United Kingdom Cohort Research Articles

Determinants of the rate of nicotine metabolism and effects on smoking behavior

Studies on cytochrome P450 (CYP) 2A6 suggest that genotype affects the rate of nicotine metabolism and, consequently, cigarette consumption. However, known alleles of CYP2A6 associated with fast or slow metabolism are relatively uncommon, and there remains considerable variation in metabolic activity among those with presumed wild-type CYP2A6 alleles, suggesting that other genetic or environmental factors also influence the rate of nicotine metabolism. We investigated determinants of the rate of nicotine metabolism and effects on smoking behavior in a United Kingdom cohort who participated in a placebo-controlled trial of smoking cessation via nicotine replacement therapy. Those who continued to smoke cigarettes at the 8-year follow-up formed our study group (N = 545). The ratio of the nicotine metabolite trans-3'-hydroxycotinine to cotinine in plasma was used as an index of CYP2A6 activity and thus as a marker of the rate of nicotine metabolism. The nicotine metabolite ratio was associated with sex (P < .0001), CYP2A6 genotype (*1B, *2, *4, *9, and *12) (P < .0001), CYP2B6 haplotype (*4-dominant) (P = .02), plasma nicotine concentration (P < .0001), and age (P = .02) but was not associated with dependence score (P > .20). The ratio also predicted the number of cigarettes smoked at will per day, although the association was weak (F(1, 492) = 4.05, P = .04). In this cohort the rate of nicotine metabolism is related to age, sex, CYP2A6 genotype, and CYP2B6 genotype and may affect the level of tobacco consumption.

Genetic variants in TNF-α but not DLG5 are associated with inflammatory bowel disease in a large United Kingdom cohort

Genetic variants in DLG5, which encodes a scaffolding protein on chromosome 10q23, and tumor necrosis factor (TNF)-alpha, encoding a proinflammatory cytokine on chromosome 6p, have recently been reported to be associated with inflammatory bowel disease (IBD). We studied these variants to seek evidence of association with IBD in a large independent dataset. We genotyped 1104 unrelated white IBD subjects-496 with Crohn's disease, 512 with ulcerative colitis, and 96 with indeterminate colitis from the Cambridge/Eastern (UK) panel-and 760 healthy control subjects for DLG5_113G/A, DLG5_4136C/A, TNF-857C/T, and TNF-1031T/C polymorphisms. Known Crohn's disease-predisposing variants in CARD15/NOD2 were also genotyped to permit analysis for reported epistatic interactions. : TNF-857 was shown to be associated with IBD overall (P = 0.0079). A formal interaction test showed that TNF-857 is associated equally with ulcerative colitis and Crohn's disease. Neither of the DLG5 alleles, however, was associated with IBD (P = 0.32 and 0.35). Subgroup analysis also failed to show evidence of association between either DLG5 allele or genotype frequencies and ulcerative colitis or Crohn's disease. Stratification of TNF-alpha and DLG5 cases by CARD15 genotype made no significant difference in the strength of associations. We have confirmed an association between the TNF-857 promoter polymorphism and IBD in a large independent UK dataset but were unable to replicate an association at the previously reported loci within DLG5. This may reflect heterogeneity between the populations, a smaller effect size than originally predicted, or possibly a false-positive result in the original study. Further fine mapping studies of the TNF promoter region and studies assessing functional consequences of TNF promoter polymorphisms are now required in IBD.

Alcohol consumption and cognitive function in the Whitehall II Study.

The authors investigated the relation between alcohol consumption and cognitive function in a United Kingdom cohort study (4,272 men, 1,761 women) with median follow-up of 11 years. Measures of alcohol consumption were obtained at baseline (1985-1988) and four subsequent phases of data collection. Cognitive function (memory test, AH4, Mill-Hill, phonemic and semantic fluency) was assessed at phase 5 (1997-1999), when participants were aged 46-68 years. Of people who reported drinking alcohol in the past year, those who consumed at least one drink in the past week, compared with those who did not, were significantly less likely to have poor cognitive function. The beneficial effect extended to those drinking more than 240 g per week (approximately 30 drinks). The effect was stronger for women than men and was not confined to those with evidence of vascular disease. Similar associations were found in cross-sectional and longitudinal analyses. The relations were not explained by confounding by smoking and by physical and mental health and, to a large extent, were not mediated by cholesterol or blood pressure. However, the relations were weakened when social position was added to the model. The authors concluded that for middle-aged subjects, increasing levels of alcohol consumption were associated with better function regarding some aspects of cognition. Nonetheless, it is not proposed that these findings be used to encourage increased alcohol consumption.

Impact of the recommendations for the redefinition of myocardial infarction on diagnosis and prognosis in an unselected United Kingdom cohort with suspected cardiac chest pain

We prospectively and blindly assessed the diagnostic and prognostic impact of implementation of the European Society of Cardiology/American College of Cardiology recommendations for redefinition of myocardial infarction (MI) in an unselected cohort of patients with suspected cardiac chest pain, with particular attention to prespecified clinical groups. All patients admitted to our institute with suspected cardiac chest pain were enrolled. Physicians provided usual care using serial electrocardiograms/creatine kinase (CK)/aspartate transaminase according to World Health Organization (WHO) criteria for MI, while blinded to additional measurements of cardiac troponin T (cTnT) and CK-MB mass. After discharge, diagnoses based on WHO and new criteria were compared, and major adverse cardiac events monitored for 6 months. Implementation of the new recommendations classified an additional 26.1% of patients as having MI compared with WHO criteria, and produced an overall diagnostic alteration in 11.5%. Two thirds of the additional patients with MI were previously diagnosed with unstable angina, whereas one third had “other cardiac” or “noncardiac” diagnoses. A similar MI cohort to the cTnT diagnosis was identified using a CK-MB mass discriminator value of 5 μg/L, but not 10 μg/L. The 6-month prognosis was similar in patients diagnosed with MI by new (cTnT) and WHO criteria, with the new criteria thus identifying a further high-risk cohort in the WHO negative group. In our cohort, the new Joint European Society of Cardiology/American College of Cardiology recommendations identify one fourth more patients as having MI. The 6-month prognosis of those patients reclassified as having MI was similar to those diagnosed with MI by both criteria.

Impact of new diagnostic criteria for myocardial infarction in an unselected United Kingdom cohort with suspected cardiac chest pain

Impact of new diagnostic criteria for myocardial infarction in an unselected United Kingdom cohort with suspected cardiac chest pain

Respiratory syncytial virus infection in high risk infants and the potential impact of prophylaxis in a United Kingdom cohort

BACKGROUNDBronchiolitis caused by respiratory syncytial virus (RSV) is an important cause of morbidity in ex-premature infants. In a randomised placebo controlled trial monoclonal antibody prophylaxis showed a 55% reduction in...

Chemokine receptor polymorphisms and human immunodeficiency virus disease progression.

The role of polymorphisms in genes encoding chemokines and their receptors (CCR2B, SDF-1, and the promoter region of CCR5) in human immunodeficiency virus (HIV) disease progression was studied in 132 white HIV type 1 (HIV-1)-infected participants from a United Kingdom cohort study. Genotyping was done by use of amplification refractory mutation system-polymerase chain reaction with sequence-specific primers, and Cox proportional hazards models were used to examine the impact of polymorphisms on time to a CD4 cell count <200x106/L and to CDC stage IV disease. The results confirm a significant association of the CCR2B-64I mutant genotype with slower progression to a CD4 count <200 (hazards ratio [HR], 0.39; 95% confidence interval [CI], 0.17-0.91) but not with the SDF-1alpha 3' UTR homozygous mutation. The effects of the CCR5 and CCR2 mutations were genetically independent and similar in the magnitude of their protective effect on progression to a CD4 count <200 cells. A novel finding was an association of borderline significance between homozygosity for C at nucleotide position 59353 in the CCR5 promoter region and a slower rate of CD4 cell decline to <200x106/L (HR, 0. 58; 95% CI, 0.34-0.996).

Clinical, laparoscopic and microbiological findings in acute salpingitis: report on a United Kingdom cohort

To determine the clinical features and microbial aetiology of acute salpingitis in women attending an inner city teaching hospital. Prospective, longitudinal cohort study. One hundred and forty-seven women presenting consecutively with acute abdominal pain and clinical signs of acute salpingitis were evaluated microbiologically and laparoscopically. One hundred and four women (70.7%) had acute salpingitis diagnosed at laparoscopy. Other pathological conditions were identified in 20 women (13.6%). No visually identifiable pathology was found in 23 (15.6%). Thirty-five women with acute salpingitis had evidence of pelvic adhesions (33.7%). Bilateral tubal occlusion was present in 6 (5.8%) cases. Chlamydia trachomatis was identified in the genital tract in 40 (38.5%) of the women with acute salpingitis and Neisseria gonorrhoeae in 15 (14.4%). A dual infection was present in eight cases (7.7%). Serological evidence suggested that a further seven women (6.7%) had acute chlamydial infections at the time of diagnosis. C. trachomatis was identified in the genital tract of 5/23 (21.7%) of the women who had no laparoscopic evidence of intra-abdominal pathology. The responsible care of women with suspected acute salpingitis depends on establishing an accurate diagnosis, so that appropriate therapy can be instigated. This study provides evidence to challenge the outpatient management of acute salpingitis on clinical grounds alone as potentially inadequate. Early laparoscopy in hospitalised women improves diagnostic precision and accurately determines disease severity, providing prognostic information for future fertility. In this urban population, sexually transmitted micro-organisms were the commonest pathogens found in the genital tract of women with acute salpingitis. The high prevalence of C. trachomatis in these women suggests that appropriate chemotherapy for acute salpingitis should always include a specific antichlamydial agent.