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PubMed2006

Synergy between mannose-binding lectin gene polymorphisms and supplementation with vitamin A influences susceptibility to HIV infection in infants born to HIV-positive mothers.

BACKGROUND: Mannose-binding lectin (MBL-2) allele variants are associated with deficiencies in innate immunity and have been found to be correlated with HIV infection in adults and children. OBJECTIVE: We tested whether MBL-2 variants among infants born to HIV-positive mothers have an increased susceptibility to HIV. DESIGN: MBL-2 allele variants were measured among 225 infants born to HIV-positive mothers enrolled in a trial in Durban, South Africa. Mothers of 108 infants were randomly assigned to receive vitamin A and beta-carotene supplementation and 117 to receive placebo. Infants were followed with regular HIV tests to determine rates of mother-to-child HIV transmission. RESULTS: A high proportion of infants were either homozygous (10.7%) or heterozygous (32.4%) for MBL-2 variants. MBL-2 variants within the placebo arm were associated with an increased risk of HIV transmission (odds ratio: 3.09; 95% CI: 1.21, 7.86); however, MBL-2 variants within the supplementation arm were not associated with an increased risk of transmission (P = 0.04; test of interaction). Among infants with MBL-2 variants, supplementation was associated with a decreased risk of HIV transmission (odds ratio: 0.37; 95% CI: 0.15, 0.91). CONCLUSION: We observed what appears to be a gene-environment interaction between MBL-2 variants and an intervention with vitamin A plus beta-carotene that is relevant to mother-to-child HIV transmission.

Adult↗
PubMed1999

Polymorphism in the angiotensin converting enzyme but not in the angiotensinogen gene is associated with hypertension and type 2 diabetes: the Skaraborg Hypertension and diabetes project.

OBJECTIVE: To study the association between polymorphisms in the angiotensin converting enzyme (ACE) gene and angiotensinogen (AGT) gene and hypertension and/or type 2 diabetes in a community population. PATIENTS AND METHODS: The insertion (I)/deletion (D) polymorphism of the ACE gene and the M235T polymorphism of the AGT gene were genotyped in 773 nondiabetic individuals with hypertension, 193 normotensive patients with type 2 diabetes, 243 patients with type 2 diabetes and hypertension, and in 820 normotensive control individuals identified in a community-based study. RESULTS: The DD genotype was associated with hypertension in individuals less than 70 years [odds ratio (OR) = 1.54, confidence interval (CI) = 1.09-2.18] and remained so when patients with type 2 diabetes were excluded from the analysis (OR = 1.45, CI = 1.01-2.09). The strongest association was with the combination of type 2 diabetes and hypertension (OR = 2.19, CI = 1.09-4.38). There was no association with type 2 diabetes without hypertension. No association was observed between the M235T variant or the 3'-microsatellite polymorphism of the AGT gene and hypertension. CONCLUSION: The D-allele of the ACE gene ID polymorphism increases susceptibility to hypertension, particularly when associated with type 2 diabetes. No association was observed between the M235T variant or 3'-microsatellite polymorphism of the AGT gene and hypertension.

Aged↗
PubMed2007

Gene-nutrient interactions among determinants of folate and one-carbon metabolism on the risk of non-Hodgkin lymphoma: NCI-SEER case-control study.

We previously reported a lower risk of non-Hodgkin lymphoma (NHL) associated with high consumption of vitamin B6 and methionine, dietary determinants of one-carbon metabolism. Evidence has linked genetic variants involved in one-carbon metabolism to NHL. We investigated 30 polymorphisms in 18 genes for their main effect on NHL among 1141 incident cases and 949 population-based controls and examined gene-nutrient interactions in a subgroup of 386 cases and 319 controls who provided detailed food-frequency information. Odds ratios (ORs) and 95% confidence intervals (CIs) were adjusted for age, sex, and race. We observed a decreased risk of NHL over-all with BHMTEx8+453A>T and increased risk with CBS Ex13+41C>T, FPGS Ex15-263T>C, and SHMT1 Ex12+138C>T and Ex12+236C>T. Furthermore, significant gene-nutrient interactions limited the protective association comparing high versus low vitamin B6 to FPGS Ex15-263T>C CC (OR = 0.22; 95% CL = 0.10-0.52), MTHFS IVS2-1411T>G TT/TG (OR = 0.54; 95% CI = 0.36-0.81), and MTR Ex26-20A>G AA (OR = 0.55; 95% CI = 0.35-0.86) genotypes, and the protective association of methionine to FTHFD Ex10-40G>TGG (OR = 0.63; 95% CI = 0.44-0.91), MTHFR Ex8-62A>C CC (OR = 0.13; 95% CI = 0.04-0.39), and MTRR Ex5+136T>CTT (OR = 0.67; 95% CI = 0.47-0.97) genotypes. Warranting replication, our finding of gene-nutrient interactions in one-carbon metabolism supports their etiologic involvement in lymphomagenesis.

Adult↗
PubMed2004

The common -866G/A polymorphism in the promoter region of the UCP-2 gene is associated with reduced risk of type 2 diabetes in Caucasians from Italy.

Uncoupling protein-2 (UCP2) regulates insulin secretion and may play an important role in linking obesity to type 2 diabetes (T2D). Previous studies of the role of the UCP2 promoter -866G/A single nucleotide polymorphisms (SNP) in T2D have given opposite results. We tested the distribution of the -866G/A SNP in 746 T2D patients and 327 healthy unrelated Caucasians from Italy. We also tested for an effect of the P12A variant of the peroxisomal proliferator-activated receptor-gamma 2 (PPAR gamma 2) gene on diabetes risk given by the UCP2 SNP. Compared with -866G/G carriers, a progressively reduced (P = 0.01) risk of T2D was observed in -866G/A and -866A/A subjects, with the latter showing an approximately 50% risk reduction [odd ratio (OR), 0.51; 95% confidence interval (CI), 0.3-0.8; P = 0.003]. Conversely, the -866G/G genotype was associated with increased risk (OR, 1.31; 95% CI, 1.01-1.71). Overall, the population risk attributable to the UCP2 -866G/G genotype was about 12%. After stratifying for the PPAR gamma 2 polymorphism, the increased risk conferred by the UCP2 G/G genotype was still evident among P12/P12 homozygous subjects (n = 801; OR, 1.38; 95% CI, 1.04-1.83), but seemed to disappear among the X12/A12 subjects (i.e. P12/A12 heterozygous or A12/A12 homozygous subjects; n = 137; OR, 0.87; 95% CI, 0.40-1.91). Whether this apparent difference is entirely due to the different number of carriers of the two PPAR gamma 2 genotypes is a likely possibility that deserves deeper investigation. In conclusion, in our population, the -866G/A SNP is associated with T2D. Additional studies in larger samples are needed to investigate the possibility of a concomitant effect of modifier genes such as PPAR gamma 2.

Adenine↗
PubMed2006

Factor VII gene haplotypes and risk of ischemic stroke.

BACKGROUND: Coagulation factor VII (FVII) plays an important role in the activation of blood coagulation and clot formation. Recent studies have provided evidence for an association between common polymorphic markers in the FVII gene and plasma FVII concentrations. The 353R>Q sequence variation, and 3 common sequence variations in the promoter of the FVII gene-the 10-bp insertion/deletion at position -323 and the -401G>T and -402G>A sequence variations-are well-known determinants of circulating FVII concentrations. METHODS: To clarify the role of these sequence variations in the pathogenesis of ischemic stroke, we performed a case-control study with 242 patients with ischemic stroke before the age of 60 years and 239 healthy controls. RESULTS: The -323 insertion/deletion and the 353R>Q and -401G>T sequence variations were in strong linkage disequilibrium, and the resulting haplotypes occurred with equal frequencies in patients and controls. The variant form of FVII (-402G>A) occurred only in combination with the common (wild-type) sequences at all other loci. This haplotype was more frequent in patients than in healthy controls (28% vs 22%). The difference in the prevalence of carriers of this haplotype among patients and controls was statistically significant (P = 0.03; odds ratio = 1.6; 95% confidence interval, 1.1-2.6). CONCLUSION: According to our results, the FVII -402A allele seems to increase the risk of early ischemic cerebrovascular events, whereas the 353R>Q, G-401T, and -323ins/del sequence variations, which are in close linkage disequilibrium, apparently do not influence the risk of stroke.

Acute Disease↗
PubMedDate not supplied

Esophageal cancer risk by ALDH2 and ADH2 polymorphisms and alcohol consumption: exploration of gene-environment and gene-gene interactions.

Alcohol drinking is a major risk factor for esophageal cancer in Japan and its impact may be modulated by levels of ALDH2, ADH2 and CYP2E1, three representative alcohol-metabolizing enzymes which display genetic polymorphisms altering individual alcohol-oxidizing capacity and drinking behavior. To assess the actual influence of ADH2 Arg47His, ALDH2 Glu487Lys and CYP2E1 variant c2 allele polymorphisms on esophageal cancer risk with conjunction with alcoholic consumption, the present 1:3 matched case-control study was conducted. The 165 histologically diagnosed Japanese esophageal cancer cases were here compared with 495 randomly selected controls, matched with respect to sex and age. Conditional logistic regression was used to calculated Odds Ratios (ORs) and 95% confidence intervals (95% CI). Significant gene-environment interactions between alcohol drinking and both ADH2 and ALDH2 were observed regarding esophageal cancer risk. The ADH2 Arg47His polymorphism showed moderately increased risk (OR for Arg/His and Arg/Arg relative to His/His: 2.01 (1.39-2.90)). In the ALDH2 case, comparing the Glu/Lys with the Glu/Glu genotype, ORs were markedly increased to 9.64 (3.23-28.8) and 95.4 (28.7-317) from 1.88 (0.42-8.37) and 4.62 (0.93-23.1) for moderate drinking and heavy drinking, respectively. No significant alteration in risk was observed with the CYP2E1 polymorphism. In conclusion, the present study revealed a significant gene-environment interaction between alcohol drinking and the ALDH2 polymorphism regarding esophageal cancer risk among a general population in Japan, providing concrete evidence of a role for acetaldehyde in neoplastic development. Interactions between ALDH2 and ADH2 need further clarification.

Aged↗
PubMed2000

A sensitive denaturing gradient-Gel electrophoresis assay reveals a high frequency of heteroplasmy in hypervariable region 1 of the human mtDNA control region.

A population study of heteroplasmy in the hypervariable region 1 (HV1) portion of the human mtDNA control region was performed. Blood samples from 253 randomly chosen individuals were examined using a sensitive denaturing gradient-gel electrophoresis (DGGE) system. This method is capable of detecting heteroplasmic proportions as low as 1% and virtually all heteroplasmy where the minor component is > or = 5%. Heteroplasmy was observed in 35 individuals (13.8%; 95% confidence interval [CI] 9.6-18.0). Of these individuals, 33 were heteroplasmic at one nucleotide position, whereas 2 were heteroplasmic at two different positions (a condition known as "triplasmy"). Although heteroplasmy occurred at a total of 16 different positions throughout HV1, it was most frequently observed at positions 16093 (n=13) and 16129 (n=6). In addition, the majority of heteroplasmic variants occurred at low proportions and could not be detected by direct sequencing of PCR products. This study indicates that low-level heteroplasmy in HV1 is relatively common and that it occurs at a broad spectrum of sites. Our results corroborate those of other recent reports indicating that heteroplasmy in the control region is more common than was previously believed-a finding that is of potential importance to evolutionary studies and forensic applications that are based on mtDNA variation.

Base Sequence↗
PubMed2003

Estimating efficacy of trivalent, cold-adapted, influenza virus vaccine (CAIV-T) against influenza A (H1N1) and B using surveillance cultures.

The authors report on a community-based, nonrandomized, open-label study, conducted during the 2000-2001 influenza season in Temple-Belton, Texas, of the protective effectiveness of trivalent, cold-adapted, influenza virus vaccine (CAIV-T) in children aged 18 months-18 years. The dominant circulating strains in 2000-2001 were influenza A/New Caledonia/20/99 (H1N1) and influenza B/Sichuan/379/99. Children had access to CAIV-T during the 1998-1999, 1999-2000, and 2000-2001 influenza seasons. The vaccine included influenza A/Sydney/5/97 (H3N2) and B/Beijing/184/93-like (B/Ann Arbor/l/94) strains in all three seasons. The vaccine included A/Beijing/262/95 (H1N1) in 1998-1999 and 1999-2000, which was replaced by A/New Caledonia/20/99 (H1N1) in 2000-2001. When medically attended acute respiratory illness (MAARI) was used as the outcome, the protective effectiveness for children vaccinated in 2000 was 18% (95% confidence interval (CI): 11, 25). Based on a combination of a validation sample of surveillance cultures and the MAARI outcome, protective efficacy against combined influenza A (H1N1) and B was 79% (95% CI: 51, 91). The efficacy estimate, after accounting for missing influenza culture status, against influenza A (H1N1) alone was 92% (95% CI: 42, 99) and against a new variant of influenza B alone was 66% (95% CI: 9, 87). CAIV-T provides substantial protection against a mixture of influenza A (H1N1) and B. Results demonstrate the powerful potential of using validation sets for outcomes in vaccine field studies.

Adolescent↗
PubMed2004

Polymorphisms in angiotensin II type 1 receptor and angiotensin I-converting enzyme genes and breast cancer risk among Chinese women in Singapore.

Angiotensin II is converted from its precursor by angiotensin I-converting enzyme (ACE) and has been shown to mediate growth in breast cancer cell lines via ligand-induced activity through the angiotensin II type 1 receptor (AGTR1). Earlier we showed that women with the low activity genotype of the ACE gene have a statistically significantly ( approximately 50%) reduced breast cancer risk compared with those possessing the high activity ACE genotype. To further test the hypothesis that angiotensin II participates in breast carcinogenesis through AGTR1, we examined genetic polymorphisms in the 5'-region of the AGTR1 gene (A-168G, C-535T and T-825A) in relation to risk of breast cancer in 258 breast cancer cases and 670 female controls within the Singapore Chinese Health Study. Relative to the homozygotes, individual genotypes with one or two copies of the respective allelic variants (putative low risk genotypes) were each associated with an approximately 30% reduction in risk of breast cancer. Risk of breast cancer decreased with increasing number of low risk AGTR1 genotypes after adjustment for potential confounders. Relative to those carrying no low risk genotypes (homozygous for A, C and T alleles for the three polymorphisms, respectively), the odds ratios (95% confidence intervals) were 0.84 (0.51-1.37) for women possessing one low risk genotype and 0.68 (0.46-1.01) for women possessing two or three low risk genotypes (P for trend = 0.05). When both AGTR1 and ACE gene polymorphisms were examined simultaneously, women possessing at least one AGTR1 low risk genotype in combination with the ACE low activity genotype had an odds ratio of 0.35 (95% confidence interval, 0.20-0.62) compared with those possessing the ACE high activity genotype and no AGTR1 low risk genotype. Our findings suggest that pharmacological inhibition of the angiotensin II effect by blockade of ACE and/or AGTR1 could be potential targets for the prevention and treatment of breast cancer.

Aged↗
PubMed1998

Hyper-CVAD and high-dose methotrexate/cytarabine followed by stem-cell transplantation: an active regimen for aggressive mantle-cell lymphoma.

PURPOSE: Diffuse and nodular forms of mantle-cell lymphoma (MCL) are consistently associated with poor prognosis. In an effort to improve the outcome, we adopted a treatment plan that consisted of four courses of fractionated cyclophosphamide (CY) 1,800 mg/m2 administered with doxorubicin (DOX), vincristine (VCR), and dexamethasone (Hyper-CVAD) that alternated with high-dose methotrexate (MTX) and cytarabine (Ara-C). After four courses, patients were consolidated with high-dose CY, total-body irradiation, and autologous or allogeneic blood or marrow stem-cell transplantation. PATIENTS AND METHODS: Forty-five patients were enrolled; 25 patients were previously untreated, 43 patients had Ann Arbor stage IV disease, and 42 patients had marrow involvement. Forty-one patients had diffuse histology, two patients had nodular, and two patients had blastic variants. RESULTS: Hyper-CVAD/MTX-Ara-C induced a response rate of 93.5% (complete response [CR], 38%; partial response [PR], 55.5%) after four cycles of pretransplantation induction chemotherapy. All patients who went on to undergo transplantation achieved CRs. For the 25 previously untreated patients, the overall survival (OS) and event-free survival (EFS) rates at 3 years were 92% (95% confidence interval [CI], 80 to 100) and 72% (95% CI, 45 to 98) compared with 25% (95% CI, 12 to 62; P = .005) and 17% (95% CI, 10 to 43; P = .007), respectively, for the previously treated patients. When compared with a historic control group who received a CY, DOX, VCR, and prednisone (CHOP)-like regimen, untreated patients in the study had a 3-year EFS rate of 72% versus 28% (P = .0001) and a better OS rate (92% v 56%; P = .05). Treatment-related death occurred in five patients: all were previously treated and two received allogeneic transplants. CONCLUSION: The Hyper-CVAD/MTX-Ara-C program followed by stem-cell transplantation is a promising new therapy for previously untreated patients with MCL.

Adult↗
PubMed2002

Tachyphylaxis associated with continuous cisatracurium versus pancuronium therapy.

STUDY OBJECTIVES: To compare dosing requirements over time among patients receiving continuous cisatracurium versus pancuronium therapy, and to identify factors that may account for changes in pancuronium versus cisatracurium infusion requirements over time. DESIGN: Retrospective, comparative cohort analysis. SETTING: A tertiary level 1 trauma center. PATIENTS: Forty-five consecutive adult patients who were admitted to intensive care units at our institution from January 1998-August 2000 and received continuous cisatracurium or pancuronium therapy for at least 48 hours. MEASUREMENTS AND MAIN RESULTS: Dosing requirements of patients treated with pancuronium or cisatracurium were recorded over time throughout the treatment period. Factors that could affect dosing requirements of a neuromuscular blocking agent (NMBA) were stratified as time invariant (admitting service, acute physiology and chronic health evaluation II score, duration of mechanical ventilation, pressure control ventilation, baseline hepatic or renal insufficiency, thermal injury, train-of-four assessment, and concurrent drug administration or disorders affecting neuromuscular transmission) or time variant (concurrent sedation and narcotic analgesia therapy; serum magnesium, potassium, and creatinine concentrations; arterial pH level; temperature; peak airway pressure; and partial pressure of oxygen:fraction of inspired oxygen ratio). Hierarchical linear modeling was used to compare the dosing requirements and to identify confounders affecting the relationship. The infusion rate escalation for the cisatracurium group was greater (0.39 microg/kg/min; 95% confidence interval [CI] 0.22-0.56; 23 patients) than for the pancuronium group (-0.06 microg/kg/min; 95% CI -0.24-0.12; 22 patients; p<0.001) and was associated with an average daily cost/patient significantly higher (p<0.001) with cisatracurium ($258+/-$114) than pancuronium ($11+/-$5). Confounder analysis revealed that only the admitting service and the number of times the NMBA infusion was suspended because no twitch was detected differed between groups. Neither of these confounders significantly affected the temporal relationship between cisatracurium and pancuronium infusion rates. CONCLUSION: Dosing requirements increase over time at a significantly greater rate for cisatracurium than pancuronium infusions. Tachyphylaxis with cisatracurium is associated with substantial drug-related costs and is not accounted for by various disease-, patient-, and therapy-related factors. Further investigation is required to elucidate the mechanisms and risk factors underlying this phenomenon.

Adult↗
PubMed2003

Breast cancer risk reduction associated with the RAD51 polymorphism among carriers of the BRCA1 5382insC mutation in Poland.

The observed heterogeneity of breast cancer risk among women who carry the same BRCA1 mutation suggests the existence of modifying environmental and genetic factors. The product of the RAD51 gene functions with BRCA1 and BRCA2 in the repair of double-stranded DNA breaks. To establish whether polymorphic variation of RAD51 modifies risk for hereditary breast cancer, we conducted a matched case-control study on 83 pairs of female carriers of the BRCA1 5382insC mutation. Cases consisted of women with breast cancer, and controls were women with the same mutation but who were unaffected. The frequency of the RAD51 135C variant allele was established in cases and controls using RFLP-PCR. The RAD51 135C allele was detected in 37% of unaffected and in 17% of affected BRCA1 carriers. Among 27 discordant matched pairs, the RAD51 135C allele was found in the healthy carrier on 22 occasions and in the affected carrier on only five occasions (odds ratio = 0.23; 95% confidence interval, 0.07-0.62; P = 0.0015). This finding suggests that RAD51 is a genetic modifier of breast cancer risk in BRCA1 carriers in the Polish population. It will be of interest to confirm this in other populations as well.

Adult↗
PubMed1990

Increased plasma levels of ED1+ cellular fibronectin precede the clinical signs of preeclampsia.

To evaluate alterations in fibronectin homeostasis in preeclampsia we measured the plasma concentrations of fibronectin bearing an extra type III domain in 33 preeclamptic and 36 control patients at varying gestational ages. This fibronectin variant is concentrated in the endothelium of blood vessels and has been shown to be released at sites of vascular injury. In addition, total circulating fibronectin levels, composed primarily of hepatic-derived fibronectin lacking the extra type III domain, were also determined. Significant elevations in the average circulating concentrations of fibronectin with an extra type III domain (5.5 micrograms/ml [95% confidence interval, 4.7,6.2] versus 3.2 micrograms/ml [95% confidence interval, 2.9,3.5]; p = 0.0001) as well as total fibronectin (387 micrograms/ml [95% confidence interval, 357,417] versus 327 micrograms/ml [95% confidence interval, 305,348]; p = 0.036) were observed in preeclamptic versus control patients. Significant elevations in fibronectin levels with an extra type III domain occurred in the first trimester before clinical evidence of preeclampsia. In addition, multivariate logistic regression demonstrated a 5.4-fold increase in the risk of preeclampsia with each 1 microgram/ml elevation in concentration of fibronectin with an extra type III domain. These findings lend support to the hypothesis that endothelial-vascular injury is a primary event in the genesis of preeclampsia.

Adult↗
PubMed2005

The association of the DNA repair gene XRCC3 Thr241Met polymorphism with susceptibility to colorectal cancer in a Chinese population.

Growing evidence suggests that the Thr241Met (T241M) polymorphism in the homologous recombination repair gene XRCC3 may alter DNA repair capacity and subsequent susceptibility to carcinogens. In a few studies of colorectal cancer (CRC), however, the results have been discrepant. A population-based nested case-control study including 140 cases and 280 cancer-free controls was conducted to evaluate the effect of XRCC3 polymorphism, environmental exposure, and family history (FH) on the risk of CRC. The variant allele frequency was low among the ethnic Han Chinese, but we observed a significant difference between cases (6.07%) and controls (2.32%). The analytic results of the unconditional logistic regression model adjusted by age, sex, alcohol intake, cigarette smoking, and FH of cancer in first-degree relatives showed a significantly increased risk of CRC (adjusted odds ratio [OR] = 3.13, 95% confidence interval [CI]: 1.41-6.95, P = 0.005) as the T/M and M/M genotypes compared with the T/T genotype, which changed weakly in consideration of the subsite (adjusted OR = 4.80, 95%CI: 1.77-12.98, P = 0.002 in colon cancer, adjusted OR = 2.41, 95%CI: 0.93-6.25, P = 0.071 in rectal cancer, respectively). Combined with environmental factors such as alcohol intake and cigarette smoking, no significant interaction could be found. However, the results revealed a significant association between FH of cancer in first-degree relatives and the risk of CRC (adjusted OR = 2.24, 95%CI: 1.18-4.25, P = 0.014). These results also suggest that XRCC3 T241M polymorphism and FH of cancer may be risk factors for CRC, and the XRCC3 241Met allele may be an effective biomarker for genetic susceptibility to CRC. Larger studies are needed to confirm our findings and identify the underlying mechanisms.

Adult↗
PubMed2004

A novel polymorphism of human CYP2A6 gene CYP2A6*17 has an amino acid substitution (V365M) that decreases enzymatic activity in vitro and in vivo.

Cytochrome P450 (CYP) 2A6 is a major CYP responsible for the metabolism of nicotine and coumarin in humans. We identified a novel allele, designated CYP2A6*17 , which contains A51G (exon 1), C209T (intron 1), G1779A (exon 3), C4489T (intron 6), G5065A (V365M, exon 7), G5163A (intron 7), C5717T (exon 8), and A5825G (intron 8). We developed a genotyping method by polymerase chain reaction-restriction fragment length polymorphism for the CYP2A6*17 allele, targeting the G5065A mutation. The allele frequency in black subjects (n = 96) was 9.4% (95% confidence interval [CI], 5.3%-13.5%). The allele was not found in white subjects (95% CI, 0%-0.9%; n = 163), Japanese subjects (95% CI, 0%-1.6%; n = 92), and Korean subjects (95% CI, 0%-0.7%; n = 209). To examine the effects of the amino acid change in the CYP2A6*17 allele on the enzymatic activity, we expressed a wild-type or variant (V365M) CYP2A6 together with NADPH-CYP reductase in Escherichia coli . For coumarin 7-hydroxylation, the apparent Michaelis-Menten constant value of variant CYP2A6 (1.06 +/- 0.11 micromol/L) was significantly (P < .005) higher than that of wild type (0.60 +/- 0.05 micromol/L). The maximum velocity values of the wild-type and variant CYP2A6 were 0.61 +/- 0.06 and 0.64 +/- 0.07 pmol . min -1 . pmol -1 CYP, respectively. For nicotine C -oxidation, the apparent Michaelis-Menten constant values of the wild-type or variant CYP2A6 were 31.6 +/- 2.9 micromol/L and 31.3 +/- 3.1 micromol/L, respectively. The maximum velocity value of variant CYP2A6 (0.72 +/- 0.21 pmol . min -1 . pmol -1 CYP) was significantly (P < .05) lower than that of the wild type (1.80 +/- 0.42 pmol . min -1 . pmol -1 CYP). Thus the intrinsic clearance values for coumarin 7-hydroxylation and nicotine C -oxidation by the variant were both significantly (P < .05) decreased to 40% to 60% compared with the wild type. Furthermore, cotinine/nicotine ratios after 1 piece of nicotine gum was chewed, used as an index of in vivo nicotine metabolism, were significantly (P < .05) decreased in heterozygotes of the CYP2A6*17 allele (5.4 +/- 2.7, n = 12) compared with homozygotes of the wild type (11.5 +/- 10.5, n = 37). A subject with CYP2A6*17 / CYP2A6*17 revealed the lowest cotinine/nicotine ratio (1.8). We found a novel allele in black subjects that affects the nicotine metabolism in vitro and in vivo.

Alleles↗
PubMed2000

Modified Norwood procedure with a high-flow cardiopulmonary bypass strategy results in low mortality without late arch obstruction.

OBJECTIVE: The results of our modification of the stage I Norwood procedure, in which we use only autologous tissue to reconstruct the aortic arch, were reviewed. A high-flow, low-pressure cardiopulmonary bypass protocol (with phenoxybenzamine), before and after a period of deep hypothermic circulatory arrest, was used. METHODS: Between 1993 and 1999, 59 patients, aged 1 to 353 days (median 4 days) and weighing 1.7 to 6.8 kg (median 3.2 kg), underwent a modified Norwood procedure. The ascending aortic diameter ranged from 1.5 to 8 mm (median 3 mm). The modified Blalock-Taussig shunt was 3 mm in 21 patients (36%) and 3.5 mm or larger in 38 patients (64%). RESULTS: Deep hypothermic circulatory arrest and cardiopulmonary bypass times ranged from 15 to 64 minutes (median 37 minutes) and 44 to 144 minutes (median 88 minutes), respectively. Early postoperative survival was 83%. By univariate analysis, early mortality was associated with an ascending aortic diameter of 2.5 mm or less (P =.01). Weight, circulatory arrest and bypass times, diagnosis (hypoplastic left heart syndrome vs variant), shunt size, and date of the procedure did not affect survival. For a median follow-up period of 37 months (range 4-63 months), 42 (61%) patients underwent bidirectional cavopulmonary shunts, 10 (17%) had Fontan operations, and 1 patient underwent transplantation after a bidirectional cavopulmonary shunt. Eight patients subsequently died, for a 1-year actuarial survival of 72% (95% confidence interval: 60%-84%). Neoaortic arch obstruction was corrected in 3 patients (5%). CONCLUSIONS: At intermediate-term follow-up, our modification of the Norwood procedure together with our perioperative strategies has resulted in acceptable outcomes with a low incidence of neoaortic arch obstruction. Patients with a small ascending aortic diameter have emerged as a high-risk group, but a recent technical modification may improve the outlook for these patients.

Aorta, Thoracic↗
PubMed2004

Genetics of endometriosis: a role for the progesterone receptor gene polymorphism PROGINS?

OBJECTIVE: Endometriosis is a steroid-dependent disease with a particular genetic background, but the locations of possible genomic aberrations are still poorly clarified. We have investigated the potential association between endometriosis and the PROGINS 306 base pair insertion polymorphism in intron G of the progesterone receptor (PR) gene, which has been reported previously to segregate with this disease. DESIGN: In a case-control study, we examined the PROGINS polymorphism of the progesterone receptor gene in 131 Italian women affected by endometriosis diagnosed according to published criteria for the definition of the definite disease. Control subjects were represented by 127 Italian women without laparoscopic evidence of the disease. MEASUREMENTS: Peripheral blood samples, DNA extraction and polymerase chain reaction (PCR) were used to genotype women for the presence of the PROGINS polymorphism. RESULTS: We found a statistically significant difference in the distribution of PROGINS genotypes between patients with and without endometriosis. The frequency of the PROGINS allele T2 was 17.2% and 11%, respectively, in affected women and in controls [odds ratio (OR) = 1.7, 95% confidence interval (CI) 1.0-2.8]. This association was stronger in patients with more severe forms of endometriosis, such as an infiltrating disease or a disease characterized by severe pelvic adhesions (OR 2.4, 95% CI 1.2-4.8; and OR 2.7, 95% CI 1.4-5.3, respectively). Combination of the results from an earlier study and the current data indicates that carrying the allele variant T2 is associated with a twofold increase in the risk of developing endometriosis (OR 2.0, 95% CI 1.3-2.9). CONCLUSIONS: Our results further support the idea that the PROGINS polymorphism of the progesterone receptor may be associated with an increased risk of endometriosis.

Adult↗
PubMed2005

Exclusion of the acyl CoA:diacylglycerol acyltransferase 1 gene (DGAT1) as a candidate for a fatty acid composition QTL on porcine chromosome 4.

DGAT1 is a microsomal enzyme that catalyses the final step in triglycerides synthesis. DGAT1-deficient mice are viable, lean, fertile and resistant to diet induced obesity. We have previously identified a quantitative trait loci (QTL) on chromosome 4 that affects fatty acid composition in an F2 cross between Iberian x Landrace. The human DGAT1 gene is located on chromosome 8q24.3, this region aligns to porcine chromosome 4, making the pig DGAT1 gene a suggestive positional candidate gene for the QTL. In this study, we sequenced 1679 bp of the mRNA from animals of five pig breeds (Iberian, Landrace, Large White, Piétrian and Meishan) to identify genetic variants. One of the polymorphisms found creates a polymorphic HinfI restriction site and it was genotyped by PCR-RFLP in these five pig breeds. Allele A was not found in the analysed Iberian and Landrace populations, whereas Meishan population presents the highest frequency (35%). The DGAT1 gene was located by radiation hybrid mapping to the porcine chromosome 4, outside the confidence interval for the fatty acid composition QTL and excludes it as a positional candidate gene.

Animals↗