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PubMed2004

Identification of sequence variation in the galactose-1-phosphate uridyl transferase gene by dHPLC.

Transferase-deficient galactosaemia is an inherited disorder of carbohydrate metabolism, caused by mutation at the galactose-1-phosphate uridyl transferase (GALT) locus. A denaturing high performance liquid chromatography (dHPLC) method was developed for variant scanning of the GALT gene. The method unequivocally identified the Duarte D1, D2, Q188R, and K285N GALT alleles and associated polymorphisms. Length polymorphism in an intronic Alu repeat was characterised and a novel Single Nucleotide Polymorphism (IVS10nt-322g-->t) associated with the D1 allele was identified.

Alu Elements↗
PubMed2002

Polymorphism in the cholesterol 24S-hydroxylase gene is associated with Alzheimer's disease.

Cholesterol and 24S-hydroxycholesterol are involved in the pathogenesis of Alzheimer's disease (AD). Increased serum cholesterol concentrations have been detected in patients with AD. 24S-Hydroxycholesterol is the primary cholesterol elimination product of the brain and possesses neurotoxic properties in vitro. The enzyme catalyzing the conversion of cholesterol to 24S-hydroxycholesterol, cholesterol 24S-hydroxylase (CYP46), is mainly expressed in neurons. Concentrations of 24S-hydroxycholesterol in cerebrospinal fluid (CSF) and serum differ significantly between AD patients and non-demented subjects. To test the hypothesis if polymorphisms in the CYP46 gene might influence the function of the respective enzyme and thus cholesterol metabolism in the human brain, we screened for polymorphisms in 114 AD patients and 144 healthy controls. Two intronic single nucleotide polymorphisms were observed and their allelic distribution was investigated. In our study sample, carriers of the C allele of the IVS3+43C --> T polymorphism were more prevalent in the group of AD patients than in healthy controls, while another IVS2-150A --> G polymorphism did not show a significant association with AD. The CC genotype of the IVS3+43C --> T polymorphism was associated with an increased 24S-hydroxycholesterol/cholesterol ratio in the CSF of AD patients. Our results indicate that the CYP46 gene locus may predispose to AD by increasing the 24S-hydroxycholesterol/cholesterol ratio in the brain.

Aged↗
PubMed2006

Expressed sequence tag analysis in tef (Eragrostis tef (Zucc) Trotter).

Tef (Eragrostis tef (Zucc.) Trotter) is the most important cereal crop in Ethiopia; however, there is very little DNA sequence information available for this species. Expressed sequence tags (ESTs) were generated from 4 cDNA libraries: seedling leaf, seedling root, and inflorescence of E. tef and seedling leaf of Eragrostis pilosa, a wild relative of E. tef. Clustering of 3603 sequences produced 530 clusters and 1890 singletons, resulting in 2420 tef unigenes. Approximately 3/4 of tef unigenes matched protein or nucleotide sequences in public databases. Annotation of unigenes associated 68% of the putative tef genes with gene ontology categories. Identification of the translated unigenes for conserved protein domains revealed 389 protein family domains (Pfam), the most frequent of which was protein kinase. A total of 170 ESTs containing simple sequence repeats (EST-SSRs) were identified and 80 EST-SSR markers were developed. In addition, 19 single-nucleotide polymorphism (SNP) and (or) insertion-deletion (indel) and 34 intron fragment length polymorphism (IFLP) markers were developed. The EST database and molecular markers generated in this study will be valuable resources for further tef genetic research.

Databases, Nucleic Acid↗
PubMed1993

Strategy for definition of DR/DQ haplotypes in the 4AOHW cell panel using noncoding sequence polymorphisms.

Our previously described intron-based DQA1-typing method provides 11 allelic and suballelic groups, including the eight alleles encoded at the second exon. Concurrent testing for the presence of the DRB3, DRB4, and DRB5 loci and the Rsa I pattern of the DRw52 group simplifies the typing requirements for allele assignment at the highly polymorphic DRB1 locus. The DRB1-allele-shortlisting process relies on known DR/DQ haplotypes. In addition to reducing the testing requirements for definitive DRB1 allele assignment, this strategy allows inference of the DR/DQ haplotype and assists in recognition of novel and/or unusual associations.

Alleles↗
PubMed1998

Endothelial nitric oxide synthase gene is positively associated with essential hypertension.

Essential hypertension has a genetic basis. Accumulating evidence, including findings of elevation of arterial blood pressure in mice lacking the endothelial nitric oxide synthase (eNOS) gene, strongly suggests that alteration in NO metabolism is implicated in hypertension. There are, however, no reports indicating that polymorphism in the eNOS gene is associated with essential hypertension. We have identified a missense variant, Glu298Asp, in exon 7 of the eNOS gene and demonstrated that it is associated with both coronary spastic angina and myocardial infarction. To explore the genetic involvement of the eNOS gene in essential hypertension, we examined the possible association between essential hypertension and several polymorphisms including the Glu298Asp variant, variable number tandem repeats in intron 4 (eNOS4b/4a), and two polymorphisms in introns 18 and 23. We performed a large-scale study of genetic association using two independent populations from Kyoto (n=458; 240 normotensive versus 218 hypertensive subjects) and Kumamoto (n=421; 223 normotensive versus 187 hypertensive subjects), Japan. In both groups, a new coding variant, Glu298Asp, showed a strong association with essential hypertension (Kyoto: odds ratio, 2.3 [95% confidence interval, 1.4 to 3.9]; Kumamoto: odds ratio, 2.4 [95% confidence interval, 1.4 to 4.0]). The allele frequencies of 298Asp in hypertensive subjects were significantly higher than those in normotensive subjects in both groups (Kyoto: 0.103 versus 0.050, P<0.0017; Kumamoto: 0.120 versus 0.058, P<0.0013, respectively). No such disequilibrium between genotypes was significantly associated with any other polymorphisms we examined; the Glu298Asp variant was also not linked to any other polymorphisms. In conclusion, the Glu298Asp missense variant was significantly associated with essential hypertension, which suggests that it is a genetic susceptibility factor for essential hypertension.

Adult↗
PubMed2005

CYP1A2 phenotype and genotype in a population from the Carboniferous Region of Coahuila, Mexico.

CYP1A2 regulation by polycyclic aromatic hydrocarbons (PAHs) exposure and polymorphism was investigated in 46 male volunteers from the Carboniferous Region in northern Coahuila, Mexico. PAH exposure was estimated by the urinary excretion of 1-hydroxypyrene (1-OHP), whereas the regulatory effects were assessed by the caffeine metabolic ratio (CMR). Genotype was evaluated by determining 5'-flanking region (-2964) and intron I (734) polymorphisms. A statistically significant difference in the urinary 1-OHP geometric means of Barroterán, Cloete and Juárez (2.30, 0.45 and 0.04, respectively) was observed. As for the genotype, the intron I distribution was 0% C/C, 46% C/A and 54% A/A, whereas that of the 5'-flanking region was 26% G/G, 42% G/A and 32% A/A. Both distributions were in agreement with the Hardy-Weinberg equilibrium model. A greater enzyme activity was observed in the A/A compared to C/A individuals according to the CMR (P<0.001), whereas the 5'-flanking region polymorphism showed no effect on CYP1A2 enzymatic activity. These results suggest that intron I polymorphism and PAH exposure are relevant factors that modulate CYP1A2 enzymatic activity.

Adult↗
PubMed2005

CYP46 T/C polymorphism is not associated with Alzheimer's dementia in a population from Hungary.

Multiple genetic and environmental factors regulate the susceptibility to Alzheimer's disease (AD). Recently, several independent studies have reported that a locus on chromosome 14q32.1, where a gene encoding a cholesterol degrading enzyme of the brain, called 24-hydroxylase (CYP46A1) is located, has been linked with AD. The single nucleotide polymorphism (T/C) in intron 2 of CYP46 gene has been found to confer the risk for AD. The water soluble 24(S)-hydroxysterol is the product of the CYP46A1, and elevated plasma and cerebrospinal fluid hydroxysterol concentrations have been found in AD, reflecting increased brain cholesterol turnover or cellular degradation, due to the neurodegenerative process. A case-control study was performed on 125 AD and 102 age- and gender-matched control subjects (CNT) from Hungary, to test the association of CYP46 T/C and apolipoprotein E (ApoE) gene polymorphisms in AD. The frequency of the CYP46 C allele was similar (chi2=0.647, df=1, P=0.421, exact P=0.466, OR=0.845; 95% CI: 0.561-1.274) in both groups (CNT: 27%; 95% CI: 21.3-33.4; AD 30%; 95% CI: 25.0-36.3). The ApoE varepsilon4 allele was significantly over-represented (chi2=11.029, df=2, P=0.004) in the AD population (23.2%; 95% CI: 18.2-29.0) when compared with the CNT (11.3%; 95% CI: 7.4-16.6). The presence or absence of one or two CYP46C alleles together with the ApoE varepsilon4 allele did not increase the risk of AD (OR=3.492; 95% CI: 1.401-8.707; P<0.007 and OR=3.714; 95% CI: 1.549-8.908; P<0.003, respectively). Our results indicate that the intron 2 T/C polymorphism of CYP46 gene (neither alone, nor together with the varepsilon4 allele) does not increase the susceptibility to late-onset sporadic AD in the Hungarian population.

Aged↗
PubMed2000

A new polymorphism in the human factor VIII gene: implications for linkage analysis in haemophilia A and for the evolution of int22h sequences.

A new polymorphism in the human factor VIII gene has been localized and characterized. It is a biallelic, single nucleotide polymorphism located in intron 22 of the gene, within the 9.5 kb int22h-1 segment. The allelic forms are G (frequency 0.65) and A (frequency 0.35), giving a predicted rate of heterozygosity of 0.46. The polymorphism occurs within a CG dinucleotide and affects an MspI site (CCGG). Int22h-1 is duplicated twice extragenically at Xq28; both extragenic copies (int22h-2 and -3) are also polymorphic with respect to MspI. Investigation of 156 MspI [-] alleles, comprising 30 intragenic and 126 extragenic sites, indicated that all were due to A alleles and none had arisen by C to T transition within the CG dinucleotide. The intragenic MspI site (designated MspI A) is located 737 bases downstream of a previously described XbaI restriction fragment length polymorphism. Despite their close proximity, the polymorphisms are not in complete linkage disequilibrium; haplotype analysis in 85 factor VIII genes from a Caucasian population predicts an informativity of approximately 60% in linkage studies using both, compared with an informativity of approximately 47% in studies using either on its own.

Chromosome Mapping↗
PubMed2006

PPARalpha gene variation and physical performance in Russian athletes.

Peroxisome proliferator-activated receptor alpha (PPARalpha) regulates genes responsible for skeletal and heart muscle fatty acid oxidation. Previous studies have shown that the PPARalpha intron 7 G/C polymorphism was associated with left ventricular growth in response to exercise. We speculated that GG homozygotes should be more prevalent within a group of endurance-oriented athletes, have normal fatty acid metabolism, and increased percentages of slow-twitch fibers. We have tested this hypothesis in the study of a mixed cohort of 786 Russian athletes in 13 different sporting disciplines prospectively stratified by performance (endurance-oriented athletes, power-oriented athletes and athletes with mixed endurance/power activity). PPARalpha intron 7 genotype and allele frequencies were compared to 1,242 controls. We found an increasing linear trend of C allele with increasing anaerobic component of physical performance (P=0.029). GG genotype frequencies in endurance-oriented and power-oriented athletes were 80.3 and 50.6%, respectively, and were significantly (P<0.0001) different compared to controls (70.0%). To examine the association between PPARalpha gene variant and fiber type composition, muscle biopsies from m. vastus lateralis were obtained and analyzed in 40 young men. GG homozygotes (n=25) had significantly (P=0.003) higher percentages of slow-twitch fibers (55.5+/-2.0 vs 38.5+/-2.3%) than CC homozygotes (n=4). In conclusion, PPARalpha intron 7 G/C polymorphism was associated with physical performance in Russian athletes, and this may be explained, in part, by the association between PPARalpha genotype and muscle fiber type composition.

Adult↗
PubMed2000

Contrasting evolutionary histories of two introns of the duchenne muscular dystrophy gene, Dmd, in humans.

The Duchenne muscular dystrophy (Dmd) locus lies in a region of the X chromosome that experiences a high rate of recombination and is thus expected to be relatively unaffected by the effects of selection on nearby genes. To provide a picture of nucleotide variability at a high-recombination locus in humans, we sequenced 5. 4 kb from two introns of Dmd in a worldwide sample of 41 alleles from Africa, Asia, Europe, and the Americas. These same regions were also sequenced in one common chimpanzee and one orangutan. Dramatically different patterns of genetic variation were observed at these two introns, which are separated by >500 kb of DNA. Nucleotide diversity at intron 44 pi = 0.141% was more than four times higher than nucleotide diversity at intron 7 pi = 0.034% despite similar levels of divergence for these two regions. Intron 7 exhibited significant linkage disequilibrium extending over 10 kb and also showed a significant excess of rare polymorphisms. In contrast, intron 44 exhibited little linkage disequilibrium and no skew in the frequency distribution of segregating sites. Intron 7 was much more variable in Africa than in other continents, while intron 44 displayed similar levels of variability in different geographic regions. Comparison of intraspecific polymorphism to interspecific divergence using the HKA test revealed a significant reduction in variability at intron 7 relative to intron 44, and this effect was most pronounced in the non-African samples. These results are best explained by positive directional selection acting at or near intron 7 and demonstrate that even genes in regions of high recombination may be influenced by selection at linked sites.

Africa↗
PubMed2006

A genetic linkage map for tef [Eragrostis tef (Zucc.) Trotter].

Tef [Eragrostis tef (Zucc.) Trotter] is the major cereal crop in Ethiopia. Tef is an allotetraploid with a base chromosome number of 10 (2n = 4x = 40) and a genome size of 730 Mbp. Ninety-four F(9) recombinant inbred lines (RIL) derived from the interspecific cross, Eragrostis tef cv. Kaye Murri x Eragrostis pilosa (accession 30-5), were mapped using restriction fragment length polymorphisms (RFLP), simple sequence repeats derived from expressed sequence tags (EST-SSR), single nucleotide polymorphism/insertion and deletion (SNP/INDEL), intron fragment length polymorphism (IFLP) and inter-simple sequence repeat amplification (ISSR). A total of 156 loci from 121 markers was grouped into 21 linkage groups at LOD 4, and the map covered 2,081.5 cM with a mean density of 12.3 cM per locus. Three putative homoeologous groups were identified based on multi-locus markers. Sixteen percent of the loci deviated from normal segregation with a predominance of E. tef alleles, and a majority of the distorted loci were clustered on three linkage groups. This map will be useful for further genetic studies in tef including mapping of loci controlling quantitative traits (QTL), and comparative analysis with other cereal crops.

Chromosome Mapping↗
PubMed1998

[Association analysis of angiotensin-converting enzyme gene polymorphism with end-stage renal disease].

BACKGROUND: Intron 16 insertion/deletion (I/D) polymorphism in the angiotensin-converting enzyme (ACE) gene may be associated with the progression of renal insufficiency in patients with renal diseases. The objective of this study was to determine whether D allele is a risk factor for the progression of the disease in end-stage renal disease (ESRD) patients. METHODS: Using PCR techniques, genetic analysis of the ACE I/D polymorphism was performed on 326 dialysis patients. We compared the distribution of genotypes and allele frequency of this polymorphism in dialysis patients and the normal Japanese population. The clinical courses of 47 patients were studied retrospectively, and the progression of chronic renal failure using time plots of the reciprocal of serum creatinine (1/Cr) was estimated. RESULTS AND CONCLUSION: The frequencies for II, ID, and DD genotypes were 134, 148 and 44, respectively. The frequency for I allele was 0.64, and for D allele 0.36. These results were similar to the frequencies found in the normal Japanese population. However, patients with polycystic kidney disease (PKD) showed a high frequency for D allele (0.54: p = 0.023 by chi 2 method). In longitudinal courses, we did not find any association between ACE gene polymorphism and the declining rate of renal function. However, in patients with PKD, the DD genotype may influence the clinical course of renal disease.

Adult↗
PubMed2006

The short vitamin D receptor is associated with increased risk for generalized aggressive periodontitis.

BACKGROUND: Generalized aggressive periodontitis (GAP) exhibits severe inflammation and alveolar bone loss. Vitamin D receptor (VDR) regulates both bone metabolism and inflammation-related genes, and its polymorphisms and haplotypes may affect the functional activity of the VDR protein in GAP. OBJECTIVE: We analysed the genetic effect of VDR start codon, intron, and exon polymorphisms, and their haplotypes on the development of GAP. MATERIALS AND METHODS: The VDR start codon 27823C > T (rs2228570, FokI), intron 8 60890G > A (rs154410, BsmI), and exon 9 61968T > C (rs731236, TaqI) polymorphisms were determined by using the polymerase chain reaction-restriction fragment length polymorphism analysis among 93 GAP patients and 143 healthy controls. RESULTS: The VDR start codon 27823*C/*C genotype was associated with an increased risk for GAP [odds ratio (OR) = 1.83, p = 0.028], but the intron 8 60880G > A and exon 9 61968T > C polymorphisms were not associated with GAP. The VDR haplotype homozygote ht1(C-G-T) carrying 27823*C allele was associated with a 1.8-fold increased risk of GAP (OR = 1.84, p = 0.030). CONCLUSION: These results demonstrate that the short VDR (27823*C/*C) protein may influence GAP susceptibility.

Adenine↗
PubMed1998

Definition of the gene encoding the minor histocompatibility antigen HA-1 and typing for HA-1 from genomic DNA.

Recipient mismatching for the minor histocompatibility antigen HA-1 has been associated with acute graft-versus-host disease after allogeneic marrow transplantation. Two polymorphic nucleotides near an exon-intron junction of the gene encoding this minor histocompatibility antigen have been identified. In this study, we determined the genomic DNA sequence of the intron downstream from this polymorphic exon. Based on this sequence, primers were designed to amplify the genomic HA-1 gene sequence, and analysis of restriction fragment length polymorphisms was used to assign the HA-1 genotypes of 160 unrelated probands and a paired sibling for each proband. Among probands, the HA-1H allele frequency was 0.441, and the HA-1R allele frequency was 0.559. The distribution of HA-1 genotypes showed close fit with Hardy-Weinberg equilibrium. Likewise, the number of sibling pairs with disparity for HA-1 alleles showed close fit with predictions based on Hardy-Weinberg equilibrium. These results provide a simple and well validated method for future studies correlating HA-1 disparity with clinical outcome after allogeneic marrow transplantation.

Alleles↗
PubMed2006

Single nucleotide polymorphism (SNP) discovery in duplicated genomes: intron-primed exon-crossing (IPEC) as a strategy for avoiding amplification of duplicated loci in Atlantic salmon (Salmo salar) and other salmonid fishes.

BACKGROUND: Single nucleotide polymorphisms (SNPs) represent the most abundant type of DNA variation in the vertebrate genome, and their applications as genetic markers in numerous studies of molecular ecology and conservation of natural populations are emerging. Recent large-scale sequencing projects in several fish species have provided a vast amount of data in public databases, which can be utilized in novel SNP discovery in salmonids. However, the suggested duplicated nature of the salmonid genome may hamper SNP characterization if the primers designed in conserved gene regions amplify multiple loci. RESULTS: Here we introduce a new intron-primed exon-crossing (IPEC) method in an attempt to overcome this duplication problem, and also evaluate different priming methods for SNP discovery in Atlantic salmon (Salmo salar) and other salmonids. A total of 69 loci with differing priming strategies were screened in S. salar, and 27 of these produced approximately 13 kb of high-quality sequence data consisting of 19 SNPs or indels (one per 680 bp). The SNP frequency and the overall nucleotide diversity (3.99 x 10-4) in S. salar was lower than reported in a majority of other organisms, which may suggest a relative young population history for Atlantic salmon. A subset of primers used in cross-species analyses revealed considerable variation in the SNP frequencies and nucleotide diversities in other salmonids. CONCLUSION: Sequencing success was significantly higher with the new IPEC primers; thus the total number of loci to screen in order to identify one potential polymorphic site was six times less with this new strategy. Given that duplication may hamper SNP discovery in some species, the IPEC method reported here is an alternative way of identifying novel polymorphisms in such cases.

Animals↗
PubMed2005

Angiotensin-converting enzyme gene polymorphisms and obesity: an examination of three black populations.

We examined the association between obesity and 13 angiotensin-converting enzyme (ACE) gene polymorphisms, including the presence (I) or absence (D) of an Alu element in intron 16 (I/D polymorphism), and performed haplotype analysis using data collected from participants of a community survey of hypertension among blacks living in Ibadan, Nigeria; Spanish Town, Jamaica; and Chicago, IL. Transmission distortion of ACE gene polymorphisms and haplotypes from heterozygous parents to affected offspring was examined in each study population. To estimate haplotypes, polymorphisms were divided into three groups based on their position on the ACE gene. No ACE gene polymorphism was consistently overtransmitted from parents to obese offspring among the three populations. However, the haplotype ACE1-ACE5 TACAT, located in the promoter region, was significantly overtransmitted from parents to obese offspring in both the U.S. and Nigerian populations. No haplotype was significantly overtransmitted from parents to obese offspring among the Jamaicans. In conclusion, we noted the overtransmission of a particular ACE gene promoter region haplotype from parents to obese offspring in two separate black populations. These data suggest that ACE gene polymorphisms may influence the development of weight gain.

Adult↗
PubMed1995

Polymorphisms in the alanine:glyoxylate aminotransferase gene and their application to the prenatal diagnosis of primary hyperoxaluria type 1.

Primary hyperoxaluria type 1 (PH1) is caused by a deficiency of the hepatic alanine:glyoxylate aminotransferase enzyme encoded by the AGXT gene on chromosome 2. Prenatal diagnosis of PH1 either by measurement of hepatic enzyme activity or DNA analysis provides a valuable contribution to the management of pregnancies at risk for the severe infantile form of this disease. DNA analysis is preferred because it can be performed earlier in pregnancy and eliminates difficulties encountered in measurement of tissue enzyme activity, particularly those related to sample instability. We have assessed the clinical value of two polymorphisms located in introns 1 and 4 of the AGXT gene as linkage markers for the prenatal diagnosis of PH1 in 12 families. Eight of the twelve families were informative when either one or a combination of the two polymorphisms was used and prenatal diagnosis has been performed in two of these. The remaining four families were only partially informative. Five additional linkage markers on chromosome 2 have been identified which are co-inherited with the AGXT gene. Assays to detect these markers are currently under development.

Alanine Transaminase↗