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PubMed2005

Glyceryl trinitrate-induced angiotensin-converting enzyme (ACE) inhibition in healthy volunteers is dependent on ACE genotype.

Evidence concerning the importance of angiotensin-converting enzyme (ACE) genotype in cardiovascular diseases is accumulating. The aim of this study was to investigate if nitric oxide (NO), generated from glyceryl trinitrate (GTN), affects human serum ACE activity in vivo, and if so, whether this effect was dependent on ACE genotype and (or) reflected in blood pressure reduction. A tablet containing 5 mg GTN was bucally administered for 5 minutes to 17 healthy volunteers. Blood pressure (BP) was recorded, and serum ACE activity, ACE genotype, and plasma cGMP was analyzed. GTN administration significantly reduced BP only in individuals with the deletion/deletion (DD) genotype. Sixty minutes after GTN administration, serum ACE activity was reduced in individuals with the insertion/insertion (II) and insertion/deletion (ID) genotypes, but not the DD genotype. Comparing the change in ACE activity over time between the genotypes resulted in the following: II vs. DD, p < 0.01; II vs. ID, p < 0.05; and ID vs. DD, p < 0.05. There was no significant difference in plasma cGMP content neither between the ACE genotypes nor before and after GTN administration. In conclusion, GTN inhibits serum ACE in vivo in individuals with the II and ID, but not the DD genotype.

Adult↗
PubMed2005

Influence of fibrillin-1 genotype on the aortic stiffness in men.

Aortic stiffness is a predictor of cardiovascular mortality. The mechanical properties of the arterial wall depend on the connective tissue framework, with variation in fibrillin-1 and collagen I genes being associated with aortic stiffness and/or pulse pressure elevation. The aim of this study was to investigate whether variation in fibrillin-1 genotype was associated with aortic stiffness in men. The mechanical properties of the abdominal aorta of 79 healthy men (range 28-81 yr) were investigated by ultrasonographic phase-locked echo tracking. Fibrillin-1 genotype, characterized by the variable tandem repeat in intron 28, and collagen type I alpha 1 genotype characterized by the 2,064 G>T polymorphism, were determined by using DNA from peripheral blood cells. Three common fibrillin-1 genotypes, 2-2, 2-3, and 2-4, were observed in 50 (64%), 10 (13%), and 11 (14%) of the men, respectively. Those of 2-3 genotype had higher pressure strain elastic modulus and aortic stiffness compared with men of 2-2 or 2-4 genotype (P = 0.005). Pulse pressure also was increased in the 2-3 genotype (P = 0.04). There was no significant association between type 1 collagen genotype and aortic stiffness in this cohort. In conclusion, the fibrillin-1 2-3 genotype in men was associated with increased aortic stiffness and pulse pressure, indicative of an increased risk for cardiovascular disease.

Adult↗
PubMedDate not supplied

[Hepatitis B virus genotypes in chronic carriers on the island of Gran Canaria. Clinical and epidemiological characteristics].

OBJECTIVE: To investigate the prevalence of hepatitis B virus (HBV) genotypes in Spanish hepatitis B carriers, and to study the differences in epidemiological characteristics, e antigen (HBeAg) seroconversion, serum DNA viral levels (VL) and liver function alterations. METHODS: This study included 108 patients. Genotyping was carried out in 84 with the INNO-LiPA HBV genotyping assay (Innogenetics). RESULTS: There were 41 women and 67 men, with a mean age of 44.1 years. The source of transmission was family contact in 26 patients (24.1%); transfusions in 10 (9.3%); sexual promiscuity in 9 (8.3%), intravenous drug use in 3 (2.8%), health care accident in 2 (1.8%); and unknown causes in 58 (53.7%). Forty patients had chronic hepatitis and 68 (63%) were healthy carriers. The time of evolution of the infection was known in only in 45 patients, and was over 10 years in 42 of them. One hundred patients (92.6%) were HbeAg-negative and 90 (83.3%) had detectable viral DNA. Genotype A was present in 46 (54.8%), D in 20 (23.8%), F in 2 (2,4%), C in 1 (1.2%), A-G coinfection in 7 (8.3%), A-D in 4 (4.8%), D-G in 2 (2,4%), A-C in 1 (1.2%), and A-D-G in 1 (1.2%). There were no significant differences between genotypes. A trend towards an association was found between VL <or= 10(5) copies/mL and the presence of chronic hepatitis in genotype A (28.9%) as opposed to genotype D (7.7%) (p non significant). CONCLUSIONS: HBV genotypes A and D, and coinfections with G are predominant in our area. Genotype A showed a tendency to produce greater inflammatory activity when VL was <or= 10(5) copies/mL.

Adult↗
PubMed2005

Human papillomavirus genotype distribution in low-grade cervical lesions: comparison by geographic region and with cervical cancer.

Low-grade squamous intraepithelial lesions (LSIL) associated with certain human papillomavirus (HPV) genotypes may preferentially progress to cervical cancer. HPV genotyping may thus have the potential to improve the effectiveness of screening programs and to reduce overtreatment. LSIL cases (n = 8,308) from 55 published studies were included in a meta-analysis. HPV genotype distribution was assessed by geographic region and in comparison with published data on cervical squamous cell carcinoma (SCC). HPV detection in LSIL was 80% in North America but less than 70% in other regions, most likely reflecting regional differences in LSIL diagnosis. Among 5,910 HPV-positive LSILs, HPV16 was the most common genotype (26.3%) followed by HPV31 (11.5%), HPV51 (10.6%), and HPV53 (10.2%). HPV-positive LSILs from Africa were 2-fold less likely to be infected with HPV16 than those in Europe, and HPV-positive LSILs from North America were more likely to be infected with HPV18 than those from Europe or South/Central America. Interpretation for rarer genotypes was hampered by variation in HPV testing methodology. SCC/LSIL prevalence ratios indicated that HPV16 was 2-fold and HPV18 was 1.5-fold more common in SCC than in HPV-positive LSIL, thus appearing more likely to progress than other high-risk genotypes (SCC/LSIL prevalence ratios between 0.05 and 0.85). HPV53 and HPV66 showed SCC/LSIL ratios of 0.02 and 0.01, respectively. HPV genotype distribution in LSIL differs from that in cervical cancer, highlighting the importance of HPV genotype in the risk of progression from LSIL to malignancy. Some regional differences in the relative importance of HPV genotypes in LSIL were noted.

Carcinoma, Squamous Cell↗
PubMed2006

Accuracy of multiplexed Illumina platform-based single-nucleotide polymorphism genotyping compared between genomic and whole genome amplified DNA collected from multiple sources.

Association studies designed to identify the genetic determinants underlying complex disease increasingly require sustainable high-quality DNA resources for large-scale single-nucleotide polymorphism (SNP) genotyping. Recent studies have shown that genomic DNA (gDNA) suitable for SNP genotyping can be obtained from buccal cells and from dried blood spots on Guthrie cards. Further, successful SNP genotyping has been done using the reaction product of multiple displacement amplification of gDNA. We evaluated genotype consistency on the Illumina genotyping platform for 717 to 1,744 SNP loci between replicate samples of gDNA and whole genome amplified DNA (wgaDNA) from a variety of sources. Nine healthy adults provided peripheral blood via venipuncture and buccal cells by mouth rinse. DNA was also obtained from urothelial cells in urine samples from five of the nine subjects. gDNA was extracted from all samples, wgaDNA was generated from each gDNA, and all samples were genotyped. To assess SNP genotyping accuracy of DNA obtained from dried blood spots, gDNA was extracted, amplified, and genotyped from peripheral blood samples and paired Guthrie card samples were obtained from eight childhood leukemia patients. Call rates and replicate concordances for all sample types, regardless of amplification, were >97%, with most sample types having call rates and replicate concordances >99%. Using the gDNA from blood samples as the reference for concordances calculated for all other sample types, we observed concordances >98% regardless of sample type or amplification. We conclude that highly multiplexed Illumina genotyping may be done on gDNA and wgaDNA obtained from whole blood, buccal samples, dried blood spots on Guthrie cards, and possibly even urine samples, with minimal misclassification.

Aged↗
PubMed2004

Methylenetetrahydrofolate reductase genotype affects risk of relapse after hematopoietic cell transplantation for chronic myelogenous leukemia.

PURPOSE: Methylenetetrahydrofolate reductase (MTHFR) directs intracellular folate toward homocysteine metabolism and away from nucleotide synthesis. Two common MTHFR polymorphisms, C677T and A1298C, are associated with reduced enzyme activity. We evaluated the association of these polymorphisms with risk of relapse and bcr-abl mRNA transcript detection among 336 Caucasian patients who underwent allogeneic hematopoietic cell transplantation for chronic myelogenous leukemia. EXPERIMENTAL DESIGN: Data on the transplant course and folate-related exposures were abstracted from medical records. MTHFR C677T and A1298C genotypes were determined using polymerase chain reaction/restriction fragment length polymorphism and TaqMan assays. Qualitative bcr-abl mRNA testing was conducted using a two-step reverse transcription-polymerase chain reaction assay. Cox regression analysis was used to assess the association between MTHFR genotypes and time to relapse and bcr-abl mRNA detection. RESULTS: A statistically significant decreased risk of relapse was observed in patients with the variant A1298C genotype [1298AC, hazard ratio (HR)=0.48 and 95% confidence interval (CI)=0.26-0.88; 1298CC, HR=0.28 and 95% CI=0.09-0.84; P-trend <0.01). For the joint C677T/A1298C genotype, variant genotypes were associated with a decreased risk of relapse when compared with the wild-type 677CC/1298AA genotype. This risk was lowest for the 677CC/1298CC genotype (HR, 0.23; 95% CI, 0.08-0.72). MTHFR genotypes were not associated with bcr-abl transcript detection. CONCLUSIONS: These findings suggest that individuals with the 677CC/1298AA genotype are at higher risk of relapse after hematopoietic cell transplantation and that the balance of intracellular folate metabolites available for nucleotide synthesis (regulated by the relative activity of the MTHFR enzyme) may affect the progression from bcr-abl positivity to clinical relapse.

Adolescent↗
PubMed2005

Hepatitis B virus genotypes in Korea: an endemic area of hepatitis B virus infection.

OBJECTIVES: It has been reported that distribution of hepatitis B virus (HBV) genotypes shows geographic difference and are associated with clinical outcomes of HBV infection, including response to antiviral therapy and progression of chronic liver diseases. In this study, we analyzed the distribution of HBV genotypes according to the various clinical outcomes of chronic HBV infection in Korea, which is one of the most endemic areas of HBV infection. METHODS: A total of 200 patients with chronic HBV infection were enrolled. Clinical diagnoses of the 200 patients with chronic liver diseases were as follows: hepatitis B e antigen (HBeAg)-positive healthy carrier (defined as HBeAg(+), anti-HBe(-), HBV DNA(+) by hybridization, normal transaminase; n = 40); inactive HBsAg carrier (n = 40); chronic hepatitis B (n = 40); liver cirrhosis (n = 40); hepatocellular carcinoma (n = 40). HBV genotypes were determined by nested polymerase chain reaction using genotype-specific primers. RESULTS: All patients except 2 (inactive HBsAg carriers) were positive for nested PCR and they have genotype C regardless of clinical outcomes. CONCLUSIONS: HBV genotype was genotype C regardless of various clinical outcomes of chronic HBV infection in Korea. Considering that HBV genotypes have clinical relevance, distribution of HBV genotype in each area should be monitored when management for chronic HBV infection is planned.

Adolescent↗
PubMed2005

APOE genotype and serum cholesterol in predicting risk for early death from ischemic stroke in men and women.

BACKGROUND: We recently discovered that APOE epsilon3/epsilon4 genotype in men and APOE epsilon2/epsilon3 genotype in women are associated with increased risk of death from ischemic stroke (IS). One of the main physiological roles of apolipoprotein E is participation in cholesterol metabolism. A significant association of low serum cholesterol level with increased risk of death from stroke was documented. So, we aimed to establish if an association exists between APOE genotype, serum cholesterol and 1-month mortality in IS. METHODS: We studied 666 patients (330 men, 336 women) with a diagnosis of IS. Total serum cholesterol (TC) was measured with the method of Abbott Spectrum (USA). APOE genotyping was performed by PCR-RFLP method. RESULTS: The highest frequency of low serum TC was associated with APOE epsilon2/epsilon3 genotype (both in men and in women). Low serum TC was associated with increased mortality rate only in women; this effect was evident only in females not possessing APOE epsilon2/epsilon3. Female patients with APOE epsilon2/epsilon3 genotype had high 1-month mortality rate independently from serum TC. In multiple regression analyses APOE epsilon3/epsilon4 genotype in men and APOE epsilon2/epsilon3 genotype in women predicted risk of death independently from serum TC and also from other potential pre- and post-stroke prognostic factors. CONCLUSION: APOE epsilon3/epsilon4 genotype in men and APOE epsilon2/epsilon3 in women are associated with increased 30-day mortality in stroke. This effect seems be independent from serum cholesterol.

Aged↗
PubMed2006

Intra- and intergenotypic variations among human cytomegalovirus gB genotypes.

OBJECTIVES: To study genotypic variations among human cytomegalovirus (HCMV) gB genotypes in clinical samples of Thai patients. METHODS: gB genotyping of 31 HCMV-DNA-positive clinical samples were determined by PCR-RFLP, gene cloning and DNA sequencing methods. RESULTS: Eight gB1, 7 gB2, 7 gB3, 6 gB untype (UT1 and UT2) and 3 mixed gB genotypes were first identified by PCR-RFLP. All 3 mixed gB genotype samples and 1 gB2 sample were cloned and confirmed gB genotype by PCR-RFLP. Altogether, 57 strains (27 unique types and 30 transformants) were further analyzed by DNA sequencing method. Discordant results between PCR-RFLP and DNA sequencing methods were demonstrated in 5 samples and 1 clone. The gB UT1 and UT2 were all classified as gB1 except 1 sample of UT1 (9D), suggesting a new variant. Each genotype had a similarity of more than 97%, whereas strains of different genotypes had 77.71-92.75% homology. The most divergent type was gB3. CONCLUSIONS: Intra- and intergenotypic variations among strains were demonstrated either in individual or distinct patients. Intragenotypic variation in a person occurs possibly due mainly to a point mutation mechanism rather than reinfection of a new gB genotype.

Base Sequence↗
PubMed1996

Genotype distribution of angiotensin-converting enzyme polymorphism in Australian healthy and coronary populations and relevance to myocardial infarction and coronary artery disease.

Angiotensin-converting enzyme is a key component of the renin-angiotensin system that plays an important role in cardiovascular regulation. An association between the angiotensin-converting enzyme insertion/deletion (I/D) polymorphism and increased coronary risk has been found in some studies but not in others. To explore this further in an Australian white population, we compared the ACE genotype distribution in 550 patients aged 37 to 65 years with coronary artery disease documented by angiography with the genotype distribution in 404 healthy school children aged 6 to 13 years. We also explored associations in the patients between the angiotensin-converting enzyme I/D polymorphism and a history of myocardial infarction and coronary artery disease severity assessed by the number of major coronary arteries with more than 50% luminal obstructions and by the Green Lane coronary score. The frequencies of the angiotensin-converting enzyme genotype in the coronary artery disease patients were 0.236 for I/I, 0.395 for I/D, and 0.369 for D/D genotypes. This distribution with an excess of the D/D genotype was significantly different (chi 2 = 23.69, P < .0001) from that in the school children, in whom the genotype distribution was in Hardy-Weinberg equilibrium (I/I, 0.21; I/D, 0.54; D/D, 0.25). There was also a significant excess of D/D genotype among patients with a history of myocardial infarction (chi 2 = 9.42, P = .009), and there was the same D/D excess in the subgroup of children (n = 60) with two or more grandparents who had had coronary artery disease. We found no associations between the angiotensin-converting enzyme polymorphism and the number of significantly stenosed coronary arteries (chi 2 = 2.069, P = .91). We conclude that the D/D genotype is a significant predictor for coronary artery disease events in the Australian white population but is not a marker for angiographically assessed coronary artery disease severity. The angiotensin-converting enzyme genotype-associated increased risk for coronary events may be mediated more by angiotensin II-induced coronary vasoconstriction than by an increase in injury-related smooth muscle cell proliferation in the coronary vasculature.

Adolescent↗
PubMed1997

Genotype-specific transcriptional regulation of PAI-1 expression by hypertriglyceridemic VLDL and Lp(a) in cultured human endothelial cells.

The hypothesized relationships between plasminogen activator inhibitor (PAI-1) genotypes, PAI-1 levels, and their potential regulation by hypertriglyceridemic (HTG) very low density lipoprotein (VLDL) and lipoprotein(a) [Lp(a)] was examined in a PAI-1 genotyped human umbilical vein endothelial cell (HUVEC) culture model system. Individual human umbilical veins were used to obtain cultured ECs and were genotyped for PAI-1 by using the HindIII restriction fragment length polymorphism (RFLP) as a marker for genetic variation. Digested genomic DNA, examined by Southern blot analysis and probed with an [alpha-32P]dCTP-labeled 2.2-kb PAI-1 cDNA, yielded three RFLPs designated 1/1 (22-kb band only), 1/2 (22-plus 18-kb bands), and 2/2 (18-kb band only). Individual PAI-1 genotyped HUVEC cultures were incubated in the absence or presence of HTG-VLDL (0 to 50 micrograms/mL) or Lp(a) (0 to 50 micrograms/mL) at 37 degrees C for various times (4 to 24 hours), followed by analyses of PAI-1 antigen (by ELISA) and mRNA (by ribonuclease protection assay) levels, EC surface-localized plasmin generation assays, and nuclear run-on transcription assays. Secreted PAI-1 antigen levels were increased approximately 2- to 3-fold by HTG-VLDL and approximately 1.6 to 2-fold by Lp(a); mRNA levels were increased approximately 3- to 4.5-fold by HTG-VLDL and approximately 2.5- to 3.2-fold by Lp(a) compared with medium-incubated controls, primarily in the 2/2 PAI-1 genotype HUVEC cultures. Increases in PAI-1 mRNA induced by HTG-VLDL or Lp(a) could be abolished by coincubation with actinomycin D (2 x 10(-6) mol/mL) or puromycin (1 microgram/mL). In addition, nuclear transcription run-on assays typically demonstrated that HTG-VLDL increased PAI-1 gene transcription rates by approximately 5- to 6-fold and approximately 4- to 5-fold, respectively, primarily in the 2/2 PAI-1 genotype HUVEC cultures compared with 1/1 PAI-1 genotype HUVEC cultures or medium-incubated controls. The positive control interleukin-1 increased both 2/2 and 1/1 PAI-1 mRNA levels by approximately 5- to 6-fold. Increased PAI-1 antigen and mRNA expression were associated with a concomitant 50% to 60% decrease in plasmin generation. These combined results demonstrate the genotype-specific regulation of PAI-1 expression by HTG-VLDL and Lp(a) and further indicate that these risk factor-associated components regulate PAI-1 gene expression at the transcriptional level in cultured HUVECs. Results from these studies further suggest that individuals with this responsive 2/2 PAI-1 genotype may reflect the additional inherent potential for later HTG-VLDL- or Lp(a)-induced fibrinolytic dysfunction, resulting in the early initiation of thrombosis, atherogenesis, and coronary artery disease.

Arteriosclerosis↗
PubMed1998

Genotype-specific transcriptional regulation of PAI-1 gene by insulin, hypertriglyceridemic VLDL, and Lp(a) in transfected, cultured human endothelial cells.

Plasminogen activator inhibitor-1 (PAI-1) has been shown to be an independent risk factor for coronary artery disease. Variations in plasma PAI-1 levels have been attributed to variations in the PAI-1 gene, and associations between PAI-1 levels and PAI-1 genotypes suggest that PAI-1 expression may be regulated in a genotype-specific manner by insulin, hypertriglyceridemic (HTG) very low density lipoprotein (VLDL), or lipoprotein(a) [Lp(a)]. Polymerase chain reaction-amplified 1106-bp fragments of the promoter of the 1/1 and 2/2 PAI-1 genotypes were sequenced and showed 5 regions of small nucleotide differences in the 1/1 versus 2/2 PAI-1 promoters that consistently occurred with high frequency. These fragments were ligated into the luciferase reporter gene, and 1/1 and 2/2 PAI-1 genotype human umbilical vein endothelial cell (HUVEC) cultures were transiently transfected with their respective p1PAI110/luc and p2PAI110/luc constructs and vice versa. Insulin induced an approximately 12- to 16-fold increase in luciferase activity in both the 1/1 and 2/2 PAI-1 genotype HUVEC cultures transfected with the p1PAI110/luc construct. HTG-VLDL and Lp(a) induced luciferase activity by approximately 14- to 16- and approximately 8- to 11-fold, respectively, in both the 1/1 and 2/2 PAI-1 genotype HUVEC cultures transfected with the p2PAI110/luc construct. The positive control interleukin-1 showed an approximately 7- to 12-fold response in the 1/1 and 2/2 PAI-1 genotype HUVEC cultures transfected with either of the constructs. These cross-over results demonstrate that regulation of either the 1/1 or 2/2 PAI-1 genotype by its respective inducer is due to the promoter itself and not to some factor(s) expressed differently in the 1/1 or 2/2 PAI-1 genotype HUVEC cultures.

Cells, Cultured↗
PubMed1995

Angiotensin-converting enzyme genotype in children and coronary events in their grandparents.

BACKGROUND: It has been suggested that the insertion/deletion (I/D) polymorphism of the angiotensin-converting enzyme (ACE) gene is an independent risk factor for coronary artery disease. The D/D genotype, which is associated with higher levels of circulating ACE than the I/D or I/I genotype, has been found significantly more frequently in patients with myocardial infarction and also in individuals with a parental history of myocardial infarction. METHODS AND RESULTS: We explored the distribution of the ACE genotype in 404 school children, aged 6 to 13 years, and related the distribution to the number of their grandparents who had had vascular events. We found a significant association between the number of grandparents who had had coronary events and the ACE genotype (P = .01). In children with two or more grandparents who had had coronary events, there was an excess of both D/D (odds ratio = 2.8 [95% confidence interval = 1.16-6.56]) and I/D (odds ratio = 1.4 [95% confidence interval = 0.62-3.25]) genotypes compared with I/I genotypes. In addition, there was an association between the ACE genotype and lipoprotein(a) levels in children (P = .07). Both the ACE genotype and lipoprotein(a) were found to contribute significantly (P = .0042) and independently to family history of coronary artery disease, with the ACE genotype proving to be more predictive than lipoprotein(a) levels. CONCLUSIONS: We conclude that the I/D polymorphism of the ACE gene is an important independent risk factor for coronary artery disease and is more predictive that lipoprotein(a). The I/D polymorphism is not only associated with a parental history of myocardial infarction but also with coronary artery disease in second-degree relatives. A further study to explore the relation between the I/D polymorphism and circulating levels of lipoprotein(a) is indicated.

Adolescent↗
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↗
PubMed1995

Enhanced predictability of myocardial infarction in Japanese by combined genotype analysis.

To explore the genes responsible for myocardial infarction and restenosis after percutaneous transluminal coronary angioplasty, we performed association studies of the polymorphisms of the angiotensinogen and angiotensin-converting enzyme (ACE) genes. In the first study, normotensive myocardial infarction patients (n = 103) and control subjects (n = 103), who were matched for established risk factors with the myocardial infarction patients, were randomly selected. The angiotensinogen-TT genotype (T indicates threonine instead of methionine at position 235) was more frequent in the myocardial infarction group than in the control group (P < .05). The ACE-DD genotype (D indicates a deletion polymorphism in intron 16) was also more frequent in the myocardial infarction group (P < .0001). The odds ratio estimated by the combined analysis of the angiotensinogen-TT and ACE-DD genotypes (11.2) was markedly increased compared with that estimated separately from the angiotensinogen-TT (1.75) or ACE-DD (4.43) genotype. In the second study, we investigated 91 consecutive patients with acute myocardial infarction who underwent successful direct angioplasty. Combined analysis showed that the angiotensinogen-TT genotype did not enhance the predictability of myocardial infarction from the ACE-DD genotype. In conclusion, the angiotensinogen-TT genotype is a predictor for myocardial infarction, as well as the ACE-DD genotype, and the combined analysis of the angiotensinogen-TT and ACE-DD genotypes further enhanced the predictability of myocardial infarction in Japanese, suggesting its future clinical usefulness.

Angioplasty, Balloon, Coronary↗
PubMed2002

Fibrillin-1 genotype is associated with aortic stiffness and disease severity in patients with coronary artery disease.

BACKGROUND: Elevated pulse pressure is associated strongly with adverse cardiovascular outcome; however, the genetic basis of this condition is unknown. This study examined whether genotypic variation in the extracellular matrix protein fibrillin-1, the Marfan gene, was associated with aortic stiffening and therefore could contribute to cardiovascular risk associated with pulse pressure elevation in coronary disease. METHODS AND RESULTS: Patients (n=145; 113 men), 62+/-9 years of age (mean+/-SD), with angiographically confirmed coronary disease, were studied. Carotid applanation tonometry was used to assess central blood pressures, and in conjunction with Doppler velocimetry, to assess aortic input and characteristic impedance. Fibrillin-1 genotype was characterized by a variable nucleotide tandem repeat and 2 single-nucleotide polymorphisms. The variable nucleotide tandem repeat was a good predictor of underlying haplotypes with 3 genotypes (2-2, 2-4, and 2-3) accounting for 86% of the population. The 2-3 genotype had higher input impedance (P=0.002), characteristic impedance (P=0.005), and carotid pulse pressure (P=0.002) compared with the 2-2 and 2-4 genotypes. Disease severity assessed by previous angioplasties and the number of patients with a stenosis >90% was also greater in the 2-3 genotype. Furthermore, in a multivariate analysis, fibrillin-1 genotype and central pulse pressure were independent of conventional risk factors in determining coronary disease severity. There was no difference in age, sex ratio, body mass index, smoking status, cholesterol level, or medication among the 3 genotypes. CONCLUSIONS: Although a causative link has not been shown, these data are consistent with an important role for fibrillin-1 genotype in cardiovascular risk associated with large-artery stiffening and pulse pressure elevation in individuals with coronary disease.

Alleles↗
PubMed2002

Glutathione S-transferase genotypes, genetic susceptibility, and outcome of therapy in childhood acute lymphoblastic leukemia.

The glutathione S-transferase (GST) genes are involved in the metabolism of environmental carcinogens and of some classes of chemotherapy drugs. GSTM1 and GSTT1 genotypes are polymorphic in humans, and the phenotypic absence of enzyme activity is caused by a homozygous inherited deletion of the gene. Previous, smaller studies of childhood acute lymphoblastic leukemia (ALL) provided contrasting data on the role of the GST genotype in susceptibility and treatment outcomes. We analyzed GST genotypes in 710 children with ALL treated by the Children's Cancer Group. Frequencies were compared with those of normal controls, and outcomes were analyzed according to genotype. Comparisons of gene frequencies in ALL case and control patients showed similar frequencies (54% vs 53% GSTM1 null in whites, P =.9; 40% versus 32% in blacks, P =.45; 16% versus 15% GSTT1 null in whites, P =.8; 17% versus 28% in blacks, P =.3). ALL was not associated with the GSTM1-null genotype or the double-null genotype in blacks or whites, in contrast to previous reports. Stratification of cases by age at diagnosis, sex, white blood cell count at diagnosis, B or T lineage, or cytogenetics revealed no differences in genotype frequencies. Analysis of treatment outcomes showed no differences in outcome according to GST genotype; in particular, there were no differences in frequencies of relapse at any site. These data, representing a larger series than any reported previously, suggest that GST genotype does not affect etiology or outcome of childhood ALL.

Biomarkers, Tumor↗
PubMed2006

LRTae: improving statistical power for genetic association with case/control data when phenotype and/or genotype misclassification errors are present.

BACKGROUND: In the field of statistical genetics, phenotype and genotype misclassification errors can substantially reduce power to detect association with genetic case/control studies. Misclassification also can bias population frequency parameters such as genotype, haplotype, or multi-locus genotype frequencies. These problems are of particular concern in case/control designs because, short of repeated sampling, there is no way to detect misclassification errors. We developed a double-sampling procedure for case/control genetic association using a likelihood ratio test framework. Different approaches have been proposed to deal with misclassification errors. We have chosen the likelihood framework because of the ease with which misclassification probabilities may be incorporated into in the statistical framework and hypothesis testing. The statistic is called the Likelihood Ratio Test allowing for errors (LRTae) and is freely available via software download. RESULTS: We applied our procedure to 10,000 replicates of simulated case/control data in which we introduced phenotype misclassification errors. The phenotype considered is Ankylosing Spondylitis (AS). The LRTae method power was always greater than LRTstd power for the significance levels considered (5%, 1%, 0.1%, 0.01%). Power gains for the LRTae method over the LRTstd method increased as the significance level became more stringent. Multi-locus genotype frequency estimates using LRTae method were more accurate than estimates using LRTstd method. CONCLUSION: The LRTae method can be applied to single-locus genotypes, multi-locus genotypes, or multi-locus haplotypes in a case/control framework and can be more powerful to detect association in case/control studies when both genotype and/or phenotype errors are present. Furthermore, the LRTae method provides asymptotically unbiased estimates of case and control genotype frequencies, as well as estimates of phenotype and/or genotype misclassification rates.

Case-Control Studies↗