Individuals with filaggrin-related eczema and asthma have increased long-term medication and hospital admission costs.

BACKGROUND: Eczema and asthma are chronic diseases with onset usually before the age of 5 years. More than 50% of individuals with eczema will develop asthma and/or other allergic diseases. Several loss-of-function mutations in filaggrin (FLG) have been identified in patients with eczema. However, the association of FLG with healthcare use is unknown. OBJECTIVES: To determine whether FLG mutations are associated with increased prescribing for eczema and asthma and whether increased prescribing is associated with increased healthcare costs. METHODS: A secondary analysis of BREATHE, a cross-sectional study of gene-environment associations with asthma severity, was undertaken. BREATHE data was collected for 1100 participants with asthma, in Tayside and Fife, Scotland during the period 2003-2005. Through collaboration with the Health Informatics Centre in Dundee, BREATHE was linked to accident and emergency, community prescribing and Scottish morbidity records. The data linkage allowed longitudinal exploration of associations between genetic variation and prescribing. RESULTS: An association was found between FLG mutations and increased prescribing for mild and moderate eczema, asthma-reliever medicine and asthma exacerbations. A strong association was found between FLG mutations and prescribing of emollients [incidence rate ratio (IRR) 2·19, 95% confidence interval (CI) 1·36-3·52], treatment for severe eczema (IRR 2·18, 95% CI 1·22-3·91) and a combination of a long-acting ß2 -agonist and corticosteroids (IRR 3·29, 95% CI 1·68-6·43). CONCLUSIONS: The presence of FLG mutations in this cohort is associated with increased prescribing for eczema and asthma. Randomized controlled trials are required to determine if these individuals could benefit from management strategies to reduce morbidity and treatment costs.

ST13 polymorphisms and their effect on exacerbations in steroid-treated asthmatic children and young adults.

BACKGROUND: The clinical response to inhaled corticosteroids (ICS) is associated with single nucleotide polymorphisms (SNPs) in various genes. This study aimed to relate variations in genes in the steroid pathway and asthma susceptibility genes to exacerbations in children and young adults treated with ICS. METHODS: We performed a meta-analysis of three cohort studies: Pharmacogenetics of Asthma Medication in Children: Medication with Anti-Inflammatory effects (n = 357, age: 4-12 years, the Netherlands), BREATHE (n = 820, age: 3-22 years, UK) and Paediatric Asthma Gene Environment Study (n = 391, age: 2-16 years, UK). Seventeen genes were selected based on a role in the glucocorticoid signalling pathway or a reported association with asthma. Two outcome parameters were used to reflect exacerbations: hospital visits and oral corticosteroid (OCS) use in the previous year. The most significant associations were tested in three independent validation cohorts; the Childhood Asthma Management Programme (clinical trial, n = 172, age: 5-12 years, USA), the Genes- environment and Mixture in Latino Americans II- study (n = 745, age: 8-21, USA) and the Pharmacogenetics of adrenal suppression cohort (n = 391, age: 5-18, UK) to test the robustness of the findings. Finally, all results were meta-analysed. RESULTS: Two SNPs in ST13 (rs138335 and rs138337), but not in the other genes, were associated at a nominal level with an increased risk of exacerbations in asthmatics using ICS in the three cohorts studied. In a meta-analysis of all six studies, ST13 rs138335 remained associated with an increased risk of asthma-related hospital visits and OCS use in the previous year; OR = 1.22 (P = 0.013) and OR = 1.22 (P = 0.0017), respectively. CONCLUSION AND CLINICAL RELEVANCE: A novel susceptibility gene, ST13, coding for a cochaperone of the glucocorticoid receptor, is associated with exacerbations in asthmatic children and young adults despite their ICS use. Genetic variation in the glucocorticoid signalling pathway may contribute to the interindividual variability in clinical response to ICS treatment in children and young adults.

FCER2 T2206C variant associated with chronic symptoms and exacerbations in steroid-treated asthmatic children.

BACKGROUND: The T2206C FCER2 variant was found previously to be associated with IgE levels, exacerbation rates and decreased FCER2 expression in children on inhaled corticosteroids (ICS) participating in a clinical trial. This finding has not been replicated. We sought to replicate the association between the FCER2 gene and exacerbations in children with asthma. In addition, we tested the hypothesis that the T2206C variant may be associated with other markers of steroid resistance such as asthma symptom scores and asthma medication use. METHODS: The influence of the T2206C variant on asthma exacerbations (emergency department visits or hospitalization), symptoms scores and medication use was explored using data from two populations of asthmatic children using ICS: Pharmacogenetics of Asthma medication in Children: Medication with ANti-inflammatory effects study (n = 386) and BREATHE study (n = 939). RESULTS: The T2206C variant was associated with increased risk of asthma-related hospital visits in both cohorts (OR: 1.91, 95% CI: 1.08-3.40), and meta-analysis with previously published results was highly significant (OR: 2.38, 95% CI: 1.47-3.85, P = 0.0004). The FCER2 variant was also associated with increased risk of uncontrolled asthma measured by Asthma Control Questionnaire (OR: 2.64, 95% CI: 1.00-6.98) and was associated with increased daily steroid dose (OR: 2.46, 95% CI: 1.38-4.39). CONCLUSION: The association between the FCER2 T2206C variant and asthma-related hospitalizations in steroid-treated asthma appears robust and may also be associated with other indicators of lack of ICS efficacy such as asthma symptoms and a requirement for higher daily doses of ICS. Our results suggest that the FCER2 T2206C variant might be a useful pharmacogenetic predictor of steroid refractory patients.

Variants in Pharmacokinetic Transporters and Glycemic Response to Metformin: A Metgen Meta-Analysis.

Therapeutic response to metformin, a first-line drug for type 2 diabetes (T2D), is highly variable, in part likely due to genetic factors. To date, metformin pharmacogenetic studies have mainly focused on the impact of variants in metformin transporter genes, with inconsistent results. To clarify the significance of these variants in glycemic response to metformin in T2D, we performed a large-scale meta-analysis across the cohorts of the Metformin Genetics Consortium (MetGen). Nine candidate polymorphisms in five transporter genes (organic cation transporter [OCT]1, OCT2, multidrug and toxin extrusion transporter [MATE]1, MATE2-K, and OCTN1) were analyzed in up to 7,968 individuals. None of the variants showed a significant effect on metformin response in the primary analysis, or in the exploratory secondary analyses, when patients were stratified according to possible confounding genotypes or prescribed a daily dose of metformin. Our results suggest that candidate transporter gene variants have little contribution to variability in glycemic response to metformin in T2D.

Adipose tissue fatty acids in Scottish men and women: results from the Scottish Heart Health Study.

The fatty acid composition of adipose tissue from 4114 men and women across 22 districts of Scotland is described. A biopsy of subcutaneous adipose tissue was obtained from the upper arm using a skin biopsy punch. Overall the proportion of saturated fatty acids was lower in women and those of monounsaturated and polyunsaturated higher than in men. There were significant effects of age on adipose tissue fatty acid composition, particularly in women, where the proportion of saturated fatty acids decreased and that of monounsaturated fatty acids increased with advancing age. The fatty acid composition of adipose tissue varied among the districts studied. The district standardised mortality ratio for coronary heart disease was positively correlated with the district mean oleic acid value and inversely correlated with the district mean linoleic acid value. This paper supports the importance of adipose tissue fatty acids as indicators of risk factor status for coronary heart disease.

Effects of delta9-tetrahydrocannabinol on the rates of oxygen consumption of mice.

1. Experiments with untreated mice confirmed that at ambient temperatures below 30 degrees C, the oxygen consumption rate of mice normally kept at about 23 degrees C varies inversely with ambient temperature. 2. At given ambient temperatures in the range 20 to 31 degrees C the oxygen consumption rate was 32 to 43% greater for restrained than for unrestrained mice. 3. Hypothermia induced in restrained mice by delta9-tetrahydrocannabinol (delta9-THC) (1.0 to 4.0 mg/kg i.v.) was accompanied by marked falls in the rate of oxygen consumption. The size of these falls parallelled the degree of hypothermia and increased both with increases in dose and with decreases in the ambient temperature. The oxygen consumption rates of unrestrained mice were also lowered by hypothermic doses (10 to 40 mg/kg i.p.) of delta9-THC. 4. The maximum falls in oxygen consumption rate occurred at earlier times after drug administration than the maximum falls in rectal temperature. 5. At none of the ambient temperatures studied did the oxygen consumption rates of delta9-THC-treated mice fall significantly below the basal levels (59 +/- 3 ml 25 g-1 h-1) of unrestrained, resting mice at 30 degrees C. 6. The hypothesis that reduced rates of heat production contribute significantly towards the hypothermia induced by delta9-THC in our experiments is discussed. The possibility that biological processes responsible for increased heat production in response to cold are more sensitive to delta9-THC than those processes governing basal rates of heat production at thermally neutral environmental temperature is also raised.

Effects of delta 9-tetrahydrocannabinol, 2.4-dinitrophenol and pentolinium tartrate on behavioural thermoregulation in mice.

1 A new apparatus in which mice are allowed to shuttle between the warm and cool parts of a continuous oval tunnel has been designed for the measurement of drug effects on behavioural thermoregulation.2 The length of time that untreated mice spent in the warmer part of the apparatus (tunnel wall temperature 38 degrees C) was found to be inversely related to the temperature of the cooler part (wall temperature 18 degrees , 24 degrees or 30 degrees C).3 Mice treated with 2,4-dinitrophenol at a dose known to be hyperthermic at an ambient temperature of 32 degrees C (20 mg/kg s.c.) spent an increased length of time in the cooler part of the apparatus (wall temperature 18 degrees C) and did not exhibit any change in rectal temperature.4 Mice treated with pentolinium tartrate at a dose known to be hypothermic at room temperature (5.0 mg/kg i.v.) spent a decreased length of time in the cooler part of the apparatus (wall temperature 24 degrees C) and did not exhibit any change in rectal temperature.5 It is concluded from the above results that the apparatus can be used to measure drug effects on behavioural thermoregulation.6 In experiments of 30 min duration, mice treated with Delta(9)-tetrahydrocannabinol (Delta(9)-THC) at doses known to be hypothermic and to lower oxygen consumption at room temperature (20 mg/kg i.p. or 2.0 mg/kg i.v.) spent a longer time in the warmer part of the apparatus between 15 and 30 min after injection. Rectal temperatures measured 30 min after injection were only slightly less than those of control mice. In these experiments the wall temperature of the cool tunnel was 24 degrees C.7 In experiments of 15 min duration, mice treated with Delta(9)-THC (20 mg/kg) and then placed in the apparatus spent more time in the cooler part of the apparatus (wall temperature 24 degrees C) and exhibited a large fall in rectal temperature.8 It is concluded that immediately after injection of Delta(9)-THC the mice do not attempt to oppose drug-induced falls in deep body temperature by moving into a warm environment and that only later do the animals demonstrate a preference for a warm environment.

The biliary elimination of amaranth, indocyanine green and nitrazepam in germ-free rats.

In anaesthetised bile duct-cannulated rats the overall rate of bile flow was 15-50% lower in both male and female germ-free (GF) rats. Except in the case of amaranth in female GF rats, this was reflected in a lower rate of biliary excretion of the three test xenobiotics, of which two (amaranth and indocyanine green) are excreted unchanged and one (nitrazepam) is excreted solely as metabolites. It was also noted that compared with conventional (CV) rats the relative liver weights (g/kg body weight) were about 20% lower in GF animals. After the intravenous injection of 14C-nitrazepam, thin-layer chromatographic separation of biliary nitrazepam-derived radioactivity revealed three loci (A, B and C in decreasing order of polarity). The relative proportions of A, B and C were similar in GF and CV rats, with C and B being the major and minor "metabolites" respectively. When 14C-nitrazepam was given intragastrically to non-anaesthetised rats, by 9 days about 20% and 70% of the dose had been recovered in the urine and faeces respectively of both GF and CV rats. The rate of elimination of urinary radioactivity was similar in GF and CV rats. However, faecal elimination was much slower in GF animals, for example after 24 hr the respective amounts of radioactivity excreted in GF and CV rats corresponded to 13% and 52% of the dose. These findings indicate that the indigenous bacterial population of an animal may indirectly affect the disposition of a xenobiotic whether or not it is metabolised by the bacteria.

Smoking characteristics and inhalation biochemistry in the Scottish population.

Data from a cross-sectional random population sample of 10,359 middle-aged Scottish men and women are used to investigate the relationships between self-reported tobacco consumption and three biochemical markers of tobacco inhalation: expired air carbon monoxide (CO), serum thiocyanate and serum cotinine. These data represent one of the largest samples of these biochemical markers yet analysed. The results show that, for each sex, the biochemical markers are highly correlated for smokers and for the entire sample of mixed smokers and non-smokers. CO is the preferred biochemical marker, in such groups, because it is the cheapest, is non-invasive and gives virtually instantaneous results. Self-reported daily cigarette consumption also correlates well with each of these biochemical markers, and so it appears that people are, in the context of population studies, mainly truthful about their smoking. The relationships with self-reported cigarette consumption are curvilinear with apparent levelling out of the gradient at around 25 cigarettes/day for cotinine and thiocyanate and at greater than 40 cigarettes/day for CO. Sex differences are small, although thiocyanate is generally higher and cotinine generally lower in women with the same self-reported cigarette consumption as men. Amongst non-smokers, only cotinine is able to discriminate between self-reported levels of exposure to passive smoking. CO and thiocyanate are not suitable for measuring low levels of smoke inhalation, such as found in passive smokers.

Cardiovascular disease in Edinburgh and north Glasgow--a tale of two cities.

Scotland has one of the highest mortality rates from coronary heart disease for both men and women. However within Scotland there are major geographical differences in the mortality rates, exemplified by the differences between the two largest Scottish cities. Glasgow on the west has a much higher mortality rate for cardiovascular diseases than Edinburgh in the east. During 1986 coronary risk factor population surveys were conducted simultaneously in Edinburgh and North Glasgow as part of the WHO MONICA study. These surveys employed standardized methods and the central quality control of the WHO project. Measures of coronary heart disease morbidity were higher in North Glasgow, except for electrocardiographic evidence of ischaemia, consistent with the mortality rates. The major coronary risk factors were uniformly higher in North Glasgow than in Edinburgh, except for serum lipids which were not significantly different. The risk factors, except the lipids, showed a gradient by socioeconomic status, so that when the risk factors levels were standardized for housing tenure the significant differences between the cities largely disappeared, and the serum cholesterol levels in women become significantly higher in Edinburgh because of their slight negative relationship with social status. This study shows that the socioeconomic differences between Edinburgh and North Glasgow largely explain the coronary risk factor differences between the cities. The socioeconomic differences in coronary disease and its major risk factors require further investigation and may be more fundamentally important than the geographical differences in the patterns of coronary heart disease.

Passive smoking by self report and serum cotinine and the prevalence of respiratory and coronary heart disease in the Scottish heart health study.

STUDY OBJECTIVE: To explore the relationship between self reported environmental tobacco smoke exposure (or passive smoking), the serum cotinine concentration, and evidence of respiratory or coronary disease in men and women who have never smoked. DESIGN: Cross sectional random population survey identifying disease markers and relating them to measures of passive smoking. Disease markers were previous medical diagnoses, response to standard symptom questionnaires, and electrocardiographic signs. SETTING: Samples of men and women aged 40-59 years drawn from general practitioner lists in 22 local government districts of Scotland, between 1984 and 1986. PARTICIPANTS: A total of 786 men and 1492 women who reported never having smoked tobacco, and who had serum cotinine concentrations below 17.5 ng/ml, the cut off point for smoking "deceivers", took part. RESULTS: Fewer than one third of never smokers reported no recent exposure to environmental tobacco smoke and the same proportion had no detectable cotinine. Women had lower cotinine values than men but reported more exposure to smoke. The correlation between the measures of exposure was poor. Self-reported exposure showed strong, statistically significant, dose response relationships with respiratory symptoms and with the coronary disease markers. These relationships were weak or absent for serum cotinine, except for diagnosed coronary heart disease. Here the dose response gradient was as strong as that for self report, with an odds ratio of 2.7 (95% CI 1.3, 5.6) for the highest v the lowest exposure group, adjusted for age, housing tenure, total cholesterol, and blood pressure, and not explained by fibrinogen. CONCLUSIONS: The validity of different measures of tobacco smoke exposure needs further investigation. The gradient of diagnosed coronary heart disease with both self reported exposure and serum cotinine was, however, surprisingly strong, statistically significant, and unexplained by other factors. These findings reinforce current policies to limit passive tobacco smoke exposure.

Plasma vitamin C and food choice in the third Glasgow MONICA population survey.

STUDY OBJECTIVE: To determine the contribution of different foods to the estimated intakes of vitamin C among those differing in plasma vitamin C levels, and thereby inform dietary strategies for correcting possible deficiency. DESIGN: Cross sectional random population survey. SETTING: North Glasgow, Scotland, 1992. PARTICIPANTS: 632 men and 635 women, aged 25 to 74 years, not taking vitamin supplements, who participated in the third MONICA study (population survey monitoring trends and determinants of cardiovascular disease). MEASUREMENTS AND MAIN RESULTS: Dietary and sociodemographic information was collected using a food frequency and lifestyle questionnaire. Plasma vitamin C was measured in non-fasted venous blood samples and subjects categorised by cut points of 11.4 and 22.7 micromol/l as being of low, marginal or optimal vitamin C status. Food sources of dietary vitamin C were identified for subjects in these categories. Plasma vitamin C concentrations were compared among groups classified according to intake of key foods. More men (26%) than women (14%) were in the low category for vitamin C status; as were a higher percentage of smokers and of those in the older age groups. Intake of vitamin C from potatoes and chips (fried potatoes) was uniform across categories; while the determinants of optimal versus low status were the intakes of citrus fruit, non-citrus fruit and fruit juice. Optimal status was achieved by a combined frequency of fruit, vegetables and/or fruit juice of three times a day or more except in older male smokers where a frequency greater than this was required even to reach a marginal plasma vitamin C level. CONCLUSION: Fruit, vegetables and/or fruit juice three or more times a day increases plasma vitamin C concentrations above the threshold for risk of deficiency.

Evidence for age-related differences in the fatty acid composition of human adipose tissue, independent of diet.

OBJECTIVE: To test the null-hypothesis that no age difference in adipose tissue fatty acid composition exists independent of dietary fat intake. DESIGN: A cross-sectional survey of coronary heart disease risk factors, the Scottish Heart Health Study, provided needle biopsy adipose tissue fatty acid data and food frequency-derived dietary data. SETTING: Twenty-two Scottish Districts between 1984 and 1986. SUBJECTS: A total of 10,359 men and women aged 40-59 y were randomly recruited in sex and five-year age bands from GP lists. A sub-set of 2308 men and 2049 women (42%) provided satisfactory adipose tissue and dietary data. MAIN OUTCOME AND MEASURES: Multiple regression analysis (adjusting for dietary fats, body mass index and smoking, with and without menopause status for women) of the relationship between individual fatty acids in adipose tissue and age, and between age and the ratio of linoleic acid (C18:2, n-6) to gamma-linolenic acid (C18:3, n-6) as an indicator of delta-6 desaturase activity. RESULTS: Sex-consistent changes with age occurred for linoleate (adjusted regression slope +/- s.e. for men -0.299 +/- 0.1339 and for women -0.504 +/- 0.1731) and gamma-linolenate (adjusted regression slope +/- s.e. for men -0.141 +/- 0.0341 and for women -0.154 +/- 0.0469) both P < 0.0001. These changes gave rise to a significant increase (P < or = 0.005) in the C18:2, n-6 to C18:3, n-6 ratio with age). Dihomo-gamma-linolenic acid (C20:3, n-6) and docosahexa- plus docosapentaenoic acids (C22:5 + C22:6, n-3) also increased significantly with age (P < or = 0.01). For the latter, the adjusted regression slopes were far greater for women (0.596 +/- 0.0575) than men (0.131 +/- 0.0417). CONCLUSIONS: The results show that ageing does influence adipose tissue fatty acid composition independent of diet. The sex differences may partially be due to inadequate adjustment for changes in sex hormone status in males with ageing. Using the current indicator, a decline in the rate limiting step of beta-6 desaturation appeared to occur with age, and was greater in women than in men. These results may indicate that an increase in dietary gamma-linolenic acid (C18:3, n-6) is necessary with age to offset the relative imbalance between PUFA levels which appears to occur. However, any direct health benefit regarding the common diseases of ageing from such a strategy still remain to be clarified.

Urinary electrolyte excretion, alcohol consumption, and blood pressure in the Scottish heart health study.

As part of a study of risk factors for coronary heart disease 24 hour urine collections were obtained from 7354 men and women aged 40-59 selected at random from 22 districts throughout Scotland (Scottish heart health study). The mean of two standardised measurements of blood pressure was related to the reported consumption of alcohol and measurements of height, weight, pulse rate, and electrolyte excretion. Several significant correlations were found with both systolic and diastolic pressure, but only the coefficients for age, body mass index, and pulse rate were greater than 0.1. Alcohol consumption showed a weak positive correlation with blood pressure in men. Sodium excretion showed a weak positive correlation with blood pressure in both sexes, and potassium excretion showed weak negative correlations. In multiple regression analysis age, pulse rate, body mass index, alcohol consumption, and potassium excretion had significant independent effects but sodium excretion did not. Although measuring blood pressure twice on one occasion and 24 hour urinary sodium excretion only once may have weakened any potential correlation, the most likely explantation of these results is that the relation between sodium and blood pressure in the population is weak and that potassium and alcohol are of greater importance.

Comparison of the prediction by 27 different factors of coronary heart disease and death in men and women of the Scottish Heart Health Study: cohort study.

OBJECTIVE: To compare prediction by 27 different factors in men and women of coronary heart disease events, coronary deaths, and deaths from all causes. DESIGN: Cohort study. SETTING: Scottish population study. SUBJECTS: In 1984-7 random sampling of residents aged 40-59 produced 11,629 men and women who generated survey clinic questionnaires, examination findings, and blood and urine specimens. MAIN OUTCOME MEASURES: Subsequent death, coronary artery surgery, and myocardial infarction. Risks were calculated for each category of factor or fifth of continuous variables. 27 factors were ranked by descending age adjusted hazard ratio of the top to bottom class in each factor, by sex and end point. RESULTS: Follow up averaged 7.6 years, during which the 5754 men had 404 coronary events, 159 coronary deaths, and 383 deaths and the 5875 women 177, 47, and 208 respectively. The rankings for factors for the three end points were mainly similar in men and women, although hazard ratios were often higher in women. Classical risk factors ranked better for predicting coronary risk than newer ones. Yet strong prediction of coronary risk was no guarantee of significant prediction of all cause mortality. Findings included an anomalous coronary protective role for type A behaviour in women; raised plasma fibrinogen as a strong predictor of all end points; and an unexpectedly powerful protective relation of dietary potassium to all cause mortality. CONCLUSIONS: These initial unifactorial rankings and comparisons must be interpreted with caution until potential interaction, confounding, and problems of measurement and causation are further explored.

Coronary risk factor and lifestyle variation across Scotland: results from the Scottish Heart Health Study.

Between 1984 and 1986 the Scottish Heart Health Study recorded coronary risk factors and lifestyle in 10,359 men and women aged 40-59 years across 22 districts of Scotland--districts whose standardised mortality ratio for coronary heart disease in men varied from 61 in Eastwood to 136 in Monklands. This paper presents the results by district. Cigarette smoking levels showed the greatest variation, from 29% to 52% in men and 24% to 51% in women. Blood pressure means varied but were not high (129-138mmHg systolic in men, 126-137mmHg in women, 81-88mmHg diastolic in men and 77-84mmHg in women). Mean serum cholesterol values were high and varied little by district in men, (6.1 to 6.5mmol/l), although there was more variation in women (6.3 to 7.0mmol/l). Body mass index (25.3 to 26.6kg/m2 in men and 24.8 to 26.3kg/m2 in women) also varied little. Distribution of other lipids, fibrinogen, exercise levels and fruit and vegetable consumption is also described. When district mean levels of major coronary risk factors are entered into predictive formulae, cigarette smoking and blood pressure could explain part of the regional variation in mortality, but much remains unaccounted for. Nonetheless, these levels provide data for local preventive initiatives. While the overall pattern and interaction of the factors will repay further study, the high levels of serum cholesterol in all districts, and the level and variation in cigarette smoking, are a challenge for action.

Concomitants of excess coronary deaths--major risk factor and lifestyle findings from 10,359 men and women in the Scottish Heart Health Study.

The Scottish Heart Health Study is a study of lifestyle and coronary heart disease risk factors in 10,359 men and women aged 40-59 years, in 22 districts of Scotland. The study was conducted during 1984-86, when Scotland had the highest national coronary heart disease mortality reported by the World Health Organisation. A self-completed questionnaire, complemented by a 40 minute visit to a survey clinic, staffed by nurses, enabled the classical major risk factors and some more newly described ones to be measured. The study emphasised quality control and representativeness, and incorporated a World Health Organisation protocol for measurement of key items to allow comparisons in place and time, and therefore also to provide a definitive baseline against which interventions can be assessed. This paper describes the overall findings. Current cigarette smokers constitute 39% of men and 38% of women, higher levels than those reported in England but lower than previous Scottish reports. Mean blood pressure levels were 134/84 mmHg for men and 131/81 mmHg in women, lower than in British studies of the 1960s and 1970s. Mean body mass index levels, 26.1 Kg/m2 in men and 25.7 Kg/m2 in women, were not high by international standards. However, mean serum cholesterol levels were 6.4 mmol/l in men and 6.6 mmol/l in women--as high as those in previous British studies and high by international standards. Levels of high density lipoprotein cholesterol, non-fasting triglycerides and fibrinogen are also reported. Physical activity both at work and in leisure time was low.(ABSTRACT TRUNCATED AT 250 WORDS)

Common nonsynonymous substitutions in SLCO1B1 predispose to statin intolerance in routinely treated individuals with type 2 diabetes: a go-DARTS study.

SLCO1B1 gene variants are associated with severe statin-induced myopathy. We examined whether these variants are also associated with general statin intolerance in a large population of patients with type 2 diabetes receiving statins as part of routine clinical care. A total of 4,196 individuals were genotyped for rs4149056 (Val174Ala) and rs2306283 (Asp130Asn). Intolerance was defined by serum biochemistry and also by discontinuation, switching, or reduction in dose of the prescribed statin drug. Ala174 was associated with higher intolerance (odds ratio = 2.05, P = 0.043), whereas Asp130 was associated with lower intolerance (odds ratio = 0.71, P = 0.026). Ala174 was associated with a lower low-density lipoprotein cholesterol (LDLc) response to statins (P = 0.01) whereas 130D was associated with a greater LDLc response to statins (P = 0.048), as previously reported; however, this association was no longer present when data for statin-intolerant individuals were removed from the analysis. This study suggests that common genetic variants selected for an extreme phenotype of statin-induced myopathy also predispose to more common milder statin intolerance and may, for this reason, impact lipid-lowering efficacy.

Loss-of-function CYP2C9 variants improve therapeutic response to sulfonylureas in type 2 diabetes: a Go-DARTS study.

Sulfonylureas are metabolized mainly by the cytochrome p450 2C9 (CYP2C9) enzyme. Two CYP2C9 variants--*2 (Arg144Cys) and *3 (Ile359Leu)--are associated with reduced enzyme activity and impaired substrate metabolism. We identified 1,073 incident users of sulfonylureas in Tayside, Scotland, and assessed the impact of the combined CYP2C9*2 and CYP2C9*3 genotypes on early and sustained sulfonylurea response. We found that patients with two copies of a loss-of-function allele were 3.4 times (P = 0.0009) more likely to achieve a treatment hemoglobin A(1c) (HbA(1c)) level <7% than patients with two wild-type CYP2C9 alleles. This corresponds to a 0.5% (P = 0.003) greater reduction in HbA(1c) concentration. In addition, *2 and *3 allele carriers were less likely to experience treatment failure with sulfonylurea monotherapy (P = 0.04; per-allele hazard ratio 0.79; 95% confidence interval 0.63-0.99). In conclusion, CYP2C9 loss-of-function alleles are associated with greater response to sulfonylureas and decreased failure of therapy consistent with the pharmacokinetic role of CYP2C9.