-
Tauseef A Khan,
Tina Shah,
David Prieto,
Weili Zhang,
Jackie Price,
Gerald R Fowkes,
Jackie Cooper,
Philippa J Talmud,
Steve E Humphries,
Johan Sundstrom, [......],
Meena Kumari,
Liam Smeeth,
Kay-Tee Khaw,
Michael Nalls,
James Meschia,
Kai Sun,
Rutai Hui,
Ian Day,
Aroon D Hingorani,
Juan P Casas
[show abstract]
[hide abstract]
ABSTRACT: BACKGROUND: At the APOE gene, encoding apolipoprotein E, genotypes of the ε2/ε3/ε4 alleles associated with higher LDL-cholesterol (LDL-C) levels are also associated with higher coronary risk. However, the association of APOE genotype with other cardiovascular biomarkers and risk of ischaemic stroke is less clear. We evaluated the association of APOE genotype with risk of ischaemic stroke and assessed whether the observed effect was consistent with the effects of APOE genotype on LDL-C or other lipids and biomarkers of cardiovascular risk. METHODS: We conducted a systematic review of published and unpublished studies reporting on APOE genotype and ischaemic stroke. We pooled 41 studies (with a total of 9027 cases and 61 730 controls) using a Bayesian meta-analysis to calculate the odds ratios (ORs) for ischaemic stroke with APOE genotype. To better evaluate potential mechanisms for any observed effect, we also conducted a pooled analysis of primary data using 16 studies (up to 60 883 individuals) of European ancestry. We evaluated the association of APOE genotype with lipids, other circulating biomarkers of cardiovascular risk and carotid intima-media thickness (C-IMT). RESULTS: The ORs for association of APOE genotypes with ischaemic stroke were: 1.09 (95% credible intervals (CrI): 0.84-1.43) for ε2/ε2; 0.85 (95% CrI: 0.78-0.92) for ε2/ε3; 1.05 (95% CrI: 0.89-1.24) for ε2/ε4; 1.05 (95% CrI: 0.99-1.12) for ε3/ε4; and 1.12 (95% CrI: 0.94-1.33) for ε4/ε4 using the ε3/ε3 genotype as the reference group. A regression analysis that investigated the effect of LDL-C (using APOE as the instrument) on ischaemic stroke showed a positive dose-response association with an OR of 1.33 (95% CrI: 1.17, 1.52) per 1 mmol/l increase in LDL-C. In the separate pooled analysis, APOE genotype was linearly and positively associated with levels of LDL-C (P-trend: 2 × 10(-152)), apolipoprotein B (P-trend: 8.7 × 10(-06)) and C-IMT (P-trend: 0.001), and negatively and linearly associated with apolipoprotein E (P-trend: 6 × 10(-26)) and HDL-C (P-trend: 1.6 × 10(-12)). Associations with lipoprotein(a), C-reactive protein and triglycerides were non-linear. CONCLUSIONS: In people of European ancestry, APOE genotype showed a positive dose-response association with LDL-C, C-IMT and ischaemic stroke. However, the association of APOE ε2/ε2 genotype with ischaemic stroke requires further investigation. This cross-domain concordance supports a causal role of LDL-C on ischaemic stroke.
International Journal of Epidemiology 04/2013; 42(2):475-492. · 6.41 Impact Factor
-
Federica Tozzi,
Alexander Teumer,
Marcus Munafò,
Rajesh Rawal,
Gbenga Kazeem,
Marcel Gerbaulet,
Wendy McArdle,
Howard Chilcoat,
Angela Döring,
Norbert Dahmen, [......],
Gérard Waeber,
Ulrich John,
Henry Völzke,
Georg Homuth,
Harald J Freyberger,
Uwe Völker, George Davey-Smith,
Christian Gieger,
Martin Preisig,
Hans J Grabe
[show abstract]
[hide abstract]
ABSTRACT: OBJECTIVES: Genomewide association studies (GWAS) have identified clear evidence of genetic markers for nicotine dependence. Other smoking phenotypes have been tested, but the results are less consistent. The tendency to relapse versus the ability to maintain long-term abstinence has received little attention in genetic studies; thus, our aim was to provide a better biological understanding of this phenotype through the identification of genetic loci associated with smoking relapse. METHODS: We carried out a GWAS on data from two European population-based collections, including a total of 835 cases (relapsers) and 990 controls (abstainers). Top-ranked findings from the discovery phase were tested for replication in two additional independent European population-based cohorts. RESULTS: Of the seven top markers from the discovery phase, none were consistently associated with smoking relapse across all samples and none reached genomewide significance. A single-nucleotide polymorphism rs1008509, within the Xylosyltransferase II (XYLT2) gene, was suggestively associated with smoking relapse in the discovery phase (β=-0.504; P=5.6E-06) and in the first replication sample (ALSPAC) (β=-0.27; P=0.004; n=1932), but not in the second sample (KORA) (β=0.19; P=0.138; n=912). We failed to identify an association between loci implicated previously in other smoking phenotypes and smoking relapse. CONCLUSION: Although no genomewide significant findings emerged from this study, we found that loci implicated in other smoking phenotypes were not associated with smoking relapse, which suggests that the neurobiology of smoking relapse and long-term abstinence may be distinct from biological mechanisms implicated in the development of nicotine dependence.
Psychiatric genetics 03/2013; · 2.33 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: OBJECTIVE:: Instrumental variable analysis can estimate treatment effects in the presence of residual or unmeasured confounding. We compared ordinary least squares regression versus instrumental variable estimates of the effects of selective cyclooxygenase-2 inhibitors (COX-2s) relative to nonselective nonsteroidal anti-inflammatory drug (NSAID) prescriptions on incidence of upper gastrointestinal complications and myocardial infarction (MI). METHODS:: We sampled a cohort of 62,933 first-time users of COX-2s or nonselective NSAIDs older than 60 years in the Clinical Practice Research Datalink. The instruments were physicians' previous prescriptions of COX-2s or nonselective NSAIDs, which are surrogates for physician preferences. We estimated risk differences of incident upper gastrointestinal complications and MI within 180 days of first COX-2 versus nonselective NSAID prescription. RESULTS:: Using ordinary least squares regression, adjusted for baseline confounders, we observed little association of COX-2 prescriptions with incident upper gastrointestinal complications (risk difference = -0.08 [95% confidence interval = -0.20 to 0.04]) or MI (0.06 [-0.06 to 0.17]) per 100 patients treated. Our adjusted instrumental variable results suggested 0.46 per 100 (-0.15 to 1.07) fewer upper gastrointestinal complications and little difference in acute MIs (0.08 per 100 [-0.61 to 0.76]), within 180 days of being prescribed COX-2s. Estimates were more precise when we used 20 previous prescriptions; the instrumental variable analysis implied 0.74 (0.28 to 1.19) fewer MIs per 100 patients prescribed COX-2s. CONCLUSIONS:: Using instrumental variable analysis, we found some evidence that COX-2 prescriptions reduced the risk of upper gastrointestinal complications, consistent with randomized controlled trials. Our results using multiple instruments suggest that COX-2s may have heterogeneous within-class effects on MI.
Epidemiology (Cambridge, Mass.) 03/2013; · 5.51 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: : Instrumental variables can be used to estimate the causal effects of exposures on outcomes in the presence of residual or uncontrolled confounding. To assess the validity of analyses using instrumental variables, specific information about whether underlying assumptions are met must be presented, in particular to demonstrate that the instrument is associated with the exposure but not with measured confounding factors. We systematically reviewed the epidemiological literature in Embase and Medline for articles containing the term "instrumental variable$" to investigate whether reporting of test statistics in studies using instrumental variables was sufficient to assess the validity of the results. We extracted the information each study reported about their instrumental variables, including specification tests used to check assumptions. The search found 756 studies of which 90 were relevant and were included. Only 25 (28%) studies reported appropriate tests of the strength of the associations between instruments and exposure. Forty-four (49%) studies reported associations between the instrumental variables and observed covariates. Studies using instrumental variables had wide confidence intervals and so effect estimates were imprecise. We propose a checklist of information and specification tests that studies using instrumental variables should report.
Epidemiology (Cambridge, Mass.) 03/2013; · 5.51 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: AimsTo explore the causal effect of long-term alcohol consumption on coronary heart disease risk factors.Methods and resultsWe used variants in ADH1B and ADH1C genes as instrumental variables (IV) to estimate the causal effect of long-term alcohol consumption on body mass index (BMI), blood pressure (BP), lipids, fibrinogen, and glucose. Analyses were undertaken in 54 604 Danes (mean age 56 years). Both confounder-adjusted multivariable and IV analyses suggested that a greater alcohol consumption among those who drank any alcohol resulted in a higher BP [mean difference in SBP per doubling of alcohol consumption among drinkers: 0.76 mmHg (95% CI: 0.63, 0.90) from multivariable analyses and 0.94 mmHg (-3.03, 4.69) from IV analyses; P-value for difference in these results = 0.95]. The positive association of alcohol with HDLc in the multivariable analyses [4.9% (4.7, 5.1)] appeared stronger than in the IV analyses [1.5% (-4.5, 7.4)], and the weak inverse association with fibrinogen in the multivariable analysis [-2.0% (-2.1, -1.8)] was not present in the IV analyses [0.6% (-3.8, 5.0)], but statistically the results for both of these could not be reliably distinguished from each other (P-values 0.21 and 0.32, respectively). The weak inverse association of alcohol with BMI [-0.13 kg/m(2) (-0.16, -0.10)] and with triglycerides [-0.4% (-0.7, 0.4)] in multivariable analyses were in contrast to the strong positive association of alcohol with BMI [1.37 kg/m(2) (0.59, 2.15)] and the strong inverse association with triglycerides [-14.9% (-25.6, -4.3)] in IV analyses; P = 0.006 and 0.01, respectively, for difference between the two. Alcohol was not associated with non-HDLc or glucose.Conclusion
Our results show adverse effects of long-term alcohol consumption on BP and BMI. We also found novel evidence for a potentially beneficial effect on triglyceride levels, which needs further replication.
European Heart Journal 03/2013; · 10.48 Impact Factor
-
Richard M Martin,
Rita Patel,
Michael S Kramer,
Lauren Guthrie,
Konstantin Vilchuck,
Natalia Bogdanovich,
Natalia Sergeichick,
Nina Gusina,
Ying Foo,
Tom Palmer,
Sheryl L Rifas-Shiman,
Matthew W Gillman, George Davey Smith,
Emily Oken
[show abstract]
[hide abstract]
ABSTRACT: IMPORTANCE Evidence that longer-term and exclusive breastfeeding reduces child obesity risk is based on observational studies that are prone to confounding. OBJECTIVE To investigate effects of an intervention to promote increased duration and exclusivity of breastfeeding on child adiposity and circulating insulin-like growth factor (IGF)-I, which regulates growth. DESIGN, SETTING, AND PARTICIPANTS Cluster-randomized controlled trial in 31 Belarusian maternity hospitals and their affiliated clinics, randomized into 1 of 2 groups: breastfeeding promotion intervention (n = 16) or usual practices (n = 15). Participants were 17 046 breastfeeding mother-infant pairs enrolled in 1996 and 1997, of whom 13 879 (81.4%) were followed up between January 2008 and December 2010 at a median age of 11.5 years. INTERVENTION Breastfeeding promotion intervention modeled on the WHO/UNICEF Baby-Friendly Hospital Initiative (World Health Organization/United Nations Children's Fund). MAIN OUTCOME MEASURES Body mass index (BMI), fat and fat-free mass indices (FMI and FFMI), percent body fat, waist circumference, triceps and subscapular skinfold thicknesses, overweight and obesity, and whole-blood IGF-I. Primary analysis was based on modified intention-to-treat (without imputation), accounting for clustering within hospitals and clinics. RESULTS The experimental intervention substantially increased breastfeeding duration and exclusivity when compared with the control (43% vs 6% exclusively breastfed at 3 months and 7.9% vs 0.6% at 6 months). Cluster-adjusted mean differences in outcomes at 11.5 years of age between experimental vs control groups were: 0.19 (95% CI, -0.09 to 0.46) for BMI; 0.12 (-0.03 to 0.28) for FMI; 0.04 (-0.11 to 0.18) for FFMI; 0.47% (-0.11% to 1.05%) for percent body fat; 0.30 cm (-1.41 to 2.01) for waist circumference; -0.07 mm (-1.71 to 1.57) for triceps and -0.02 mm (-0.79 to 0.75) for subscapular skinfold thicknesses; and -0.02 standard deviations (-0.12 to 0.08) for IGF-I. The cluster-adjusted odds ratio for overweight/obesity (BMI ≥85th vs <85th percentile) was 1.18 (95% CI, 1.01 to 1.39) and for obesity (BMI ≥95th vs <85th percentile) was 1.17 (95% CI, 0.97 to 1.41). CONCLUSIONS AND RELEVANCE Among healthy term infants in Belarus, an intervention that succeeded in improving the duration and exclusivity of breastfeeding did not prevent overweight or obesity, nor did it affect IGF-I levels at age 11.5 years. Breastfeeding has many advantages but population strategies to increase the duration and exclusivity of breastfeeding are unlikely to curb the obesity epidemic. TRIAL REGISTRATION isrctn.org: ISRCTN37687716; and clinicaltrials.gov: NCT01561612.
JAMA The Journal of the American Medical Association 03/2013; 309(10):1005-1013. · 30.03 Impact Factor
-
Diana L Cousminer,
Diane J Berry,
Nicholas J Timpson,
Wei Ang,
Elisabeth Thiering,
Enda Byrne,
H Rob Taal,
Ville Huikari,
Jonathan P Bradfield,
Marjan Kerkhof, [......],
Joachim Heinrich,
Craig E Pennell,
Olli Raitakari,
Johan G Eriksson, George Davey Smith,
Elina Hyppönen,
Marjo-Riitta Järvelin,
Mark I McCarthy,
Samuli Ripatti,
Elisabeth Widén
[show abstract]
[hide abstract]
ABSTRACT: The pubertal height growth spurt is a distinctive feature of childhood growth reflecting both the central onset of puberty and local growth factors. While little is known about the underlying genetics, growth variability during puberty correlates with adult risks for hormone-dependent cancer and adverse cardiometabolic health. The only gene so far associated with pubertal height growth, LIN28B, pleiotropically influences childhood growth, puberty, and cancer progression, pointing to shared underlying mechanisms.To discover genetic loci influencing pubertal height and growth and place them in context of overall growth and maturation, we performed genome-wide association (GWA) meta-analyses in up to 18,737 European samples utilizing longitudinally collected height measurements. We found significant associations (P<1.67 x 10-8) at 10 loci, including LIN28B. Five loci associated with pubertal timing, all impacting multiple aspects of growth. In particular, a novel variant correlated with expression of MAPK3, and associated both with increased prepubertal growth and earlier menarche. Another variant near ADCY3-POMC associated with increased BMI, reduced pubertal growth, and earlier puberty.While epidemiological correlations suggest that early puberty marks a pathway from rapid prepubertal growth to reduced final height and adult obesity, our study shows that individual loci associating with pubertal growth have variable longitudinal growth patterns that may differ from epidemiological observations. Overall this study uncovers part of the complex genetic architecture linking pubertal height growth, the timing of puberty, and childhood obesity, and provides new information to pinpoint processes linking these traits.
Human Molecular Genetics 02/2013; · 7.64 Impact Factor
-
Carolina Bonilla,
Rebecca Gilbert,
John P Kemp,
Nic Timpson,
David M Evans,
Jenny L Donovan,
Freddie C Hamdy,
David E Neal,
William D Fraser, George Davey Smith,
S J Lewis,
Mark Lathrop,
Richard M Martin
[show abstract]
[hide abstract]
ABSTRACT: BACKGROUND: Ecological and epidemiological studies have identified an inverse association of intensity and duration of sunlight exposure with prostate cancer, which may be explained by a reduction in vitamin D synthesis. Pigmentation traits influence sun exposure and therefore may affect prostate cancer risk. Because observational studies are vulnerable to confounding and measurement error, we used Mendelian randomization to examine the relationship of sun exposure with both prostate cancer risk and the intermediate phenotype, plasma levels of vitamin D. METHODS: We created a tanning, a skin color and a freckling score as combinations of SNPs that have been previously associated with these phenotypes. A higher score indicates propensity to burn, have a lighter skin color and freckles. The scores were tested for association with vitamin D levels (25-hydroxyvitamin-D and 1,25-dihydroxyvitamin-D) and PSA-detected prostate cancer in 3123 white British individuals enrolled in the Prostate Testing for cancer and Treatment (ProtecT) study. RESULTS: The freckling score was inversely associated with 25(OH)D levels (change in 25(OH)D per score unit -0.27; 95%CI: -0.52, -0.01), and the tanning score was positively associated with prostate cancer risk (OR 1.05; 95%CI: 1.02,1.09), after adjustment for population stratification and potential confounders. CONCLUSIONS: Individuals who tend to burn are more likely to spend less time in the sun and consequently have lower plasma vitamin D levels and higher susceptibility to prostate cancer. Impact: The use of pigmentation related genetic scores is valuable for the assessment of the potential benefits of sun exposure with respect to prostate cancer risk.
Cancer Epidemiology Biomarkers & Prevention 02/2013; · 4.12 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: To investigate whether light drinking in pregnancy is associated with adverse child mental health and academic outcomes.
Using data from the prospective, population-based Avon Longitudinal Study of Parents and Children (ALSPAC), we investigated the associations between light drinking in pregnancy (<1 glass per week in the first trimester) and child mental health (using both parent and teacher rated Strengths and Difficulties Questionnaires (SDQs)) and academic outcomes based on Key Stage 2 examination results at age 11 years.
11-year-old children from ALSPAC with parent (n=6587) and teacher (n=6393) completed SDQs and data from Key Stage 2 examination results (n=10 558).
39% of women had consumed <1 glass per week and 16% ≥1 glass per week of alcohol during the first trimester (45% abstaining). After adjustment, relative to abstainers, there was no effect of light drinking on teacher-rated SDQ scores or examination results. In girls, although there was a suggestion of worse outcomes (adjusted regression coefficient=0.38; 95% CI 0.01 to 0.74) on the parent-rated total SDQ score in those exposed to light drinking compared to abstainers, no dose-response relationship was evident.
Although the pattern of findings involving parent ratings for girls exposed to light drinking is consistent with earlier findings from this cohort, the overall lack of any adverse effects of light drinking is similar to findings from other recent cohort studies. Light drinking in pregnancy does not appear to be associated with clinically important adverse effects for mental health and academic outcomes at the age of 11 years.
Archives of Disease in Childhood 02/2013; 98(2):107-11. · 2.88 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Objective. Epidemiological studies have shown an association between OA and increased BMD. To explore the nature of this relationship, we examined whether the risk of OA is increased in individuals with high bone mass (HBM), in whom BMD is assumed to be elevated due to a primary genetic cause.Methods. A total of 335 115 DXA scans were screened to identify HBM index cases (defined by DXA scan as an L1 Z-score of ≥+3.2 and total hip Z-score ≥+1.2, or total hip Z-score ≥+3.2 and L1 Z-score ≥+1.2). In relatives, the definition of HBM was L1 Z-score plus total hip Z-score ≥+3.2. Controls comprised unaffected relatives and spouses. Clinical indicators of OA were determined by structured assessment. Analyses used logistic regression adjusting for age, gender, BMI and social deprivation.Results. A total of 353 HBM cases (mean age 61.7 years, 77% female) and 197 controls (mean age 54.1 years, 47% female) were included. Adjusted NSAID use was more prevalent in HBM cases versus controls [odds ratio (OR) 2.17 (95% CI 1.10, 4.28); P = 0.03]. The prevalence of joint replacement was higher in HBM cases (13.0%) than controls (4.1%), with an adjusted OR of 2.42 (95% CI 1.06, 5.56); P = 0.04. Adjusted prevalence of joint pain and knee crepitus did not differ between cases and controls.Conclusion. HBM is associated with increased prevalence of joint replacement surgery and NSAID use compared with unaffected controls.
Rheumatology (Oxford, England) 01/2013; · 4.24 Impact Factor
-
Celia L Gregson,
Margaret A Paggiosi,
Nicola Crabtree,
Sue A Steel,
Eugene McCloskey,
Emma L Duncan,
Bo Fan,
John A Shepherd,
William D Fraser, George Davey Smith,
Jon H Tobias
[show abstract]
[hide abstract]
ABSTRACT: Context:High bone mass (HBM), detected in 0.2% of dual-energy x-ray absorptiometry (DXA) scans, is characterized by raised body mass index, the basis for which is unclear.Objective:To investigate why body mass index is elevated in individuals with HBM, we characterized body composition and examined whether differences could be explained by bone phenotypes, eg, bone mass and/or bone turnover.Design, Setting, and Participants:We conducted a case-control study of 153 cases with unexplained HBM recruited from 4 UK centers by screening 219 088 DXA scans. A total of 138 first-degree relatives (of whom 51 had HBM) and 39 spouses were also recruited. Unaffected individuals served as controls.Main Outcome Measures:We measured fat mass, by DXA, and bone turnover markers.Results:Among women, fat mass was inversely related to age in controls (P = .01), but not in HBM cases (P = .96) in whom mean fat mass was 8.9 [95% CI 4.7, 13.0] kg higher compared with controls (fully adjusted mean difference, P < .001). Increased fat mass in male HBM cases was less marked (gender interaction P = .03). Compared with controls, lean mass was also increased in female HBM cases (by 3.3 [1.2, 5.4] kg; P < .002); however, lean mass increases were less marked than fat mass increases, resulting in 4.5% lower percentage lean mass in HBM cases (P < .001). Osteocalcin was also lower in female HBM cases compared with controls (by 2.8 [0.1, 5.5] μg/L; P = .04). Differences in fat mass were fully attenuated after hip bone mineral density (BMD) adjustment (P = .52) but unchanged after adjustment for bone turnover (P < .001), whereas the greater hip BMD in female HBM cases was minimally attenuated by fat mass adjustment (P < .001).Conclusions:HBM is characterized by a marked increase in fat mass in females, statistically explained by their greater BMD, but not by markers of bone turnover.
The Journal of clinical endocrinology and metabolism 01/2013; · 6.50 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: BACKGROUND: A recent review found little evidence for substantial effects of modifiable maternal exposures on offspring blood pressure (BP), but this may have been because almost all the studies reported on BP in early and mid-childhood. METHODS: This study uses data on 4723 mother-child pairs, collected as part of the Avon Longitudinal Study of Parents and Children, Bristol, England between 1991 and 1997; associations between three maternal variables (smoking during pregnancy, age at childbirth and prenatal diet) and offspring BP at approximately 15 years were assessed. Comparisons of maternal and paternal associations with offspring BP were carried out as a way of evaluating whether prenatal exposures exerted an influence through intrauterine effects. RESULTS: The selected maternal exposures were not associated with offspring BP, after minimal or full adjustment for potential confounders. Maternal and paternal associations with offspring BP for each exposure were found to be similar. CONCLUSIONS: The findings of this study suggest that associations between the selected maternal exposures and offspring BP do not emerge with age up to adolescence.
Journal of epidemiology and community health 01/2013; · 3.04 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: OBJECTIVE: This study uses a prospective design to examine the association between self-reported job insecurity and incident coronary heart disease; an association which has been little investigated previously. METHODS: Participants were 4174 British civil servants (1236 women and 2938 men), aged 42 to 56 with self-reported data on job insecurity and free from coronary heart disease at baseline (1995-6). These participants were followed until 2002-4, an average of 8.6 years, for incident fatal coronary heart disease, clinically verified incident non-fatal myocardial infarction, or definite angina (a total of 168 events). RESULTS: Cox proportional hazard models adjusted for socio-demographic characteristics showed job insecurity to be associated with a 1.42-fold (95% CI, 1.05-1.93) risk of incident coronary heart disease compared with secure employment. Adjustment for physiological and behavioral cardiovascular risk factors had little effect on this estimate; 1.38 (1.01-1.88). CONCLUSION: This study suggests that job insecurity may adversely affect coronary health.
Atherosclerosis 01/2013; · 3.79 Impact Factor
-
Vipin Gupta,
Donipadi Guru Vinay,
Ulla Sovio,
Sajjad Rafiq,
Madamchetty Venkata Kranthi Kumar,
Charles Spurgeon Janipalli,
David Evans,
Kulathu Radha Mani,
Madana Narasimha Sandeep,
Amy Taylor, [......],
Ruth Sullivan,
Liza Bowen,
Nicholas Timpson, George Davey Smith,
Frank Dudbridge,
Dorairaj Prabhakaran,
Yoav Ben-Shlomo,
Kolli Srinath Reddy,
Shah Ebrahim,
Giriraj Ratan Chandak
[show abstract]
[hide abstract]
ABSTRACT: Obesity is an established risk factor for type 2 diabetes (T2D) and they are metabolically related through the mechanism of insulin resistance. In order to explore how common genetic variants associated with T2D correlate with body mass index (BMI), we examined the influence of 25 T2D associated loci on obesity risk. We used 5056 individuals (2528 sib-pairs) recruited in Indian Migration Study and conducted within sib-pair analysis for six obesity phenotypes. We found associations of variants in CXCR4 (rs932206) and HHEX (rs5015480) with higher body mass index (BMI) (β = 0.13, p = 0.001) and (β = 0.09, p = 0.002), respectively and weight (β = 0.13, p = 0.001) and (β = 0.09, p = 0.001), respectively. CXCR4 variant was also strongly associated with body fat (β = 0.10, p = 0.0004). In addition, we demonstrated associations of CXCR4 and HHEX with overweight/obesity (OR = 1.6, p = 0.003) and (OR = 1.4, p = 0.002), respectively, in 1333 sib-pairs (2666 individuals). We observed marginal evidence of associations between variants at six loci (TCF7L2, NGN3, FOXA2, LOC646279, FLJ3970 and THADA) and waist hip ratio (WHR), BMI and/or overweight which needs to be validated in larger set of samples. All the above findings were independent of daily energy consumption and physical activity level. The risk score estimates based on eight significant loci (including nominal associations) showed associations with WHR and body fat which were independent of BMI. In summary, we establish the role of T2D associated loci in influencing the measures of obesity in Indian population, suggesting common underlying pathophysiology across populations.
PLoS ONE 01/2013; 8(1):e53944. · 4.09 Impact Factor
-
Jeremy A Guggenheim,
George McMahon,
John P Kemp,
Saeed Akhtar,
Beate St Pourcain,
Kate Northstone,
Susan M Ring,
David M Evans, George Davey Smith,
Nicholas J Timpson,
Cathy Williams
[show abstract]
[hide abstract]
ABSTRACT: Corneal curvature is a key determinant of the refractive power of the eye. Variants in two genes, FKBP12-rapamycin complex-associated protein 1 (FRAP1) on chromosome 1p36.2 and platelet-derived growth factor receptor alpha (PDGFRA) on chromosome 4q12, have shown genome-wide significant association with normal variation in corneal curvature in a study of subjects of Asian origin. Variants at the PDGFRA locus have also shown genome-wide significant association with corneal astigmatism. Whether these variants influence other ocular parameters such as axial length has yet to be reported. We performed a genome-wide association study for corneal curvature in white European subjects from a population-based birth cohort, with the aim of replicating and extending the above findings.
White European children participating in the Avon Longitudinal Study of Parents and Children (ALSPAC) birth cohort were examined at age about 15.5 years (95% confidence interval=15.45 to 15.48 years). Radius of corneal curvature and axial eye length were measured with an IOLmaster. DNA samples were genotyped with Illumina HumanHap550 arrays and untyped variants imputed using MACH, with CEU individuals from HapMap release 22, Phase II NCBI B36, Single Nucleotide Polymorphism database 126 as the reference panel. Association between corneal curvature and single nucleotide polymorphism (SNP) genotype was tested, genome-wide, using mach2qtl, with sex as a covariate (n=2023; 46.6% male).
The variant exhibiting the strongest evidence for association with corneal curvature (rs6554163; p=2.8×10(-6)) was located in the same linkage disequilibrium block as the previously discovered PDGFRA variants. Meta-analysis of the current and prior findings enhanced the evidence for association (rs17084051, p=4.5×10(-14)). rs6554163 genotype predicted 1.0% of variation in corneal curvature. In addition, these PDGFRA variants were associated with axial eye length, predicting 0.6% of the normal trait variation (p=5.3×10(-4)). Each copy of the minor allele of variants at the locus also increased the risk of corneal astigmatism in this white European cohort (odds ratio [OR]=1.24, 95% confidence interval=1.07-1.45; p=0.006).
As in Asians, variants at the PDGFRA locus influence corneal curvature (and corneal astigmatism). However, rather than affecting corneal curvature in isolation, this locus influences the size of the eye while maintaining its scaling.
Molecular vision 01/2013; 19:243-53. · 2.20 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: The nutritional aetiology of obesity remains unclear, especially with regard to the role of dairy products in developing countries.
To examine whether milk/milk product consumption is associated with obesity and high waist circumference among adult Indians.
Information on plain milk, tea, curd and buttermilk/lassi consumption assessed using a Food Frequency Questionnaire was obtained from the cross-sectional sib-pair designed Indian Migration Study (3698 men and 2659 women), conducted at four factory locations across north, central and south India. The anthropometric measures included were Body Mass Index (BMI) and Waist Circumference (WC). Mixed-effect logistic regression models were conducted to accommodate sib-pair design and adjust for potential confounders.
After controlling for potential confounders, the risk of being obese (BMI≥25 kg/m(2)) was lower among women (OR = 0.57;95%CI:0.43-0.76;p≤0.0001) and men (OR = 0.67;95%CI: 0.51-0.87;p = 0.005), and the risk of a high WC (men: >90 cm; women: >80 cm) was lower among men (OR = 0.71;95%CI:0.54-0.93;p = 0.005) and women (OR = 0.79;95%CI:0.59-1.05;p>0.05) who consume ≥1 portions of plain milk daily than those who do not consume any milk. The inverse association between daily plain milk consumption and obesity was also confirmed in sibling-pair analyses. Daily tea consumption of ≥1 portion was associated with obesity (OR = 1.51;95%CI:1.00-2.25;p>0.050) and high WC (OR = 1.65;95%CI:1.08-2.51;p>0.019) among men but not among women but there was no strong evidence of association of curd and buttermilk/lassi consumption with obesity and high waist circumference among both men and women.
The independent, inverse association of daily plain milk consumption with the risk of being obese suggests that high plain milk intake may lower the risk of obesity in adult Indians. However, this is an observational finding and uncontrolled confounding cannot be excluded as an explanation for the association. Therefore, confirmatory studies are needed to clarify this relationship.
PLoS ONE 01/2013; 8(4):e60739. · 4.09 Impact Factor
-
Hannah R. Elliott,
Gagandeep Kaur Walia,
Aparna Duggirala,
Alix Groom,
S. Umakar Reddy,
Giriraj R. Chandak,
Vipin Gupta,
Markku Laakso,
Jacqueline M. Dekker,
The Risc Consortium,
Mark Walker,
Shah Ebrahim, George Davey Smith,
Caroline L. Relton
[show abstract]
[hide abstract]
ABSTRACT: Background: Type 2 diabetes is a global problem that is increasingly prevalent in low and middle income countries including India, and is partly attributed to increased urbanisation. Genotype clearly plays a role in type 2 diabetes susceptibility. However, the role of DNA methylation and its interaction with genotype and metabolic measures is poorly understood. This study aimed to establish whether methylation patterns of type 2 diabetes genes differ between distinct Indian and European populations and/or change following rural to urban migration in India.
Methods: Quantitative DNA methylation analysis in Indians and Europeans using Sequenom® EpiTYPER® technology was undertaken in three genes: ADCY5, FTO and KCNJ11. Metabolic measures and genotype data were also analysed.
Results: Consistent differences in DNA methylation patterns were observed between Indian and European populations in ADCY5, FTO and KCNJ11. Associations were demonstrated between FTO rs9939609 and BMI and between ADCY5 rs17295401 and HDL levels in Europeans. However, these observations were not linked to local variation in DNA methyla-tion levels. No differences in methylation patterns were observed in urban-dwelling migrants compared to their non-mi-grant rural-dwelling siblings in India.
Conclusions: Analysis of DNA methylation at three type 2 diabetes susceptibility loci highlighted geographical and ethnic differences in methylation patterns. These differences may be attributed to genetic and/or region-specific environmental factors.
Journal of Diabetes Research and Clinical Metabolism. 01/2013; 2(1).
-
Hannah R. Elliott,
Gagandeep Kaur Walia,
Aparna Duggirala,
Alix Groom,
S. Umakar Reddy,
Giriraj R. Chandak,
Vipin Gupta,
Markku Laakso,
Jacqueline M. Dekker,
The Risc Consortium,
Mark Walker,
Shah Ebrahim, George Davey Smith,
Caroline L. Relton
[show abstract]
[hide abstract]
ABSTRACT: Background: Type 2 diabetes is a global problem that is increasingly prevalent in low and middle income countries including India, and is partly attributed to increased urbanisation. Genotype clearly plays a role in type 2 diabetes susceptibility. However, the role of DNA methylation and its interaction with genotype and metabolic measures is poorly understood. This study aimed to establish whether methylation patterns of type 2 diabetes genes differ between distinct Indian and European populations and/or change following rural to urban migration in India.
Methods: Quantitative DNA methylation analysis in Indians and Europeans using Sequenom® EpiTYPER® technology was undertaken in three genes: ADCY5, FTO and KCNJ11. Metabolic measures and genotype data were also analysed.
Results: Consistent differences in DNA methylation patterns were observed between Indian and European populations in ADCY5, FTO and KCNJ11. Associations were demonstrated between FTO rs9939609 and BMI and between ADCY5 rs17295401 and HDL levels in Europeans. However, these observations were not linked to local variation in DNA methyla-tion levels. No differences in methylation patterns were observed in urban-dwelling migrants compared to their non-mi-grant rural-dwelling siblings in India.
Conclusions: Analysis of DNA methylation at three type 2 diabetes susceptibility loci highlighted geographical and ethnic differences in methylation patterns. These differences may be attributed to genetic and/or region-specific environmental factors.
Journal of Diabetes Research and Clinical Metabolism. 01/2013; 2(1).
-
Pim van der Harst,
Weihua Zhang,
Irene Mateo Leach,
Augusto Rendon,
Niek Verweij,
Joban Sehmi,
Dirk S Paul,
Ulrich Elling,
Hooman Allayee,
Xinzhong Li, [......],
Manuel A Ferreira,
Serena Sanna,
Manuela Uda,
Andrew A Hicks,
Josef Martin Penninger,
Christian Gieger,
Jaspal S Kooner,
Willem H Ouwehand,
Nicole Soranzo,
John C Chambers
[show abstract]
[hide abstract]
ABSTRACT: Anaemia is a chief determinant of global ill health, contributing to cognitive impairment, growth retardation and impaired physical capacity. To understand further the genetic factors influencing red blood cells, we carried out a genome-wide association study of haemoglobin concentration and related parameters in up to 135,367 individuals. Here we identify 75 independent genetic loci associated with one or more red blood cell phenotypes at P < 10(-8), which together explain 4-9% of the phenotypic variance per trait. Using expression quantitative trait loci and bioinformatic strategies, we identify 121 candidate genes enriched in functions relevant to red blood cell biology. The candidate genes are expressed preferentially in red blood cell precursors, and 43 have haematopoietic phenotypes in Mus musculus or Drosophila melanogaster. Through open-chromatin and coding-variant analyses we identify potential causal genetic variants at 41 loci. Our findings provide extensive new insights into genetic mechanisms and biological pathways controlling red blood cell formation and function.
Nature 12/2012; · 36.28 Impact Factor
-
Momoko Horikoshi,
Hanieh Yaghootkar,
Dennis O Mook-Kanamori,
Ulla Sovio,
H Rob Taal,
Branwen J Hennig,
Jonathan P Bradfield,
Beate St Pourcain,
David M Evans,
Pimphen Charoen, [......],
Debbie A Lawlor, George Davey Smith,
Timothy M Frayling,
Mark I McCarthy,
Struan F A Grant,
Vincent W V Jaddoe,
Marjo-Riitta Jarvelin,
Nicholas J Timpson,
Inga Prokopenko,
Rachel M Freathy
[show abstract]
[hide abstract]
ABSTRACT: Birth weight within the normal range is associated with a variety of adult-onset diseases, but the mechanisms behind these associations are poorly understood. Previous genome-wide association studies of birth weight identified a variant in the ADCY5 gene associated both with birth weight and type 2 diabetes and a second variant, near CCNL1, with no obvious link to adult traits. In an expanded genome-wide association meta-analysis and follow-up study of birth weight (of up to 69,308 individuals of European descent from 43 studies), we have now extended the number of loci associated at genome-wide significance to 7, accounting for a similar proportion of variance as maternal smoking. Five of the loci are known to be associated with other phenotypes: ADCY5 and CDKAL1 with type 2 diabetes, ADRB1 with adult blood pressure and HMGA2 and LCORL with adult height. Our findings highlight genetic links between fetal growth and postnatal growth and metabolism.
Nature Genetics 12/2012; · 35.53 Impact Factor
