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Articles by G. D Smith
Total Records ( 6 ) for G. D Smith
  C. L Hart , G. D Smith , M. N Upton and G. C. M. Watt

Aims: The aim of this study was to investigate relationships between alcohol consumption and social mobility in a cohort study in Scotland. Methods: 1040 sons and 1298 daughters aged 30–59 from 1477 families reported their alcohol consumption from which was derived: weekly units (1 UK unit being 8 g ethanol), exceeding daily or weekly limits, binge drinking and consuming alcohol on 5+ days per week. Own and father's social class were available enabling social mobility to be investigated. Results: More downwardly mobile men exceeded the weekly limit, the daily limit, were defined as binge drinkers and drank the most units per week of the four social mobility groups. Stable non-manual women were more likely to consume alcohol on 5+ days a week but very few were binge drinkers. Stable non-manual and upwardly mobile men and women were more likely to drink wine, and downwardly mobile men to drink beer. Conclusions: Downward mobility was associated with less favourable alcohol behaviours, especially in men. Wine consumption was more closely related to the social mobility groups than beer and spirits consumption. Drinking patterns could both influence and be influenced by social mobility.

  R Sofat , A. D Hingorani , L Smeeth , S. E Humphries , P. J Talmud , J Cooper , T Shah , M. S Sandhu , S. L Ricketts , S. M Boekholdt , N Wareham , K. T Khaw , M Kumari , M Kivimaki , M Marmot , F. W Asselbergs , P van der Harst , R. P.F Dullaart , G Navis , D. J van Veldhuisen , W. H Van Gilst , J. F Thompson , P McCaskie , L. J Palmer , M Arca , F Quagliarini , C Gaudio , F Cambien , V Nicaud , O Poirer , V Gudnason , A Isaacs , J. C.M Witteman , C. M van Duijn , M Pencina , R. S Vasan , R. B D'Agostino , J Ordovas , T. Y Li , S Kakko , H Kauma , M. J Savolainen , Y. A Kesaniemi , A Sandhofer , B Paulweber , J. V Sorli , A Goto , S Yokoyama , K Okumura , B. D Horne , C Packard , D Freeman , I Ford , N Sattar , V McCormack , D. A Lawlor , S Ebrahim , G. D Smith , J. J.P Kastelein , J Deanfield and J. P. Casas

Background— Cholesteryl ester transfer protein (CETP) inhibitors raise high-density lipoprotein (HDL) cholesterol, but torcetrapib, the first-in-class inhibitor tested in a large outcome trial, caused an unexpected blood pressure elevation and increased cardiovascular events. Whether the hypertensive effect resulted from CETP inhibition or an off-target action of torcetrapib has been debated. We hypothesized that common single-nucleotide polymorphisms in the CETP gene could help distinguish mechanism-based from off-target actions of CETP inhibitors to inform on the validity of CETP as a therapeutic target.

Methods and Results— We compared the effect of CETP single-nucleotide polymorphisms and torcetrapib treatment on lipid fractions, blood pressure, and electrolytes in up to 67 687 individuals from genetic studies and 17 911 from randomized trials. CETP single-nucleotide polymorphisms and torcetrapib treatment reduced CETP activity and had a directionally concordant effect on 8 lipid and lipoprotein traits (total, low-density lipoprotein, and HDL cholesterol; HDL2; HDL3; apolipoproteins A-I and B; and triglycerides), with the genetic effect on HDL cholesterol (0.13 mmol/L, 95% confidence interval [CI] 0.11 to 0.14 mmol/L) being consistent with that expected of a 10-mg dose of torcetrapib (0.13 mmol/L, 95% CI 0.10 to 0.15). In trials, 60 mg of torcetrapib elevated systolic and diastolic blood pressure by 4.47 mm Hg (95% CI 4.10 to 4.84 mm Hg) and 2.08 mm Hg (95% CI 1.84 to 2.31 mm Hg), respectively. However, the effect of CETP single-nucleotide polymorphisms on systolic blood pressure (0.16 mm Hg, 95% CI –0.28 to 0.60 mm Hg) and diastolic blood pressure (–0.04 mm Hg, 95% CI –0.36 to 0.28 mm Hg) was null and significantly different from that expected of 10 mg of torcetrapib.

Conclusions— Discordance in the effects of CETP single-nucleotide polymorphisms and torcetrapib treatment on blood pressure despite the concordant effects on lipids indicates the hypertensive action of torcetrapib is unlikely to be due to CETP inhibition or shared by chemically dissimilar CETP inhibitors. Genetic studies could find a place in drug-development programs as a new source of randomized evidence for drug-target validation in humans.

  Z Pausova , C Syme , M Abrahamowicz , Y Xiao , G. T Leonard , M Perron , L Richer , S Veillette , G. D Smith , O Seda , J Tremblay , P Hamet , D Gaudet and T. Paus

Background— FTO is the first gene established as contributing to common forms of obesity. The gene is highly expressed in the hypothalamus and is thought to mediate this effect through its influence on energy homeostasis. The hypothalamus, however, also regulates blood pressure (BP). Therefore, we investigated whether the FTO-risk variant is associated not only with increased adiposity but also with elevated BP and whether the latter may be mediated, in part, by increased sympathetic modulation of vasomotor tone.

Methods and Results— The primary study was carried out in 485 adolescents recruited from a French Canadian founder population who underwent detailed body-composition and cardiovascular phenotyping. Body fat was examined with MRI, bioimpedance, and anthropometry. BP was recorded beat to beat at rest and during physical and mental challenges. Sympathetic modulation of vasomotor tone was assessed with power spectral analysis of BP. We found that individuals with the FTO-risk genotype compared with those without it demonstrate greater adiposity, including the amount of intra-abdominal fat (by 38%). They also showed higher systolic BP throughout the entire protocol, with a maximum difference during a mental stress (6.4 [1.5 to 11.3] mm Hg). The difference in BP was accompanied by elevated index of sympathetic modulation of vasomotor tone. A replication in an independent sample of adults from the same founder population confirmed the association between FTO and BP.

Conclusions— These results suggest that, in a French Canadian founder population, FTO may increase not only risk for obesity, as demonstrated in other populations, but also for hypertension. The latter may be related, at least in part, to the regulation of sympathetic vasomotor tone.

  B. E Alvarado , S Harper , R. W Platt , G. D Smith and J. Lynch

Background— The US Healthy People 2010 (HP2010) agenda set targets for major risk factors for coronary heart disease (CHD). However, the potential impact of achieving those risk factor reductions on both population levels and social disparities in CHD has not been quantified.

Methods and Results— Data on 10-year risk of CHD (from the First National Health and Nutrition Examination Epidemiological Follow-Up study 1971 to 1982), prevalence of major CHD risk factors (from the National Health and Nutrition Examination Survey 2003 to 2004), and HP2010 targets for CHD risk factors (reduction of smoking rate to 12%, hypertension to 14%, high cholesterol levels to 17%, diabetes to 2.5%, and obesity to 15%) were used to estimate effects of different scenarios on population levels and social disparities in CHD. Over a 10-year period, the largest relative reductions in population levels of CHD (20.0% in men; 23.9% in women) would be achieved if all social groups met the HP2010 targets. CHD disparities would be most reduced if the less educated (absolute disparities reduced by 66.1% in men; 56.3% in women) and the low income group (absolute disparities reduced by 93.7% in men; 94.3% in women) achieved the targets before the most advantaged. These reductions are larger than those expected if targets were achieved overall for the population but relative social group differences in risk factors remained, or under leveling-up approaches in which the least advantaged achieved the current levels of risk factors of the most advantaged.

Conclusions— Interventions to reduce CHD risk factors to HP2010 targets that focus on all social groups would produce the best overall scenario for both population levels and disparities in CHD.

  L Zhou , R. A Palais , G. D Smith , D Anderson , L. R Rowe and C. T. Wittwer

Background: Selective amplification of minority alleles is often necessary to detect cancer mutations in clinical samples.

Methods: Minor-allele enrichment and detection were performed with snapback primers in the presence of a saturating DNA dye within a closed tube. A 5' tail of nucleotides on 1 PCR primer hybridizes to the variable locus of its extension product to produce a hairpin that selectively enriches mismatched alleles. Genotyping performed after rapid-cycle PCR by melting of the secondary structure identifies different variants by the hairpin melting temperature (Tm). Needle aspirates of thyroid tissue (n = 47) and paraffin-embedded biopsy samples (n = 44) were analyzed for BRAF (v-raf murine sarcoma viral oncogene homolog B1) variant p.V600E, and the results were compared with those for dual hybridization probe analysis. Needle aspirates of lung tumors (n = 8) were analyzed for EGFR [epidermal growth factor receptor (erythroblastic leukemia viral (v-erb-b) oncogene homolog, avian)] exon 19 in-frame deletions.

Results: Use of 18-s cycles and momentary extension times of "0 s" with rapid-cycle PCR increased the selective amplification of mismatched alleles. A low Mg2+ concentration and a higher hairpin Tm relative to the extension temperature also improved the detection limit of mismatched alleles. The detection limit was 0.1% for BRAF p.V600E and 0.02% for EGFR exon 19 in-frame deletions. Snapback and dual hybridization probe methods for allele quantification of the thyroid samples correlated well (R2 = 0.93) with 2 more BRAF mutations (45 and 43, respectively, of 91 samples) detected after snapback enrichment. Different EGFR in-frame deletions in the lung samples produced different hairpin Tms.

Conclusions: Use of snapback primers for enrichment and detection of minority alleles is simple, is inexpensive to perform, and can be completed in a closed tube in <25 min.

  R. M Freathy , A. J Bennett , S. M Ring , B Shields , C. J Groves , N. J Timpson , M. N Weedon , E Zeggini , C. M Lindgren , H Lango , J. R.B Perry , A Pouta , A Ruokonen , E Hypponen , C Power , P Elliott , D. P Strachan , M. R Jarvelin , G. D Smith , M. I McCarthy , T. M Frayling and A. T. Hattersley

Low birth weight is associated with an increased risk of type 2 diabetes. The mechanisms underlying this association are unknown and may represent intrauterine programming or two phenotypes of one genotype. The fetal insulin hypothesis proposes that common genetic variants that reduce insulin secretion or action may predispose to type 2 diabetes and also reduce birth weight, since insulin is a key fetal growth factor. We tested whether common genetic variants that predispose to type 2 diabetes also reduce birth weight.


We genotyped single-nucleotide polymorphisms (SNPs) at five recently identified type 2 diabetes loci (CDKAL1, CDKN2A/B, HHEX-IDE, IGF2BP2, and SLC30A8) in 7,986 mothers and 19,200 offspring from four studies of white Europeans. We tested the association between maternal or fetal genotype at each locus and birth weight of the offspring.


We found that type 2 diabetes risk alleles at the CDKAL1 and HHEX-IDE loci were associated with reduced birth weight when inherited by the fetus (21 g [95% CI 11–31], P = 2 x 10–5, and 14 g [4–23], P = 0.004, lower birth weight per risk allele, respectively). The 4% of offspring carrying four risk alleles at these two loci were 80 g (95% CI 39–120) lighter at birth than the 8% carrying none (Ptrend = 5 x 10–7). There were no associations between birth weight and fetal genotypes at the three other loci or maternal genotypes at any locus.


Our results are in keeping with the fetal insulin hypothesis and provide robust evidence that common disease-associated variants can alter size at birth directly through the fetal genotype.

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