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PubMed1995

[Deletion polymorphism of the angiotensin I-converting enzyme gene associates with increased risk for ischemic heart diseases in the Japanese].

The Angiotensin I-converting enzyme (ACE) is a key component of the renin-angiotensin system thought to be important in the pathogenesis of hypertension and cardiovascular diseases. Previous studies showed that deletion polymorphism in the the ACE gene might be a risk factor for myocardial infarction in the Caucasian population, but, this finding has not yet been reported in a Japanese population. In this study, a 287 base pair (bp) insertion/deletion polymorphism in intron 16 of the ACE gene was examined by the polymerase chain reaction (PCR) in a cross-sectional study of 100 healthy subjects and 218 patients with ischemic heart diseases (IHD) (70 angina pectoris, 148 myocardial infarction). Polymorphism of the ACE gene was characterized by three genotypes: two deletion alleles (genotype DD), two insertion allele (genotype II) and heterozygotes alleles (genotype ID). No differences could be detected among the three genotypes for total cholesterol, high-density lipoprotein cholesterol, blood pressure and body mass index. The serum ACE activity in each II, ID and DD genotype was 11.4 +/- 2:7 microU/ml, 14.5 +/- 3.5 microU/ml, 16.6 +/- 4.6 microU/ml, respectively. In the population study, genotype DD was significantly associated with IHD when compared with the other two genotypes (ID and II). The frequency of deletion allele was higher (0.56) in the IHD group than in the normal individuals (0.42) (p < 0.05). These frequencies were not varied whether they had classic risk factors or not. Furthermore, coronary multivessel impairment was significantly associated with a deletion allele than with an insertion allele (p < 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1999

Angiotensin-converting enzyme insertion-deletion polymorphism in normotensive and pre-eclamptic pregnancies.

OBJECTIVE: To investigate the hypothesis that pre-eclampsia is associated with a common insertion-deletion polymorphism in the angiotensin-converting enzyme gene. DESIGN: Seventy-two women with pre-eclampsia and 83 normotensive pregnant women participated in the study. Pre-eclampsia was defined as a blood pressure exceeding 140/90 mm Hg in a previously normotensive woman, associated with proteinuria in excess of 300 mg/l in a 24 h collection. Samples for fetal genotyping were available from 66 pregnancies complicated by pre-eclampsia and 79 normotensive pregnancies. METHODS: Maternal and fetal samples were genotyped at the insertion-deletion (I-D) polymorphism in intron 16 of the angiotensin-converting enzyme gene by the polymerase chain reaction followed by agarose electrophoresis. RESULTS: Neither the I-D genotype distributions nor the allele frequencies differed significantly between pre-eclamptic and normotensive pregnancies in maternal or fetal samples (phi2 <0.3, not significant). The odds ratio for pre-eclampsia in women with the DD genotype, compared with the ID and II genotype, was 1.09 (95% confidence interval 0.55-2.16). The odds ratio associated with the DD genotype in the fetus was 1.14 (0.56-2.32). CONCLUSION: This study has found no evidence that the insertion-deletion polymorphism in the angiotensin-converting enzyme gene is associated with pre-eclampsia.

DNA↗
PubMed2006

Candidate gene analysis of the succinic semialdehyde dehydrogenase gene (ALDH5A1) in patients with idiopathic generalized epilepsy and photosensitivity.

Succinic semialdehyde dehydrogenase (SSADH) is involved in the degradation of the inhibitory neurotransmitter GABA and about 50% of patients with SSADH deficiency suffer from seizures. The gene encoding SSADH (gene symbol: ALDH5A1) maps in proximity to susceptibility loci for juvenile myoclonic epilepsy (JME) and photosensitivity on chromosome 6p22. The present study tested whether variation of the ALDH5A1 gene confers susceptibility to common syndromes of idiopathic generalized epilepsy (IGE) and an abnormal photoparoxysmal response (PPR). Mutation screening of the ALDH5A1 coding sequence of 35IGE/PPR patients and four healthy control subjects identified 17 sequence variants, of which three resulted in an exchange of amino acids (H180Y, P182L, A237S). Association analysis was carried out for six single nucleotide polymorphisms (SNPs) and one trinucleotide repeat polymorphism (TNR, intron 1), covering the genomic ALDH5A1 sequence. The study sample comprised 566 unrelated German IGE patients, including 218 JME and 95 photosensitive IGE patients, 78 PPR probands without IGE, and 662 German population controls. None of the investigated ALDH5H1 polymorphisms showed evidence for an allelic or genotypic association with either IGE, JME, or PPR, when corrected for multiple tests. A tentative haplotypic association of the two-marker haplotype (rs1883415-TNR) covering the 5'-regulatory region in IGE patients (chi2=11.65, d.f.=3, P=0.009) warrants further replication studies. The present results do not provide evidence that any ALDH5A1 missense variant itself contributes a common and substantial susceptibility effect (RR>2) to IGE syndromes or an increased liability to visually-induced cortical synchronization.

Epilepsy, Generalized↗
PubMed2002

Lack of evidence for contribution of Glu298Asp (G894T) polymorphism of endothelial nitric oxide synthase gene to plasma nitric oxide levels.

INTRODUCTION: Both positive and negative associations between a rare allele of 27-bp repeat polymorphism in intron 4 of endothelial nitric oxide synthase and plasma nitric oxide (NO) levels were previously reported, and further, these conflicting results were suggested to be partly accounted for smoking status of subjects. However, the genetic contribution of Glu298Asp (G894T) polymorphism to plasma NO levels with respect to smoking status has not been published. METHODS: In a group of 411 healthy Korean subjects aged 19-81 years, the end product of NO (NO(x): nitrite plus nitrate) as an index of plasma NO levels was measured by the Griess method. The genotypes of G894T polymorphism were determined by the banding patterns on gel electrophoresis after restriction enzyme digestion. RESULTS: Comparison of plasma NO(x) levels revealed no significant differences across the genotypes and alleles of G894T polymorphism, which is independently of smoking status. However, significant differences in plasma NO(x) levels between nonsmokers and smokers were observed (P = 0.0040). Furthermore, only the common G allele was found to be responsible for these differences. Multiple regression analysis showed that the most independent contributing factor for plasma NO(x) levels was smoking (P = 0.0119) and followed by triglycerides (P = 0.0384). CONCLUSIONS: Our results indicate no substantial effect of G894T polymorphism on the variance of plasma NO(x) levels in healthy Korean population.

Adult↗
PubMed1998

Microsatellite polymorphism within the MICB gene among Japanese patients with Behçet's disease.

Behçet's disease (BD) is known to be associated with HLA-B51. In order to investigate the influence of the MICB gene, located about 120 kb centromeric of the HLA-B gene, on the susceptibility to BD, (CA/TG) dinucleotide repeat microsatellite polymorphism in intron 1 of the MICB gene was investigated among 77 Japanese patients with BD, 60 randomly selected controls and 28 HLA-B51-positive unrelated healthy controls. There was no significant difference in the phenotype frequency of the microsatellite polymorphism between the BD patients and controls. This result suggests that the MICB gene itself is not responsible for the development of BD, and that the candidate gene(s) for BD is located between the MICA and HLA-C genes.

Behcet Syndrome↗
PubMed2002

Two new single-nucleotide polymorphisms in the COL1A1 upstream regulatory region and their relationship to bone mineral density.

Single-nucleotide polymorphisms (SNPs) in regulatory regions of candidate genes may determine variability in bone mineral density (BMD) because they may be responsible for differences in levels of a gene product in response to external signals. Under this hypothesis, we scanned an 800-base pair (bp) region within the COL1A1 promoter, known to harbor cis elements important for in vivo expression, and we found two new polymorphisms: -1663indelT and -1997 G/T. The G to T transversion at -1997 was associated with lumbar spine BMD (p = 0.015) when tested in a cohort of 256 postmenopausal women after adjusting by age, body weight, and years since menopause; a lower degree of association was detected also for femoral neck BMD in a subgroup of 146 women in univariate analysis and after adjusting by age (p = 0.044). The polymorphism -1663indelT, which corresponds to a deletion of a T in a tract of eight T residues (-1670 to -1663), did not show significant association with BMD. Interestingly, -1663indelT is in strong linkage disequilibrium (LD) with the previously described Sp1 polymorphism of intron 1, which in this study did not show association with BMD either. Significant interaction between -1997 G/T and -1663indelT (p = 0.019), and between -1997 G/T and Sp1 (p = 0.045) was observed also. Individuals heterozygous for the three polymorphisms showed the highest mean BMD value. Gel retardation assays showed that oligonucleotides containing either the -1663 or the -1997 polymorphic sites specifically bind primary osteoblast nuclear proteins. We named these binding sites as PCOL1 and PCOL2, respectively. In summary, this study describes two new SNPs in the COL1A1 promoter, which may affect bone mass determination.

Alleles↗
PubMed2004

Association of angiotensin converting enzyme gene polymorphism with tachycardia cardiomyopathy.

Despite incessant tachycardia, not all patients develop tachycardia-mediated cardiomyopathy. The cardiac renin-angiotensin system may be involved in cardiac remodelling and fibrosis. The level of angiotension-converting enzyme (ACE) in the serum is associated with a 287 bp insertion (I)/deletion (D) polymorphism in intron 16 of the ACE gene. The DD genotype is associated with increased serum ACE levels and a higher incidence of idiopathic dilated and ischemic cardiomyopathy. The objective of this study was to assess whether the ACE gene I/D polymorphism is responsible for development of tachycardia-mediated cardiomyopathy. We identified 20 consecutive patients with persistent tachycardia and cardiomyopathy who showed significant improvement in ejection fraction after rate control (group A, tachycardia cardiomyopathy group). We compared the I/D genotype frequency of group A with the gene frequency of a separate group of 20 patents who, despite rapid atrial arrhythmias had preserved left ventricular ejection fraction (group B, tachycardia without cardiomyopathy group). These two groups were then compared with 24 healthy normal volunteers (group C). After a mean follow-up of 30 months, group A patients showed improvement in ejection fraction from 20+/-7 to 43+/-9% (p<0.001). Group A had a significantly higher frequency of the DD genotype than groups B and C (p-value <0.035 and <0.009 respectively). The profile of group B patients was intermediate between normal and patients with tachycardia-mediated cardiomyopathy. I/D polymorphism of the ACE gene may account for cardiomyopathy secondary to tachycardia.

Aged↗
PubMed1997

An intron capture strategy used to identify and map a lysyl oxidase-like gene on chromosome 9 in the mouse.

An intron capture strategy involving use of polymerase chain reaction was used to identify and map the mouse homologue of a human lysyl oxidase-like gene (LOXL). Oligonucleotides complementary to conserved domains within exons 4 and 5 of the human lysyl oxidase-like gene were used to amplify the corresponding segment from mouse genomic DNA. Sequencing of the resulting mouse DNA fragment of approximately 1 kb revealed that the exon sequences at the ends of the amplified fragment are highly homologous (90% nucleotide identity) to exons 4 and 5 of the human lysyl oxidase-like gene. An AluI restriction site polymorphism within intron 4 was used to map the mouse lysyl oxidase-like gene (Loxl) to mouse Chromosome 9 in a region that shares linkage conservation with human chromosome 15q24, to which the LOXL was recently mapped.

Animals↗
PubMed2005

Association of estrogen receptor alpha gene polymorphisms with bone mineral density in postmenopausal Indian women.

Bone mineral density (BMD) is the major determinant of osteoporotic fracture risk with a particular genetic background. However, consensus on the association of BMD with specific gene locus has not been reached. In the present study, we investigated the potential association of estrogen receptor alpha (ER alpha) gene intron I polymorphisms with BMD in 246 postmenopausal Indian women (average age 54.2+/-3.4 years). All the subjects were genotyped for XbaI and PvuII polymorphisms and underwent BMD measurements at spine and hip by dual energy X-ray absorptiometery. The average BMD of subjects with the genotypes XX and PP (absence of restriction sites for XbaI and PvuII, respectively) was 12.7 and 5.4% higher at the spine and 13.1 and 4.6% higher at the hip, respectively, than those with genotypes xx and pp. In age vs. BMD scatterplot, the intercept and slope of regression lines for genotypes xx and pp at spine and hip demonstrated comparatively rapid decrease in BMD across the age. The genotype XX was significantly prevalent (p<0.001) in women with normal bone mass (32%) and genotype xx in women with osteoporotic bone mass (35.3%), within the group. A significantly higher relative risk was associated with xx genotype. The study concludes that genetic variations at ER alpha gene locus, perhaps, are associated with BMD in Indian women and may influence some determinant of bone metabolism resulting in accelerated bone loss with age.

Asian People↗
PubMed2002

Endothelial nitric oxide synthase gene polymorphisms and genetic susceptibility to prostate cancer.

The endothelial cell-specific form of nitric oxide synthases (ecNOS) is localized at 7q35-q36 and is involved in vascular development and tumour growth in human prostate cancer. We have conducted a case-control study to investigate the prevalence of two polymorphisms at intron 4 (ecNOS4a/b) and exon 7 (Glu-Asp298) of ecNOS gene in 125 prostate cancer (PCa) patients and in 153 controls. We observed that the a-allele (aa or ab genotypes from ecNOS4a/b) was over-presented in the group of PCa with Gleason histological grade >or=7 (P=0.041). With regard to the Glu-Asp298 polymorphism, patients with the T-allele were younger than patients with no T-allele (P=0.037), and a statistically significant difference was noted in the Glu-Asp298 genotype distribution between cases with advanced disease and cases with localized disease (P=0.0013). When comparing cases and controls with logistic regression analysis we observed that the presence of the a-allele is associated with prostate cancer risk (odds ratio (OR) 1.83; 95% confidence interval (CI) 1.06-3.17; P=0.029), to high histological grade (Gleason >or=7) of PCa (OR 2.18; 95% CI 0.95-4.98; P=0.062) and with the risk of progression of the cancer disease (OR 2.85; 95% CI 1.19-6.82; P=0.018). Furthermore, we found that carriers with the combination of the a-allele (aa and ab ecNOS4a/b genotypes) and T-allele (GT and TT from Glu-Asp298) have a threefold increase in prostate cancer risk (OR 3.13; 95% CI 1.41-6.91, P=0.004). In summary, we have identified an NO-related genetic risk factor for prostate cancer that may help in understanding the molecular mechanism involved in the individual susceptibility to prostate cancer.

Adult↗
PubMed2003

Inducible and endothelial constitutive nitric oxide synthase gene polymorphisms in Kawasaki disease.

BACKGROUND: Nitric oxide (NO) is secreted by immune and vascular endothelial cells, and appears to play important roles in the pathophysiology of Kawasaki disease (KD). Thus, genetic variations in NO synthase (NOS) genes may be involved in the development of coronary artery lesions (CAL) in KD. METHODS: The present study investigated the association of endothelial constitutive NOS (ecNOS) and inducible NOS (iNOS) gene polymorphisms with the development of CAL in KD in a Japanese population. RESULTS: The genotype distributions of 27-bp tandem repeat polymorphism within intron 4 of ecNOS gene did not show any significant difference between controls and KD patients with or without CAL. In addition, there was no significant association between whole-allele distribution of iNOS gene promoter (penta-repeat CCTTT) polymorphism and KD with or without CAL. CONCLUSION: These results did not support any association of ecNOS and iNOS gene polymorphisms to the development of CAL in KD patients in a Japanese population.

Asian People↗
PubMed2002

Angiotensin-converting enzyme I/D polymorphism and hypertension: the Ohasama study.

OBJECTIVE: Angiotensin-converting enzyme (ACE) I/D polymorphism in intron 16 of the ACE gene was analyzed in a general Japanese population in relation to self-blood pressure (BP) measurement at home (home BP) and ambulatory BP monitoring (ABPM) to determine the association between genetic variants of this polymorphism and hypertension. DESIGN: A cross-sectional study. METHODS AND RESULTS: We genotyped the ACE I/D polymorphism in 1245 subjects with home BP and 803 subjects with ABPM in Ohasama, a rural community in Japan. All the subjects were 40 years of age and over, and gave written informed consent for the present genetic analysis. Hypertensive subjects were defined as those receiving antihypertensive drugs and those who had a home BP higher than 135 mmHg in systole and/or higher than 85 mmHg in diastole. The frequencies of the II, ID, and DD genotypes in these Japanese subjects were 0.45, 0.45, and 0.10, indicating a lower frequency of the D allele (0.33) than in Caucasians. There was no significant difference of BP level, prevalence of hypertension or nocturnal decline in BP among the genotypes. There were no differences in the prevalence of previous cardiovascular disease, age, body mass index, male gender, smoking, or biochemical and hormonal parameters among the three genotypes. CONCLUSION: The present results indicate the absence of direct effects of the ACE D-allele on BP level, prevalence of hypertension, prevalence of cardiovascular disease, and circadian BP variation. We conclude there is little association between ACE I/D polymorphism and hypertension in the general Japanese population.

Adult↗
PubMed2001

[Study on the relation between the angiotensin converting enzyme gene and pregnancy induced hypertension].

OBJECTIVE: To study the relationship between the 16th intron insertion/deletion (I/D) polymorphism of angiotensin converting enzyme (ACE) gene and pregnancy induced hypertension (PIH). METHODS: The 16th intron I/D polymorphism of ACE gene in 60 PIH women (PIH group) and 50 normal pregnant women (control group) was detected by PCR. The type of ACE gene in PIH group was assessed and the serum concentration of angiotensin II (AngII) was compared between PIH group and control group. RESULTS: ACE gene types in the PIH women included: insertion homozygote II, deletion homozygote (DD) and insertion/deletion heterozygote (ID). The gene frequency was 55.0% (33/60) for II, 26.7% (16/60) for ID and 18.3% (11/60) for DD respectively. The frequency of insertion allelotype (0.7) of PIH group was higher than that of control group (0.3) (P < 0.05). The Ang II concentration in DD type PIH women was higher than that in control group although the Ang II concentration in II type and I D type PIH was not different from control. CONCLUSIONS: ACE gene polymorphism in the PIH women included: insertion homozygote II, deletion homozygote (DD) and insertion/deletion heterozygote (ID). The concentration of Ang II in DD type PIH women was higher than in control. It is suggested that the pathogenesis of PIH may be connected with multiple genes and factors.

Adult↗
PubMed2000

Allele frequency of human endothelial nitric oxide synthase gene polymorphism in abdominal aortic aneurysm.

OBJECTIVE: This study was performed to examine the role of the endothelial constitutive NO synthase (ecNOS) gene in patients with abdominal aortic aneurysm (AAA). METHODS: We determined the distributions of polymorphism in intron 4 of the ecNOS (ecNOS4) gene, amplified by polymerase chain reaction, and compared the allele frequencies between subjects with abdominal aortic aneurysms (AAAs) and healthy individuals. PATIENTS: Fifty-eight patients with AAAs and 410 race-matched healthy controls were studied. RESULTS: Two alleles of the ecNOS4 gene, containing 4 (a-allele) and 5 (b-allele) repeats, were identified. We found that the a-allele frequency of this gene was significantly higher in the surgical than in the non-surgical group. CONCLUSION: The results of this study suggest that the a-allele of the ecNOS4 gene is indicative of the need for surgery for AAA. Analysis of the alleles of the ecNOS4 gene polymorphism could provide useful information concerning the clinical course of AAA progression.

Aged↗
PubMed2006

Adipocyte fatty-acid binding protein is closely associated to the porcine FAT1 locus on chromosome 4.

We identified 22 polymorphisms in the adipocyte fatty-acid binding protein (FABP4) gene, a strong positional candidate gene for the FAT1 locus in porcine chromosome 4. The most informative polymorphism, an insertion/deletion in intron 1, together with a single nucleotide polymorphism in intron 3, was genotyped in a cross between Iberian and Landrace pigs. After performing QTL, single marker, and haplotype analyses, we showed that there were at least 2 quantitative trait genes in the FAT1 region and that the FABP4 polymorphism was tightly associated to fatness. A comparison of allelic frequencies in a panel of pig breeds suggested that the Del2634C polymorphism was under indirect selection. We also showed that FABP4 is tightly associated to fatness but not growth. Furthermore, a haplotype analysis suggests that there is genetic heterogeneity at the FAT1 locus within the Landrace breed.

Animals↗
PubMed2000

Lipid-lowering response of the HMG-CoA reductase inhibitor fluvastatin is influenced by polymorphisms in the low-density lipoprotein receptor gene in Brazilian patients with primary hypercholesterolemia.

Although the efficacy of fluvastatin (HMG-CoA reductase inhibitor) in the treatment of primary hypercholesterolemia is well documented, a wide interindividual variation treatment response has been observed. We have studied the possible role of the AvaII (exon 13), HincII (exon 12), and PvuII (intron 15) polymorphisms at the low-density lipoprotein receptor (LDLR) gene on lipid-lowering response in 55 patients (36 to 70 years old) with primary hypercholesterolemia treated with fluvastatin for 16 weeks. LDLR genotypes were determined by PCR-RFLP. The results indicate that the AvaII and PvuII polymorphisms influence the cholesterol-lowering response of the HMG-CoA reductase inhibitor Fluvastatin. Patients carrying A+A+ (AvaII) or P1P1 (PvuII) homozygous genotypes presented lower reduction in total cholesterol, LDL-C and apolipoprotein B levels after 16 weeks of treatment with fluvastatin, when compared to other genotypes (P<0.05). Our data also support the previous assumption that the AvaII, HincII, and PvuII polymorphisms of the LDLR gene are associated with variation of serum cholesterol levels. Therefore, the identification of the LDLR genetic profile may provide better prediction of a patient's clinical response to fluvastatin.

Brazil↗
PubMed2003

A simple tandem repeat polymorphism is present in the eighth intron of FLJ12960, a possible queuine salvage enzyme gene.

The putative gene FLJ12960 was identified from sequence analysis of the human genome and predicted to be a member of the family of tRNA-guanine-transglycosylases for queuine biosynthesis by protein sequence similarity at the Zn-binding site (Locus Link #79691 at http://www.ncbi.nlm.gov/LocusLink/). FLJ12960 is immediately downstream of the Dopamine Receptor D3 (DRD3) gene. A Simple Tandem Repeat (STR) polymorphism was identified in intron 8 of the FLJ12960 gene. Primers designed to amplify the CA repeat detect 16 alleles from 121 to 151 base pairs, with a heterozygosity of 0.74.

Base Sequence↗