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PubMed2002

Polymorphisms of the CYP1B1 gene have higher risk for prostate cancer.

Various carcinogenic factors including estrogen metabolites play a role in malignant transformation. These metabolites are formed in part, as a result of the hydroxylation activity of cytochrome P450 (CYP) 1B1. Variant forms of this enzyme have been shown to enhance its activity, and thus, we hypothesize that single nucleotide polymorphisms of the CYP1B1 gene can be a risk factor for prostate cancer. To test this hypothesis, the genetic distribution of six different CYP1B1 polymorphisms at intron 1 (C-->T), codon 48 (C-->G), codon 119 (G-->T), codon 432 (C-->G), codon 449 (C-->T), and codon 453 (A-->G) was analyzed in 117 prostate cancer samples and 200 healthy normal subjects from a Japanese population. Results of these experiments demonstrate that the genotype at codon 119 is significantly different between prostate cancer patients and controls (P<0.001). The odds ratio of genotype T/T compared to G/G (reference) was calculated as 4.02 with a 95% confidence interval of 1.73-9.38. All other codons, except 453, showed polymorphisms but were not significantly different between cancer patients and controls. No association was found between stage and grade of cancer with any of the polymorphic sites. This is the first report that demonstrates the polymorphism at codon 119 of CYP1B1 to be associated with prostatic carcinogenesis. These results are important in understanding the role of CYP1B1 polymorphisms in the pathogenesis of prostate cancer.

Alleles↗

PubMed1997

Polymorphism of the angiotensin-converting enzyme (ACE) gene in patients with thrombotic brain infarction.

The relationship between cerebrovascular disease and an insertion/deletion (I/D) polymorphism in intron 16 of the angiotensin-converting enzyme (ACE) gene is still being debated. We examined its role as a risk factor in patients with thrombotic brain infarction. The association between ACE polymorphism and ischemic stroke was examined in 181 patients with thrombotic brain infarction and 271 controls without strokes. The I/D polymorphism was examined using the polymerase chain reaction. Distributions of the ACE genotypes and alleles did not differ between the infarcted patients and the controls. Both distributions in patients with onset at age 60 years or younger were significantly higher than those in younger controls (genotype: chi 2 = 7.6, P = 0.02; allele: chi 2 = 5.6, P = 0.02). There were no significant differences in the distributions of ACE genotypes and alleles between the patients with lacunar infarcts and with cortical infarcts in all ages. There were also significant differences in the distribution of ACE genotypes and alleles between the younger and the elderly subgroup of patients with brain infarction (genotype: chi 2 = 12.9, P = 0.002; allele: chi 2 = 11.1, P = 0.0009). Furthermore, there was a significant decline in the frequency of the ACE D allele with increasing age in all patients with thrombotic brain infarction. These observations demonstrated a significant association between the ACE gene polymorphism and thrombotic brain infarction in patients age 60 years or younger in a Japanese population. Furthermore, there may be an association between the ACE D allele and mortality after cerebral infarction.

Aged↗

PubMed2005

Allelic heterogeneity at the serotonin transporter locus (SLC6A4) confers susceptibility to autism and rigid-compulsive behaviors.

Autism is a spectrum of neurodevelopmental disorders with a primarily genetic etiology exhibiting deficits in (1) development of language and (2) social relationships and (3) patterns of repetitive, restricted behaviors or interests and resistance to change. Elevated platelet serotonin (5-HT) in 20%-25% of cases and efficacy of selective 5-HT reuptake inhibitors (SSRIs) in treating anxiety, depression, and repetitive behaviors points to the 5-HT transporter (5-HTT; SERT) as a strong candidate gene. Association studies involving the functional insertion/deletion polymorphism in the promoter (5-HTTLPR) and a polymorphism in intron 2 are inconclusive, possibly because of phenotypic heterogeneity. Nonetheless, mounting evidence for genetic linkage of autism to the chromosome 17q11.2 region that harbors the SERT locus (SLC6A4) supports a genetic effect at or near this gene. We confirm recent reports of sex-biased genetic effects in 17q by showing highly significant linkage driven by families with only affected males. Association with common alleles fails to explain observed linkage; therefore, we hypothesized that preferential transmission of multiple alleles does explain it. From 120 families, most contributing to linkage at 17q11.2, we found four coding substitutions at highly conserved positions and 15 other variants in 5' noncoding and other intronic regions transmitted in families exhibiting increased rigid-compulsive behaviors. In the aggregate, these variants show significant linkage to and association with autism. Our data provide strong support for a collection of multiple, often rare, alleles at SLC6A4 as imposing risk of autism.

Alanine↗

PubMed1998

Measured haplotype analysis of the angiotensin-I converting enzyme gene.

Linkage and segregation analysis have shown that circulating angiotensin-I converting enzyme (ACE) levels are influenced by a major quantitative trait locus that maps within or close to the ACE gene. The D variant of a 287 bp insertion/deletion (I/D) polymorphism in intron 16 of the gene is associated with high ACE levels and may also be related to increased risk of cardiovascular disease. Multiple variants that are in linkage disequilibrium with the I/D polymorphism have been described, but it is unknown if any of these are directly implicated, alone or in combination with as yet undiscovered variants, in the determination of ACE levels. An analysis of 10 polymorphisms spanning 26 kb of the ACE gene revealed a limited number of haplotypes in Caucasian British families due to strong linkage disequilibrium operating over this small chromosomal region. A haplotype tree (cladogram) was constructed with three main branches (clades A-C) which account for 90% of the observed haplotypes. Clade C is most likely derived from clades A and B following an ancestral recombination event. This evolutionary information was then used to direct a series of nested, measured haplotype analyses that excluded upstream sequences, including the ACE promoter, from harbouring the major ACE-linked variant that explains 36% of the total trait variability. Residual familial correlations were highly significant, suggesting the influence of additional unlinked genes. Our results demonstrate that a combined cladistic/measured haplotype analysis of polymorphisms within a gene provides a powerful means to localize variants that directly influence a quantitative trait.

England↗

PubMed2006

A screen for mutations in the transducin gene GNB1 in patients with autosomal dominant retinitis pigmentosa.

PURPOSE: To search for mutations in the GNB1 gene (coding for the transducin beta1-subunit protein) in patients with autosomal dominant retinitis pigmentosa. METHODS: We screened 185 unrelated patients with autosomal dominant retinitis pigmentosa (ADRP) using direct genomic sequencing of the three non-coding exons and 9 coding exons, along with immediately flanking intron DNA. RESULTS: We found 2 polymorphisms, one in intron 1 with a minor allele frequency of 24%, and one in intron 6 with a minor allele frequency of 12% among the 185 patients. Two rare variants (minor allele frequency <1%) were found in the 3' untranslated region of exon 12. No changes were found in the open reading frame (exons 3-11) or in the noncoding exons 1 and 2. CONCLUSIONS: No likely pathogenic GNB1 mutations have been found in any of 185 unrelated patients with ADRP. This result would be expected if hemizygosity for GNB1 does not result in ADRP or is a rare cause of ADRP.

3' Untranslated Regions↗

PubMed2001

SEL1L microsatellite polymorphism in Japanese patients with autoimmune thyroid diseases.

The autoimmune thyroid diseases (AITDs), comprising Graves' disease (GD) and Hashimoto's thyroiditis (HT), appear to develop as a result of complex interactions between predisposing genes and environmental triggers. A recently performed genome-wide linkage study identified six loci that showed evidence for linkage to AITD. One locus, GD-1, on chromosome 14q31 was mapped to within 2 centimorgans (cM) of the recently reported multinodular goiter (MNG)-1 locus. Furthermore, microsatellite markers for the thyroid stimulating hormone receptor gene on chromosome 14q31 were associated with AITDs in the Japanese population. A newly isolated growth factor, SEL1L, was recently mapped to 14q31, and we considered it an interesting candidate gene to examine with respect to both GD and MNG. We therefore have analyzed a dinucleotide (CA)n repeat polymorphism in the intron 20 of the SEL1L gene in patients with AITDs and in normal subjects. The polymorphic marker was analyzed by polymerase chain reaction (PCR) followed by electrophoresis on denaturing polyacrylamide gels. There was no significant difference in the distributions of SEL1L alleles between patients and controls. The present results do not support an association between a dinucleotide repeat polymorphism in intron 20 of the SEL1L gene and AITD in Japanese women.

Female↗

PubMed1985

rDNA in Locusta migratoria is very variable: two introns and extensive restriction site polymorphisms in the spacer.

Cloned ribosomal DNA (rDNA) of Locusta migratoria was analyzed by restriction site mapping and SI nuclease experiments. The repeat unit is 18 kb long. The nontranscribed spacer region (NTS) is very large (11 kb) and homogeneous in length, but many of the restriction sites are heterogeneous among the repeat units. Two introns of different length were found at different positions in the 28S gene. They are present in less than 5% of the genes.

Animals↗

PubMed2002

Analysis of single nucleotide polymorphisms in uridine/cytidine kinase gene encoding metabolic enzyme of 3'-ethynylcytidine.

We investigated single nucleotide polymorphisms (SNPs) in uck2 gene encoding metabolic enzyme of 3'-ethynylcytidine (ECyd) which were associated with drug response of ECyd, and the newly synthesized antitumor ribonucleoside analog. We analized that on exon-intron junction and exon region to affect the qualitative alteration of gene product directly in ECyd sensitive and resistant human cancer cell lines. As the results, cSNP and sSNP were detected in exon 4. In the promoter region, 3 SNPs were detected. Our data seem to be able to give an important knowledge, when ECyd is applied clinically.

Cytidine↗

PubMed1994

Left ventricular size, mass, and function in relation to angiotensin-converting enzyme gene polymorphism in humans.

Angiotensin-converting enzyme (ACE) exhibits genetic variation related to insertion/deletion (I/D) polymorphism in intron 16 of the ACE gene. The DD genotype results in high ACE activity and is overrepresented in diseases characterized by left ventricular (LV) hypertrophy and dysfunction. We studied whether the ACE gene polymorphism predicts LV mass or function in the absence of heart disease. Polymerase chain reaction of leukocyte DNA was used to determine the I/D genotype, and M-mode and Doppler echocardiography were used to quantify LV mass and function in 86 human subjects, 36-37 yr of age. All were free of clinical heart disease. The LV mass-to-body height ratio averaged 99 +/- 19 (SD) g/m in subjects with the II genotype (n = 25), 99 +/- 30 g/m in those with the ID genotype (n = 35), and 94 +/- 24 g/m in those with the DD genotype (n = 26; P = 0.790). The indexes of LV systolic and diastolic function were also unrelated to the ACE genotype. We conclude that in the absence of heart disease the ACE gene variation has no major influence on LV mass or function that is detectable at echocardiography.

Adult↗

PubMed2006

Challenging the spliceosome machine.

BACKGROUND: Using cDNA copies of transcripts and corresponding genomic sequences from the Berkeley Drosophila Genome Project, a set of 24,753 donor and acceptor splice sites were computed with a scanning algorithm that tested for single nucleotide insertion, deletion and substitution polymorphisms. Using this dataset, we developed a progressive partitioning approach to examining the effects of challenging the spliceosome system. RESULTS: Our analysis shows that information content increases near splice sites flanking progressively longer introns and exons, suggesting that longer splice elements require stronger binding of spliceosome components. Information also increases at splice sites near very short introns and exons, suggesting that short splice elements have crowding problems. We observe that the information found at individual splice sites depends upon a balance of splice element lengths in the vicinity, including both flanking and non-adjacent introns and exons. CONCLUSION: These results suggest an interdependence of multiple splicing events along the pre-mRNA, which may have implications for how the macromolecular spliceosome machine processes sets of neighboring splice sites.

Animals↗

PubMed1988

A second BamHI DNA polymorphism and haplotype association in the factor IX gene.

A second BamHI DNA polymorphism has been identified in the factor IX gene in an American black population at an allelic frequency of 0.13. This site has been localized within 500 basepairs (bp) 5' to the XmnI intron 3 polymorphic site and increases the heterozygosity of black females at the factor IX gene locus. In addition, haplotype analysis of factor IX genes at five polymorphic loci indicates that although there is conservation of sequences between the races, factor IX genes show more heterogeneity in an American black population and thus more heterozygosity is observed in black females compared with whites. This increased heterogeneity is due to DNA polymorphisms unique to black populations and to linkage equilibrium between the most 5' and 3' polymorphic sites in factor IX genes in blacks.

Alleles↗

PubMed2005

RANTES gene polymorphisms predict all-cause and cardiac mortality in type 2 diabetes mellitus hemodialysis patients.

INTRODUCTION: Patients with type 2 diabetes (DM2) and end stage renal disease (ESRD) have a dismal survival prognosis, mainly due to cardiovascular events. There is sparse data on genetic predictors. Chemokines and their receptors are important in regulating leukocyte influx and activation in atherosclerosis, and functional polymorphisms in the respective genes are associated with cardiovascular disease risk. METHODS: We enrolled 225 prevalent Caucasian DM2 patients receiving maintenance hemodialysis in 30 centres in Southern Germany (time from dialysis initiation <2.0 years) from August 1999 to January 2000 for prospective study until December 2003. The CX3CR1 T280M, and MCP-1 -2518 and RANTES -403 and -28 promoter and intronic In1.1T/C polymorphisms were assessed by real-time PCR. Primary end point was all-cause mortality (ACM). RESULTS: Patients carrying the RANTES -403A or In1.1C allele had a significantly higher ACM risk (multivariate hazard ratio for -403A, dominant model=1.81 [95% CI: 1.22-2.67], p=0.003), mainly due to cardiac events. Similar data were obtained by haplotype analysis. The other SNPs showed no effect on survival. DISCUSSION: In DM2 patients with ESRD, ACM due to cardiac events is associated with RANTES gene variants that are known to alter the expression of this chemokine important in atherosclerosis. Further study of the role of chemokine and chemokine receptor gene variation in determining vascular end points is needed.

Aged↗

PubMed2001

Analysis of the human progesterone receptor gene polymorphism progins in Austrian ovarian carcinoma patients.

Ovarian carcinoma is the highest death cause in gynecologic malignancies. Although the molecular basis for familial breast and ovarian cancer is elucidated, few genetic markers have been associated with sporadic ovarian carcinoma. A polymorphism in intron G of the human progesterone receptor (PgR), caused by an Alu insertion, was described to be associated with ovarian carcinoma in a pooled German/Irish population. Later on, a G to T substitution in exon 4, causing a Valine to Leucine change in the hinge region of the receptor, and a synonymous C to T substitution in exon 5 were reported to be linked to the Alu insertion. This complex of the PgR gene polymorphism was designated PROGINS. In order to investigate if PROGINS is associated with risk for ovarian cancer in Austrian women, we analyzed DNA from 226 Austrian patients with sporadic ovarian carcinoma and a control group with 194 healthy volunteers for the PROGINS complex. The PROGINS status was studied in association with risk for ovarian carcinoma, the age of the ovarian patients, the protein level of PgR and estrogen receptor (ER) and histopathological parameters. The results indicate that the frequency of PROGINS carriers in Austrian women is similar to those in women in North America and England. There is no significant difference between the PROGINS allele distribution in ovarian carcinoma patients and healthy women. The PROGINS is not associated with increased risk for ovarian carcinomas. Additionally, the protein levels of ER and PgR were independent of the PROGINS status.

Alleles↗

PubMed1992

Carrier detection and prenatal diagnosis of cystic fibrosis using an intragenic TA-repeat polymorphism.

We have analysed the segregation of a TA-repeat polymorphism in intron 17b of the cystic fibrosis transmembrane conductance regulator gene responsible for cystic fibrosis (CF) in 23 French CF families non-informative for the delta F508 mutation (i.e. with at least one parent not carrying delta F508) or closely linked DNA markers. At least 13 different alleles ranging from 7 to 45 repeats were observed and the detected heterozygosity was 89%. Of the 23 families studied, 19 were fully informative for prenatal diagnosis or carrier detection, 3 were partially informative and one was not informative. In 6 families, prenatal diagnosis for CF or carrier detection in siblings of CF cases were performed using this polymorphism.

Base Sequence↗

PubMed2004

Nicotine dependence in a prospective population-based study of adolescents: the protective role of a functional tyrosine hydroxylase polymorphism.

Dopamine is a key neurotransmitter of the mesolimbic reward pathway in the human brain, and tyrosine hydroxylase (TH) is the rate-limiting enzyme in dopamine biosynthesis. Consequently, the gene encoding TH is a strong candidate for involvement in the genetic component of addiction. The importance of this gene in nicotine dependence is supported by many studies showing a link between nicotine administration and TH expression. A functional tetranucleotide repeat polymorphism within intron 1 of the TH gene (HUMTH01-VNTR) has been shown to modify tobacco use in two independent Caucasian samples from the USA and Australia. Using information drawn from an eight-wave Australian population-based longitudinal study of adolescent health, we tested the effect of the HUMTH01-VNTR on nicotine dependence. Comparisons were made between dependent smokers and non-dependent smokers. These data provide further support for a protective association between the K4 allele and dependent smoking (odds ratio 0.54, 95% confidence interval 0.28-1.0). No associations were observed at any of three other common TH polymorphisms (rs6356, rs6357 and HUMTH01-PstI). Including these data, three independent studies, two of which use identical phenotypes, have now identified a protective relationship between the K4 allele of the functional HUMTH01-VNTR polymorphism and high-level smoking.

Adolescent↗

PubMed2004

MICA intron 1 sequences of conserved extended HLA haplotypes: implications for sequencing-based typing.

The human major histocompatibility complex (MHC) class I chain-related gene A (MICA) has a high degree of genetic diversity. Several methods have been used in MICA typing. Recent studies reported different results for the same reference cell lines typed by different methods. By searching the GenBank, we found an indel polymorphism in MICA intron 1 corresponding to the area where one of the sequencing-based typing primers used by others is located. We investigated this polymorphism in 43 reference samples by primer cycle sequencing. This approach revealed three haplotype-specific patterns of polymorphisms in intron 1. This study provided evidence that one of the primers commonly used in MICA typing may fail to amplify both alleles in certain heterozygous combinations. Our data showed a correlation between the three patterns in MICA intron 1 and exon 5 short tandem repeat (STR) alleles. Being neutral ones, the intron 1 and STR polymorphisms appeared to mark the ancestral lineages better than the coding region polymorphisms.

Base Sequence↗

PubMed1995

Diagnosis of hemophilia B carriers using two novel dinucleotide polymorphisms and Hha I RFLP of the factor IX gene in Japanese subjects.

We identified two novel dinucleotide polymorphisms in intron A at nucleotide 192 (FIX192) and in the 5' flanking region at nucleotide -793 (FIX-793) of the factor IX gene, which are present in normal Japanese. The Hha I restriction fragment length polymorphism (FIX-HhaI) located 8 kb 3' to the factor IX gene was also found to be an efficient marker for detecting carriers in a Japanese family with hemophilia B. Each of these polymorphisms was able to be rapidly ascertained by the polymerase chain reaction (PCR) technique. In 22 Japanese families with hemophilia B, 18 families (81.8%) were heterozygous for at least one of these polymorphisms, whereas 11 (50%) were informative for the extragenic DXS99/Sac I RFLP which was previously reported as a useful gene marker for Japanese hemophilia B. Using all 4 polymorphisms together, the informative rate improved to 86.4%. Carrier detection and, possibly, the prenatal diagnosis of hemophilia B can be achieved effectively and rapidly in Japanese with these polymorphisms.

Base Sequence↗

PubMed1998

[Educational symposium: DNA diagnosis of malignancies; strategies and applications of PCR-mediated DNA diagnosis in a case of hemophilia B].

Advances in molecular biology have improved the screening of carriers and allows prenatal diagnosis of many genetic disorders, including hemophilia B. For instance, based on the eight described dimorphic restriction fragment length polymorphisms within the factor IX gene, a Caucasian female has a 94% chance of being heterozygous (informative) for at least one of these markers. However, ethnic limitations of molecular genetic techniques have been found in diagnosing hemophilia B families in Japanese and other populations. We identified two novel dinucleotide polymorphisms in intron A at nucleotide 192 (FIX192) and in the 5' flanking region at nucleotide-793 (FIX-793) of the factor IX gene, which are present in normal Japanese. The Hha I restriction fragment length polymorphism (FIXHhaI) located 8 kb 3' to the factor IX gene was also found to be an efficient marker for detecting carriers in a Japanese family with hemophilia B. Each of these polymorphisms was able to be rapidly ascertained by the polymerase chain reaction (PCR) technique. In 23 Japanese families with hemophilia B, 19 families (82.6%) were heterozygous for at least one of these polymorphisms. Carrier detection and, possibly, prenatal diagnosis of hemophilia B can be achieved effectively and rapidly in Japanese with these polymorphisms. These polymorphisms may also be present and useful for hemophilia B carrier detection in other Asian populations.

Factor IX↗