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PubMed2025

Association of the pri-miR-34b/c rs4938723 T > C polymorphism with hepatoblastoma susceptibility in Eastern Chinese children: A five-center case-control study.

BACKGROUND: Hepatoblastoma is the most prevalent liver cancer affecting children, and its intricate causes are closely linked to genetic variations. This study interrogated the influence of the miR-34b/c rs4938723 T > C polymorphism in hepatoblastoma predisposition in a Han Chinese children study population, comprising 193 cases and 773 controls from East China. METHODS: Genotyping was performed via the TaqMan technique. The association between this genetic variant and hepatoblastoma susceptibility was determined via logistic regression models adjusted for age and sex. RESULTS: Our results show that the TC genotype of the miR-34b/c rs4938723 polymorphism is associated with a significantly reduced risk of hepatoblastoma under a heterozygous model (adjusted OR = 0.59, 95% CI = 0.41-0.84, P = 0.003), whereas the CC genotype is associated with an increased risk under a recessive model (adjusted OR = 1.79, 95% CI = 1.17-2.73, P = 0.008). Further stratified analysis revealed that the TC/CC genotypes were linked to a lower risk of hepatoblastoma in girls and those with advanced clinical stages (III + IV). Furthermore, we identified the miR-34b/c rs4938723 polymorphism as an expression quantitative trait locus that affects the expression of nearby genes. The CC genotype was related to a decrease in LAYN expression in the colon, brain, and lung and decreased PPP2R1B expression in the testis. These findings suggest that miR-34b/c rs4938723 T > C has the potential to modify hepatoblastoma predisposition through its regulatory effects on gene expression. CONCLUSIONS: This study provides evidence for the association between the miR-34b/c rs4938723 polymorphism and hepatoblastoma risk in Chinese Han children from East China, suggesting that this polymorphism may have potential as a biomarker for predicting hepatoblastoma susceptibility in this specific population.

Child↗
PubMed2005

Prostate cancer risk and IRS1, IRS2, IGF1, and INS polymorphisms: strong association of IRS1 G972R variant and cancer risk.

BACKGROUND: As cellular proliferation is central to the carcinogenic process, pathways that regulate proliferation may be important. Therefore, genes in the insulin and the insulin-like growth factor signaling pathways are plausible candidates for susceptibility genes for prostate cancer. We hypothesized that functional polymorphisms in INS, IRS1, IRS2, and IGF1 may be associated with prostate cancer. METHODS: We studied 199 incident prostate cancer cases and 267 age-matched controls. Genotyping was performed for the INS +1127 Ins-PstI, IRS1 G972R, IRS2 G1079D, and the IGF1 CA-repeat polymorphisms. Outcomes were prostate cancer, Gleason score, and AJCC stage. RESULTS: The IRS1 G972R GR/RR genotypes were associated with a significant 2.8-fold increased risk for prostate cancer (95% CI 1.5-5.1, P = 0.0007). The other variants were not significantly associated with prostate cancer. The IRS1 G972R GR/RR genotypes were also significantly associated with more advanced Gleason score (P = 0.001) and AJCC stage (P = 0.004). CONCLUSIONS: These results support a role of the insulin and/or insulin-like growth factor pathways in the etiology of prostate cancer.

Adult↗
PubMed2007

Lack of association of IL8 gene polymorphisms with familial vesico-ureteral reflux.

Vesico-ureteral reflux (VUR) is the most common inherited disorder of the lower urinary tract. Children with VUR are at risk for ongoing renal damage with subsequent infections. IL8 is an important inflammatory mediator which can be produced by epithelial cells of the renal tract in response to a variety of inflammatory stimuli. High serum concentrations of IL-8 have been reported in patients with chronic renal failure. Elevated IL-8 levels have been reported in the urine of patients with VUR and renal parenchymal scarring (RPS). More recently it was reported that urine IL-8 levels remain elevated in infants with VUR even in the absence of a urinary tract infection (UTI). Increased IL-8 expression has been shown to be associated with polymorphism at position -251 (rs4073) of the IL-8 promoter. The aim of this study was to examine the association of IL-8 gene polymorphism with familial VUR in a cohort of 219 siblings from 109 families affected with VUR, the largest such cohort tested to date. RPS was assessed using dimercaptosuccinic acid scintigraphy. Genotyping was performed in 219 siblings with VUR (157 without RPS, 62 with RPS) and 292 controls for the position -251 of IL-8 gene by polymerase chain reaction with tetra primers and gel analysis. Genotype was compared using the chi square test. Statistical significance was taken as a value of P < 0.05. There were no significant differences in IL-8 -251 genotype frequency between VUR patients and controls. Similarly, gender, severity of VUR and renal parenchymal scarring had no effect on IL-8 -251 genotype frequency. Although IL-8 urinary levels have been reported to be elevated in VUR, our data indicate that IL-8 gene is not involved in the pathogenesis of familial VUR or reflux nephropathy.

Chelating Agents↗
PubMed2006

The differential effects of age on the association of KLOTHO gene polymorphisms with coronary artery disease.

The Klotho knockout mouse is thought to be a good animal model for human aging. Recent studies have reported on the association of KLOTHO gene mutation with cardiovascular disease in humans. We observed the frequencies of single nucleotide polymorphisms, that is, G-395A in the promoter region, C1818T in exon 4, and a functional variant, KL-VS, of KLOTHO gene in Koreans, and we investigated their relationships with the presence of coronary artery disease (CAD) in patients who had undergone coronary angiograms. A total of 274 subjects who underwent coronary angiograms because of chest pain were enrolled, and their blood pressure, body mass index, fasting blood glucose level, and lipid profiles were measured. Genotypings were performed on samples of their blood with real-time polymerase chain reaction. Two single nucleotide polymorphisms, G-395A and C1818T, complied with Hardy-Weinberg equilibrium. For the KL-VS genotype, 1 homozygote subject for the adverse allele was detected among the entire population (GG for F352V and CC for C370S). When the subjects were classified into 4 groups according to the number of stenotic vessels, there were no differences among the mean values of the cardiovascular risk factors, except for age and the fasting blood glucose levels, which showed a significant difference between that of the normal and the diseased vessel groups. There were no differences in the prevalence of CAD according to the genotypes of the G-395A polymorphism; however, for the C1818T polymorphism, those subjects with the T allele showed a lower prevalence of CAD than those with the CC genotype. When the subjects were divided into 2 groups according to age, in the group younger than 60 years, T allele carriers of the C1818T polymorphism showed a lower prevalence of CAD than did the noncarriers. In the group older than 60 years, A allele carriers of the G-395A polymorphism showed a lower prevalence of CAD than did the noncarriers. On the haplotype analysis, the GG-CC haplotype showed an increased risk for CAD with an odds ratio of 2.594 (95% confidence interval, 1.385-4.858; P = 0.003). Differential effects of age were observed in the association of KLOTHO G-395A and C1818T polymorphisms with CAD in Koreans. The KL-VS variant seems to be rarely found in the Korean population. These results infer the possibility of the KLOTHO gene being a candidate gene of atherosclerosis in humans, and further research on this topic needs to be done.

Aged↗
PubMed2002

Clinical significance of T.T. virus infection in maintenance hemodialysis patients of an endemic area for hepatitis C infection.

Clinical significance of TTV infection was analyzed in Egyptian hemodialysis (HD) patients. Forty-seven Egyptian patients on maintenance HD and 50 age-matched volunteer blood donors were investigated. TT virus (TTV) DNA detection and genotyping were performed using a semi-nested polymerase chain reaction with specific primers. The prevalence of TTV DNA in patients on HD (66%) was significantly (P<0.001) higher than in blood donors (24%) with genotype 1b predominance (89%) in both. Clinical background including mean age, sex, history of blood transfusion, and positive markers for either hepatitis B virus (HBV) or hepatitis C virus (HCV) did not differ between TTV DNA positive and negative HD patients. However, the mean duration of HD was significantly (P=0.032) shorter in the TTV positive patients (28+/-19 months) than in the negative ones (45+/-34 months). Mean alanine aminotransferase level in patients with HCV infection alone (41+/-24 IU/l) did not differ from that in patients with both co-infection (33+/-28 IU/l), but was significantly higher than that in patients with TTV infection alone (26+/-10 IU/l). Occurrence of chronic hepatic changes in patients with TTV infection alone (7%) was significantly less common than those with HCV infection alone (100%, P<0.001) or those with both co-infection (100%, P<0.001). Serum level of HCV core protein was similar between patients with HCV infection alone and those with co-infection with TTV. In conclusion, the prevalence of TTV infection is high in Egyptian patients on regular HD, especially with shorter duration on HD. No clinical significance of TTV virus could be elicited in HD Egyptian patients; neither it showed any clinical impact as a co-infection with HCV.

Journal Article↗
PubMed1995

Genetic heterogeneity of hepatitis C virus: quasispecies and genotypes.

Worldwide, HCV is a major etiologic agent of chronic hepatitis that may lead to the development of liver cirrhosis and hepatocellular carcinoma. Thus, significant morbidity and mortality is caused by HCV infection and effective control measures against the spread of this virus are needed. Originally, the extent of genetic heterogeneity of HCV was not fully appreciated. However, the breadth of the genetic heterogeneity of HCV is great, and this may have important implications in diagnosis, pathogenesis, treatment, and vaccine development. In an infected individual the HCV genome population circulates as a quasispecies distribution of closely related yet heterogeneous RNA sequences centered around one dominant sequence. The dominant sequence, as well as the consensus sequence, changes sequentially during the course of the infection. A hypervariable region (HVR1) within one of the envelope proteins of HCV (E2) evolves very rapidly. Patients infected with HCV mount a humoral immune response to epitopes of HVR1. However, sequential changes in the consensus sequence of HVR1 during infection result in the generation of variants that are not recognized by preexisting antibodies. This might represent a mechanism by which HCV evades host immune surveillance and establishes and maintains persistent infection. It will be important to determine whether HVR1 of HCV, as was found for the V3 loop of HIV, contains epitopes that elicit neutralizing antibodies against HCV. Furthermore, it will be important to determine whether the quasispecies nature of HCV helps the virus evade the cytotoxic T-cell response of the host. Analysis of complete or partial HCV genomic sequences revealed that HCV exists as multiple, distinct genotypes. A total of nine major genetic groups and at least 30 subgroups have been recognized. To evaluate the current classification of HCV genotypes, we performed phylogenetic analyses of complete and partial nucleotide sequences from isolates that represent all published variants of HCV. Analysis of complete HCV sequences, which represent three major genetic groups, supports the currently used genotype classification scheme. However, analysis of the partial genomic regions (ie, C, E1, and NS5b) of HCV isolates that represent all recognized variants of HCV demonstrates that the genetic relatedness among some of the genotypes was not equivalent in the different gene regions. Furthermore, the distinction among isolates, subtypes, and types of HCV was not always clear. This finding might reflect the shortcomings of analyzing only limited gene regions or may reflect the wide spectrum of genetic variation of HCV.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed2005

Influence of the endothelial nitric oxide synthase gene on conventional and ambulatory blood pressure: sib-pair analysis and haplotype study.

BACKGROUND: Nitric oxide is involved in the regulation of vascular basal tone and blood pressure. Polymorphisms of NOS3, the gene that codes for endothelial nitric oxide synthase, have been associated with essential hypertension. OBJECTIVE: To look for linkage and association of three di-allelic polymorphisms (Glu298Asp, intron 4 VNTR and T-786C) and the intron 13 CA-repeat of NOS3 with blood pressure as a continuous trait. METHODS: Genotyping was performed in 110 dizygotic white twin pairs from Flanders, Belgium. The influence of NOS3 polymorphisms on conventional and ambulatory blood pressure was assessed by sib-pair analysis and haplotype association analysis. RESULTS: Genotype frequencies were similar to those previously reported in white populations. Sib-pair analysis did not show a significant influence of either polymorphism on blood pressure. Haplotype analysis disclosed a significant association between NOS3 haplotypes and daytime ambulatory diastolic (P = 0.02) and systolic (P < 0.0001) blood pressure, the latter remaining significant after multiple testing was taken into account (P = 0.032). The association between daytime ambulatory systolic blood pressure and NOS3 haplotypes was mainly attributable to four haplotypes accounting for 11.9% of all represented haplotypes. CONCLUSION: We show for the first time a highly significant association of ambulatory blood pressure with NOS3 haplotypes in well-characterized white individuals from Flanders. These results pave the way for studies looking for the influence of NOS3 on blood pressure in high-risk subsets such as diabetic or hypertensive patients. They indicate the importance of ambulatory blood pressure and haplotype analysis in revealing the moderate effect of polymorphisms on blood pressure.

Adult↗
PubMedDate not supplied

Prevalence and genotypes of hepatitis G virus among hemodialysis patients in Eastern Anatolia, Turkey.

OBJECTIVES: To study the prevalence and genotype distribution of hepatitis G virus (HGV) in hemodialysis patients in East Anatolia, Turkey. SUBJECTS AND MATERIALS: Eighty-nine hemodialysis patients and 30 healthy individuals were analyzed by using reverse-transcriptase nested polymerase chain reaction with primers specific for 5' untranslated region. HGV genotyping was performed by PCR and three randomly selected HGV-positive samples were sequenced. RESULTS: Of the 89 hemodialysis patients, HGV RNA was detected in 9 (10.2%). All of our isolates were assigned to genotype 2. CONCLUSION: Our results showed that hemodialysis patients carry the risk for HGV infection in East Anatolia, Turkey.

Adult↗
PubMed1995

Angiotensin-I converting enzyme genotypes and left ventricular hypertrophy in patients with hypertrophic cardiomyopathy.

BACKGROUND: The variability of the phenotypic expression of left ventricular hypertrophy (LVH) in patients with hypertrophic cardiomyopathy (HCM) indicates a potential role for additional modifying genes. Variants of angiotensin-I converting enzyme (ACE) gene have been implicated in cardiac hypertrophy. To assess whether ACE genotypes influence the phenotypic expression of hypertrophy, we determined the left ventricular mass index (LVMI) and extent of hypertrophy in 183 patients with HCM. METHODS AND RESULTS: LVMI was derived by the area-length method using two-dimensional echocardiograms. Extent of LVH was determined by a point score method (1 to 10 points). DNA was extracted from blood, and ACE genotyping was performed by polymerase chain reaction (PCR) with an established protocol. Amplification of DNA in the region of polymorphism by PCR of alleles I and D showed 490- and 190-bp products, respectively. ACE genotypes DD, ID, and II were present in 60, 90, and 33 patients with HCM, respectively. In genetically independent patients (n = 108), the mean LVMI (g/m2) was 148 +/- 35.3 in those with DD (n = 35) and 134.2 +/- 33.3 in those with ID and II (n = 73) genotypes (P = .046). LVH score was 6.69 +/- 1.71 in patients with DD and 5.55 +/- 2.19 in those with ID and II genotypes (P = .004). Regression analysis showed that ACE genotypes accounted for 3.7% and 6.5% of the variability of LVMI and LVH score (P = .046 and P = .008, respectively). In 26 patients from a single family, LVMI and LVH score were also greater in patients with DD than in those with ID and II genotypes. ACE genotypes accounted for 14.7% and 10.4% of the variability of the LVMI and extent of hypertrophy, respectively. CONCLUSIONS: ACE genotypes influence the phenotypic expression of hypertrophy in HCM.

Adult↗
PubMed2005

SULT1A1 genotype, active and passive smoking, and breast cancer risk by age 50 years in a German case-control study.

INTRODUCTION: Sulfotransferase 1A1 (encoded by SULT1A1) is involved in the metabolism of procarcinogens such as heterocyclic amines and polycyclic aromatic hydrocarbons, both of which are present in tobacco smoke. We recently reported a differential effect of N-acetyltransferase (NAT) 2 genotype on the association between active and passive smoking and breast cancer. Additional investigation of a common SULT1A1 genetic polymorphism associated with reduced enzyme activity and stability might therefore provide deeper insight into the modification of breast cancer susceptibility. METHODS: We conducted a population-based case-control study in Germany. A total of 419 patients who had developed breast cancer by age 50 years and 884 age-matched control individuals, for whom risk factor information and detailed smoking history were available, were included in the analysis. Genotyping was performed using a fluorescence-based melting curve analysis method. Multivariate logistic regression analysis was used to estimate breast cancer risk associated with the SULT1A1 Arg213His polymorphism alone and in combination with NAT2 genotype in relation to smoking. RESULTS: The overall risk for breast cancer in women who were carriers of at least one SULT1A1*2 allele was not significantly different from that for women with the SULT1A1*1/*1 genotype (adjusted odds ratio 0.83, 95% confidence interval 0.66-1.06). Risk for breast cancer with respect to several smoking variables did not differ substantially between carriers of the *2 allele and noncarriers. However, among NAT2 fast acetylators, the odds ratio associated with passive smoking only (3.23, 95% confidence interval 1.05-9.92) was elevated in homozygous carriers of the SULT1A1*1 allele but not in carriers of the SULT1A1*2 allele (odds ratio 1.28, 95% confidence interval 0.50-3.31). CONCLUSION: We found no evidence that the SULT1A1 genotype in itself modifies breast cancer risk associated with smoking in women up to age 50 years. In combination with NAT2 fast acetylator status, however, the SULT1A1*1/*1 genotype might increase breast cancer risk in women exposed to tobacco smoke.

Adult↗
PubMed2003

Impact of genotypic resistance testing on selection of salvage regimen in clinical practice.

OBJECTIVE: To determine whether genotypic resistance testing leads to selection of more potent drug regimens when compared to regimens based on treatment history only. DESIGN: Prospective, tertiary care centre-based study. PATIENTS: One-hundred-and-forty-five HIV-infected adults on stable antiretroviral therapy (ART) for >6 months experiencing virological failure. METHODS: The physicians' decision-making process when choosing a salvage regimen was prospectively documented: at time of virological failure, on 'failing ART', genotyping was performed and a hypothetical 'clinical expert ART' based upon patient's drug history was documented. Subsequently, data on resistance mutations, rating by a decision support software and drug history were used to define 'genotyping ART'. After discussion with the patient, final treatment, 'new personalized ART' was chosen and prescribed. To compare the relative potency of the four ART regimens in a standardized manner, a resistance score ranging from 1 (best) to 8 (worst) based on drug ranking by decision support software was attributed to each ART regimen. Virological and immunological outcomes were analysed based on the magnitude of the resistance score. RESULTS: Median follow-up was 1.5 years. In all 145 patients, median resistance scores for the stepwise selected ART regimens were: 'failing ART': 4.5, 'clinical expert ART': 1.8, 'genotyping ART': 1.5 and 'new personalized ART': 2. The latter was 1.5 in patients who effectively switched to 'new personalized ART' (n=89). Lower resistance scores translated into significantly improved virological response after initiation of 'new personalized ART'. In multivariable analysis, lower resistance scores, lower baseline HIV RNA levels and use of novel antiretroviral drugs were associated with the probability of reducing plasma viraemia to <50 copies/ml. CONCLUSIONS: This study suggests that treatment choices including genotype and decision support software were virologically superior to those based on drug history only.

Adult↗
PubMed2003

Growth performance, dry matter and nitrogen digestibilities, serum profile, and carcass and meat quality of pigs with distinct genotypes.

We investigated the effect of distinct genotypes on growth performance, DM and N digestibilities, serum metabolite and hormonal profiles, and carcass and meat quality of pigs. Eight control-line and eight select-line pigs with an equal number of gilts and castrated males per genotype were chosen from the group of pigs subjected to selection for lean growth efficiency. Pigs were housed individually and allowed ad libitum access to common grower, finisher 1, and finisher 2 diets when they reached approximately 20, 50, and 80 kg, respectively, and water throughout the study. Although genotype had no effect on growth performance during the finisher 2 phase and overall, select-line pigs grew faster and more efficiently (P < 0.05) during the grower and finisher 1 phases than did control-line pigs. Dry matter and N digestibilities during the grower phase were lower (P < 0.05) in select-line pigs compared with control-line pigs. Select-line pigs had less ultrasound backfat (P < 0.05) at the end of the grower and finisher 2 phases. Serum urea N (P < 0.05) and leptin concentrations were lower in select-line pigs than in control-line pigs, but the effect of genotype on serum glucose, triglyceride, or insulin concentration was rather inconsistent. Select-line pigs had heavier heart (P < 0.05), liver (P = 0.08), and kidneys (P < 0.01), implying a higher metabolic activity. Less 10th-rib carcass backfat (P < 0.01) and a trend for larger carcass longissimus muscle area (P = 0.10) were reflected in the greater (P < 0.01) rate and efficiency of lean accretion in select-line pigs. Select-line pigs had lower subjective meat color (P < 0.01), marbling (P < 0.05), and firmness (P < 0.01) scores. Final serum leptin concentration was correlated positively with carcass backfat thickness (r = 0.73; P < 0.01) and negatively with overall feed intake (r = -0.77; P < 0.01). These results indicate that pigs with distinct genotypes exhibited differences in the growth rate, metabolite and hormonal profiles, and body composition. Further research is necessary to determine whether pigs with distinct genotypes respond differently to dietary manipulations, which would have an effect on developing optimal feeding strategies for efficient and sustainable pig production.

Adipose Tissue↗
PubMed2005

Pro- and anti-inflammatory cytokine gene polymorphism profiles in Bulgarian multiple sclerosis patients.

Dysregulation in the expression of pro- and anti-inflammatory cytokines is one of the milestones in multiple sclerosis (MS) development and progression. The aim of this study was to investigate the possible influence of TNF-alpha (-308), TGF-beta (codons 10 and 25), IL-10 (-1082, -819, -592), IL-6 (-174) and IFN-gamma (+874) polymorphisms on susceptibility to multiple sclerosis (MS). Genotyping was performed by PCR-SSP method in 55 MS patients with relapsing-remitting form of the disease and 86 healthy subjects from Bulgarian population. We observed a statistically significant increase in the CC genotype of IL-10 -819 and -592 SNPs coupled with a decreased frequency of the TGF-beta +915 CG genotype in our MS patients (Pc<0.05). No significant differences were observed between MS patients and controls with respect to the distribution of the other cytokine gene polymorphisms investigated. Although the size of the study group is small, these results indicate that polymorphic variations of two of the major anti-inflammatory cytokines, IL-10 and TGF-beta, may play a role in MS susceptibility.

Adult↗
PubMed2003

The T-786C and Glu298Asp polymorphisms of the endothelial nitric oxide gene affect the forearm blood flow responses of Caucasian hypertensive patients.

OBJECTIVES: We sought to investigate whether two polymorphisms located in the promoter (T(-786)C) and exon 7 (Glu298Asp) of the endothelial nitric oxide (NO) synthase (eNOS) gene affected agonists-mediated NO release. BACKGROUND: Endothelial dysfunction can be genetically determined. Therefore, we investigated whether two polymorphisms located in the eNOS gene affected agonists-mediated NO release. METHODS: We compared endothelial-dependent and -independent vasodilation of the different eNOS genotypes in a cross-sectional study on 187 subjects, of whom 137 were uncomplicated essential hypertensive patients (PH) (49 +/- 9 years, 151 +/- 11/99 +/- 5 mm Hg) and 50 healthy normotensive subjects (NT) (43 +/- 16 years, 123 +/- 10/78 +/- 7 mm Hg). Endothelial-dependent and -independent vasodilation was assessed as the forearm blood flow response to incrementally increasing doses of acetylcholine (0.15, 0.45, 1.5, 4.5, 15 microg/100 ml/min) and sodium nitroprusside (1, 2, 4 microg/100 ml/min), respectively. Genotyping was performed with melting curve analysis (Lightcycler) of polymerase chain reaction products from acceptor (5' end-labeled with LCRed 640) and donor probes (3' end-labeled with fluorescein) specific for each polymorphism. The genotype distribution of T(-786)C (CC = 21.9%, CT = 48.7%, TT = 29.4%) and Glu298Asp (GG = 39.0%, GT =51.9%, TT = 9.1%) was similar in PH and NT. A repeated measure analysis of variance showed a blunting of endothelium-dependent vasodilation in PH compared with NT (p < 0.001). A significant effect of the T(-786)C (p = 0.002) but not of the Glu298Asp (p = NS) eNOS polymorphism on endothelial-dependent vasodilation was found. However, we also detected a significant interaction between the T(-786)C and Glu298Asp polymorphism (p < 0.001). No effect on either polymorphism on endothelial-independent vasodilation was seen. CONCLUSIONS: The T(-786)C promoter polymorphism and its interaction with exon 7 Glu298Asp affect endothelium-dependent vasodilation in mild-to-moderate PH patients and NT Caucasian subjects.

Adult↗
PubMed2002

CTLA-4 49 A/G dimorphism and type 1 diabetes susceptibility: a French case-control study and segregation analysis. Evidence of a maternal effect.

Several studies have demonstrated an association of cytotoxic T lymphocyte-associated molecule 4 (CTLA-4) (IDDM 12) alanine 17 with type 1 diabetes, but we wished to study the parental effect of CTLA-4 49 A/G dimorphism in diabetic families. The CTLA-4 exon 1 polymorphism (49 A/G), HLA-DRB1 and insulin gene (INS) variable number tandem repeats (VNTR) were analysed in 134 type 1 diabetic patients vs. 273 control subjects. The segregation analysis for transmission was carried out in 70 informative diabetic families using the transmission distortion test (TDT). All genotyping was performed by PCR-RFLP. CTLA-4 49 G allele frequency was not increased in diabetic patients compared to controls (41 vs. 38%, not significant). The distribution of GG, AG and AA CTLA-4 genotypes was similar in the two groups (13, 57 and 30% vs. 11, 54 and 35%, respectively) and was independent of HLA-DRB1 or INS VNTR polymorphism. The CTLA-4 49 G allele showed weak distorted transmission to the diabetic offspring, whereas random transmission was observed in unaffected offspring. This distortion is attributable to a maternal effect (71% compared to the 50% expected ratio; tdt = 4.8; P < 0.03). The combined transmission of maternal CTLA-4 G with HLA-DRB1*03 (90%; tdt = 6.4; P < 0.01) and VNTR class I (80%; tdt = 5.4; P < 0.02) enhanced the susceptibility effect of each marker separately. We noted a slight CTLA-4 49 G and HLA-DRB1*04 distortion of transmission shared in paternal and maternal diabetic meiosis. In non-diabetic offspring, the CTLA-4 49 A allele confers a protective effect in the presence of maternal HLA-DRB1*03 and paternal HLA-DRB1*04 alleles. Despite the absence of a positive association of the CTLA-4 49 G allele with type 1 diabetes, our segregation analysis supports the hypothesis of a modulation by CTLA-4 49 G/A dimorphism of the susceptibility conferred by maternal HLA-DRB1*03 inheritance. This potential parental effect needs to be confirmed in a larger data set.

Adenine↗
PubMed2006

Cytokine genotyping in preeclampsia.

PROBLEM: Considering that cytokines are involved in preeclampsia (PE) pathogenesis and that cytokine gene polymorphism may affect cytokine production, our purpose was to investigate the association of PE with tumor necrosis factor (TNF)-alpha (-308), transforming growth factor-beta1 (+10; 25), interleukin (IL)-10 (-1082), IL-6 (-174), and interferon-gamma (+874) polymorphisms. METHOD OF STUDY: Genotyping was performed in women with PE (56 White and 95 non-White women) and in women without obstetric pathology (92 White and 97 non-White women). Data were analyzed by the chi-square or Fisher exact test. We performed a meta-analysis encompassing these and results from other laboratories on the association of TNF-alpha polymorphisms and PE. RESULTS: We observed a lower frequency of the IL-10 -1082-G/G genotype in White women with PE (PE: 5%; Control (C): 15%, P = 0.02) and no association for all other polymorphisms, including meta-analysis of TNF-alpha results. CONCLUSION: Our study suggests that PE is associated with IL-10-(1082) polymorphism but not with TNF-(308) polymorphism. On the basis of meta-analysis, we confirm the need for more studies for the evaluation of cytokine genotype in disease.

Adult↗
PubMed2002

Pharmacogenetics of acenocoumarol: cytochrome P450 CYP2C9 polymorphisms influence dose requirements and stability of anticoagulation.

BACKGROUND AND OBJECTIVES: Cytochrome P4502C9 (CYP2C9) is the main enzyme implicated in coumarinic metabolism. Variant alleles, CYP2C9*2 and CYP2C9*3, have been related to decreased enzymatic activity, but their clinical relevance in acenocoumarol metabolism has not been established. We investigated CYP2C9 polymorphisms in relation to acenocoumarol dose requirement, stability of anticoagulation and bleeding. DESIGN AND METHODS: CYP2C9 genotyping was performed in 325 acenocoumarol-treated patients (INR target between 2.0 and 3.0) and in an additional group of 84 patients with repeated bleeding. RESULTS: Patients with the wild-type CYP2C9*1/*1 genotype (n=169) required a higher maintenance dose of acenocoumarol (17.1 8.7 mg/week) than did patients with the CYP2C9*2 (14.6 6.4 mg/week, p<0.05, N=97) or the CYP2C9*3 allele (11.2 6.2 mg/week, p<0.001, n=59). Out of 170 patients requiring a low-dose of acenocoumarol ( 70 years (OR=3.73, 95%CI=2.29-6.08, p<0.001), and the CYP2C9*3 allele (OR=4.75, 95%CI=2.36-9.55, p <0.001). Carriers of CYP2C9*3 spent less time within the therapeutic range (64.7 23.1%) than did patients with the CYP2C9*1/*1 genotype (75.1 22.0%, p<0.01), and more frequently had an INR >4.5 at the initiation of treatment (43.9% vs.11.6%, p<0.001), but did not show repeated bleeding more frequently (19.0% vs.15.5%, p=NS). INTERPRETATION AND CONCLUSIONS: CYP2C9*3 is related to lower acenocoumarol dose requirements, a higher frequency of over-anticoagulation at the initiation of therapy and an unstable anticoagulant response.

Acenocoumarol↗
PubMed2006

Genetic variants in peroxisome proliferator-activated receptor gamma influence insulin resistance and testosterone levels in normal women, but not those with polycystic ovary syndrome.

OBJECTIVE: To investigate the relationship of the peroxisome proliferator-activated receptor gamma (PPARG) Pro12Ala and silent exon 6 (His447His) polymorphisms with the clinical features of polycystic ovary syndrome (PCOS). DESIGN: Patients with PCOS and control subjects were genotyped for Pro12Ala and His447His. Associations between genotype, diagnosis, and hormonal/metabolic parameters were assessed. SETTING: Subjects were recruited from the reproductive endocrinology clinic at the University of Alabama at Birmingham, Birmingham, Alabama. Control subjects were recruited from the surrounding community. Genotyping was performed at the Cedars-Sinai Medical Center in Los Angeles, California. PATIENT(S): Participants included 285 white women with PCOS and 187 controls. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): The Pro12Ala and His447His genotypes, and hormonal and metabolic phenotypes. RESULT(S): The Pro12Ala and His447His genotypes did not influence risk of PCOS or its component phenotypes in patients with PCOS. In controls, Pro12Ala did not influence measures of insulin resistance or androgen production. However, carriers of the His447His T-allele had significantly decreased free and total T levels, and a significantly decreased homeostasis model assessment index of insulin resistance. Furthermore, haplotypes in controls bearing the His447His T-allele were also associated with decreased T. CONCLUSION(S): Peroxisome proliferator-activated receptor gamma does not appear to be an important modifier gene in PCOS. In controls, however, the His447His T-allele may be in linkage disequilibrium with a functional variant that influences insulin resistance and T production.

Adolescent↗