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PubMed1999

A point mutation Thr(799)Met on the alpha(2) integrin leads to the formation of new human platelet alloantigen Sit(a) and affects collagen-induced aggregation.

A new platelet-specific alloantigen, termed Sit(a), was identified in a severe case of neonatal alloimmune thrombocytopenia. The Sit(a) alloantigen is of low frequency (1/400) in the German population. Immunochemical studies demonstrated that the Sit(a) epitopes reside on platelet glycoprotein (GP) Ia. Nucleotide sequence analysis of GPIa cDNA derived from Sit(a)-positive platelets showed C(2531)-->T(2531) point mutation, resulting in Thr(799)Met dimorphism. Analysis of genomic DNA from 22 Sit(a)-negative normal individuals showed that the Thr(799) is encoded by ACG(2532) (90.9%) or ACA(2532) (9.1%). To establish a DNA typing technique, we elucidated the organization of the GPIa gene adjacent to the polymorphic bases. The introns (421 bp and 1.2 kb) encompass a 142-bp exon with the 2 polymorphic bases 2531 and 2532. Polymerase chain reaction-restriction fragment length polymorphism analysis on DNA derived from 100 donors using the restriction enzyme Mae III showed that the Met(799) form of GPIa is restricted to Sit(a) (+) phenotype. Analysis of stable Chinese hamster ovary transfectants expressing allele-specific recombinant forms of GPIa showed that anti-Sit(a) exclusively reacted with the Glu(505)Met(799), but not with the Glu(505)Thr(799) and the Lys(505)Thr(799) isoforms. In contrast, anti-Br(a) (HPA-5b) only recognized the Lys(505)Thr(799) form, whereas anti-Br(b) (HPA-5a) reacted with both Glu(505)Thr(799) and Glu(505)Met(799) isoforms. These results demonstrated that the Met(799) is responsible for formation of the Sit(a) alloantigenic determinants, whereas amino acid 505 (Lys or Glu) specifically controls the expression of Br(a) and Br(b) epitopes, respectively. Platelet aggregation responses of Sit(a) (+) individuals were diminished in response to collagen, indicating that the Thr(799)Met mutation affects the function of the GPIa/IIa complex.

Animals↗
PubMed2004

Associations of polymorphisms in the Pit-1 gene with growth and carcass traits in Angus beef cattle.

The Pit-1 gene was studied as a candidate for genetic markers of growth and carcass traits. Angus beef cattle that were divergently selected for high- or low-blood serum IGF-I concentration were used in this study. The single-strand conformation polymorphism method was used to identify polymorphism in the Pit-1 gene including regions from intron 2 to exon 6. Two polymorphisms, Pit1I3H (HinfI) and Pit1I3NL (NlaIII), were detected in intron 3 of the Pit-1 gene. One polymorphism, Pit1I4N (BstNI), was found in intron 4, and a single nucleotide polymorphism, Pit1I5, was found in intron 5. The previously reported polymorphism in exon 6, Pit1E6H (HinfI), was also studied in 416 Angus beef cattle. Associations of the polymorphisms with growth traits, carcass traits, and IGF-I concentration were analyzed using a general linear model procedure. No significant associations were observed between these polymorphisms and growth and carcass traits.

Animals↗
PubMedDate not supplied

Prenatal diagnosis of von Willebrand disease in a family.

We report the successful prenatal diagnosis of von Willebrand disease (VWD) in a family with type 3 severe VWD by the indirect method of gene tracking using polymorphic markers of intron 40 of the von Willebrand factor (VWF) gene. The couple had a daughter diagnosed to have type 3 VWD. Chorionic villus sampling (CVS) was done in the eleventh week of gestation of a subsequent pregnancy. The 3 VNTR polymorphic markers VWF1, VWF2 and VWF3 of intron 40 of the VWF gene were used for linkage studies. DNA in the affected VWD patient, the father and mother as well as in the CVS using VWF1 and VWF3 polymorphic markers revealed that the foetus was affected. The family chose to abort the foetus. In a subsequent pregnancy, similar investigation revealed a normal foetus. Prenatal diagnosis in families with a diagnosed case of VWD can be used to determine the status of the foetus. The technique is inexpensive.

Chorionic Villi Sampling↗
PubMed1991

Genetic mapping of the beta 1 GABA receptor gene to human chromosome 4, using a tetranucleotide repeat polymorphism.

As more coding loci for functional human genes are described, there is a growing need to identify DNA polymorphisms in specific genes. By examining DNA sequences within the introns of the beta 1 subunit of the gamma-aminobutyric acid receptor gene, GABARB1, we found a tetranucleotide repeat sequence (GATA). Amplification of this region by using PCR revealed seven alleles and a high degree of polymorphism (PIC = .75) in human populations. DNAs from the CEPH families were typed for the GABARB1 intron polymorphism and were analyzed with respect to 20 linked markers on chromosome 4. The results permit placement of GABARB1 on the linkage map of chromosome 4, between D4S104 and ALB. These results affirm that sequence analysis of noncoding segments included within or adjacent to functional genes has value as a strategy to detect highly informative polymorphisms.

Alleles↗
PubMed2000

[Analysis of the interaction of the polymorphisms of presenilin-1 gene and ApoE gene in Alzheimerns disease].

OBJECTIVE: To explore the interaction of the polymorphism of 3' -terminal intron of the eighth exon of presenilin-1(PS-1) gene with the polymorphism of apolipoprotein E(ApoE) gene in the pathogenesis of sporadic Alzheimerns disease(SAD). METHODS: The polymorphisms of 3'-terminal intron of the eighth exon of presenilin-1 gene and ApoE gene were detected by using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) technique in 75 patients with SAD and 73 normal controls. RESULTS: The polymorphisms of PS-1 gene and ApoE gene were associated obviously with SAD. The onset of SAD was negatively associated with allele 2 of PS-1 gene and E(2) allele of ApoE gene,and it was positively associated with allele 1 of PS-1 gene. The onset of SAD was not associated with E(3) allele and E(4) allele of ApoE gene. CONCLUSION: These results indicated that allele 2 of PS-1 gene and E(2) allele of ApoE gene might protect people from SAD, that allele 1 of PS-1 gene might increase the risk of the onset of SAD, and that the onset of SAD was not associated with the interaction of the polymorphisms of PS-1 gene and ApoE gene.

Aged↗
PubMed1998

Angiotensin I-converting enzyme and angiotensinogen gene interaction and prediction of essential hypertension.

To prove whether the interaction between insertion/deletion (I/D) angiotensin I converting enzyme (ACE) and M235T angiotensinogen (AGT) gene polymorphic alleles could contribute to causing essential hypertension, we examined subjects from the Czech Republic (365 Caucasians total; 202 normotensives and 163 hypertensives). Subjects were genotyped for insertion/deletion polymorphism of ACE (I/D ACE, intron 16) and for M235T polymorphism of angiotensinogen gene (AGT, exon 2) by means of the polymerase chain reaction (PCR) method. The case-control approach was used. Fisher's exact test followed by Holmes's test to overcome the problem of multiple comparisons were used for the statistical analysis of data. No association of single gene allelic variants with essential hypertension was found in our population. Having compared only double homozygote combinations, the association of the DDMM genotype with essential hypertension was proven (P = 0.0081). To the contrary, IITT (P = 0.0086) was found more frequently in normotensive subjects. We conclude that the interaction of the I/D ACE and M235T AGT polymorphic alleles can contribute to essential hypertension, despite the absence of single gene associations with the condition.

Adult↗
PubMed2005

The presence of tandem endothelial nitric oxide synthase gene polymorphisms identifying brain aneurysms more prone to rupture.

OBJECT: It is becoming apparent that the presence of certain genetic variations (polymorphisms) may increase the individual's susceptibility to cardiovascular diseases, even in the absence of a family history. We hypothesized that brain aneurysms more prone to rupture may be identified on the basis of an individual's genotype for endothelial nitric oxide synthase (eNOS), a critical vasomodulatory protein found to be increasingly relevant to the pathobiology of aneurysms. METHODS: Patients' clinical data were recorded prospectively. Genomic DNA was isolated from blood samples obtained from individuals presenting consecutively to the Mayo Clinic with ruptured (58 patients) or unruptured (49 patients) intracranial saccular aneurysms. Using polymerase chain reaction and gene microarray technology, the following eNOS genetic polymorphisms were studied: intron-4 27-base pair variable number of tandem repeats (27 VNTR); promoter single nucleotide polymorphism (T-786C SNP); and exon-7 SNP (G894T SNP). Both groups of patients had similar demographic and clinical characteristics. For all three polymorphisms, variant alleles (p < or = 0.003) and their corresponding genotypes (p < or = 0.006) were found two to four times more frequently in patients with ruptured aneurysms than in patients with unruptured aneurysms. Strikingly, the odds ratio for presenting with a ruptured brain aneurysm among individuals demonstrating the copresence of all three variant alleles was 11.4 (95% confidence interval 1.7-75.9, p = 0.004). CONCLUSIONS: The authors have uniquely identified a set of tandem eNOS gene variations whose presence can be used to identify patients with aneurysms likely to rupture. We believe that if this finding is reproducible in a large multicenter study, in addition to known anatomical factors a rapid and cost-effective screening tool will become available to clinicians as a genetic aid to predict the risks of rupture in patients presenting with unruptured intracranial aneurysms.

Aneurysm, Ruptured↗
PubMed2004

Association between the neurofibromatosis-1 (NF1) locus and autism in the Japanese population.

Autistic patients have a 100 to 190-fold increased risk of neurofibromatosis compared to the general population. This suggests that the two diseases may share a common etiological background. Recently, a new allele (or the six-repeat allele) of the (AAAT)(n) repeat polymorphism in an Alu sequence in the neurofibromatosis-1 (NF1) gene was observed exclusively in severe autistic patients, not in controls, in Caucasians of French ancestry. This suggests a role of the NF1 gene in the development of autism. We investigated three microsatellite polymorphisms within the intron-27b and intron-38 of the NF1 region, including the (AAAT)(n) and two (CA)n repeat polymorphisms, in Japanese subjects with autism (n = 74) and controls (n = 122). The six-repeat allele of the (AAAT)(n) polymorphism was not found either in patients or controls, possibly indicating an ethnic difference in the polymorphism. However, significant differences were observed in the allele distributions of the (AAAT)(n) and a (CA)(n), which were located at intron-27b, between patients and controls, although an association was not significant between autism and another polymorphism at intron-38. This may suggest an involvement of the NF1 locus in susceptibility to autism, although further investigations are recommended.

Adolescent↗
PubMed2005

Start codon polymorphisms in the vitamin D receptor and colorectal cancer risk.

The expression of the nuclear vitamin D receptor (VDR), which is involved in regulating cell growth and proliferation, may contribute to the development of colorectal cancer. Polymorphisms in the VDR gene (OMIM 601769) may influence the expression or function of the VDR protein. A population-based, case-control study of VDR start codon, intron, and exon polymorphisms, haplotypes for these polymorphisms, and the relationships between these polymorphisms and clinicopathological parameters in 190 colorectal cancer patients and 318 controls was conducted. The start codon variant VDR 27823*C/*C genotype was associated with an increased risk for colorectal cancer, while the 27823*T/*T genotype was associated with a decreased risk. In addition, the VDR 61888*G/*G genotype was associated with reduced colorectal cancer risk. The intron 8 60880G>A and exon 9 61968T>C polymorphisms were not associated with colorectal cancer risk. The VDR 27823*C-60890*G-61888*T-61968*T haplotype was associated with an increased risk of colorectal cancer, whereas the VDR 27823*T-60890*G-61888*G-61968*T haplotype was associated with a decreased risk of colorectal cancer. Moreover, the 27823*C/*C genotype was more frequently identified in patients with preoperative serum carcinoembryonic antigen (CEA) levels over 6ng/mL. These results suggest that the VDR start codon 27823*C allele may be linked to high risk for colorectal cancer, especially in a subset of colorectal cancers showing specific biological behaviors.

Adult↗
PubMed2006

The association between intron 4 VNTR, E298A and IVF 23+10 G/T polymorphisms of ecNOS gene and sildenafil responsiveness in patients with erectile dysfunction.

The objective of the study was to determine the association between intron 4 variable number of tandem repeats (VNTR), E298A and IVF 23+10 G/T polymorphisms of ec-NOS gene and sildenafil responsiveness in patients with erectile dysfunction (ED). Ninety-six patients who were evaluated for ED between November 2003 and June 2004 and 167 healthy individuals representing the normal population as controls were included in the present study. The patients were evaluated by medical history, five-item version of International Index of Erectile Function, serum glucose, testosterone levels and lipid profiles. Sixty-seven patients received four consecutive doses of sildenafil from 25 to 100 mg according to the response. The ec-NOS gene intron 4 VNTR, E298A and IVF 23+10 G/T polymorphisms were evaluated in the isolated DNA blood samples obtained from the patient group with ED (n=96), from the group received sildenafil (n=67) and from the healthy group (n=167). Genotype distributions of ec-NOS gene intron 4, E298A and IVF 23+10 G/T polymorphisms in the patient group were similar to those in the healthy group. The frequency of the ec-NOS gene intron 4 genotype were found as bb=41.7%, ab=50% and aa=8.3% in the sildenafil responders and bb=93.5% and ba=6.5% in the sildenafil non-responders. This finding was statistically significant. Statistical analysis of ec-NOS gene E298A and IVF 23+10 G/T polymorphisms did not reveal any significant difference between sildenafil responders and non-responders. These findings may indicate that 'a' allele of ec-NOS gene intron 4 VNTR polymorphism associates with a better sildenafil response.

3',5'-Cyclic-GMP Phosphodiesterases↗
PubMed2004

Genetic variants in human sterol regulatory element binding protein-1c in syndromes of severe insulin resistance and type 2 diabetes.

The transcription factor sterol regulatory element binding protein (SREBP)-1c is intimately involved in the regulation of lipid and glucose metabolism. To investigate whether mutations in this gene might contribute to insulin resistance, we screened the exons encoding the aminoterminal transcriptional activation domain in a cohort of 85 unrelated human subjects with severe insulin resistance. Two missense mutations (P87L and P416A) were found in single affected patients but not in 47 control subjects. However, these variants were indistinguishable from the wild-type in their ability to bind DNA or to transactivate an SREBP-1 responsive promoter construct. We also identified a common intronic single nucleotide polymorphism (C/T) located between exon 18c and 19c. In a case-control study of 517 U.K. Caucasian case subjects and 517 age- and sex-matched control subjects, the T-allele at this locus was significantly associated with type 2 diabetes in men (odds ratio = 1.42 [1.11-1.82], P = 0.005) but not women. In a separate population-based study of 1,100 Caucasians, carriers of the T-allele showed significantly higher levels of total and LDL cholesterol (P < 0.05) compared with wild-type individuals. In summary, we have conducted the first study of the SREBP-1c gene as a candidate for human insulin resistance. Although the rare mutations identified were functionally silent in the assays used, we obtained some evidence, which requires conformation in other populations, that a common variant in the SREBP-1c gene might influence diabetes risk and plasma cholesterol level.

Base Sequence↗
PubMedDate not supplied

Absence of high-risk "s" allele associated with osteoporosis at the intronic SP1 binding-site of collagen Ialpha1 gene in Southern Chinese.

The Sp1 polymorphism in the first intron of the collagen Ialpha1 gene was recently described to be associated with low bone mineral density (BMD) and increased fracture risk in Caucasian populations. The impact of this gene was assessed in a Southern Chinese population. One hundred and eighty-one women, aged 51.1+/-8.8 yr were evaluated for the Sp1 polymorphism. Twenty-two per cent of the women were classified as having osteoporosis on the basis of a T-score at the lumbar spine or the hip below -2.5 with or without a prevalent fracture. Genotype analysis was performed by PCR amplification and restriction enzyme digestion. Single-strand conformational polymorphism analysis (SSCP) was performed in 65 randomly selected samples to search for any polymorphic site in the PCR amplified region. The results showed that no restriction enzyme site could be identified in any of the 181 samples analyzed. Moreover, SSCP analysis revealed no polymorphism in the PCR amplified region of the first intron of the collagen Ialpha1 gene. In conclusion, the "s" allele, associated with low BMD and increased fracture risk in Caucasians, is non-existent or very rare in the Southern Chinese population. The absence of this "high risk" allele may in part account for the reduced fracture risk observed in the Chinese in comparison to Western populations.

Adult↗
PubMed1998

Nucleotide sequence diversity at the alcohol dehydrogenase 1 locus in wild barley (Hordeum vulgare ssp. spontaneum): an evaluation of the background selection hypothesis.

The background selection hypothesis predicts a reduction in nucleotide site diversity and an excess of rare variants, owing to linkage associations with deleterious alleles. This effect is expected to be amplified in species that are predominantly self-fertilizing. To examine the predictions of the background selection hypothesis in self-fertilizing species, we sequenced 1,362 bp of adh1, a gene for alcohol dehydrogenase (Adh; alcohol:NAD+ oxidoreductase, EC 1.1.1.1), in a sample of 45 accessions of wild barley, Hordeum vulgare ssp. spontaneum, drawn from throughout the species range. The region sequenced included 786 bp of exon sequence (part of exon 4, all of exons 5-9, and part of exon 10) and 576 bp of intron sequence (all of introns 4-9). There were 19 sites polymorphic for nucleotide substitutions, 8 in introns, and 11 in exons. Of the 11 nucleotide substitutions in codons, 4 were synonymous and 7 were nonsynonymous, occurring uniquely in the sample. There was no evidence of recombination in the region studied, and the estimated effective population size (Ne) based on synonymous sites was approximately 1.8-4.2 x 10(5). Several tests reveal that the pattern of nonsynonymous substitutions departs significantly from neutral expectations. However, the data do not appear to be consistent with recovery from a population bottleneck, recent population expansion, selective sweep, or strong positive selection. Though several features of the data are consistent with background selection, the distributions of polymorphic synonymous and intron sites are not perturbed toward a significant excess of rare alleles as would be predicted by background selection.

Alcohol Dehydrogenase↗
PubMed2006

Pharmacogenetics of opioid receptors and addiction.

It is generally assumed that combinations of polymorphic alleles of different genes contribute to polygenetic disorders. Variants of the opioid receptors are the obvious candidates underlying addiction. Most research has focused on the coding variation A118G of the mu opioid receptor (MOPr), which replaces asparagine at position 40 by aspartate (Asn40Asp). However, to date, no conclusive evidence exists regarding which physiological effects this mutation may cause. Other rare polymorphisms in the MOPr cause marked effects (e.g. impairment of G-protein coupling) but, due to their low frequency, their role in addiction is questionable. A large number of polymorphic sites have been found in the putative promoter region of the mu opioid receptor. These variations may alter the expression level of the receptors in neurones, but the functional relevance of promoter polymorphisms is hard to predict. In the delta opioid receptor, surprisingly few polymorphisms have been detected within the coding region, and a clear association with addiction has not been shown to date. The kappa opioid receptor contains mainly silent polymorphisms. Nevertheless, there are studies reporting positive associations of silent mutations in the three opioid receptors with drug addiction. The underlying mechanism remains unclear, but examples exist indicating that silent mutations affect mRNA stability. Taken together, the coding polymorphisms, which are rather frequent, reveal no convincing association. The vast number of non-coding, intronic or promoter polymorphisms in the opioid receptors may influence addictive behaviour, but these polymorphisms are far less studied, and their physiological significance remains to be demonstrated.

Alleles↗
PubMed2006

Insertion-deletion polymorphism in the angiotensin-converting enzyme (ACE) gene among Sudanese, Somalis, Emiratis, and Omanis.

The angiotensin-converting enzyme (ACE) gene in humans contains an insertion-deletion polymorphism in its intron 16. Because of its involvement with the renin-angiotensin system, the insertion-deletion polymorphism of the ACE gene has been widely investigated in different populations and in case-control studies. However, similar studies for Arab populations are limited in number. Therefore we have investigated the frequencies of the *I and *D alleles of the ACE gene among Sudanese, Somalis, and Arab nationals of the United Arab Emirates and Oman using previously described methods. Our data indicate a preponderance of the *D allele among the Arab and African populations studied (Sudanese, 0.64; Somalis, 0.73; Emiratis, 0.61; and Omanis, 0.71).

Africa, Eastern↗
PubMed1986

Haplotypes identified by DNA polymorphisms at the apolipoprotein A-1 and C-III loci and hypertriglyceridaemia. A study in a Japanese population.

A Japanese group comprising 40 hypertriglyceridaemic and 35 normolipidaemic subjects were genotyped for two intragenic DNA restriction fragment length polymorphisms (RFLPs) at the A-1 and C-III gene loci. An Sst-1 polymorphism is located at the 3' end of the C-III gene and a Msp-1 polymorphism in the third intron of the A-1 gene. The polymorphic restriction sites are 3.8kb apart. The polymorphism with Sst-1 was present at allelic frequencies of 0.67 (S1 allele) and 0.33 (S2 allele), and the polymorphism with Msp-1 was present at allelic frequencies of 0.55 (M1 allele) and 0.45 (M2 allele). The alleles S1, S2, M1, and M2 are in linkage disequilibrium and three haplotypes were identified S1-M1, S1-M2, and S2-M2. Unlike the previously reported association of the S2 allele with hypertriglyceridaemia found in Caucasians there was no difference in the frequency of S2 allele between normolipidaemic and hyperlipidaemic Japanese. However one of the haplotypes S1-M2 was significantly increased in the hypertriglyceridaemic subjects (32% versus 11% P less than 0.025). Thus in Japanese there is an association with genotypes at this locus and hypertriglyceridaemia but with a different haplotype than in Caucasians.

Alleles↗
PubMed2004

Multiple organ failure due to 5-fluorouracil chemotherapy in a patient with a rare dihydropyrimidine dehydrogenase gene variant.

BACKGROUND: Dihydropyrimidine dehydrogenase (DPD) is the initial and rate-limiting enzyme in the metabolism of the chemotherapeutic drug 5-fluorouracil (5-FU). Application of 5-FU is restricted by a narrow therapeutic index because of severe toxicity of WHO grades III-IV. The exon 14-skipping mutation (c.1905+1G>A) accounts for approximately a quarter of all severely toxic cases. However, numerous other polymorphisms have been identified within the DPYD gene in affected patients, and the pathophysiological significance of most of them is unclear. PATIENT AND METHODS: We report a patient with advanced caecum cancer who twice received 950 mg 5-FU and 45 mg folinic acid as adjuvant by bolus injection. 2 days after onset of chemotherapy, the patient developed a multiple organ dysfunction exhibiting a cardiogenic shock with severe left ventricular insufficiency, marked reduction of renal function, and beginning hepatic encephalopathy with somnolence, myoclonus, and a seizure. In order to investigate a possible defect within the DPYD gene direct sequencing of all 23 exons was carried out. RESULTS: Genotyping revealed a rare c.1601G>A polymorphism which causes a change in the protein sequence (S534N). Data regarding the clinical relevance are ambiguous. The polymorphism has been detected together with an intronic mutation and both polymorphisms have consistently been reported with reduced enzyme activity. CONCLUSION: The present case provides further evidence of an etiologic role of the c.1601G>A mutation for DPD deficiency and the occurrence of severe 5-FU-related toxicity and underlines the value of comprehensive pharmakogenetic diagnostics with respect to the dihydropyrimidine dehydrogenase.

Adenocarcinoma↗