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PubMed1994

Allele frequencies and molecular diagnosis in haemophilia A and B patients from Russia and from some Asian republics of the former U.S.S.R.

RFLP analysis of some intra- and extra-genic polymorphic sites of Factor VIII (FVIII) and Factor IX (FIX) genes with relevant DNA probes or by polymerase chain reaction (PCR) was carried out in Slavic populations from the European part of Russia and also in the native ethnic groups of Uzbekistan and Kazahstan. The allele frequencies for the HindIII (intron 19) and XbaI (intron 22) polymorphic sites (PSs) in the FVIII gene were very similar in the two populations studied, but different for the intron 13 (CA)n repeat. Significant variations in the TaqI (intron d) and DdeI (intron a) polymorphisms of the FIX gene were evident between the Russian and Asian populations. Two unusual alleles (4.35 and 4.2 kb) for the extragenic PS St14/TaqI were registered in Slavs and one new allele (380 bp) for the DdeI polymorphic site of FIX was discovered in both Asian populations. Altogether, 210 haemophilia A (HA) and 24 haemophilia B (HB) families were subjected to molecular studies. So far, 160 HA and 12 HB families have been found to be informative for DNA analysis. Carrier status was ascertained in 42 HA and 6 HB female relatives, and rejected in 52 and 10 of them, respectively. The origin of some HA and HB mutations was traced with relevant polymorphic markers in several at-risk families. Prenatal diagnosis was accomplished in 28 HA and three HB families, resulting in the identification of 20 affected male fetuses.

Alleles↗
PubMed1998

Polymorphic tetranucleotide repeat site within intron 7 of the beta-amyloid precursor protein gene and its lack of association with Alzheimer's disease.

Mutations found in the beta-amyloid precursor protein (APP) gene in a small subset of patients with Alzheimer's disease (AD) are associated with the development of the disease. Several lines of evidence indicate that specific isoforms of APP generated by alternative splicing of the primary transcript may contribute to the etiology of AD. One of the isoforms, APP695, lacks the Kunitz protease inhibitor (KPI) domain and is produced predominantly in neurons by skipping exon 7 of the APP gene. Previous studies imply that the controlling elements for exon 7 skipping exist in the flanking sequences of the exon. Therefore, we have sequenced the human intron 7 of the APP gene and found a polymorphic tetranucleotide (ATTT)n repeat site within the intron 7. In 183 genetically unrelated subjects (97 AD patients and 86 controls), we found four alleles by polymerase chain reaction (PCR) amplification of the repeat site. Although no particular alleles are associated with AD, this newly identified polymorphic site may be useful in other genetic analyses since preliminary evidence suggests allele frequency differences between African Americans and Caucasians.

Age of Onset↗
PubMed2007

Association of interleukin (IL)-4 intron-3 and IL-6 -174 G/C gene polymorphism with susceptibility to end-stage renal disease.

Earlier studies suggest that end-stage renal disease (ESRD) is associated with inflammatory state and have become a major cause of morbidity and mortality worldwide. This study speculated the role of interleukins (IL)-2, -4, and -6 cytokines gene polymorphism with risk of susceptibility to ESRD. Polymorphism in IL-2 (-330 T/G, polymerase chain reaction [PCR]-restriction fragment length polymorphism), IL-4 (intron-3, variable number of tandem repeat, variable number tandem repeats analysis), and IL-6 (-174 G/C, amplification refractory mutation system, i.e. ARMS-PCR) were genotyped in 193 ESRD patients and 180 controls. Significant difference was observed in genotype frequencies of IL-4 and IL-6 between ESRD patients and control group (p<0.001 and p=0.032, respectively). Patients had higher frequency of homozygous B2B2 genotype (IL-4) than controls (62.7% vs 46.7) and GG genotype of IL-6 (73.1% vs 60.6%). The genotypic frequencies of IL-2 were comparable in patients and controls (p=0.102). Significant association of IL-4 was also observed in patients with glomerulonephritis (p=0.001). Combination of low IL-4 and high IL-6 genotypes were significantly associated with ESRD showing the highest risk, i.e. >threefolds risk (odds ratio=3.48, 95%CI=1.88-6.42; p < 0.001) among the four possible combinations taking high IL-4 and low IL-6 as reference. Our study suggests that polymorphism in IL-4 and IL-6 may be associated with susceptibility to ESRD. Further, combined analysis implicated a higher risk in ESRD patients with low IL-4 and high IL-6 producing genotypes. This study provided the basis for defined anti-inflammatory approaches to limit renal disease progression.

Adolescent↗
PubMedDate not supplied

A new rare allele at the CGG repeat polymorphism in the first intron of human c-H-ras gene.

We have examined a region in the first intron of the human c-H-ras gene containing a CGG repeat. This region was previously shown to be variable in length. The length variation was attributed to the presence of the CGG repeat after estimation of its electrophoretic mobility. In the present report we have characterized in detail this region by PCR-RFLP and automated sequencing, in a total of 102 histologically normal tissues from unrelated individuals affected by lung and breast cancer. Four alleles were detected and analysis of their internal sequence showed that the length alterations of this region were due to the presence of 5, 6, 8 and 9 CGG triplets respectively. The last three occur most often (44.1%, 34.8%, 20.6% respectively) and coincide with three previously reported alleles (Riggins et al, Hum Mol Genet 9: 775, 1992). The fourth allele consisting of 5 repeats is a rare one (0.5%), whilst alleles with 7, and a previously reported one suggested to comprise 11 repeats (1%) were not present in our cohort. This polymorphism coincides in position with an element that was previously shown to possess regulatory activity.

Alleles↗
PubMed2002

Genotype frequencies of the +874T-->A single nucleotide polymorphism in the first intron of the interferon-gamma gene in a sample of Sicilian patients affected by tuberculosis.

In the light of the key role played by interferon (IFN)-gamma in the control of tuberculosis, in the present paper we have evaluated the distribution of the functional +874T --> A IFN-gamma single nucleotide polymorphism (SNP) in Sicilian patients affected by tuberculosis. Our aim was to determine whether there is an association between the TT genotype, which has been suggested to be linked to an increased production of IFN-gamma, and resistance to chronic tuberculosis. DNA samples were obtained from 45 patients and 97 healthy controls. Polymorphism at +874 was identified using amplification refractory mutational system methodology. The +874T SNP was less frequent in patients than in controls (0.42 vs. 0.50) but the difference was not significant. The +874TT genotype, which has been suggested to be associated with high IFN-gamma production, was significantly decreased in the patients. Thus, resistance to chronic lung tuberculosis might be associated with a genetically determined high IFN-gamma production capacity. In conclusion, the present data add another piece of evidence to the complex puzzle of genetic and environmental factors involved in control of infectious diseases. Studies on cytokine gene polymorphisms may elucidate the complex network of trans-interactive genes influencing the type and strength of responses to environmental stressors and may help to identify the genetic factors that affect survival in humans.

Adult↗
PubMed1996

Polymorphism within the second intron of the IL-1 receptor antagonist gene in patients with hematopoietic malignancies.

Alleles of the IL-1 genes are associated with several autoimmune and inflammatory diseases, where they tend to have a role in the severity of the disease rather than in susceptibility to the disease itself. Allele 2 of the variable number tandem repeat (VNTR) polymorphism in the IL-1 receptor antagonist (IL-1ra) gene was the first marker of the IL-1 cluster to be associated in this way with severity of chronic, systemic and local inflammatory diseases. Because of the role that IL-1 also plays in the pathobiology of certain hematopoietic disorders, we aimed at examining the allelic distribution of the IL-1ra VNTR in leukemias, lymphomas and related malignancies. While in patients with chronic lymphocytic leukemia (CLL), hairy cell leukemia (HCL), multiple myeloma (MM) and related disorders, primary acute myeloid leukemia (AML), chronic myeloid leukemia (CML), and Hodgkin's disease (HD), the allelic distribution of IL-1RN was comparable to that seen in healthy control subjects, in a small group of patients with secondary AML the frequency of the IL-1RN*4 allele appeared to be significantly increased.

Alleles↗
PubMed2005

[Allelic polymorphism of endothelial NO-synthase gene and its functional activity].

Investigation of phenotypic realization of the eNOS gene allelic polymorphism has shown that eNOS RNA content and eNOS activity in platelets depends on genotype. Using the reverse transcription and polymerase chain reaction it was shown that eNOS mRNA content is the lowest at -786C/C promoter's genotype. In exon 7 homozygotes (894T/T) the RNA level is lower than in normal homozygotes (894G/G), but it is higher than in heterozygotes (894G/T). Contrary, at intron 4 polymorphism the RNA level in the platelets from people with 4a/4a genotype is higher than in normal homozygotes and heterozygotes. Measuring of eNOS activity in platelets using diaminofluorescein diacetate (DAF-2A) showed that in carriers of 786C/C promoter genotype NO-producing activity is 2.1 times lower than in normal homozygotes (P=0.03) and 2.9 times lower comparing to heterozygotes (P>0.05). eNOS activity at 894T/T variant of 7-th exon is also lower than in normal homozygotes (P>0.05). Analogous data has been obtained while comparing eNOS activity at intron 4 polymorphism--enzyme activity was 1.7 times lower in carriers of 4a/4a genotype comparing to normal homozygotes (P>0.05) and 1.9 times lower than in heterozygotes (P>0.05). Data obtained permits to conclude, that T-786-->C polymorphism of eNOS gene promoter effects the gene expression and eNOS activity the most significantly.

Adolescent↗
PubMed1994

Multiplex analysis of two intragenic microsatellite repeat polymorphisms in the genetic diagnosis of haemophilia A.

Use of molecular genetic studies for carrier detection and prenatal diagnosis of haemophilia A will be informative in approximately 75% of kindreds with a prior history of the disorder if previously reported bi-allelic intragenic polymorphisms are used. In this study we report the use of two multi-allelic, microsatellite repeat polymorphisms within the factor VIII gene in genetic testing for this disease. These two, dinucleotide repeat, polymorphisms have been analysed using a multiplex polymerase chain reaction (PCR) protocol, and results can be available within 3 d of receipt of samples. At the intron 13 polymorphic locus we have confirmed the original observation of eight alleles, whilst at the intron 22 locus, in contrast to a preliminary report of this polymorphism, we have seen five alleles. We have analysed 32 families (174 subjects) with the two microsatellite repeat markers and have found that using these two polymorphisms alone, 81% of families are informative for linkage analysis. The intron 13 repeat was informative in 22/31 families tested (71%) and the intron 22 polymorphism was informative in 12/17 families (71%). We have also found that in 11/32 families tested (34%) the microsatellite repeats were the only informative intragenic markers. In view of these observations, we believe that the most effective strategy for initiating haemophilia A genetic testing is to combine the multiplex PCR analysis of the intron 13 and 22 dinucleotide repeats with the PCR analysis of the intron 18 BclI marker. In our population this protocol provided informative results in approximately 88% of families and results can be available within 3 d of receiving the samples for testing.

Alleles↗
PubMed2001

[Polymorphism of MAO-B gene and NAD(P)H: quinone oxidoreductase gene in Parkinson's disease].

OBJECTIVE: To investigate whether Parkinson's disease(PD) is associated with genetic polymorphism of intron 13 of monoamine oxidase B(MAO-B) and NAD(P)H: quinone oxidoreductase(NQO1) gene cDNA 609C to T. METHODS: Association study was performed in 126 PD patients and 136 healthy control subjects matched for age, sex and origin. The NQO1 gene polymorphism was analyzed with the polymerase chain reaction-restriction fragment length polymorphism, the polymorphism of intron 13 of MAO-B was analyzed by allele- specific PCR. RESULTS: The allelic frequency of the mutant T allele of NQO1 gene was significantly higher in the PD patients as compared to the controls(P<0.05). The relative risk of suffering from PD increased (OR=3.8) in the individuals with T allelic genotype of NQO1 gene, and the odds ratio was as high as 5.7 when the individuals with A or AA genotype of MAO-B gene coexisted with the T allele genotype of NQO1 gene. CONCLUSION: The cDNA 609T allele of NQO1 gene might be a risk factor of PD, which could be associated with the genetic susceptibility of PD. The high activity A or AA genotype of MAO-B and the low activity genotype of NQO1 gene might have synergistic effect. When both genotypes coexist, the risk of suffering PD will be increased greatly.

Aged↗
PubMed2006

ACE polymorphisms.

Angiotensin converting enzyme (ACE) plays an essential role in two physiological systems, one leading to the production of angiotensin II and the other to the degradation of bradykinin. The wide distribution and multifunctional properties of these peptides suggest that ACE could be involved in various pathophysiological conditions. The discovery that ACE levels are under genetic control ushered in a new era of investigation; most studies focused on an insertion/deletion (I/D) polymorphism in intron 16 of the ACE gene as a marker for a functional polymorphism. Recently, many single nucleotide polymorphisms were detected in the gene and the search for the locations of functional polymorphisms became a topic of extensive investigation. Nevertheless, association studies on the I/D polymorphism and clinical outcomes continued, mostly with conflicting results. This article reviews the current state of knowledge regarding ACE polymorphisms and suggests that a functional polymorphism is most likely located between intron 18 and the 3' UTR. The potential existence of another functional polymorphism in the 5' UTR, however, cannot be excluded. This review also presents an overview of ACE function in different pathophysiological systems, and summarizes previous reports on ACE and clinical outcomes. Although findings on the I/D polymorphism and disorders like diabetic nephropathy and Alzheimer disease can be considered conclusive, reports on most of the cardiovascular phenotypes are still controversial. Genotypic and phenotypic misclassifications, insufficient power in some studies, and the presence of interaction with other genes or environmental factors are possible explanations for the contradictory findings.

Humans↗
PubMed1996

Population variation at the polymorphic ApaLI restriction enzyme site in intron 5 of the WT1 gene.

We examined 63 unrelated individuals from the United States for the Apa-LI polymorphism in intron 5 of the WT1 gene. Allele frequencies of 0.13 and 0.87 for the A and B alleles, respectively, and a heterozygosity index of 24% contrast sharply with previous data obtained in the Japanese population where allele frequencies of 0.55 and 0.45 for the A and B alleles and a heterozygosity index of 59% were reported. These data suggest genetic heterogeneity at the WT1 locus, which may contribute to the differences in the incidence of Wilms tumor between the two population groups.

Alleles↗
PubMed2005

Anxiety- and novelty seeking-related personality traits and serotonin transporter gene polymorphisms.

The affection of human personality by the promoter and the intron 2 polymorphism in the serotonin transporter gene (SERT) is inconsistently reported. We aimed to clarify this situation by gender-specific haplotype-phenotype association. 98 women and 97 men completed the personality inventories NEO-PI-R and TPQ. The subjects were genotyped for the two SERT polymorphisms and the haplotypes were calculated. The short (S) and long (L) promoter alleles and the 12 and 10 repeat intron 2 alleles formed the haplotypes S 12, S 10, L 12 and L 10. In men, scores in the anxiety-related dimensions were higher in S 12 than in L 12 carriers. Opposite in direction, scores tended to be lower in S 10 than in L 10 carriers. In the novelty seeking-related dimensions, scores were higher in S 10 than in S 12 carriers. No association was observed in women. In conclusion, anxiety- and novelty seeking-related personality dimensions are differentially associated with different SERT haplotypes; the consistent restriction to men suggests common androgen regulation. Opposite trends with haplotypes including the same promoter alleles suggest contribution of group stratification to earlier inconsistent findings and call to further differentiate the molecular function and clinical implications of the SERT promoter polymorphism.

Adult↗
PubMed2006

A common haplotype of the dopamine transporter gene associated with attention-deficit/hyperactivity disorder and interacting with maternal use of alcohol during pregnancy.

CONTEXT: Attention-deficit/hyperactivity disorder (ADHD) is a common heritable childhood behavioral disorder. Identifying risk factors for ADHD may lead to improved intervention and prevention. The dopamine transporter gene (DAT1) is associated with ADHD in several studies, with an average 1.2 odds ratio and evidence of heterogeneity across data sets. OBJECTIVE: To investigate sources of heterogeneity by refining the DAT1 association using additional markers and investigating gene-environment interaction between DAT1 and maternal use of alcohol and tobacco during pregnancy. DESIGN: Prospective study. SETTING AND PATIENTS: Children with ADHD from child behavior clinics in the southeast of England and in the Taipei area of Taiwan. INTERVENTIONS: Within-family tests of association using 2 repeat polymorphisms in the 3' untranslated region and intron 8 plus additional markers in the English sample. MAIN OUTCOME MEASURES: Transmission ratios of risk alleles from heterozygote parents to affected offspring and comparison of the transmission ratios in high- and low-exposure groups for the environmental variables. RESULTS: A novel association was identified between ADHD, the intron 8 polymorphism, and a specific risk haplotype in both English and Taiwanese samples. The risk haplotype showed significant interactions with maternal use of alcohol during pregnancy. CONCLUSIONS: The identification of a common haplotype in 2 independent populations is an important step toward identifying functionally significant regions of DAT1. Interaction between DAT1 genotypes and maternal use of alcohol during pregnancy suggests that DAT1 moderates the environmental risk and has implications for the prevention of ADHD. Further studies are required to delineate the precise causal risk factor involved in this interaction.

Alcohol Drinking↗
PubMed2006

Functional splicing assay shows a pathogenic intronic mutation in neurofibromatosis type 1 (NF1) due to intronic sequence exonization.

Genomic variations with no apparent effect ("neutral polymorphisms") may have a significant effect on splicing. The effect of this type of mutation is difficult to spot, unless a functional assay is undertaken. In our study, DNA sequencing of a patient with clinically defined neurofibromatosis type 1 (NF1) showed only a single polymorphism in intron 30 due to an A>G transition 279 nucleotides from the 3' splice site. Using a minigene splicing assay we conclusively show that this change produces a cryptic exon with a 3' SS defined by the nucleotide change and the unexpected activation of a very weak 5'SS. Further site directed mutagenesis studies aimed at identifying the signals involved in the cryptic exon inclusion were carried out. Interestingly we find that particular characteristics of the cryptic 5' SS are essential for its inclusion. Significantly an additional single nucleotide change disrupting the cryptic 5'ss consensus sequence rescues the effect of the pathogenetic mutation resulting in normal splicing.

Base Sequence↗
PubMed2004

The tomato resistance protein Bs4 is a predicted non-nuclear TIR-NB-LRR protein that mediates defense responses to severely truncated derivatives of AvrBs4 and overexpressed AvrBs3.

The Lycopersicon esculentum Bs4 resistance (R) gene specifies recognition of Xanthomonas campestris pv. vesicatoria (Xcv) strains that express the cognate AvrBs4 avirulence protein. Bs4 was isolated by positional cloning and is predicted to encode a nucleotide-binding leucine-rich repeat (NB-LRR) protein that is homologous to tobacco N and potato Y-1 resistance proteins. Xcv infection tests demonstrate that Bs4 confers perception of AvrBs4 but not the 97% identical AvrBs3 protein. However, when delivered via Agrobacterium T-DNA transfer, both, avrBs4 and avrBs3 trigger a Bs4-dependent hypersensitive response, indicating that naturally occurring AvrBs3-homologues provide a unique experimental platform for molecular dissection of recognition specificity. Transcript studies revealed intron retention in Bs4 transcripts. Yet, an intron-deprived Bs4 derivative still mediates AvrBs4 detection, suggesting that the identified splice variants are not crucial to resistance. The L. pennellii bs4 allele, which is >98% identical to L. esculentum Bs4, has a Bs4-like exon-intron structure with exception of a splice polymorphism in intron 2 that causes truncation of the predicted bs4 protein. To test if the receptor-ligand model is a valid molecular description of Bs4-mediated AvrBs4 perception, we conducted yeast two-hybrid studies. However, a direct interaction was not observed. Defense signaling of the Bs4-governed reaction was studied in Nicotiana benthamiana by virus-induced gene silencing and showed that Bs4-mediated resistance is EDS1- and SGT1-dependent.

Agrobacterium tumefaciens↗
PubMedDate not supplied

New DNA polymorphisms define ethnically distinct haplotypes in the human transferrin receptor gene.

In a study of transferrin receptor (TFR) polymorphism in different ethnic groups using PCR and restriction cleavage we found a new Hin6I polymorphism in intron 7 and confirmed a tentative BanI polymorphism in exon 4 reported by Evans and Kemp [Gene 1997;199:123-131]. In all ethnic groups there was a complete and highly significant (p < 10(-10)) linkage disequilibrium where all BanI 1 alleles were linked to Hin6I 1 alleles. Furthermore in the European populations, but not in the Chinese, there was a close correlation between the three BanI-Hin6I haplotypes and the alleles of a previously described three-allelic RsaI polymorphism in the TFR gene studied by Southern blotting. There were distinct ethnic differences in TFR allele and haplotype frequencies. Thus the Saamis were significantly different from the other European ethnic groups, and the Lithuanians had a significantly increased frequency of the BanI 2-Hin6I 1 haplotype, suggesting that this marker may be informative in tracing prehistoric migrations and admixture by Baltic peoples. The new TFR polymorphisms and haplotypes may also be useful markers in studies of interactions with the transferrin and hemochromatosis genes, the genetic influence on body iron stores and disease associations.

Alleles↗
PubMed2005

Genotypes at 11beta-hydroxysteroid dehydrogenase type 11B1 and hexose-6-phosphate dehydrogenase loci are not risk factors for apparent cortisone reductase deficiency in a large population-based sample.

CONTEXT: Apparent cortisone reductase deficiency (ACRD) is a rarely ascertained condition characterized by signs of androgen excess in women or children and decreased urinary excretion of cortisol metabolites compared with cortisone metabolites. These findings suggest a deficiency of 11beta-hydroxysteroid dehydrogenase type 1 (11-HSD1; encoded by the HSD11B1 gene), which normally converts cortisone to cortisol. Common polymorphisms in both HSD11B1 and the hexose-6-phosphate dehydrogenase (H6PD) gene encoding hexose-6-phosphate dehydrogenase have been found together in ACRD patients, who carry three of a possible four minor alleles at the two loci. OBJECTIVE: The objective of this study was to confirm the postulated digenic inheritance mechanism for ACRD. DESIGN: This was a population-based association study (Dallas Heart Study). Subjects were genotyped for the 1971T>G polymorphism in intron 3 of HSD11B1 and the R453Q polymorphism in H6PD. SUBJECTS: The study comprised 3551 individuals in a population-based sample (50% black, 35% white, and 15% Hispanic). MAIN OUTCOME MEASURE: The main outcome measure was association between genotypes and risk for polycystic ovarian syndrome. RESULTS: Both polymorphisms occurred more frequently than previously reported. Thus, ACRD genotypes (at least three of four minor alleles) occurred in 7.0% of subjects. There were no associations between genotype and body mass index; waist/hip ratio; visceral adiposity; measures of insulin sensitivity; levels of testosterone, FSH, or LH (in females); or risk of polycystic ovarian syndrome. There was no genotype effect on urinary free cortisol/cortisone or corticosteroid metabolite ratios, which were measured in 10 subjects, each carrying zero, three, or four minor alleles. CONCLUSIONS: Previously reported associations of ACRD with HSD11B1 and H6PD alleles represent ascertainment bias. However, rare severe mutations in these genes cannot be ruled out.

11-beta-Hydroxysteroid Dehydrogenases↗