized by impaired insulin secretion. Although we did not detect a mutation within the characterized portion of the PAX6 gene in one of the five aniridia patients, diabetes was cosegregated with aniridia in her family, and a single nucleotide polymorphism in intron 9 of the PAX6 gene was correlated with the disorders, suggesting that a mutation, possibly located in an uncharacterized portion of the PAX6 gene, can explain both diabetes and aniridia in this family. In contrast, the patient with Peters' anomaly, for which a PAX6 gene mutation is a relatively rare cause, showed normal glucose tolerance (NGT) and did not show a Pax6 gene mutation. Taken together, our present observations suggest that heterozygous mutations in the PAX6 gene can induce eye anomaly and glucose intolerance in individuals harboring these mutations.

Adolescent↗

PubMed2002

Genetic analysis of vascular factors in Alzheimer's disease.

Genetic risk factors for Alzheimer's disease (AD) have been extensively examined. Several risk factors for AD are shared with vascular dementia (VaD). We performed genetic case-control studies on polymorphisms of the apolipoprotein E (ApoE) gene, the methylene tetrahydrofolate reductase (MTHFR) gene, and the angiotensin-converting enzyme (ACE) gene. The most acceptable genetic risk factor for the development of AD is the ApoE epsilon-4 (ApoE epsilon4) allele. ApoE promoter polymorphisms have also been reported to be associated with AD. As expected, the ApoE epsilon4 allele had strong association with AD in our samples. The ApoE epsilon4 allele was also estimated as a risk factor for VaD. An ApoE promoter polymorphism (-291T/G) did not show positive association with AD or any other diseases. Common MTHFR phenotypes are thought to genetically regulate blood homocysteine level, which has been associated with AD. We failed to show independent associations between AD and the common MTHFR polymorphisms (C677T and A1298C). A deletion polymorphism at intron 16 of the ACE gene has also been associated with AD. In our study, we found a significant ethnic difference of the genotype distribution, but failed to replicate the positive association between the I allele and AD.

Alleles↗

PubMed2005

Human genetic evidence that OX40 is implicated in myocardial infarction.

We recently showed that genetic variants in OX40L are associated with myocardial infarction (MI) and severity of coronary artery disease in human. A number of studies also suggest a possible role for OX40 (the OX40L receptor) as a factor contributing to atherosclerosis. In the present study, the OX40 gene was screened for variants associated with precocious MI, using individuals with MI before the age of 60 and controls. Despite the fact that the OX40 gene is highly conserved between species and that relatively few common genetic variants were encountered, an association with MI was seen for a polymorphism in intron 5 (rs2298212). In silico investigation suggested that genetic variation (rs2298211), linked to this intronic variant, is possibly affecting spliceosome function. Our results provide evidence that variants in human OX40 might influence susceptibility to MI. The relevance of these findings is supported by the vital functions fulfilled by OX40 in mammals as reflected by the high level of evolutionary conservation.

Adolescent↗

PubMed2004

Polymorphism in the surfactant protein-B gene, gender, and the risk of direct pulmonary injury and ARDS.

STUDY OBJECTIVE: Major risk factors for ARDS have been identified. However, only a minority of patients with such risks develops ARDS. It is likely that, given the same type and degree of insult, there are heritable determinants of susceptibility to ARDS. To investigate the possibility of variable genetic susceptibility to ARDS, we examined the association between ARDS and a polymorphism in intron 4 of the surfactant protein-B (SP-B) gene. DESIGN: Nested case-control study conducted from September 1999 to March 2001. SETTING: Four adult medical and surgical ICUs at a tertiary academic center. PATIENTS: One hundred eighty-nine patients meeting study criteria for a defined risk factor for ARDS were enrolled and prospectively followed. MEASUREMENTS AND RESULTS: Seventy-two patients (38%) developed ARDS. After stratification by gender and adjustment for potential confounders, there was a significantly increased odds for women with the variant SP-B gene to develop ARDS compared to women homozygous for the wild-type allele (odds ratio [OR], 4.5; 95% confidence interval [CI], 1.1 to 18.8; p = 0.03). Women with the variant SP-B polymorphism also had significantly increased odds of having a direct pulmonary injury such as aspiration or pneumonia as a risk factor for ARDS as opposed to an indirect pulmonary risk for ARDS (OR, 4.6; 95% CI, 1.1 to 19.9; p = 0.04). No such association with ARDS or direct pulmonary injury was found for men. CONCLUSION: The variant polymorphism of the SP-B gene is associated with ARDS and with direct pulmonary injury in women, but not in men. Further study is needed to confirm the association between the variant SP-B gene, and gender, ARDS, and direct pulmonary injury.

Adolescent↗