Roger Tavendale

An obesity-associated FTO gene variant and increased energy intake in children

BACKGROUND Variation in the fat mass and obesity-associated (FTO) gene has provided the most robust associations with common obesity to date. However, the role of FTO variants in modulating specific components of energy balance is unknown. METHODS We studied 2726 Scottish children, 4 to 10 years of age, who underwent genotyping for FTO variant rs9939609 and were measured for height and weight. A subsample of 97 children was examined for possible association of the FTO variant with adiposity, energy expenditure, and food intake. RESULTS In the total study group and the subsample, the A allele of rs9939609 was associated with increased weight (P=0.003 and P=0.049, respectively) and body-mass index (P=0.003 and P=0.03, respectively). In the intensively phenotyped subsample, the A allele was also associated with increased fat mass (P=0.01) but not with lean mass. Although total and resting energy expenditures were increased in children with the A allele (P=0.009 and P=0.03, respectively), resting energy expenditure was identical to that predicted for the age and weight of the child, indicating that there is no defect in metabolic adaptation to obesity in persons bearing the risk-associated allele. The A allele was associated with increased energy intake (P=0.006) independently of body weight. In contrast, the weight of food ingested by children who had the allele was similar to that in children who did not have the allele (P=0.82). CONCLUSIONS The FTO variant that confers a predisposition to obesity does not appear to be involved in the regulation of energy expenditure but may have a role in the control of food intake and food choice, suggesting a link to a hyperphagic phenotype or a preference for energy-dense foods.

Common variants in WFS1 confer risk of type 2 diabetes

We studied genes involved in pancreatic β cell function and survival, identifying associations between SNPs in WFS1 and diabetes risk in UK populations that we replicated in an Ashkenazi population and in additional UK studies. In a pooled analysis comprising 9,533 cases and 11,389 controls, SNPs in WFS1 were strongly associated with diabetes risk. Rare mutations in WFS1 cause Wolfram syndrome; using a gene-centric approach, we show that variation in WFS1 also predisposes to common type 2 diabetes.

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.

Abstract 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. Key messages Among Scottish men and women studied for 27 risk factors for coronary heart disease and followed up for eight years classical risk factors scored strongly in predicting coronary risk but the performance of new ones was more variable Risk factors for coronary disease, and also for death, showed few, albeit interesting, differences between men and women Relative risk was often higher for risk factors in women but they had low levels of absolute risk when risk factor levels were low Smoking, blood pressure, and fibrinogen predicted coronary disease and also death, but other factors are less consistent Unifactorial results should not be overinterpreted, but the protective effect of potassium consumption is of particular interest

Chromosome 17q21 Gene Variants Are Associated with Asthma and Exacerbations but Not Atopy in Early Childhood

RATIONALE An asthma predisposition locus on chromosome 17q12-q21 has recently been replicated in different ethnic groups. OBJECTIVES To characterize the asthma and atopy phenotypes in early childhood that associate with the 17q12-21 locus. METHODS The single nucleotide polymorphism (SNP), rs7216389, was genotyped in 376 of 411 children from the Copenhagen Prospective Study on Asthma in Childhood (COPSAC) birth cohort born to mothers with asthma together with 305 mothers and 224 fathers. Nineteen additional SNPs in the region were genotyped in the children. Investigator-diagnosed clinical endpoints were based on diary cards and clinic visits every 6 months and at acute symptoms from birth. Lung function, bronchial responsiveness, and sensitization were tested longitudinally from early infancy. MEASUREMENTS AND MAIN RESULTS rs7216389 was significantly associated with the development of wheeze (hazard ratio 1.64 [1.05-2.59], P value = 0.03), asthma (hazard ratio, 1.88 [1.15-3.07], P = 0.01), and acute severe exacerbations (hazard ratio 2.66 [1.58-4.48], P value = 0.0002). The effect on wheeze and asthma was observed for early onset but not late onset of disease. The increased risk of exacerbations persisted from 1 to 6 years of age (incidence ratio 2.48 [1.42-4.32], P value = 0.001), and increased bronchial responsiveness was present in infancy and at 4 years of age, but not at 6 years. In contrast, rs7216389 conferred no risk of eczema, rhinitis, or allergic sensitization. CONCLUSIONS Variation at the chromosome 17q12-q21 locus was associated with approximately twofold increased risk of recurrent wheeze, asthma, asthma exacerbations, and bronchial hyperresponsiveness from early infancy to school age but without conferring risk of eczema, rhinitis, or allergic sensitization. These longitudinal clinical data show this locus to be an important genetic determinant of nonatopic asthma in children.

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.

A polymorphism controlling ORMDL3 expression is associated with asthma that is poorly controlled by current medications

BACKGROUND The specific genetic contributions to childhood asthma have been difficult to elucidate. A recent whole-genome association study suggested that single nucleotide polymorphisms at loci controlling the expression of the ORMDL3 gene and others in the neighborhood of the NRG1 and ERO1LB genes might be important. OBJECTIVE We sought to replicate the associations of these genetic markers with asthma in a large population of asthmatic patients from Scotland and to assess the effect of these variants on asthma outcomes. METHODS Using mouthwash-derived DNA and clinical interviews and measurements, we investigated the association of 3 single nucleotide polymorphisms in the candidate genes with susceptibility to asthma in a case-control study and also exacerbations in a group of 1054 patients aged 3 to 22 years. RESULTS A common C/T polymorphism at a locus controlling ORMDL3 gene expression (rs7216389) was significantly associated with the risk of childhood asthma (P = 1.73 x 10(-12)), with a single copy of the T allele conferring an odds ratio of 1.50 (95% CI, 1.24-1.81) and 2 copies of the T allele conferring an odds ratio of 2.11 (95% CI, 1.71-2.61), respectively. In asthmatic patients the T allele was associated with exacerbations of the condition (P = .008). Polymorphisms at the loci of nearby genes for NRG1 (rs4512342) and ERO1LB (rs10924993) were associated with neither the occurrence of nor exacerbations of asthma. CONCLUSION A common genetic variation at a locus controlling the expression of the ORMDL3 locus increases the susceptibility to asthma and is associated with poor control of the condition in children and young adults.

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.

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 A1c (HbA1c) level <7% than patients with two wild‐type CYP2C9 alleles. This corresponds to a 0.5% (P = 0.003) greater reduction in HbA1c 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.

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 1.0mmol/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. Many participants did not eat fresh fruit or green vegetables. High cholesterol and cigarette smoking levels provide a classical explanation for the excess of coronary deaths in Scotland, justifying action, but other factors, such as the dietary deficiencies, also merit further investigation.