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1.  Genome-wide association analysis identifies three new susceptibility loci for childhood body mass index 
Felix, Janine F. | Bradfield, Jonathan P. | Monnereau, Claire | van der Valk, Ralf J.P. | Stergiakouli, Evie | Chesi, Alessandra | Gaillard, Romy | Feenstra, Bjarke | Thiering, Elisabeth | Kreiner-Møller, Eskil | Mahajan, Anubha | Pitkänen, Niina | Joro, Raimo | Cavadino, Alana | Huikari, Ville | Franks, Steve | Groen-Blokhuis, Maria M. | Cousminer, Diana L. | Marsh, Julie A. | Lehtimäki, Terho | Curtin, John A. | Vioque, Jesus | Ahluwalia, Tarunveer S. | Myhre, Ronny | Price, Thomas S. | Vilor-Tejedor, Natalia | Yengo, Loïc | Grarup, Niels | Ntalla, Ioanna | Ang, Wei | Atalay, Mustafa | Bisgaard, Hans | Blakemore, Alexandra I. | Bonnefond, Amelie | Carstensen, Lisbeth | Eriksson, Johan | Flexeder, Claudia | Franke, Lude | Geller, Frank | Geserick, Mandy | Hartikainen, Anna-Liisa | Haworth, Claire M.A. | Hirschhorn, Joel N. | Hofman, Albert | Holm, Jens-Christian | Horikoshi, Momoko | Hottenga, Jouke Jan | Huang, Jinyan | Kadarmideen, Haja N. | Kähönen, Mika | Kiess, Wieland | Lakka, Hanna-Maaria | Lakka, Timo A. | Lewin, Alexandra M. | Liang, Liming | Lyytikäinen, Leo-Pekka | Ma, Baoshan | Magnus, Per | McCormack, Shana E. | McMahon, George | Mentch, Frank D. | Middeldorp, Christel M. | Murray, Clare S. | Pahkala, Katja | Pers, Tune H. | Pfäffle, Roland | Postma, Dirkje S. | Power, Christine | Simpson, Angela | Sengpiel, Verena | Tiesler, Carla M. T. | Torrent, Maties | Uitterlinden, André G. | van Meurs, Joyce B. | Vinding, Rebecca | Waage, Johannes | Wardle, Jane | Zeggini, Eleftheria | Zemel, Babette S. | Dedoussis, George V. | Pedersen, Oluf | Froguel, Philippe | Sunyer, Jordi | Plomin, Robert | Jacobsson, Bo | Hansen, Torben | Gonzalez, Juan R. | Custovic, Adnan | Raitakari, Olli T. | Pennell, Craig E. | Widén, Elisabeth | Boomsma, Dorret I. | Koppelman, Gerard H. | Sebert, Sylvain | Järvelin, Marjo-Riitta | Hyppönen, Elina | McCarthy, Mark I. | Lindi, Virpi | Harri, Niinikoski | Körner, Antje | Bønnelykke, Klaus | Heinrich, Joachim | Melbye, Mads | Rivadeneira, Fernando | Hakonarson, Hakon | Ring, Susan M. | Smith, George Davey | Sørensen, Thorkild I.A. | Timpson, Nicholas J. | Grant, Struan F.A. | Jaddoe, Vincent W.V.
Human Molecular Genetics  2015;25(2):389-403.
A large number of genetic loci are associated with adult body mass index. However, the genetics of childhood body mass index are largely unknown. We performed a meta-analysis of genome-wide association studies of childhood body mass index, using sex- and age-adjusted standard deviation scores. We included 35 668 children from 20 studies in the discovery phase and 11 873 children from 13 studies in the replication phase. In total, 15 loci reached genome-wide significance (P-value < 5 × 10−8) in the joint discovery and replication analysis, of which 12 are previously identified loci in or close to ADCY3, GNPDA2, TMEM18, SEC16B, FAIM2, FTO, TFAP2B, TNNI3K, MC4R, GPR61, LMX1B and OLFM4 associated with adult body mass index or childhood obesity. We identified three novel loci: rs13253111 near ELP3, rs8092503 near RAB27B and rs13387838 near ADAM23. Per additional risk allele, body mass index increased 0.04 Standard Deviation Score (SDS) [Standard Error (SE) 0.007], 0.05 SDS (SE 0.008) and 0.14 SDS (SE 0.025), for rs13253111, rs8092503 and rs13387838, respectively. A genetic risk score combining all 15 SNPs showed that each additional average risk allele was associated with a 0.073 SDS (SE 0.011, P-value = 3.12 × 10−10) increase in childhood body mass index in a population of 1955 children. This risk score explained 2% of the variance in childhood body mass index. This study highlights the shared genetic background between childhood and adult body mass index and adds three novel loci. These loci likely represent age-related differences in strength of the associations with body mass index.
PMCID: PMC4854022  PMID: 26604143
2.  Reproducibility and Validity of a Food Frequency Questionnaire Designed to Assess Diet in Children Aged 4-5 Years 
PLoS ONE  2016;11(11):e0167338.
The food frequency questionnaire (FFQ) is the most efficient and cost-effective method to investigate the relationship between usual diet and disease in epidemiologic studies. Although FFQs have been validated in many adult populations worldwide, the number of valid FFQ in preschool children is very scarce. The aim of this study was to evaluate the reproducibility and validity of a semi-quantitative FFQ designed for children aged 4 to 5 years.
Materials and methods
In this study, we have included 169 children aged 4–5 years from the INMA project in Valencia, a population-based prospective cohort study of mothers and children in Spain. The 105-items FFQ was administered twice to the parents or care-givers of children over a 9-month period. Reproducibility was explored by comparing intake of nutrients by the FFQs, while validity was examined by comparing the nutrient values from the FFQs with the average nutrient values of three 24 hour dietary recall (24hDR) taken in the period, and also, with the concentration in blood specimens for several vitamins (carotenoids, folate, vitamin B12, vitamin C and α-tocopherol). Pearson correlation coefficients and de-attenuated correlation coefficients were calculated and we also evaluated misclassification by quintile distribution.
All correlation coefficients for reproducibility for nutrients and major food groups were statistically significant; the average correlation coefficients for daily intake were 0.43 for food groups and 0.41 for nutrients. The average correlation coefficients for validity for daily intakes against 24hDR was r = 0.30, and the average for de-attenuated correlation coefficients was r = 0.44. When evaluating validity against the blood concentration of vitamins, statistically significant correlations were observed for vitamin C (0.35), lycopene (0.31), β-Cryptoxantin (0.40), and vitamin E (0.29); the average of correlation coefficients was r = 0.21.
Despite some low to moderate correlations for reproducibility and validity, overall this study suggests that the FFQ may be a good method for assessing a wide range of food groups and nutrients intake in children aged 4–5 years.
PMCID: PMC5127574  PMID: 27898731
3.  Dietary Intake of Trans Fatty Acids in Children Aged 4–5 in Spain: The INMA Cohort Study 
Nutrients  2016;8(10):625.
Trans fatty acid (TFA) intake has been identified as a health hazard in adults, but data on preschool children are scarce. We analyzed the data from the Spanish INMA Project to determine the intake of total, industrial and natural TFA, their main sources and the associated socio-demographic and lifestyle factors in children aged 4–5 (n = 1793). TFA intake was estimated using a validated Food Frequency Questionnaire, and multiple linear regression was used to explore associated factors. The mean daily intakes of total, industrial and natural TFA were 1.36, 0.60, and 0.71 g/day, respectively. Ten percent of the children obtained >1% of their energy intake from TFA. The main sources of industrial TFA were fast food, white bread and processed baked goods. Milk, red and processed meat and processed baked goods were the main sources of natural TFA. Having parents from countries other than Spain was significantly associated with higher natural TFA (in mg/day) intake (β 45.5) and television viewing was significantly associated with higher industrial TFA intake (β 18.3). Higher fruits and vegetables intake was significantly associated with lower intakes of all TFAs, whereas higher sweetened beverages intake was significantly associated with lower total and natural TFA intake. Thus, total and industrial TFA intake was associated with less healthy food patterns and lifestyles in Spanish preschool children.
PMCID: PMC5084013  PMID: 27735864
trans fatty acids; dietary fats; risk factors; preschool child
4.  Relationship of the adherence to the Mediterranean diet with health-related quality of life and treatment satisfaction in patients with type 2 diabetes mellitus: a post-hoc analysis of a cross-sectional study 
The main aim of this study was to assess the association between adherence to the traditional Mediterranean diet (MedDiet) and health-related quality of life (HRQoL) and treatment satisfaction in patients with type 2 diabetes mellitus (T2DM).
This cross-sectional study included 294 patients with T2DM (146 with diabetic retinopathy and 148 without retinopathy). HRQoL and treatment satisfaction were assessed with the Audit Diabetes-Dependent Quality of Life and Diabetes Treatment Satisfaction Questionnaires, respectively. Adherence to the MedDiet was evaluated with the relative Mediterranean Diet Score (rMED). The rMED was added to multivariate linear regression models to assess its relative contribution as a quantitative as well as a qualitative variable after recoding to maximize each of the model’s coefficients of determination to explain quality of life as well as treatment satisfaction dimensions.
The adherence to the Mediterranean diet showed no significant association with the overall quality of life score. However, rMED was associated with some HRQoL dimensions: travels, self-confidence and freedom to eat and drink (p = 0.020, p = 0.015, p = 0.037 and p = 0.015, respectively). Concerning treatment satisfaction, rMED was positively associated with its overall score (p = 0.046), and especially with the understanding of diabetes (p = 0.0004) and treatment recommendation (p = 0.036), as well as with the perceived frequency of hyperglycaemias (p = 0.039).
Adherence to the Mediterranean diet was associated with greater treatment satisfaction in patients with T2DM. Although we found no association with overall HRQoL, adherence to this dietary pattern was associated with some quality of life dimensions.
PMCID: PMC4855697  PMID: 27141952
Type 2 diabetes mellitus; Relative Mediterranean Diet score; Quality of life; Treatment satisfaction; Mediterranean diet
5.  Use of high doses of folic acid supplements in pregnant women in Spain: an INMA cohort study 
BMJ Open  2015;5(11):e009202.
We examined the use of low (<400 μg/day, including no use) and high folic acid supplement (FAS) dosages (≥1000 μg/day) among pregnant women in Spain, and explored factors associated with the use of these non-recommended dosages.
Population-based cohort study.
We analysed data from 2332 pregnant women of the INMA study, a prospective mother-child cohort study in Spain.
Main outcome measures
We assessed usual dietary folate and the use of FAS from preconception to the 3rd month (first period) and from the 4th to the 7th month (second period), using a validated food frequency questionnaire. We used multinomial logistic regression to estimate relative risk ratios (RRRs).
Over a half of the women used low dosages of FAS in the first and second period while 29% and 17% took high dosages of FAS, respectively. In the first period, tobacco smoking (RRR=1.63), alcohol intake (RRR=1.40), multiparous (RRR=1.44), unplanned pregnancy (RRR=4.20) and previous spontaneous abortion (RRR=0.58, lower use of high FAS dosages among those with previous abortions) were significantly associated with low FAS dosages. Alcohol consumption (RRR=1.42), unplanned pregnancy (RRR=2.66) and previous spontaneous abortion (RRR=0.68) were associated with high dosage use. In the second period, only tobacco smoking was significantly associated with high FAS dosage use (RRR=0.67).
A high proportion of pregnant women did not reach the recommended dosages of FAS in periconception and a considerable proportion also used FAS dosages ≥1000 μg/day. Action should be planned by the Health Care System and health professionals to improve the appropriate periconceptional use of FAS, taking into consideration the associated factors.
PMCID: PMC4663411  PMID: 26603248
6.  Complement factor H genetic variant and age-related macular degeneration: effect size, modifiers and relationship to disease subtype 
Background Variation in the complement factor H gene (CFH) is associated with risk of late age-related macular degeneration (AMD). Previous studies have been case–control studies in populations of European ancestry with little differentiation in AMD subtype, and insufficient power to confirm or refute effect modification by smoking.
Methods To precisely quantify the association of the single nucleotide polymorphism (SNP rs1061170, ‘Y402H’) with risk of AMD among studies with differing study designs, participant ancestry and AMD grade and to investigate effect modification by smoking, we report two unpublished genetic association studies (n = 2759) combined with data from 24 published studies (26 studies, 26 494 individuals, including 14 174 cases of AMD) of European ancestry, 10 of which provided individual-level data used to test gene–smoking interaction; and 16 published studies from non-European ancestry.
Results In individuals of European ancestry, there was a significant association between Y402H and late-AMD with a per-allele odds ratio (OR) of 2.27 [95% confidence interval (CI) 2.10–2.45; P = 1.1 x 10−161]. There was no evidence of effect modification by smoking (P = 0.75). The frequency of Y402H varied by ancestral origin and the association with AMD in non-Europeans was less clear, limited by paucity of studies.
Conclusion The Y402H variant confers a 2-fold higher risk of late-AMD per copy in individuals of European descent. This was stable to stratification by study design and AMD classification and not modified by smoking. The lack of association in non-Europeans requires further verification. These findings are of direct relevance for disease prediction. New research is needed to ascertain if differences in circulating levels, expression or activity of factor H protein explain the genetic association.
PMCID: PMC3304526  PMID: 22253316
Age-related macular degeneration (AMD); Complement factor H gene; meta-ananlysis
7.  Evidence of association of APOE with age-related macular degeneration - a pooled analysis of 15 studies 
Human mutation  2011;32(12):1407-1416.
Age-related macular degeneration (AMD) is the most common cause of incurable visual impairment in high-income countries. Previous studies report inconsistent associations between AMD and apolipoprotein E (APOE), a lipid transport protein involved in low-density cholesterol modulation. Potential interaction between APOE and sex, and smoking status, has been reported. We present a pooled analysis (n=21,160) demonstrating associations between late AMD and APOε4 (OR=0.72 per haplotype; CI: 0.65–0.74; P=4.41×10−11) and APOε2 (OR=1.83 for homozygote carriers; CI: 1.04–3.23; P=0.04), following adjustment for age-group and sex within each study and smoking status. No evidence of interaction between APOE and sex or smoking was found. Ever smokers had significant increased risk relative to never smokers for both neovascular (OR=1.54; CI: 1.38–1.72; P=2.8×10−15) and atrophic (OR=1.38; CI: 1.18–1.61; P=3.37×10−5) AMD but not early AMD (OR=0.94; CI: 0.86–1.03; P=0.16), implicating smoking as a major contributing factor to disease progression from early signs to the visually disabling late forms. Extended haplotype analysis incorporating rs405509 did not identify additional risks beyondε2 and ε4 haplotypes. Our expanded analysis substantially improves our understanding of the association between the APOE locus and AMD. It further provides evidence supporting the role of cholesterol modulation, and low-density cholesterol specifically, in AMD disease etiology.
PMCID: PMC3217135  PMID: 21882290
age-related macular degeneration; AMD; apolipoprotein E; APOE; case-control association study
8.  Variations in Apolipoprotein E Frequency With Age in a Pooled Analysis of a Large Group of Older People 
American Journal of Epidemiology  2011;173(12):1357-1364.
Variation in the apolipoprotein E gene (APOE) has been reported to be associated with longevity in humans. The authors assessed the allelic distribution of APOE isoforms ε2, ε3, and ε4 among 10,623 participants from 15 case-control and cohort studies of age-related macular degeneration (AMD) in populations of European ancestry (study dates ranged from 1990 to 2009). The authors included only the 10,623 control subjects from these studies who were classified as having no evidence of AMD, since variation within the APOE gene has previously been associated with AMD. In an analysis stratified by study center, gender, and smoking status, there was a decreasing frequency of the APOE ε4 isoform with increasing age (χ2 for trend = 14.9 (1 df); P = 0.0001), with a concomitant increase in the ε3 isoform (χ2 for trend = 11.3 (1 df); P = 0.001). The association with age was strongest in ε4 homozygotes; the frequency of ε4 homozygosity decreased from 2.7% for participants aged 60 years or less to 0.8% for those over age 85 years, while the proportion of participants with the ε3/ε4 genotype decreased from 26.8% to 17.5% across the same age range. Gender had no significant effect on the isoform frequencies. This study provides strong support for an association of the APOE gene with human longevity.
PMCID: PMC3145394  PMID: 21498624
aged; apolipoprotein E2; apolipoprotein E3; apolipoprotein E4; apolipoproteins E; longevity; meta-analysis; multicenter study
9.  Esophageal cancer risk by type of alcohol drinking and smoking: a case-control study in Spain 
BMC Cancer  2008;8:221.
The effect of tobacco smoking and alcohol drinking on esophageal cancer (EC) has never been explored in Spain where black tobacco and wine consumptions are quite prevalent. We estimated the independent effect of different alcoholic beverages and type of tobacco smoking on the risk of EC and its main histological cell type (squamous cell carcinoma) in a hospital-based case-control study in a Mediterranean area of Spain.
We only included incident cases with histologically confirmed EC (n = 202). Controls were frequency-matched to cases by age, sex and province (n = 455). Information on risk factors was elicited by trained interviewers using structured questionnaires. Multiple logistic regression was used to estimate adjusted odds ratios and 95% confidence intervals (CI).
Alcohol drinking and tobacco smoking were strong and independent risk factors for esophageal cancer. Alcohol was a potent risk factor with a clear dose-response relationship, particularly for esophageal squamous-cell cancer. Compared to never-drinkers, the risk for heaviest drinkers (≥ 75 g/day of pure ethanol) was 7.65 (95%CI, 3.16–18.49); and compared with never-smokers, the risk for heaviest smokers (≥ 30 cigarettes/day) was 5.07 (95%CI, 2.06–12.47). A low consumption of only wine and/or beer (1–24 g/d) did not increase the risk whereas a strong positive trend was observed for all types of alcoholic beverages that included any combination of hard liquors with beer and/or wine (p-trend<0.00001). A significant increase in EC risk was only observed for black-tobacco smoking (2.5-fold increase), not for blond tobacco. The effects for alcohol drinking were much stronger when the analysis was limited to the esophageal squamous cell carcinoma (n = 160), whereas a lack of effect for adenocarcinoma was evidenced. Smoking cessation showed a beneficial effect within ten years whereas drinking cessation did not.
Our study shows that the risk of EC, and particularly the squamous cell type, is strongly associated with alcohol drinking. The consumption of any combination of hard liquors seems to be harmful whereas a low consumption of only wine may not. This may relates to the presence of certain antioxidant compounds found in wine but practically lacking in liquors. Tobacco smoking is also a clear risk factor, black more than blond.
PMCID: PMC2529333  PMID: 18673563

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