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PubMed2003

Lack of association between the promoter polymorphisms at positions -308 and -238 of the tumor necrosis factor alpha gene and psoriasis vulgaris in Japanese patients.

BACKGROUND: Psoriasis features an increased level and activity of tumor necrosis factor alpha (TNF-alpha). The TNF-alpha gene has single nucleotide polymorphisms (SNPs) at positions -308 (-308G>A) and -238 (-238G>A) in the promoter region, and the -238G>A SNP has been reported to be associated with psoriasis vulgaris (PV) and psoriatic arthritis in Caucasians. OBJECTIVE: To examine whether these SNPs are associated with susceptibility to PV in Japanese patients, we investigated the genotype and allele frequencies at each SNP in Japanese PV patients and in controls. METHODS: We examined 163 PV patients and 96 healthy individuals. Genotyping was performed using the polymerase chain reaction-restriction fragment length polymorphism method. RESULTS: No significant association between the genotypes or alleles of these SNPs and susceptibility to PV was observed. CONCLUSION: These SNPs themselves are not associated with susceptibility to PV in the Japanese.

Gene Frequency↗
PubMed2002

Novel haptoglobin insertion/deletion polymorphism is associated with the lipid profile and C-reactive protein (CRP) concentration.

We discovered a hitherto undescribed insertion/deletion (I/D) polymorphism of 7 base pairs in intron 4 of the HP1 allele and intron 4 and 6 of the HP2 allele. Genotyping was performed in 311 Belgian subjects. The association between serum haptoglobin (Hp) and lipid concentrations and the Hp I/D genotypes was investigated. Genotype distribution in 103 Hp 1-1 phenotypes (50.5% DD, 39.8% DI, 9.7% II) and D allele frequency (0.70) were in close agreement with the Hardy-Weinberg equilibrium. No association between Hp concentrations and the Hp I/D genotypes could be found. Apolipoprotein (apo)A2, apoB and cholesterol concentrations were slightly lower in Hp II compared to DI and DD. Low-density lipoprotein (LDL)-cholesterol and ultrasensitive C-reactive protein (CRP) concentrations and the apoA1/apoA2 ratios differed significantly between Hp D/I genotypes. We added a further component to the molecular heterogeneity of Hp by the detection of an I/D polymorphism. Studies on the Hp I/D polymorphism in various populations open perspectives for further investigation of the distribution pattern of the human Hp gene. The association of the Hp I/D polymorphism with various lipid parameters might add a further component to the complex and multifaceted lipid metabolism.

Adult↗
PubMed2002

[Relationship between SA gene Pst1 polymorphism and predisposition to H-gestosis].

Genetic factors have been reported to play an important role in the predisposition to development of pregnancy-induced hypertension (PIH). On the other hand, there is strong evidence that genetic factors play important role in the predisposition to essential hypertension. Recently, the plausible "candidate gene" for the development of hypertension is SA gene. The aim of our study was to assess the association of the SA gene with the susceptibility to PIH. For that purpose, the SA gene A1A2 polymorphism was studied in 124 women (median age 28 yrs) suffering from PIH in comparison with 148 healthy pregnant women (median age 28 yrs). Genotyping was performed using methods based on polymerase chain reaction. In this study we found statistically significant more frequent of genotype A1A1 occurrence in the patients with PIH when compared to healthy pregnant controls. The frequency of A1 allele was also significant higher in PIH in comparison with controls (chi 2 test.) Based upon the results of our study we can suspect that the SA gene Pst1 polymorphism is associated with the predisposition to PIH in caucasian women.

Adult↗
PubMed2005

Apolipoprotein E genotype in matched men and women with coronary heart disease.

Apolipoprotein E (apo E) plays an important role in lipid metabolism and its polymorphism may be a risk determinant of coronary heart disease (CHD). Since evidence suggested a gender-specific effect of apo E polymorphism, we studied the influence of gender-specific interaction of the polymorphism on CHD. From a total of 463 Greek Caucasians (314 men and 149 postmenopausal women) with angiographically documented CHD, we selected 79 women (68+/- 9 yr old) and 79 men (66+/- 9 yr old) who were matched for clinical characteristics. Apo E genotyping was performed by PCR and RFLP analysis. Biochemical parameters were also measured. The results were as follows: the E3/3 genotype occurred in 78.5% of the patients, followed by E3/4, E2/3, E2/4, and E4/4 genotypes, which occurred in 9.5%, 9.5%, 1.9%, and 0.6% of the patients, respectively. No significant differences were observed in the apo E allele or apo E genotype distributions between the matched Greek men and women with CHD. The E3/3 men patients were more frequently part of a family with a history of CHD, compared to women (p=0.035).

Aged↗
PubMed1998

Human platelet antigen genotyping using a fluorescent SSCP technique with an automatic sequencer.

The typing of human platelet antigens (HPA) can be useful in many clinical situations such as neonatal alloimmune thrombocytopenia, post-transfusion purpura, and platelet transfusion refractoriness. The fluorescent-based single-strand conformation polymorphism (F-SSCP) technique is a fast and convenient way to perform HPA genotyping. Universal sequences from phage M13 were introduced at both ends of specific PCR-products by using 5'-tailed primers. A short second round of PCR with universal primers coupled to Cy-5 enabled the PCR-products to be fluorescently labelled. F-SSCP was performed by gel electrophoresis on an automated fluorescent DNA analyser. Genotyping of the three major HPA systems carried by the GP IIb-IIIa complex showed the F-SSCP technique to be accurate and reliable. A single gel procedure has been sufficient to detect HPA genetic polymorphisms tested to date. Neither restriction enzyme, radioactive material, nor any other hazardous chemicals such as ethidium bromide were required. This technique enabled us to genotype HPA-1, -3 and -4 alleles easily and to diagnose materno-fetal incompatibility in a rare alloantigenic system. F-SSCP is a promising technique for the detection of new mutations and/or DNA polymorphisms on a large scale.

Adult↗
PubMedDate not supplied

Genotyping HCV isolates from Italy by type-specific PCR assay in the core region.

A revision of the polymerase chain reaction (PCR) core procedure was performed for genotyping hepatitis C virus (HCV) in 139 patients from Italy. This procedure, developed prior to the identification of new genotypes, may be inadequate in several geographical areas. We proposed a new typing mixture in which primers for types 2c and 4, that are reported to be circulating in Italy, were added and a primer for type 2b was substituted. Using the modified procedure, 139 HCV-positive patients were analysed. The HCV genotype was identified in 96.4% of the cases. We observed double infections and unclassified genotypes in 5 (3.6%) and 5 (3.6%) patients, respectively. The classification of isolates into genotypes and subtypes 2b, 2c and 4 was confirmed by sequence analysis. Furthermore, the efficiency and accuracy of the modified core procedure were evaluated by parallel testing of 107 out of 139 samples using the line probe assay, and demonstrated a 98.9% degree of concordance. The results demonstrated the specificity of the selected primers for type 2c, 2b and 4 and confirmed the circulation of types 2c and 4 in Italy. In conclusion, the proposed modified PCR procedure is the only primer-specific PCR genotyping method available for identification of the 2c and 4 genotypes reported to be circulated in Italy and other European countries.

5' Untranslated Regions↗
PubMed2006

A common A340T variant in PINK1 gene associated with late-onset Parkinson's disease in Chinese.

Parkinson's disease (PD) is a complex neurodegenerative disease with genetic risk factors. Common variants in genes implicated in hereditary forms of parkinsonism may be predisposing factors for sporadic PD. Recent studies have demonstrated that mutations in PINK1 (PARK6 locus) gene, encoding PTEN-induced kinase 1, are associated with both familial recessive and sporadic early onset parkinsonism. In order to assess whether the coding variant A340T contributes to the risk of late-onset PD, we performed an association study of 539 PD patients with an onset age at or older than 50 and 525 controls in Chinese Han. Genotyping was performed by denaturing high performance liquid chromatography (DHPLC) combined with sequencing analyses. The A-allele frequency was 6.2% in PD and 4.2% in controls (p=0.0404), while G/A genotype frequencies were 12.4% in PD and 8.4% in the controls (p=0.0350). Our results yielded significant evidence for disease association between PINK1 A340T and PD with later onset (OR 1.55, 95% CI 1.04-2.32, p=0.0393), thus suggesting that PINK1 A340T variant may contribute to the risk for late-onset PD in Chinese.

Aged↗
PubMed2006

Collaborative analysis of alpha-synuclein gene promoter variability and Parkinson disease.

CONTEXT: Identification and replication of susceptibility genes for Parkinson disease at the population level have been hampered by small studies with potential biases. Alpha-synuclein (SNCA) has been one of the most promising susceptibility genes, but large-scale studies have been lacking. OBJECTIVE: To determine whether allele-length variability in the dinucleotide repeat sequence (REP1) of the SNCA gene promoter is associated with Parkinson disease susceptibility, whether SNCA promoter haplotypes are associated with Parkinson disease, and whether REP1 variability modifies age at onset. DESIGN, SETTING, AND PARTICIPANTS: We performed a collaborative analysis of individual-level data on SNCA REP1 and flanking markers in patients with Parkinson disease and controls. Study site recruitment, data collection, and analyses were performed between April 5, 2004, and December 31, 2005. Eighteen participating sites of a global genetics consortium provided clinical data. Genotyping was performed for SNCA REP1, -770, and -116 markers at individual sites; however, each site also provided 20 DNA samples for regenotyping centrally. MAIN OUTCOME MEASURES: Measures included estimations of Hardy-Weinberg equilibrium in controls; a test of heterogeneity; analyses for association of single variants or haplotypes; and survival analyses for age at onset. RESULTS: Of the 18 sites, 11 met stringent criteria for concordance with Hardy-Weinberg equilibrium and low genotyping error rate. These 11 sites provided complete data for 2692 cases and 2652 controls. There was no heterogeneity across studies (P>.60). The SNCA REP1 alleles differed in frequency for cases and controls (P<.001). Genotypes defined by the 263 base-pair allele were associated with Parkinson disease (odds ratio, 1.43; 95% confidence interval, 1.22-1.69; P<.001 for trend). Multilocus haplotypes differed in frequency for cases and controls (global score statistic, P<.001). Two-loci haplotypes were associated with Parkinson disease only when they included REP1 as one of the loci. However, genotypes defined by REP1 alleles did not modify age at onset (P = .55). CONCLUSION: This large-scale collaborative analysis demonstrates that SNCA REP1 allele-length variability is associated with an increased risk of Parkinson disease.

Adult↗
PubMed2005

C1858T functional variant of PTPN22 gene is not associated with celiac disease genetic predisposition.

Recent findings have demonstrated that the single nucleotide polymorphism 1858C-->T located at the P1 motif of the PTPN22 (protein tyrosine phosphatase nonreceptor 22) gene has functional relevance and is associated with a variety of autoimmune diseases. The aim of this study was to assess the role of the PTPN22 1858C-->T polymorphism in the genetic predisposition to celiac disease (CD). We analyzed a case-control cohort composed by 534 patients with CD and 653 healthy controls and additionally a panel of 271 celiac families. The PTPN22 1858C-->T genotyping was performed by TaqMan 5' allelic discrimination assay. We did not observed any statistically significant deviation after comparing allele and genotypic frequencies of PTPN22 1858C-->T between patients with CD and controls. Accordingly, the familial analysis did not reach statistically significant deviation in the transmission of PTPN22 1858C-->T alleles to the affected offspring. Therefore, our data suggest that the PTPN22 1858 single nucleotide polymorphism has no, or only a negligible, effect on CD susceptibility in this Spanish population.

Autoimmune Diseases↗
PubMed2003

Vitamin D receptor polymorphism and susceptibility to type 1 diabetes in the Dalmatian population.

Several studies have found a relationship between polymorphisms of the vitamin D receptor gene (VDR) and development of type 1 diabetes (T1DM). The meaning of this observation remains unclear and its relevance must be checked in different population samples. To examine the association of VDR polymorphisms and susceptibility to T1DM in the Dalmatian population of South Croatia we studied 134 individuals with type 1 diabetes and 132 control subjects. VDR genotyping was performed using PCR and BsmI, ApaI and TaqI restriction enzymes. Data were analysed using the chi(2)-test. The genotype combination which conferred strongest susceptibility to T1DM was BBAAtt (P=0.002). Interestingly, the BAt haplotype was found to be a risk factor in a German population, the only European population tested thus far. Our results indicate that VDR polymorphisms are associated with increased risk of T1DM in the Dalmatian population of South Croatia and warrant further studies.

Child↗
PubMed2006

Genotypes of hepatitis C virus (HCV) among positive Lebanese patients: comparison of data with that from other Middle Eastern countries.

Recently we identified hepatitis C virus (HCV) genotype 4 as the principle genotype among Lebanese thalassaemics. In an attempt to confirm the predominance of genotype 4 in Lebanon and perhaps in the Middle East, genotyping was attempted on 142 HCV-infected Lebanese patients from five different hospitals in the country. These included 38 HCV-positive patients with symptomatic liver disease who were referred to gastroenterologists and 104 HCV-positive patients with no symptoms of liver disease: 27 patients with thalassaemia, 30 patients on haemodialysis, 32 multi-transfused and 15 intravenous drug users. HCV genotyping was performed on PCR HCV RNA-positive samples using a commercial line probe assay (LiPA; Innogenetics, Ghent, Belgium). HCV genotype 4 is found to be the predominant genotype among HCV-infected Lebanese patients (ranging from 34.2% to 53.3%) followed by 1a (ranging from 12.5% to 43.3%) and 1b (ranging from 8.0% to 34.4%). In patients with symptomatic liver disease, however, genotype 4 (34.2%) was preceded by genotype 1a (39.5%). The predominance of HCV genotype 4 in our population (45.7%) confirms the predominance of HCV genotype 4 in Lebanon and most of the Arab countries in the Middle East but contrasts with data reported from non-Arab Middle Eastern Countries as can be seen from the literature review. Implications of genotyping for clinical outcome of HCV infection, response to treatment as well as for vaccine development are discussed.

Adult↗
PubMed2005

Insertion/deletion polymorphism of the angiotensin-converting enzyme gene and preeclampsia in Japanese patients.

To clarify whether the homozygous deletion (DD) genotype of angiotensin-converting enzyme gene ( ACE) is a genetic risk factor for preeclampsia in Japanese women, we performed ACE genotyping in patients with preeclampsia and healthy pregnant women, and analyzed the relationship between preeclampsia and ACE genotype, taking into account some well-known contributing factors for preeclampsia, such as primiparity, positive family history of hypertension, prepregnancy body mass index < 24, and heterozygosity and homozygosity of T235 (MT+TT) genotypes of the angiotensinogen ( AGT) gene. Among all of the subjects, the frequency of the DD genotype was not different between patients with preeclampsia and controls (16% and 12%, respectively). Regarding primiparity, prepregnancy body mass index < 24, and MT+TT genotypes of AGT, no significant differences in the frequency of the DD genotype of ACE were found between patients with preeclampsia and controls, although in a subgroup positive for family history of hypertension, the frequency of the DD genotype tended to be higher in patients with preeclampsia (25%) than in controls (8%; p = 0.061). Carrying the DD genotype may have some influence on the pathogenesis of preeclampsia, perhaps through effects on placental hypoxia or the interaction of hypertensive disease and atherosclerosis, although this influence may not be strong. Additional studies using a larger number of patients and analyses that include other genetic and environmental factors will be necessary to confirm these results.

Adult↗
PubMed2005

1166C mutation of angiotensin II type 1 receptor gene is correlated with umbilical blood flow velocimetry in women with preeclampsia.

OBJECTIVE: To ascertain the frequency of polymorphic variants of the gene coding for angiotensin II type 1 receptor (AT1) and its correlation with umbilical artery (UA) blood flow velocity in a group of women with preeclampsia (PE). STUDY DESIGN: AT1 polymorphism, pulsatility index (PI) in UA, and perinatal outcome in 47 women with PE and in 113 healthy pregnant women were investigated. Investigation of AT1 receptor genotypes was performed by PCR/RFLP assays. PI value has been measured by Doppler velocimetry technique. RESULTS: The overrepresentation of CC homozygotic genotype in PE group (6.4% vs. 2.7%) and the overrepresentation of mutated C allele in the PE group were observed (28.7% vs. 23.0%). Analyzing PI index we observed statistically significant differences between PE and control groups. Comparing PI values in PE group between genotypes: AA vs. AC + CC statistically significant differences (p < 0.05) have been observed. CONCLUSIONS: Observed overrepresentation of mutated C allele of the AT1 gene was correlated with increased blood flow in umbilical artery in women with preeclampsia. Doppler velocimetry might be a useful tool for indication in the high-risk group with overrepresentation of C alleles.

Adult↗
PubMed2002

The CYP2C9 genotype predicts the blood pressure response to irbesartan: results from the Swedish Irbesartan Left Ventricular Hypertrophy Investigation vs Atenolol (SILVHIA) trial.

BACKGROUND: The cytochrome P450 CYP2C9 enzyme (CYP2C9) metabolizes many clinically important drugs, for example, phenytoin, warfarin and the angiotensin II type 1 (AT(1)) receptor antagonists, losartan and irbesartan. Single nucleotide polymorphisms in the CYP2C9 gene result in the expression of three important variants, CYP2C9*1(wild-type), CYP2C9*2 and CYP2C9*3, the last two exhibiting reduced catalytic activity compared with the wild-type. The CYP2C9 genotype is known to determine sensitivity to and dose requirements for both warfarin and phenytoin, and also the rate of metabolism of losartan. However, its influence on clinical response to treatment with the AT(1) receptor antagonist, irbesartan, has not been investigated. OBJECTIVE: To determine whether the CYP2C9genotype influences the blood pressure-decreasing response to antihypertensive treatment with irbesartan. DESIGN AND METHODS: One hundred and two patients with essential hypertension and left ventricular hypertrophy were allocated randomly to groups to receive double-blind treatment with either irbesartan (n = 49) or the beta(1)-adrenergic receptor blocker, atenolol ( n= 53). Blood pressure was measured before and after 12 weeks of treatment. genotyping was performed using solid-phase minisequencing. RESULTS: The diastolic blood pressure (DBP) response differed in relation to the CYP2C9 genotype in patients given irbesartan: the reduction in patients with genotype CYP2C9*1/CYP2C9*1 (n = 33) was 7.5% and that with CYP2C9*1/CYP2C9*2 (n = 12) was 14.4% ( P= 0.036). A similar trend was seen for systolic blood pressure. In contrast, no relation was seen between the CYP2C9 genotype and blood pressure response to atenolol, a drug not metabolized via CYP2C9. CONCLUSIONS: The CYP2C9 genotype seems to predict the DBP response to irbesartan, but not to atenolol, in patients with essential hypertension.

Adult↗
PubMed2003

A microarray minisequencing system for pharmacogenetic profiling of antihypertensive drug response.

We aimed to develop a microarray genotyping system for multiplex analysis of a panel of single nucleotide polymorphisms (SNPs) in genes encoding proteins involved in blood pressure regulation, and to apply this system in a pilot study demonstrating its feasibility in the pharmacogenetics of hypertension. A panel of 74 SNPs in 25 genes involved in blood pressure regulation was selected from the SNP databases, and genotyped in DNA samples of 97 hypertensive patients. The patients had been randomized to double-blind treatment with either the angiotensin II type 1 receptor blocker irbesartan or the beta 1-adrenergic receptor blocker atenolol. Genotyping was performed using a microarray based DNA polymerase assisted 'minisequencing' single nucleotide primer extension assay with fluorescence detection. The observed genotypes were related to the blood pressure reduction using stepwise multiple regression analysis. The allele frequencies of the selected SNPs were determined in the Swedish population. The established microarray-based genotyping system was validated and allowed unequivocal multiplex genotyping of the panel of 74 SNPs in every patient. Almost 7200 SNP genotypes were generated in the study. Profiles of four or five SNP-genotypes that may be useful as predictors of blood pressure reduction after antihypertensive treatment were identified. Our results highlight the potential of microarray-based technology for SNP genotyping in pharmacogenetics.

Adrenergic beta-Antagonists↗
PubMed2004

Endothelial venodilator response in carriers of genetic polymorphisms involved in NO synthesis and degradation.

AIMS: Polymorphisms of the NOSIII gene and of the CYBA gene have been associated with a number of pathological conditions such as arterial hypertension, coronary artery disease, and myocardial infarction. Because endothelium-dependent vasodilation is impaired in these disorders, we hypothesized that polymorphisms of NOSIII or CYBA might modulate endothelial function of venous capacitance vessels already before cardiovascular disease becomes overt. METHODS: Endothelium-dependent and -independent venodilation was assessed by measuring local vascular responses to bradykinin and sodium nitroprusside in the dorsal hand vein after preconstriction with phenylephrine in 72 healthy male Caucasians after careful exclusion of cardiovascular risk factors. Genotyping was performed for polymorphisms of the NOSIII gene (T-786C, G894T, (CA)(n)) and the CYBA gene (C242T). RESULTS: Genotype distribution for each polymorphism followed the Hardy-Weinberg equilibrium. In all studied single nucleotide polymorphisms no significant difference between the respective genotypes and the venodilator response to either sodium nitroprusside or bradykinin was observed, and the number of CA repeat copies was not related to the venodilator response to bradykinin. Mean venodilation induced by bradykinin 50 ng min(-1) (+/-SEM) for homozygote carriers of the single nucleotide polymorphisms was 48.9 +/- 8.5% venodilation (G894T; wild type: 49.8 +/- 6.9), 50.3 +/- 11.0% venodilation (T-786C; wild type: 42.6 +/- 5.2), and 30.4 +/- 9.1% venodilation (C242T; wild type: 49.2 +/- 6.0), respectively. CONCLUSIONS: This study suggests that the studied polymorphisms of NOSIII and CYBA do not significantly modulate endothelium-dependent venodilation in individuals without vascular risk factors.

Bradykinin↗
PubMedDate not supplied

Interleukin-6 polymorphisms and the risk of cervical cancer.

Recent data implicate that cytokine gene polymorphisms are important in pathogenesis of various neoplastic and nonneoplastic human diseases, and it was recently suggested that polymorphisms in interleukin (IL)-6 might increase the risk of gynecological malignancies, including cervical carcinomas. The aim of this case-control study is to compare the IL-6 polymorphisms in cervical cancer patients and healthy controls and to assess whether any of these polymorphisms would increase the risk of developing cervical cancer. The material in this case-control study consists of 56 patients with cervical carcinoma and 253 population-based control subjects, all ethnic Brazilian women. Control subjects were cancer-free women, following a negative cervical cytology and colposcopy. IL-6 genotyping was performed using a polymerase chain reaction-based restriction fragment length polymorphism. Distribution of the GG, GC, and CC genotypes in cases and controls was significantly different (P= 0.033). Compared with the GG genotype as reference, the adjusted odds ratio for the combined GC and CC genotypes in cancer patients was 1.90 (95% confidence interval, 1.1-3.4). These data suggest that women carrying at least one C genotype in their IL-6 promoter region (-174G-->C) are at higher risk of developing cervical cancer.

Adult↗
PubMed2005

Association analysis of malic enzyme 2 gene polymorphisms with idiopathic generalized epilepsy.

PURPOSE: Linkage disequilibrium mapping revealed allelic and haplotypic associations between single-nucleotide polymorphisms (SNPs) of the gene encoding the malic enzyme 2 (ME2) and adolescent-onset idiopathic generalized epilepsy (IGE). Homozygote carriers of the associated ME2 haplotype had a sixfold higher risk of IGE compared with any other genotype. The present population-based association study tested whether genetic variation of the ME2 gene confers susceptibility to common IGE syndromes in the German population. METHODS: The study included 666 German healthy control subjects and 660 German IGE patients (IGE group), of which 416 patients had an age at onset in adolescence (IGEado group). Genotyping was performed for six SNPs and one dinucleotide repeat polymorphism, all located in the ME2 region. RESULTS: Neither allele nor genotype frequencies of any ME2 polymorphism differed significantly between the controls and the IGE groups (p > 0.22). No hint of an association of the putative risk-conferring haplotype was seen, when present homozygously, in both IGE groups compared with controls (p > 0.18). CONCLUSIONS: These results do not support previous evidence that genetic variation of the ME2 gene predisposes to common IGE syndromes. Thus if a recessively inherited ME2 mutation is present, then the size of the epileptogenic effect might be too small or not frequent enough to detect it in the present IGE sample.

Age of Onset↗