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1.  MicroRNA Related Polymorphisms and Breast Cancer Risk 
Khan, Sofia | Greco, Dario | Michailidou, Kyriaki | Milne, Roger L. | Muranen, Taru A. | Heikkinen, Tuomas | Aaltonen, Kirsimari | Dennis, Joe | Bolla, Manjeet K. | Liu, Jianjun | Hall, Per | Irwanto, Astrid | Humphreys, Keith | Li, Jingmei | Czene, Kamila | Chang-Claude, Jenny | Hein, Rebecca | Rudolph, Anja | Seibold, Petra | Flesch-Janys, Dieter | Fletcher, Olivia | Peto, Julian | dos Santos Silva, Isabel | Johnson, Nichola | Gibson, Lorna | Aitken, Zoe | Hopper, John L. | Tsimiklis, Helen | Bui, Minh | Makalic, Enes | Schmidt, Daniel F. | Southey, Melissa C. | Apicella, Carmel | Stone, Jennifer | Waisfisz, Quinten | Meijers-Heijboer, Hanne | Adank, Muriel A. | van der Luijt, Rob B. | Meindl, Alfons | Schmutzler, Rita K. | Müller-Myhsok, Bertram | Lichtner, Peter | Turnbull, Clare | Rahman, Nazneen | Chanock, Stephen J. | Hunter, David J. | Cox, Angela | Cross, Simon S. | Reed, Malcolm W. R. | Schmidt, Marjanka K. | Broeks, Annegien | Veer, Laura J. V. a. n't. | Hogervorst, Frans B. | Fasching, Peter A. | Schrauder, Michael G. | Ekici, Arif B. | Beckmann, Matthias W. | Bojesen, Stig E. | Nordestgaard, Børge G. | Nielsen, Sune F. | Flyger, Henrik | Benitez, Javier | Zamora, Pilar M. | Perez, Jose I. A. | Haiman, Christopher A. | Henderson, Brian E. | Schumacher, Fredrick | Le Marchand, Loic | Pharoah, Paul D. P. | Dunning, Alison M. | Shah, Mitul | Luben, Robert | Brown, Judith | Couch, Fergus J. | Wang, Xianshu | Vachon, Celine | Olson, Janet E. | Lambrechts, Diether | Moisse, Matthieu | Paridaens, Robert | Christiaens, Marie-Rose | Guénel, Pascal | Truong, Thérèse | Laurent-Puig, Pierre | Mulot, Claire | Marme, Frederick | Burwinkel, Barbara | Schneeweiss, Andreas | Sohn, Christof | Sawyer, Elinor J. | Tomlinson, Ian | Kerin, Michael J. | Miller, Nicola | Andrulis, Irene L. | Knight, Julia A. | Tchatchou, Sandrine | Mulligan, Anna Marie | Dörk, Thilo | Bogdanova, Natalia V. | Antonenkova, Natalia N. | Anton-Culver, Hoda | Darabi, Hatef | Eriksson, Mikael | Garcia-Closas, Montserrat | Figueroa, Jonine | Lissowska, Jolanta | Brinton, Louise | Devilee, Peter | Tollenaar, Robert A. E. M. | Seynaeve, Caroline | van Asperen, Christi J. | Kristensen, Vessela N. | Slager, Susan | Toland, Amanda E. | Ambrosone, Christine B. | Yannoukakos, Drakoulis | Lindblom, Annika | Margolin, Sara | Radice, Paolo | Peterlongo, Paolo | Barile, Monica | Mariani, Paolo | Hooning, Maartje J. | Martens, John W. M. | Collée, J. Margriet | Jager, Agnes | Jakubowska, Anna | Lubinski, Jan | Jaworska-Bieniek, Katarzyna | Durda, Katarzyna | Giles, Graham G. | McLean, Catriona | Brauch, Hiltrud | Brüning, Thomas | Ko, Yon-Dschun | Brenner, Hermann | Dieffenbach, Aida Karina | Arndt, Volker | Stegmaier, Christa | Swerdlow, Anthony | Ashworth, Alan | Orr, Nick | Jones, Michael | Simard, Jacques | Goldberg, Mark S. | Labrèche, France | Dumont, Martine | Winqvist, Robert | Pylkäs, Katri | Jukkola-Vuorinen, Arja | Grip, Mervi | Kataja, Vesa | Kosma, Veli-Matti | Hartikainen, Jaana M. | Mannermaa, Arto | Hamann, Ute | Chenevix-Trench, Georgia | Blomqvist, Carl | Aittomäki, Kristiina | Easton, Douglas F. | Nevanlinna, Heli
PLoS ONE  2014;9(11):e109973.
Genetic variations, such as single nucleotide polymorphisms (SNPs) in microRNAs (miRNA) or in the miRNA binding sites may affect the miRNA dependent gene expression regulation, which has been implicated in various cancers, including breast cancer, and may alter individual susceptibility to cancer. We investigated associations between miRNA related SNPs and breast cancer risk. First we evaluated 2,196 SNPs in a case-control study combining nine genome wide association studies (GWAS). Second, we further investigated 42 SNPs with suggestive evidence for association using 41,785 cases and 41,880 controls from 41 studies included in the Breast Cancer Association Consortium (BCAC). Combining the GWAS and BCAC data within a meta-analysis, we estimated main effects on breast cancer risk as well as risks for estrogen receptor (ER) and age defined subgroups. Five miRNA binding site SNPs associated significantly with breast cancer risk: rs1045494 (odds ratio (OR) 0.92; 95% confidence interval (CI): 0.88–0.96), rs1052532 (OR 0.97; 95% CI: 0.95–0.99), rs10719 (OR 0.97; 95% CI: 0.94–0.99), rs4687554 (OR 0.97; 95% CI: 0.95–0.99, and rs3134615 (OR 1.03; 95% CI: 1.01–1.05) located in the 3′ UTR of CASP8, HDDC3, DROSHA, MUSTN1, and MYCL1, respectively. DROSHA belongs to miRNA machinery genes and has a central role in initial miRNA processing. The remaining genes are involved in different molecular functions, including apoptosis and gene expression regulation. Further studies are warranted to elucidate whether the miRNA binding site SNPs are the causative variants for the observed risk effects.
doi:10.1371/journal.pone.0109973
PMCID: PMC4229095  PMID: 25390939
2.  Daytime napping, sleep duration and serum C reactive protein: a population-based cohort study 
BMJ Open  2014;4(11):e006071.
Objectives
To explore whether daytime napping and sleep duration are linked to serum C reactive protein (CRP), a pro-inflammatory marker, in an older aged British population.
Design
Cross-sectional study.
Setting
European Prospective Investigation into Cancer and Nutrition (EPIC)-Norfolk study.
Participants
A total of 5018 men and women aged 48–92 years reported their sleep habits and had serum CRP levels measured.
Outcome and measures
CRP was measured (mg/L) during 2006–2011 in fresh blood samples using high-sensitivity methods. Participants reported napping habits during 2002–2004, and reported sleep quantity during 2006–2007. Multivariable linear regression models were used to examine the association between napping and log-transformed CRP, and geometric mean CRP levels were calculated.
Results
After adjustment for age and sex, those who reported napping had 10% higher CRP levels compared with those not napping. The association was attenuated but remained borderline significant (β=0.05 (95% CI 0.00 to 0.10)) after further adjustment for social class, education, marital status, body mass index, physical activity, smoking, alcohol intake, self-reported health, pre-existing diseases, systolic blood pressure, hypnotic drug use, depression and in women-only hormone replacement therapy use. The geometric means (95% CI) of CRP levels were 2.38 (2.29 to 2.47) mg/L and 2.26 (2.21 to 2.32) mg/L for those who reported napping and no napping, respectively. A U-shaped association was observed between time spent in bed at night and CRP levels, and nighttime sleep duration was not associated with serum CRP levels. The association between napping and CRP was stronger for older participants, and among extremes of time spent in bed at night.
Conclusions
Daytime napping was associated with increased CRP levels in an older aged British population. Further studies are needed to determine whether daytime napping is a cause for systemic inflammation, or if it is a symptom or consequence of underlying health problems.
doi:10.1136/bmjopen-2014-006071
PMCID: PMC4244397  PMID: 25387759
Sleep; Napping; C-reactive protein; Inflammation; Population
3.  A systematic review and meta-analysis of 130,000 individuals shows smoking does not modify the association of APOE genotype on risk of coronary heart disease 
Atherosclerosis  2014;237(1):5-12.
Background
Conflicting evidence exists on whether smoking acts as an effect modifier of the association between APOE genotype and risk of coronary heart disease (CHD).
Methods and results
We searched PubMed and EMBASE to June 11, 2013 for published studies reporting APOE genotype, smoking status and CHD events and added unpublished data from population cohorts. We tested for presence of effect modification by smoking status in the relationship between APOE genotype and risk of CHD using likelihood ratio test.
In total 13 studies (including unpublished data from eight cohorts) with 10,134 CHD events in 130,004 individuals of European descent were identified. The odds ratio (OR) for CHD risk from APOE genotype (ε4 carriers versus non-carriers) was 1.06 (95% confidence interval (CI): 1.01, 1.12) and for smoking (present vs. past/never smokers) was OR 2.05 (95%CI: 1.95, 2.14). When the association between APOE genotype and CHD was stratified by smoking status, compared to non-ε4 carriers, ε4 carriers had an OR of 1.11 (95%CI: 1.02, 1.21) in 28,789 present smokers and an OR of 1.04 (95%CI 0.98, 1.10) in 101,215 previous/never smokers, with no evidence of effect modification (P-value for heterogeneity = 0.19). Analysis of pack years in individual participant data of >60,000 with adjustment for cardiovascular traits also failed to identify evidence of effect modification.
Conclusions
In the largest analysis to date, we identified no evidence for effect modification by smoking status in the association between APOE genotype and risk of CHD.
Highlights
•We examined evidence for an interaction between APOE genotype, smoking and risk of coronary heart disease.•This was conducted in the largest meta-analysis of published and unpublished data sets to date (>130,000 individuals).•Our analysis did not identify evidence of interaction.•These findings bring into question presence of a clinically meaningful interaction between APOE genotype and smoking.
doi:10.1016/j.atherosclerosis.2014.07.038
PMCID: PMC4232362  PMID: 25173947
APOE genotype; Smoking; Coronary heart disease; Gene–environment interaction
4.  Lipoprotein (a) and risk of coronary, cerebrovascular and peripheral artery disease; the EPIC-Norfolk prospective population study 
Objective
While the association between circulating levels of lipoprotein(a) (Lp(a)) and risk of coronary artery disease (CAD) and stroke is well established, its role in risk of peripheral artery disease (PAD) remains unclear. Here, we examine the association between Lp(a) levels and PAD in a large prospective cohort. To contextualise these findings, we also examined the association between Lp(a) levels and risk of stroke and CAD and studied the role of LDL as an effect modifier of Lp(a) associated cardiovascular risk.
Methods and Results
Lp(a) levels were measured in apparently healthy participants in the EPIC-Norfolk cohort. Cox regression was used to quantify the association between Lp(a) levels and risk of PAD, stroke and CAD outcomes. During 212,981 person-years at risk, a total of 2365 CAD, 284 ischemic stroke and 596 PAD events occurred in 18,720 participants. Lp(a) was associated with PAD and CAD outcomes but not with ischemic stroke (HR per 2.7 fold increase in Lp(a) of 1.37, 95% CI 1.25-1.50, 1.13, 95% CI 1.04-1.22 and 0.91, 95%CI 0.79-1.03 respectively). LDL-C levels did not modify these associations.
Conclusion
Lp(a) levels were associated with future PAD and CAD events. The association between Lp(a) and cardiovascular disease was not modified by LDL-C levels.
doi:10.1161/ATVBAHA.112.255521
PMCID: PMC4210842  PMID: 23065826
5.  Cod Liver Oil Supplement Consumption and Health: Cross-sectional Results from the EPIC-Norfolk Cohort Study 
Nutrients  2014;6(10):4320-4337.
Supplement users (SU) make healthy lifestyle choices; on the other hand, SU report more medical conditions. We hypothesised that cod liver oil (CLO) consumers are similar to non-supplement users, since CLO use might originate from historical motives, i.e., rickets prevention, and not health consciousness. CLO consumers were studied in order to identify possible confounders, such as confounding by indication. The European Prospective Investigation into Cancer (EPIC) investigates causes of chronic disease. The participants were 25,639 men and women, aged 40–79 years, recruited from general practices in Norfolk, East-Anglia (UK). Participants completed questionnaires and a health examination between 1993 and 1998. Supplement use was measured using 7-day diet diaries. CLO was the most common supplement used, more prevalent among women and associated with not smoking, higher physical activity level and more favourable eating habits. SU had a higher occurrence of benign growths and bone-related diseases, but CLO was negatively associated with cardiovascular-related conditions. Although the results of SU characteristics in EPIC-Norfolk are comparable with studies worldwide, the CLO group is different from SU in general. Confounding by indication takes place and will need to be taken into account when analysing prospective associations of CLO use with fracture risk and cardiovascular diseases.
doi:10.3390/nu6104320
PMCID: PMC4210919  PMID: 25325252
dietary supplement; cod liver oil; socio-demographics; health; confounding; cardiovascular disease
6.  Serum 25-hydroxyvitamin D, mortality, and incident cardiovascular disease, respiratory disease, cancers, and fractures: a 13-y prospective population study1234 
Background: Vitamin D is associated with many health conditions, but optimal blood concentrations are still uncertain.
Objectives: We examined the prospective relation between serum 25-hydroxyvitamin D [25(OH)D] concentrations [which comprised 25(OH)D3 and 25(OH)D2] and subsequent mortality by the cause and incident diseases in a prospective population study.
Design: Serum vitamin D concentrations were measured in 14,641 men and women aged 42–82 y in 1997–2000 who were living in Norfolk, United Kingdom, and were followed up to 2012. Participants were categorized into 5 groups according to baseline serum concentrations of total 25(OH)D <30, 30 to <50, 50 to <70, 70 to <90, and ≥90 nmol/L.
Results: The mean serum total 25(OH)D was 56.6 nmol/L, which consisted predominantly of 25(OH)D3 (mean: 56.2 nmol/L; 99% of total). The age-, sex-, and month-adjusted HRs (95% CIs) for all-cause mortality (2776 deaths) for men and women by increasing vitamin D category were 1, 0.84 (0.74, 0.94), 0.72 (0.63, 0.81), 0.71 (0.62, 0.82), and 0.66 (0.55, 0.79) (P-trend < 0.0001). When analyzed as a continuous variable and with additional adjustment for body mass index, smoking, social class, education, physical activity, alcohol intake, plasma vitamin C, history of cardiovascular disease, diabetes, or cancer, HRs for a 20-nmol/L increase in 25(OH)D were 0.92 (0.88, 0.96) (P < 0.001) for total mortality, 0.96 (0.93, 0.99) (P = 0.014) (4469 events) for cardiovascular disease, 0.89 (0.85, 0.93) (P < 0.0001) (2132 events) for respiratory disease, 0.89 (0.81, 0.98) (P = 0.012) (563 events) for fractures, and 1.02 (0.99, 1.06) (P = 0.21) (3121 events) for incident total cancers.
Conclusions: Plasma 25(OH)D concentrations predict subsequent lower 13-y total mortality and incident cardiovascular disease, respiratory disease, and fractures but not total incident cancers. For mortality, lowest risks were in subjects with concentrations >90 nmol/L, and there was no evidence of increased mortality at high concentrations, suggesting that a moderate increase in population mean concentrations may have potential health benefit, but <1% of the population had concentrations >120 nmol/L.
doi:10.3945/ajcn.114.086413
PMCID: PMC4196486  PMID: 25332334
7.  Distribution of lipid parameters according to different socio-economic indicators- the EPIC-Norfolk prospective population study 
BMC Public Health  2014;14(1):782.
Background
Data on the relationship between plasma levels of cholesterol and triglycerides and social class have been inconsistent. Most previous studies have used one classification of social class.
Methods
This was a cross-sectional population based study with data on occupational social class, educational level obtained using a detailed health and lifestyle questionnaire. A total of 10,147 men and 12,304 women aged 45–80 years living in Norfolk, United Kingdom, were recruited using general practice age-sex registers as part of the European Prospective Investigation into Cancer (EPIC-Norfolk). Plasma levels of cholesterol and triglycerides were measured in baseline samples. Social class was classified according to three classifications: occupation, educational level, and area deprivation score according to Townsend deprivation index. Differences in lipid levels by socio-economic status indices were quantified by analysis of variance (ANOVA) and multiple linear regression after adjusting for body mass index and alcohol consumption.
Results
Total cholesterol levels were associated with occupational level among men, and with educational level among women. Triglyceride levels were associated with educational level and occupational level among women, but the latter association was lost after adjustment for age and body mass index. HDL-cholesterol levels were associated with both educational level and educational level among men and women. The relationships with educational level were substantially attenuated by adjustment for age, body mass index and alcohol use, whereas the association with educational class was retained upon adjustment. LDL-cholesterol levels were not associated with social class indices among men, but a positive association was observed with educational class among women. This association was not affected by adjustment for age, body mass index and alcohol use.
Conclusions
The findings of this study suggest that there are sex differences in the association between socio-economic status and serum lipid levels. The variations in lipid profile with socio-economic status may be largely attributed to potentially modifiable factors such as obesity, physical activity and dietary intake.
doi:10.1186/1471-2458-14-782
PMCID: PMC4155077  PMID: 25179437
8.  Systemic Medication and Intraocular Pressure in a British Population 
Ophthalmology  2014;121(8):1501-1507.
Objective
To determine the association between systemic medication use and intraocular pressure (IOP) in a population of older British men and women.
Design
Population-based, cross-sectional study.
Participants
We included 7093 participants from the European Prospective Investigation into Cancer–Norfolk Eye Study. Exclusion criteria were a history of glaucoma therapy (medical, laser, or surgical), IOP asymmetry between eyes of >5 mmHg, and missing data for any covariables. The mean age of participants was 68 years (range, 48–92) and 56% were women.
Methods
We measured IOP using the Ocular Response Analyzer. Three readings were taken per eye and the best signal value of the Goldmann-correlated IOP value considered. Participants were asked to bring all their medications and related documentation to the health examination, and these were recorded by the research nurse using an electronic case record form. The medication classes examined were angiotensin-converting enzyme inhibitors, angiotensin-receptor blockers, α-blockers, β-blockers, calcium channel blockers, diuretics, nitrates, statins, insulin, biguanides, sulfonylureas, aspirin, and other nonsteroidal anti-inflammatory drugs. We examined associations between medication use and IOP using multivariable linear regression models adjusted for age, sex, and body mass index. Models containing diabetic medication were further adjusted for glycosylated hemoglobin levels.
Main Outcome Measures
Mean IOP of the right and left eyes.
Results
Use of systemic β-blockers (−0.92 mmHg; 95% CI, −1.19, −0.65; P<0.001) and nitrates (−0.63 mmHg; 95% CI, −1.12, −0.14; P = 0.011) were independently associated with lower IOP. The observed associations between statin or aspirin use with IOP were no longer significant after adjustment for β-blocker use.
Conclusions
This is the first population-based study to demonstrate and quantify clinically significant differences in IOP among participants using systemic β-blockers or nitrates. Lower IOP observed in participants using statins or aspirin was explained by concurrent systemic β-blocker use. The study findings may have implications for the management of glaucoma patients with comorbidity, and may provide insight into the pathophysiologic processes underlying IOP.
doi:10.1016/j.ophtha.2014.02.009
PMCID: PMC4109027  PMID: 24702754
BMI, body mass index; BP, blood pressure; EPIC, European Prospective Investigation into Cancer; IOP, intraocular pressure; SPB, systolic BP; ORA, Ocular Response Analyzer
9.  Serum carbon and nitrogen stable isotopes as potential biomarkers of dietary intake and their relation with incident type 2 diabetes: the EPIC-Norfolk study123 
Background: Stable-isotope ratios of carbon (13C/12C, expressed as δ13C) and nitrogen (15N/14N, or δ15N) have been proposed as potential nutritional biomarkers to distinguish between meat, fish, and plant-based foods.
Objective: The objective was to investigate dietary correlates of δ13C and δ15N and examine the association of these biomarkers with incident type 2 diabetes in a prospective study.
Design: Serum δ13C and δ15N (‰) were measured by using isotope ratio mass spectrometry in a case-cohort study (n = 476 diabetes cases; n = 718 subcohort) nested within the European Prospective Investigation into Cancer and Nutrition (EPIC)–Norfolk population-based cohort. We examined dietary (food-frequency questionnaire) correlates of δ13C and δ15N in the subcohort. HRs and 95% CIs were estimated by using Prentice-weighted Cox regression.
Results: Mean (±SD) δ13C and δ15N were −22.8 ± 0.4‰ and 10.2 ± 0.4‰, respectively, and δ13C (r = 0.22) and δ15N (r = 0.20) were positively correlated (P < 0.001) with fish protein intake. Animal protein was not correlated with δ13C but was significantly correlated with δ15N (dairy protein: r = 0.11; meat protein: r = 0.09; terrestrial animal protein: r = 0.12, P ≤ 0.013). δ13C was inversely associated with diabetes in adjusted analyses (HR per tertile: 0.74; 95% CI: 0.65, 0.83; P-trend < 0.001], whereas δ15N was positively associated (HR: 1.23; 95% CI: 1.09, 1.38; P-trend = 0.001).
Conclusions: The isotope ratios δ13C and δ15N may both serve as potential biomarkers of fish protein intake, whereas only δ15N may reflect broader animal-source protein intake in a European population. The inverse association of δ13C but a positive association of δ15N with incident diabetes should be interpreted in the light of knowledge of dietary intake and may assist in identifying dietary components that are associated with health risks and benefits.
doi:10.3945/ajcn.113.068577
PMCID: PMC4095667  PMID: 24990425
10.  Corneal Biomechanical Properties and Glaucoma-Related Quantitative Traits in the EPIC-Norfolk Eye Study 
Purpose.
We examined the association of corneal hysteresis (CH) with Heidelberg retina tomograph (HRT)– and Glaucoma Detection with Variable Corneal Compensation scanning laser polarimeter (GDxVCC)–derived measures in a British population.
Methods.
The EPIC-Norfolk Eye Study is nested within a multicenter cohort study—the European Prospective Investigation of Cancer. Ocular response analyzer (ORA), HRT3, and GDxVCC measurements were taken at the research clinic. Three ORA measurements were taken per eye, and the single best value used. Participants meeting predefined criteria were referred for a second examination, including Goldmann applanation tonometry (GAT) and central corneal thickness (CCT) measurement. Generalized estimating equation models were used to examine the associations of CH with HRT and GDxVCC parameters, adjusted for disc area. The GDxVCC analyses were adjusted further for typical scan score to handle atypical retardation.
Results.
There were complete research clinic data from 5134 participants. Corneal hysteresis was associated positively with HRT rim area (P < 0.001), and GDxVCC retinal nerve fiber layer (RNFL) average thickness (P = 0.006) and modulation (P = 0.003), and associated negatively with HRT linear cup-to-disc ratio (LCDR, P < 0.001), after adjustment for Goldmann-correlated IOP and other possible confounders. In the 602 participants undergoing the second examination, CH was associated negatively with LCDR (P = 0.008) after adjustment for GAT, CCT, and other possible confounders.
Conclusions.
Lower CH was associated with HRT and GDxVCC parameters in a direction that is seen in glaucoma and with ageing. Further research is required to establish if this is a causal relationship, or due to residual confounding by age, IOP, or CCT.
In this cross-sectional population-based study, lower corneal hysteresis was associated with changes in HRT and GDxVCC parameters that are seen in glaucoma. The associations were statistically independent of age and intraocular pressure.
doi:10.1167/iovs.13-13290
PMCID: PMC3885137  PMID: 24334448
biomechanics; cornea; epidemiology; glaucoma; optic disk; scanning laser polarimetry
11.  Identification of heart rate–associated loci and their effects on cardiac conduction and rhythm disorders 
den Hoed, Marcel | Eijgelsheim, Mark | Esko, Tõnu | Brundel, Bianca J J M | Peal, David S | Evans, David M | Nolte, Ilja M | Segrè, Ayellet V | Holm, Hilma | Handsaker, Robert E | Westra, Harm-Jan | Johnson, Toby | Isaacs, Aaron | Yang, Jian | Lundby, Alicia | Zhao, Jing Hua | Kim, Young Jin | Go, Min Jin | Almgren, Peter | Bochud, Murielle | Boucher, Gabrielle | Cornelis, Marilyn C | Gudbjartsson, Daniel | Hadley, David | Van Der Harst, Pim | Hayward, Caroline | Heijer, Martin Den | Igl, Wilmar | Jackson, Anne U | Kutalik, Zoltán | Luan, Jian’an | Kemp, John P | Kristiansson, Kati | Ladenvall, Claes | Lorentzon, Mattias | Montasser, May E | Njajou, Omer T | O’Reilly, Paul F | Padmanabhan, Sandosh | Pourcain, Beate St. | Rankinen, Tuomo | Salo, Perttu | Tanaka, Toshiko | Timpson, Nicholas J | Vitart, Veronique | Waite, Lindsay | Wheeler, William | Zhang, Weihua | Draisma, Harmen H M | Feitosa, Mary F | Kerr, Kathleen F | Lind, Penelope A | Mihailov, Evelin | Onland-Moret, N Charlotte | Song, Ci | Weedon, Michael N | Xie, Weijia | Yengo, Loic | Absher, Devin | Albert, Christine M | Alonso, Alvaro | Arking, Dan E | de Bakker, Paul I W | Balkau, Beverley | Barlassina, Cristina | Benaglio, Paola | Bis, Joshua C | Bouatia-Naji, Nabila | Brage, Søren | Chanock, Stephen J | Chines, Peter S | Chung, Mina | Darbar, Dawood | Dina, Christian | Dörr, Marcus | Elliott, Paul | Felix, Stephan B | Fischer, Krista | Fuchsberger, Christian | de Geus, Eco J C | Goyette, Philippe | Gudnason, Vilmundur | Harris, Tamara B | Hartikainen, Anna-liisa | Havulinna, Aki S | Heckbert, Susan R | Hicks, Andrew A | Hofman, Albert | Holewijn, Suzanne | Hoogstra-Berends, Femke | Hottenga, Jouke-Jan | Jensen, Majken K | Johansson, Åsa | Junttila, Juhani | Kääb, Stefan | Kanon, Bart | Ketkar, Shamika | Khaw, Kay-Tee | Knowles, Joshua W | Kooner, Angrad S | Kors, Jan A | Kumari, Meena | Milani, Lili | Laiho, Päivi | Lakatta, Edward G | Langenberg, Claudia | Leusink, Maarten | Liu, Yongmei | Luben, Robert N | Lunetta, Kathryn L | Lynch, Stacey N | Markus, Marcello R P | Marques-Vidal, Pedro | Leach, Irene Mateo | McArdle, Wendy L | McCarroll, Steven A | Medland, Sarah E | Miller, Kathryn A | Montgomery, Grant W | Morrison, Alanna C | Müller-Nurasyid, Martina | Navarro, Pau | Nelis, Mari | O’Connell, Jeffrey R | O’Donnell, Christopher J | Ong, Ken K | Newman, Anne B | Peters, Annette | Polasek, Ozren | Pouta, Anneli | Pramstaller, Peter P | Psaty, Bruce M | Rao, Dabeeru C | Ring, Susan M | Rossin, Elizabeth J | Rudan, Diana | Sanna, Serena | Scott, Robert A | Sehmi, Jaban S | Sharp, Stephen | Shin, Jordan T | Singleton, Andrew B | Smith, Albert V | Soranzo, Nicole | Spector, Tim D | Stewart, Chip | Stringham, Heather M | Tarasov, Kirill V | Uitterlinden, André G | Vandenput, Liesbeth | Hwang, Shih-Jen | Whitfield, John B | Wijmenga, Cisca | Wild, Sarah H | Willemsen, Gonneke | Wilson, James F | Witteman, Jacqueline C M | Wong, Andrew | Wong, Quenna | Jamshidi, Yalda | Zitting, Paavo | Boer, Jolanda M A | Boomsma, Dorret I | Borecki, Ingrid B | Van Duijn, Cornelia M | Ekelund, Ulf | Forouhi, Nita G | Froguel, Philippe | Hingorani, Aroon | Ingelsson, Erik | Kivimaki, Mika | Kronmal, Richard A | Kuh, Diana | Lind, Lars | Martin, Nicholas G | Oostra, Ben A | Pedersen, Nancy L | Quertermous, Thomas | Rotter, Jerome I | van der Schouw, Yvonne T | Verschuren, W M Monique | Walker, Mark | Albanes, Demetrius | Arnar, David O | Assimes, Themistocles L | Bandinelli, Stefania | Boehnke, Michael | de Boer, Rudolf A | Bouchard, Claude | Caulfield, W L Mark | Chambers, John C | Curhan, Gary | Cusi, Daniele | Eriksson, Johan | Ferrucci, Luigi | van Gilst, Wiek H | Glorioso, Nicola | de Graaf, Jacqueline | Groop, Leif | Gyllensten, Ulf | Hsueh, Wen-Chi | Hu, Frank B | Huikuri, Heikki V | Hunter, David J | Iribarren, Carlos | Isomaa, Bo | Jarvelin, Marjo-Riitta | Jula, Antti | Kähönen, Mika | Kiemeney, Lambertus A | van der Klauw, Melanie M | Kooner, Jaspal S | Kraft, Peter | Iacoviello, Licia | Lehtimäki, Terho | Lokki, Marja-Liisa L | Mitchell, Braxton D | Navis, Gerjan | Nieminen, Markku S | Ohlsson, Claes | Poulter, Neil R | Qi, Lu | Raitakari, Olli T | Rimm, Eric B | Rioux, John D | Rizzi, Federica | Rudan, Igor | Salomaa, Veikko | Sever, Peter S | Shields, Denis C | Shuldiner, Alan R | Sinisalo, Juha | Stanton, Alice V | Stolk, Ronald P | Strachan, David P | Tardif, Jean-Claude | Thorsteinsdottir, Unnur | Tuomilehto, Jaako | van Veldhuisen, Dirk J | Virtamo, Jarmo | Viikari, Jorma | Vollenweider, Peter | Waeber, Gérard | Widen, Elisabeth | Cho, Yoon Shin | Olsen, Jesper V | Visscher, Peter M | Willer, Cristen | Franke, Lude | Erdmann, Jeanette | Thompson, John R | Pfeufer, Arne | Sotoodehnia, Nona | Newton-Cheh, Christopher | Ellinor, Patrick T | Stricker, Bruno H Ch | Metspalu, Andres | Perola, Markus | Beckmann, Jacques S | Smith, George Davey | Stefansson, Kari | Wareham, Nicholas J | Munroe, Patricia B | Sibon, Ody C M | Milan, David J | Snieder, Harold | Samani, Nilesh J | Loos, Ruth J F
Nature genetics  2013;45(6):621-631.
Elevated resting heart rate is associated with greater risk of cardiovascular disease and mortality. In a 2-stage meta-analysis of genome-wide association studies in up to 181,171 individuals, we identified 14 new loci associated with heart rate and confirmed associations with all 7 previously established loci. Experimental downregulation of gene expression in Drosophila melanogaster and Danio rerio identified 20 genes at 11 loci that are relevant for heart rate regulation and highlight a role for genes involved in signal transmission, embryonic cardiac development and the pathophysiology of dilated cardiomyopathy, congenital heart failure and/or sudden cardiac death. In addition, genetic susceptibility to increased heart rate is associated with altered cardiac conduction and reduced risk of sick sinus syndrome, and both heart rate–increasing and heart rate–decreasing variants associate with risk of atrial fibrillation. Our findings provide fresh insights into the mechanisms regulating heart rate and identify new therapeutic targets.
doi:10.1038/ng.2610
PMCID: PMC3696959  PMID: 23583979
12.  Large-scale genotyping identifies 41 new loci associated with breast cancer risk 
Michailidou, Kyriaki | Hall, Per | Gonzalez-Neira, Anna | Ghoussaini, Maya | Dennis, Joe | Milne, Roger L | Schmidt, Marjanka K | Chang-Claude, Jenny | Bojesen, Stig E | Bolla, Manjeet K | Wang, Qin | Dicks, Ed | Lee, Andrew | Turnbull, Clare | Rahman, Nazneen | Fletcher, Olivia | Peto, Julian | Gibson, Lorna | Silva, Isabel dos Santos | Nevanlinna, Heli | Muranen, Taru A | Aittomäki, Kristiina | Blomqvist, Carl | Czene, Kamila | Irwanto, Astrid | Liu, Jianjun | Waisfisz, Quinten | Meijers-Heijboer, Hanne | Adank, Muriel | van der Luijt, Rob B | Hein, Rebecca | Dahmen, Norbert | Beckman, Lars | Meindl, Alfons | Schmutzler, Rita K | Müller-Myhsok, Bertram | Lichtner, Peter | Hopper, John L | Southey, Melissa C | Makalic, Enes | Schmidt, Daniel F | Uitterlinden, Andre G | Hofman, Albert | Hunter, David J | Chanock, Stephen J | Vincent, Daniel | Bacot, François | Tessier, Daniel C | Canisius, Sander | Wessels, Lodewyk F A | Haiman, Christopher A | Shah, Mitul | Luben, Robert | Brown, Judith | Luccarini, Craig | Schoof, Nils | Humphreys, Keith | Li, Jingmei | Nordestgaard, Børge G | Nielsen, Sune F | Flyger, Henrik | Couch, Fergus J | Wang, Xianshu | Vachon, Celine | Stevens, Kristen N | Lambrechts, Diether | Moisse, Matthieu | Paridaens, Robert | Christiaens, Marie-Rose | Rudolph, Anja | Nickels, Stefan | Flesch-Janys, Dieter | Johnson, Nichola | Aitken, Zoe | Aaltonen, Kirsimari | Heikkinen, Tuomas | Broeks, Annegien | Van’t Veer, Laura J | van der Schoot, C Ellen | Guénel, Pascal | Truong, Thérèse | Laurent-Puig, Pierre | Menegaux, Florence | Marme, Frederik | Schneeweiss, Andreas | Sohn, Christof | Burwinkel, Barbara | Zamora, M Pilar | Perez, Jose Ignacio Arias | Pita, Guillermo | Alonso, M Rosario | Cox, Angela | Brock, Ian W | Cross, Simon S | Reed, Malcolm W R | Sawyer, Elinor J | Tomlinson, Ian | Kerin, Michael J | Miller, Nicola | Henderson, Brian E | Schumacher, Fredrick | Le Marchand, Loic | Andrulis, Irene L | Knight, Julia A | Glendon, Gord | Mulligan, Anna Marie | Lindblom, Annika | Margolin, Sara | Hooning, Maartje J | Hollestelle, Antoinette | van den Ouweland, Ans M W | Jager, Agnes | Bui, Quang M | Stone, Jennifer | Dite, Gillian S | Apicella, Carmel | Tsimiklis, Helen | Giles, Graham G | Severi, Gianluca | Baglietto, Laura | Fasching, Peter A | Haeberle, Lothar | Ekici, Arif B | Beckmann, Matthias W | Brenner, Hermann | Müller, Heiko | Arndt, Volker | Stegmaier, Christa | Swerdlow, Anthony | Ashworth, Alan | Orr, Nick | Jones, Michael | Figueroa, Jonine | Lissowska, Jolanta | Brinton, Louise | Goldberg, Mark S | Labrèche, France | Dumont, Martine | Winqvist, Robert | Pylkäs, Katri | Jukkola-Vuorinen, Arja | Grip, Mervi | Brauch, Hiltrud | Hamann, Ute | Brüning, Thomas | Radice, Paolo | Peterlongo, Paolo | Manoukian, Siranoush | Bonanni, Bernardo | Devilee, Peter | Tollenaar, Rob A E M | Seynaeve, Caroline | van Asperen, Christi J | Jakubowska, Anna | Lubinski, Jan | Jaworska, Katarzyna | Durda, Katarzyna | Mannermaa, Arto | Kataja, Vesa | Kosma, Veli-Matti | Hartikainen, Jaana M | Bogdanova, Natalia V | Antonenkova, Natalia N | Dörk, Thilo | Kristensen, Vessela N | Anton-Culver, Hoda | Slager, Susan | Toland, Amanda E | Edge, Stephen | Fostira, Florentia | Kang, Daehee | Yoo, Keun-Young | Noh, Dong-Young | Matsuo, Keitaro | Ito, Hidemi | Iwata, Hiroji | Sueta, Aiko | Wu, Anna H | Tseng, Chiu-Chen | Van Den Berg, David | Stram, Daniel O | Shu, Xiao-Ou | Lu, Wei | Gao, Yu-Tang | Cai, Hui | Teo, Soo Hwang | Yip, Cheng Har | Phuah, Sze Yee | Cornes, Belinda K | Hartman, Mikael | Miao, Hui | Lim, Wei Yen | Sng, Jen-Hwei | Muir, Kenneth | Lophatananon, Artitaya | Stewart-Brown, Sarah | Siriwanarangsan, Pornthep | Shen, Chen-Yang | Hsiung, Chia-Ni | Wu, Pei-Ei | Ding, Shian-Ling | Sangrajrang, Suleeporn | Gaborieau, Valerie | Brennan, Paul | McKay, James | Blot, William J | Signorello, Lisa B | Cai, Qiuyin | Zheng, Wei | Deming-Halverson, Sandra | Shrubsole, Martha | Long, Jirong | Simard, Jacques | Garcia-Closas, Montse | Pharoah, Paul D P | Chenevix-Trench, Georgia | Dunning, Alison M | Benitez, Javier | Easton, Douglas F
Nature genetics  2013;45(4):353-361e2.
Breast cancer is the most common cancer among women. Common variants at 27 loci have been identified as associated with susceptibility to breast cancer, and these account for ~9% of the familial risk of the disease. We report here a meta-analysis of 9 genome-wide association studies, including 10,052 breast cancer cases and 12,575 controls of European ancestry, from which we selected 29,807 SNPs for further genotyping. These SNPs were genotyped in 45,290 cases and 41,880 controls of European ancestry from 41 studies in the Breast Cancer Association Consortium (BCAC). The SNPs were genotyped as part of a collaborative genotyping experiment involving four consortia (Collaborative Oncological Gene-environment Study, COGS) and used a custom Illumina iSelect genotyping array, iCOGS, comprising more than 200,000 SNPs. We identified SNPs at 41 new breast cancer susceptibility loci at genome-wide significance (P < 5 × 10−8). Further analyses suggest that more than 1,000 additional loci are involved in breast cancer susceptibility.
doi:10.1038/ng.2563
PMCID: PMC3771688  PMID: 23535729
13.  Laser Scanning Tomography in the EPIC-Norfolk Eye Study: Principal Components and Associations 
Purpose.
To describe Heidelberg Retina Tomograph (HRT) measures, their principal components, and their associations in a British population.
Methods.
The European Prospective Investigation of Cancer (EPIC)-Norfolk Eye Study is nested within a multicenter cohort study. Measurements were taken with the HRT-2 and the software subsequently updated to yield HRT-3 parameters. Principal components analysis (PCA) was used to identify distinct components of the HRT variables. Generalized estimating equation models were used to examine associations of these components with age, sex, height, body mass index (BMI), blood pressure, social class, education, alcohol intake, smoking status, axial length, IOP, and lens status.
Results.
Complete data were available from 10,859 eyes of 6430 participants with a mean age of 68 years. Principal components analysis identified three components with an eigenvalue greater than 1, explaining 79.9% of the variance of all the HRT measures. These were named cup, retinal nerve fiber layer (RNFL), and rim based on the factor loadings they were most correlated with. Older age was significantly associated with a greater cup (P = 0.003), smaller RNFL (P < 0.001), and smaller rim (P < 0.001). Female sex (P = 0.001), higher education (P < 0.001), and shorter axial length (P < 0.001) were associated with a greater RNFL. Lower BMI and higher IOP were associated with a greater cup (both, P < 0.001) and a smaller rim (BMI, P = 0.001; IOP, P < 0.001).
Conclusions.
Heidelberg Retina Tomograph measures in this cohort were largely explained by three principal components related to optic disc cup, RNFL, and rim. Associations with cup and rim were distinct to associations with RNFL, suggesting different underlying determinants.
Analysis of Heidelberg Retina Tomograph measurements from a large population-based sample identified three distinct components (optic disc “cup”, “rim” and retinal nerve fiber layer [“RNFL”]). Associations with “cup” and “rim” were distinct to associations with “RNFL”, suggesting different underlying determinants.
doi:10.1167/iovs.13-12490
PMCID: PMC3803136  PMID: 24030456
diagnostic techniques; epidemiology; axial length; glaucoma; body mass index; optic disk
14.  Daytime Napping and the Risk of All-Cause and Cause-Specific Mortality: A 13-Year Follow-up of a British Population 
American Journal of Epidemiology  2014;179(9):1115-1124.
Epidemiologic studies have reported conflicting results on the relationship between daytime napping and mortality risk, and there are few data on the potential association in the British population. We investigated the associations between daytime napping and all-cause or cause-specific mortality in the European Prospective Investigation Into Cancer-Norfolk study, a British population-based cohort study. Among the 16,374 men and women who answered questions on napping habits between 1998 and 2000, a total of 3,251 died during the 13-year follow-up. Daytime napping was associated with an increased risk of all-cause mortality (for napping less than 1 hour per day on average, hazard ratio = 1.14, 95% confidence interval: 1.02, 1.27; for napping 1 hour or longer per day on average, hazard ratio = 1.32, 95% confidence interval: 1.04, 1.68), independent of age, sex, social class, educational level, marital status, employment status, body mass index, physical activity level, smoking status, alcohol intake, depression, self-reported general health, use of hypnotic drugs or other medications, time spent in bed at night, and presence of preexisting health conditions. This association was more pronounced for death from respiratory diseases (for napping less than 1 hour, hazard ratio = 1.40, 95% confidence interval: 0.95, 2.05; for napping 1 hour or more, hazard ratio = 2.56, 95% confidence interval: 1.34, 4.86) and in individuals 65 years of age or younger. Excessive daytime napping might be a useful marker of underlying health risk, particularly of respiratory problems, especially among those 65 years of age or younger. Further research is required to clarify the nature of the observed association.
doi:10.1093/aje/kwu036
PMCID: PMC3992821  PMID: 24685532
aging; mortality; napping; respiratory; siesta; sleep; survival analysis
15.  A new tool for converting food frequency questionnaire data into nutrient and food group values: FETA research methods and availability 
BMJ Open  2014;4(3):e004503.
Objectives
To describe the research methods for the development of a new open source, cross-platform tool which processes data from the European Prospective Investigation into Cancer and Nutrition Norfolk Food Frequency Questionnaire (EPIC-Norfolk FFQ). A further aim was to compare nutrient and food group values derived from the current tool (FETA, FFQ EPIC Tool for Analysis) with the previously validated but less accessible tool, CAFÉ (Compositional Analyses from Frequency Estimates). The effect of text matching on intake data was also investigated.
Design
Cross-sectional analysis of a prospective cohort study—EPIC-Norfolk.
Setting
East England population (city of Norwich and its surrounding small towns and rural areas).
Participants
Complete FFQ data from 11 250 men and 13 602 women (mean age 59 years; range 40–79 years).
Outcome measures
Nutrient and food group intakes derived from FETA and CAFÉ analyses of EPIC-Norfolk FFQ data.
Results
Nutrient outputs from FETA and CAFÉ were similar; mean (SD) energy intake from FETA was 9222 kJ (2633) in men, 8113 kJ (2296) in women, compared with CAFÉ intakes of 9175 kJ (2630) in men, 8091 kJ (2298) in women. The majority of differences resulted in one or less quintile change (98.7%). Only mean daily fruit and vegetable food group intakes were higher in women than in men (278 vs 212 and 284 vs 255 g, respectively). Quintile changes were evident for all nutrients, with the exception of alcohol, when text matching was not executed; however, only the cereals food group was affected.
Conclusions
FETA produces similar nutrient and food group values to the previously validated CAFÉ but has the advantages of being open source, cross-platform and complete with a data-entry form directly compatible with the software. The tool will facilitate research using the EPIC-Norfolk FFQ, and can be customised for different study populations.
doi:10.1136/bmjopen-2013-004503
PMCID: PMC3975761  PMID: 24674997
16.  Self-reported sleep patterns in a British population cohort☆ 
Sleep Medicine  2014;15(3):295-302.
Highlights
•Our study provides a subjective sleep profile of a large British population–based cohort.•The reported time in bed (TIB) was more than 1.5 h longer than sleep duration.•All sociodemographic factors varied with TIB and sleep duration.•Sleep proportion may be a useful indicator of sleep patterns in this population.
Objectives
Sleep patterns have been linked to various health outcomes, but sleep patterns in the British population have not been extensively reported. We aimed to describe the sleep characteristics reported by the European Prospective Investigation of Cancer (EPIC)-Norfolk participants, with a particular emphasis on the comparison of measures of sleep quantity.
Methods
From 2006 to 2007, a total of 8480 participants aged 45–90 years reported sleep timing, nighttime sleep duration, and sleep difficulties. Time in bed (TIB) was calculated from the difference between rise time and bedtime, and sleep proportion was defined as the ratio of sleep duration and TIB.
Results
On average, the reported TIB was more than 1.5 h longer than sleep durations. Compared to men, women spent 15 min longer in bed, but they slept for 11 min less and reported more sleep difficulties. In multivariate analysis sleep duration and TIB varied with socioeconomic factors, but sleep proportion was consistently lower among women, nonworkers, and older individuals, as well as those who were widowed, separated, or divorced; those who reported sleep difficulties and more frequently used sleep medication; and those who had lower education, poorer general health, or a major depressive disorder (MDD).
Conclusions
Self-reported sleep duration and TIB have different meanings and implications for health. Sleep proportion may be a useful indicator of sleep patterns in the general population.
doi:10.1016/j.sleep.2013.10.015
PMCID: PMC3988958  PMID: 24503473
Sleep quantity; Sleep patterns; Sleep research; England; Population; Epidemiology
17.  Dietary dairy product intake and incident type 2 diabetes: a prospective study using dietary data from a 7-day food diary 
Diabetologia  2014;57(5):909-917.
Aim/hypothesis
The aim of this study was to investigate the association between total and types of dairy product intake and risk of developing incident type 2 diabetes, using a food diary.
Methods
A nested case-cohort within the EPIC-Norfolk Study was examined, including a random subcohort (n = 4,000) and cases of incident diabetes (n = 892, including 143 cases in the subcohort) followed-up for 11 years. Diet was assessed using a prospective 7-day food diary. Total dairy intake (g/day) was estimated and categorised into high-fat (≥3.9%) and low-fat (<3.9% fat) dairy, and by subtype into yoghurt, cheese and milk. Combined fermented dairy product intake (yoghurt, cheese, sour cream) was estimated and categorised into high- and low-fat. Prentice-weighted Cox regression HRs were calculated.
Results
Total dairy, high-fat dairy, milk, cheese and high-fat fermented dairy product intakes were not associated with the development of incident diabetes. Low-fat dairy intake was inversely associated with diabetes in age- and sex-adjusted analyses (tertile [T] 3 vs T1, HR 0.81 [95% CI 0.66, 0.98]), but further adjustment for anthropometric, dietary and diabetes risk factors attenuated this association. In addition, an inverse association was found between diabetes and low-fat fermented dairy product intake (T3 vs T1, HR 0.76 [95% CI 0.60, 0.99]; ptrend = 0.049) and specifically with yoghurt intake (HR 0.72 [95% CI 0.55, 0.95]; ptrend = 0.017) in multivariable adjusted analyses.
Conclusions/interpretation
Greater low-fat fermented dairy product intake, largely driven by yoghurt intake, was associated with a decreased risk of type 2 diabetes development in prospective analyses. These findings suggest that the consumption of specific dairy types may be beneficial for the prevention of diabetes, highlighting the importance of food group subtypes for public health messages.
Electronic supplementary material
The online version of this article (doi:10.1007/s00125-014-3176-1) contains peer-reviewed but unedited supplementary material, which is available to authorised users.
doi:10.1007/s00125-014-3176-1
PMCID: PMC3980034  PMID: 24510203
Cheese; Dairy; Fermented dairy; Milk; Type 2 diabetes; Yoghurt
18.  Body Mass Index, Smoking, and Alcohol and Risks of Barrett’s Esophagus and Esophageal Adenocarcinoma: A UK Prospective Cohort Study 
Digestive Diseases and Sciences  2014;59(7):1552-1559.
Background
The timing of the risk factors cigarette smoking, alcohol and obesity in the development of Barrett’s esophagus (BE) and esophageal adenocarcinoma (EAC) is unclear.
Aims
To investigate these exposures in the aetiology of BE and EAC in the same population.
Methods
The cohort included 24,068 men and women, aged 39–79 years, recruited between 1993 and 1997 into the prospective EPIC-Norfolk Study who provided information on anthropometry, smoking and alcohol intake. The cohort was monitored until December 2008 and incident cases identified.
Results
One hundred and four participants were diagnosed with BE and 66 with EAC. A body mass index (BMI) above 23 kg/m2 was associated with a greater risk of BE [BMI ≥23 vs. 18.5 to <23, hazard ratio (HR) 3.73, 95 % CI 1.37–10.16], and within a normal BMI, the risk was greater in the higher category (HR 3.76, 95 % CI 1.30–10.85, BMI 23–25 vs. 18.5 to >23 kg/m2). Neither smoking nor alcohol intake were associated with risk for BE. For EAC, all BMI categories were associated with risk, although statistically significant for only the highest (BMI >35 vs. BMI 18.5 to <23, HR 4.95, 95 % CI 1.11–22.17). The risk was greater in the higher category of a normal BMI (HR 2.73, 95 % CI 0.93–8.00, p = 0.07, BMI 23–25 vs. 18.5 to >23 kg/m2). There was an inverse association with ≥7 units alcohol/week (HR 0.51, 95 % CI 0.29–0.88) and with wine (HR 0.49, 95 % CI 0.23–1.04, p = 0.06, drinkers vs. non-drinkers).
Conclusions
Obesity may be involved early in carcinogenesis and the association with EAC and wine should be explored. The data have implications for aetiological investigations and prevention strategies.
doi:10.1007/s10620-013-3024-z
PMCID: PMC4067535  PMID: 24500448
Barrett’s esophagus; Adenocarcinoma; Smoking; Alcohol; BMI
19.  Genetic variants influencing circulating lipid levels and risk of coronary artery disease 
Objectives
Genetic studies might provide new insights into the biological mechanisms underlying lipid metabolism and risk of CAD. We therefore conducted a genome-wide association study to identify novel genetic determinants of LDL-c, HDL-c and triglycerides.
Methods and results
We combined genome-wide association data from eight studies, comprising up to 17,723 participants with information on circulating lipid concentrations. We did independent replication studies in up to 37,774 participants from eight populations and also in a population of Indian Asian descent. We also assessed the association between SNPs at lipid loci and risk of CAD in up to 9,633 cases and 38,684 controls.
We identified four novel genetic loci that showed reproducible associations with lipids (P values 1.6 × 10−8 to 3.1 × 10−10). These include a potentially functional SNP in the SLC39A8 gene for HDL-c, a SNP near the MYLIP/GMPR and PPP1R3B genes for LDL-c and at the AFF1 gene for triglycerides. SNPs showing strong statistical association with one or more lipid traits at the CELSR2, APOB, APOE-C1-C4-C2 cluster, LPL, ZNF259-APOA5-A4-C3-A1 cluster and TRIB1 loci were also associated with CAD risk (P values 1.1 × 10−3 to 1.2 × 10−9).
Conclusions
We have identified four novel loci associated with circulating lipids. We also show that in addition to those that are largely associated with LDL-c, genetic loci mainly associated with circulating triglycerides and HDL-c are also associated with risk of CAD. These findings potentially provide new insights into the biological mechanisms underlying lipid metabolism and CAD risk.
doi:10.1161/ATVBAHA.109.201020
PMCID: PMC3891568  PMID: 20864672
lipids; lipoproteins; genetics; epidemiology
20.  Subclinical Thyroid Dysfunction and the Risk of Heart Failure Events: An Individual Participant Data Analysis from Six Prospective Cohorts 
Circulation  2012;126(9):10.1161/CIRCULATIONAHA.112.096024.
Background
ACC/AHA Guidelines for the Diagnosis and Management of Heart Failure (HF) recommend investigating exacerbating conditions, such as thyroid dysfunction, but without specifying impact of different TSH levels. Limited prospective data exist regarding the association between subclinical thyroid dysfunction and HF events.
Methods and Results
We performed a pooled analysis of individual participant data using all available prospective cohorts with thyroid function tests and subsequent follow-up of HF events. Individual data on 25,390 participants with 216,248 person-years of follow-up were supplied from 6 prospective cohorts in the United States and Europe. Euthyroidism was defined as TSH 0.45–4.49 mIU/L, subclinical hypothyroidism as TSH 4.5–19.9 mIU/L and subclinical hyperthyroidism as TSH <0.45 mIU/L, both with normal free thyroxine levels. Among 25,390 participants, 2068 had subclinical hypothyroidism (8.1%) and 648 subclinical hyperthyroidism (2.6%). In age- and gender-adjusted analyses, risks of HF events were increased with both higher and lower TSH levels (P for quadratic pattern <0.01): hazard ratio (HR) was 1.01 (95% confidence interval [CI] 0.81–1.26) for TSH 4.5–6.9 mIU/L, 1.65 (CI 0.84–3.23) for TSH 7.0–9.9 mIU/L, 1.86 (CI 1.27–2.72) for TSH 10.0–19.9 mIUL/L (P for trend <0.01), and was 1.31 (CI 0.88–1.95) for TSH 0.10–0.44 mIU/L and 1.94 (CI 1.01–3.72) for TSH <0.10 mIU/L (P for trend = 0.047). Risks remained similar after adjustment for cardiovascular risk factors.
Conclusions
Risks of HF events were increased with both higher and lower TSH levels, particularly for TSH ≥10 mIU/L and for TSH <0.10 mIU/L.
doi:10.1161/CIRCULATIONAHA.112.096024
PMCID: PMC3884576  PMID: 22821943
cohort study; epidemiology; heart failure; meta-analysis; thyroid
21.  Associations With Retinal Nerve Fiber Layer Measures in the EPIC-Norfolk Eye Study 
Purpose.
To describe GDxVCC retinal nerve fiber layer (RNFL) measures and associations in a predominantly white British population.
Methods.
The EPIC-Norfolk Eye Study is nested within a large multicenter cohort study, the European Prospective Investigation of Cancer. RNFL measurements were taken using the GDxVCC. Generalized estimating equation models were used to assess associations of RNFL measures with age, sex, body mass index (BMI), height, blood pressure, social class, education level, alcohol intake, smoking status, axial length, intraocular pressure, and lens status. Models were linearly adjusted for typical scan score to handle scans with atypical retardation.
Results.
There were complete data from 11,030 eyes of 6309 participants with mean age 68 years (48–90 years). Older age (−1.53 μm/decade [95% confidence interval {CI} −1.73, −1.33], P < 0.001), male sex (−0.44 μm [95% CI −0.04, −0.84], P = 0.031), shorter axial length (−0.15 μm/mm [95% CI −0.02, −0.28], P = 0.024), and pseudophakia (−0.49 μm [95% CI −0.94, −0.04], P = 0.033) were associated with thinner RNFL after adjustment for possible confounders. Higher BMI was associated with a thinner RNFL in men only (−0.30 μm/5 kg/m2 [95% CI −0.58, −0.02], P = 0.039).
Conclusions.
This analysis of associations with RNFL thickness in a largely healthy population may provide insight into the determinants of glaucoma, suggesting higher risk in those who are older, in men, and in men with a higher BMI.
In this predominantly white British cohort, thinner GDxVCC retinal nerve fiber layer measurements were found in participants who were older, male, of higher BMI (in men only), pseudophakic or had shorter axial length.
doi:10.1167/iovs.13-11971
PMCID: PMC3726240  PMID: 23821204
scanning laser polarimetry; epidemiology; axial length; eye; glaucoma; body mass index
22.  Subclinical Hyperthyroidism and the Risk of Coronary Heart Disease and Mortality 
Archives of internal medicine  2012;172(10):10.1001/archinternmed.2012.402.
Background
Data from prospective cohort studies regarding the association between subclinical hyperthyroidism and cardiovascular outcomes are conflicting. We aimed to assess the risks of total and coronary heart disease (CHD) mortality, CHD events, and atrial fibrillation (AF) associated with endogenous subclinical hyperthyroidism among all available large prospective cohorts.
Methods
Individual data on 52 674 participants were pooled from 10 cohorts. Coronary heart disease events were analyzed in 22 437 participants from 6 cohorts with available data, and incident AF was analyzed in 8711 participants from 5 cohorts. Euthyroidism was defined as thyrotropin level between 0.45 and 4.49 mIU/L and endogenous subclinical hyperthyroidism as thyrotropin level lower than 0.45 mIU/L with normal free thyroxine levels, after excluding those receiving thyroid-altering medications.
Results
Of 52 674 participants, 2188 (4.2%) had subclinical hyperthyroidism. During follow-up, 8527 participants died (including 1896 from CHD), 3653 of 22 437 had CHD events, and 785 of 8711 developed AF. In age-and sex-adjusted analyses, subclinical hyperthyroidism was associated with increased total mortality (hazard ratio [HR], 1.24, 95% CI, 1.06–1.46), CHD mortality (HR, 1.29; 95% CI, 1.02–1.62), CHD events (HR, 1.21; 95% CI, 0.99–1.46), and AF (HR, 1.68; 95% CI, 1.16–2.43). Risks did not differ significantly by age, sex, or preexisting cardiovascular disease and were similar after further adjustment for cardiovascular risk factors, with attributable risk of 14.5% for total mortality to 41.5% for AF in those with subclinical hyperthyroidism. Risks for CHD mortality and AF (but not other outcomes) were higher for thyrotropin level lower than 0.10 mIU/L compared with thyrotropin level between 0.10 and 0.44 mIU/L (for both, P value for trend, ≤.03).
Conclusion
Endogenous subclinical hyperthyroidism is associated with increased risks of total, CHD mortality, and incident AF, with highest risks of CHD mortality and AF when thyrotropin level is lower than 0.10 mIU/L.
doi:10.1001/archinternmed.2012.402
PMCID: PMC3872478  PMID: 22529182
23.  The association of cycling with all-cause, cardiovascular and cancer mortality: findings from the population-based EPIC-Norfolk cohort 
BMJ Open  2013;3(11):e003797.
Objectives
To investigate associations between modest levels of total and domain-specific (commuting, other utility, recreational) cycling and mortality from all causes, cardiovascular disease and cancer.
Design
Population-based cohort study (European Prospective Investigation into Cancer and Nutrition study-Norfolk).
Setting
Participants were recruited from general practices in the east of England and attended health examinations between 1993 and 1997 and again between 1998 and 2000. At the first health assessment, participants reported their average weekly duration of cycling for all purposes using a simple measure of physical activity. At the second health assessment, participants reported a more detailed breakdown of their weekly cycling behaviour using the EPAQ2 physical activity questionnaire.
Participants
Adults aged 40–79 years at the first health assessment.
Primary outcome measure
All participants were followed for mortality (all-cause, cardiovascular and cancer) until March 2011.
Results
There were 22 450 participants with complete data at the first health assessment, of whom 4398 died during follow-up; and 13 346 participants with complete data at the second health assessment, of whom 1670 died during follow-up. Preliminary analyses using exposure data from the first health assessment showed that cycling for at least 60 min/week in total was associated with a 9% reduced risk of all-cause mortality (adjusted HR 0.91, 95% CI 0.84 to 0.99). Using the more precise measures of cycling available from the second health assessment, all types of cycling were associated with greater total moderate-to-vigorous physical activity; however, there was little evidence of an association between overall or domain-specific cycling and mortality.
Conclusions
Cycling, in particular for utility purposes, was associated with greater moderate-to-vigorous and total physical activity. While this study provides tentative evidence that modest levels of cycling may reduce the risk of mortality, further research is required to confirm how much cycling is sufficient to induce health benefits.
doi:10.1136/bmjopen-2013-003797
PMCID: PMC3831097  PMID: 24231462
active travel; active commuting; physical activity
24.  Multiple independent variants at the TERT locus are associated with telomere length and risks of breast and ovarian cancer 
Bojesen, Stig E | Pooley, Karen A | Johnatty, Sharon E | Beesley, Jonathan | Michailidou, Kyriaki | Tyrer, Jonathan P | Edwards, Stacey L | Pickett, Hilda A | Shen, Howard C | Smart, Chanel E | Hillman, Kristine M | Mai, Phuong L | Lawrenson, Kate | Stutz, Michael D | Lu, Yi | Karevan, Rod | Woods, Nicholas | Johnston, Rebecca L | French, Juliet D | Chen, Xiaoqing | Weischer, Maren | Nielsen, Sune F | Maranian, Melanie J | Ghoussaini, Maya | Ahmed, Shahana | Baynes, Caroline | Bolla, Manjeet K | Wang, Qin | Dennis, Joe | McGuffog, Lesley | Barrowdale, Daniel | Lee, Andrew | Healey, Sue | Lush, Michael | Tessier, Daniel C | Vincent, Daniel | Bacot, Françis | Vergote, Ignace | Lambrechts, Sandrina | Despierre, Evelyn | Risch, Harvey A | González-Neira, Anna | Rossing, Mary Anne | Pita, Guillermo | Doherty, Jennifer A | Álvarez, Nuria | Larson, Melissa C | Fridley, Brooke L | Schoof, Nils | Chang-Claude, Jenny | Cicek, Mine S | Peto, Julian | Kalli, Kimberly R | Broeks, Annegien | Armasu, Sebastian M | Schmidt, Marjanka K | Braaf, Linde M | Winterhoff, Boris | Nevanlinna, Heli | Konecny, Gottfried E | Lambrechts, Diether | Rogmann, Lisa | Guénel, Pascal | Teoman, Attila | Milne, Roger L | Garcia, Joaquin J | Cox, Angela | Shridhar, Vijayalakshmi | Burwinkel, Barbara | Marme, Frederik | Hein, Rebecca | Sawyer, Elinor J | Haiman, Christopher A | Wang-Gohrke, Shan | Andrulis, Irene L | Moysich, Kirsten B | Hopper, John L | Odunsi, Kunle | Lindblom, Annika | Giles, Graham G | Brenner, Hermann | Simard, Jacques | Lurie, Galina | Fasching, Peter A | Carney, Michael E | Radice, Paolo | Wilkens, Lynne R | Swerdlow, Anthony | Goodman, Marc T | Brauch, Hiltrud | García-Closas, Montserrat | Hillemanns, Peter | Winqvist, Robert | Dürst, Matthias | Devilee, Peter | Runnebaum, Ingo | Jakubowska, Anna | Lubinski, Jan | Mannermaa, Arto | Butzow, Ralf | Bogdanova, Natalia V | Dörk, Thilo | Pelttari, Liisa M | Zheng, Wei | Leminen, Arto | Anton-Culver, Hoda | Bunker, Clareann H | Kristensen, Vessela | Ness, Roberta B | Muir, Kenneth | Edwards, Robert | Meindl, Alfons | Heitz, Florian | Matsuo, Keitaro | du Bois, Andreas | Wu, Anna H | Harter, Philipp | Teo, Soo-Hwang | Schwaab, Ira | Shu, Xiao-Ou | Blot, William | Hosono, Satoyo | Kang, Daehee | Nakanishi, Toru | Hartman, Mikael | Yatabe, Yasushi | Hamann, Ute | Karlan, Beth Y | Sangrajrang, Suleeporn | Kjaer, Susanne Krüger | Gaborieau, Valerie | Jensen, Allan | Eccles, Diana | Høgdall, Estrid | Shen, Chen-Yang | Brown, Judith | Woo, Yin Ling | Shah, Mitul | Azmi, Mat Adenan Noor | Luben, Robert | Omar, Siti Zawiah | Czene, Kamila | Vierkant, Robert A | Nordestgaard, Børge G | Flyger, Henrik | Vachon, Celine | Olson, Janet E | Wang, Xianshu | Levine, Douglas A | Rudolph, Anja | Weber, Rachel Palmieri | Flesch-Janys, Dieter | Iversen, Edwin | Nickels, Stefan | Schildkraut, Joellen M | Silva, Isabel Dos Santos | Cramer, Daniel W | Gibson, Lorna | Terry, Kathryn L | Fletcher, Olivia | Vitonis, Allison F | van der Schoot, C Ellen | Poole, Elizabeth M | Hogervorst, Frans B L | Tworoger, Shelley S | Liu, Jianjun | Bandera, Elisa V | Li, Jingmei | Olson, Sara H | Humphreys, Keith | Orlow, Irene | Blomqvist, Carl | Rodriguez-Rodriguez, Lorna | Aittomäki, Kristiina | Salvesen, Helga B | Muranen, Taru A | Wik, Elisabeth | Brouwers, Barbara | Krakstad, Camilla | Wauters, Els | Halle, Mari K | Wildiers, Hans | Kiemeney, Lambertus A | Mulot, Claire | Aben, Katja K | Laurent-Puig, Pierre | van Altena, Anne M | Truong, Thérèse | Massuger, Leon F A G | Benitez, Javier | Pejovic, Tanja | Perez, Jose Ignacio Arias | Hoatlin, Maureen | Zamora, M Pilar | Cook, Linda S | Balasubramanian, Sabapathy P | Kelemen, Linda E | Schneeweiss, Andreas | Le, Nhu D | Sohn, Christof | Brooks-Wilson, Angela | Tomlinson, Ian | Kerin, Michael J | Miller, Nicola | Cybulski, Cezary | Henderson, Brian E | Menkiszak, Janusz | Schumacher, Fredrick | Wentzensen, Nicolas | Marchand, Loic Le | Yang, Hannah P | Mulligan, Anna Marie | Glendon, Gord | Engelholm, Svend Aage | Knight, Julia A | Høgdall, Claus K | Apicella, Carmel | Gore, Martin | Tsimiklis, Helen | Song, Honglin | Southey, Melissa C | Jager, Agnes | van den Ouweland, Ans M W | Brown, Robert | Martens, John W M | Flanagan, James M | Kriege, Mieke | Paul, James | Margolin, Sara | Siddiqui, Nadeem | Severi, Gianluca | Whittemore, Alice S | Baglietto, Laura | McGuire, Valerie | Stegmaier, Christa | Sieh, Weiva | Müller, Heiko | Arndt, Volker | Labrèche, France | Gao, Yu-Tang | Goldberg, Mark S | Yang, Gong | Dumont, Martine | McLaughlin, John R | Hartmann, Arndt | Ekici, Arif B | Beckmann, Matthias W | Phelan, Catherine M | Lux, Michael P | Permuth-Wey, Jenny | Peissel, Bernard | Sellers, Thomas A | Ficarazzi, Filomena | Barile, Monica | Ziogas, Argyrios | Ashworth, Alan | Gentry-Maharaj, Aleksandra | Jones, Michael | Ramus, Susan J | Orr, Nick | Menon, Usha | Pearce, Celeste L | Brüning, Thomas | Pike, Malcolm C | Ko, Yon-Dschun | Lissowska, Jolanta | Figueroa, Jonine | Kupryjanczyk, Jolanta | Chanock, Stephen J | Dansonka-Mieszkowska, Agnieszka | Jukkola-Vuorinen, Arja | Rzepecka, Iwona K | Pylkäs, Katri | Bidzinski, Mariusz | Kauppila, Saila | Hollestelle, Antoinette | Seynaeve, Caroline | Tollenaar, Rob A E M | Durda, Katarzyna | Jaworska, Katarzyna | Hartikainen, Jaana M | Kosma, Veli-Matti | Kataja, Vesa | Antonenkova, Natalia N | Long, Jirong | Shrubsole, Martha | Deming-Halverson, Sandra | Lophatananon, Artitaya | Siriwanarangsan, Pornthep | Stewart-Brown, Sarah | Ditsch, Nina | Lichtner, Peter | Schmutzler, Rita K | Ito, Hidemi | Iwata, Hiroji | Tajima, Kazuo | Tseng, Chiu-Chen | Stram, Daniel O | van den Berg, David | Yip, Cheng Har | Ikram, M Kamran | Teh, Yew-Ching | Cai, Hui | Lu, Wei | Signorello, Lisa B | Cai, Qiuyin | Noh, Dong-Young | Yoo, Keun-Young | Miao, Hui | Iau, Philip Tsau-Choong | Teo, Yik Ying | McKay, James | Shapiro, Charles | Ademuyiwa, Foluso | Fountzilas, George | Hsiung, Chia-Ni | Yu, Jyh-Cherng | Hou, Ming-Feng | Healey, Catherine S | Luccarini, Craig | Peock, Susan | Stoppa-Lyonnet, Dominique | Peterlongo, Paolo | Rebbeck, Timothy R | Piedmonte, Marion | Singer, Christian F | Friedman, Eitan | Thomassen, Mads | Offit, Kenneth | Hansen, Thomas V O | Neuhausen, Susan L | Szabo, Csilla I | Blanco, Ignacio | Garber, Judy | Narod, Steven A | Weitzel, Jeffrey N | Montagna, Marco | Olah, Edith | Godwin, Andrew K | Yannoukakos, Drakoulis | Goldgar, David E | Caldes, Trinidad | Imyanitov, Evgeny N | Tihomirova, Laima | Arun, Banu K | Campbell, Ian | Mensenkamp, Arjen R | van Asperen, Christi J | van Roozendaal, Kees E P | Meijers-Heijboer, Hanne | Collée, J Margriet | Oosterwijk, Jan C | Hooning, Maartje J | Rookus, Matti A | van der Luijt, Rob B | van Os, Theo A M | Evans, D Gareth | Frost, Debra | Fineberg, Elena | Barwell, Julian | Walker, Lisa | Kennedy, M John | Platte, Radka | Davidson, Rosemarie | Ellis, Steve D | Cole, Trevor | Paillerets, Brigitte Bressac-de | Buecher, Bruno | Damiola, Francesca | Faivre, Laurence | Frenay, Marc | Sinilnikova, Olga M | Caron, Olivier | Giraud, Sophie | Mazoyer, Sylvie | Bonadona, Valérie | Caux-Moncoutier, Virginie | Toloczko-Grabarek, Aleksandra | Gronwald, Jacek | Byrski, Tomasz | Spurdle, Amanda B | Bonanni, Bernardo | Zaffaroni, Daniela | Giannini, Giuseppe | Bernard, Loris | Dolcetti, Riccardo | Manoukian, Siranoush | Arnold, Norbert | Engel, Christoph | Deissler, Helmut | Rhiem, Kerstin | Niederacher, Dieter | Plendl, Hansjoerg | Sutter, Christian | Wappenschmidt, Barbara | Borg, Åke | Melin, Beatrice | Rantala, Johanna | Soller, Maria | Nathanson, Katherine L | Domchek, Susan M | Rodriguez, Gustavo C | Salani, Ritu | Kaulich, Daphne Gschwantler | Tea, Muy-Kheng | Paluch, Shani Shimon | Laitman, Yael | Skytte, Anne-Bine | Kruse, Torben A | Jensen, Uffe Birk | Robson, Mark | Gerdes, Anne-Marie | Ejlertsen, Bent | Foretova, Lenka | Savage, Sharon A | Lester, Jenny | Soucy, Penny | Kuchenbaecker, Karoline B | Olswold, Curtis | Cunningham, Julie M | Slager, Susan | Pankratz, Vernon S | Dicks, Ed | Lakhani, Sunil R | Couch, Fergus J | Hall, Per | Monteiro, Alvaro N A | Gayther, Simon A | Pharoah, Paul D P | Reddel, Roger R | Goode, Ellen L | Greene, Mark H | Easton, Douglas F | Berchuck, Andrew | Antoniou, Antonis C | Chenevix-Trench, Georgia | Dunning, Alison M
Nature genetics  2013;45(4):371-384e2.
TERT-locus single nucleotide polymorphisms (SNPs) and leucocyte telomere measures are reportedly associated with risks of multiple cancers. Using the iCOGs chip, we analysed ~480 TERT-locus SNPs in breast (n=103,991), ovarian (n=39,774) and BRCA1 mutation carrier (11,705) cancer cases and controls. 53,724 participants have leucocyte telomere measures. Most associations cluster into three independent peaks. Peak 1 SNP rs2736108 minor allele associates with longer telomeres (P=5.8×10−7), reduced estrogen receptor negative (ER-negative) (P=1.0×10−8) and BRCA1 mutation carrier (P=1.1×10−5) breast cancer risks, and altered promoter-assay signal. Peak 2 SNP rs7705526 minor allele associates with longer telomeres (P=2.3×10−14), increased low malignant potential ovarian cancer risk (P=1.3×10−15) and increased promoter activity. Peak 3 SNPs rs10069690 and rs2242652 minor alleles increase ER-negative (P=1.2×10−12) and BRCA1 mutation carrier (P=1.6×10−14) breast and invasive ovarian (P=1.3×10−11) cancer risks, but not via altered telomere length. The cancer-risk alleles of rs2242652 and rs10069690 respectively increase silencing and generate a truncated TERT splice-variant.
doi:10.1038/ng.2566
PMCID: PMC3670748  PMID: 23535731
25.  Longitudinal Association of C-Reactive Protein and Lung Function Over 13 Years 
American Journal of Epidemiology  2013;179(1):48-56.
Chronic obstructive pulmonary disease is known to be associated with systemic inflammation. We examined the longitudinal association of C-reactive protein (CRP) and lung function in a cohort of 18,110 men and women from the European Prospective Investigation Into Cancer in Norfolk who were 40–79 years of age at baseline (recruited in 1993–1997) and followed-up through 2011. We assessed lung function by measuring forced vital capacity (FVC) and forced expiratory volume in 1 second (FEV1) at baseline, 4 years, and 13 years. Serum CRP levels were measured using a high-sensitivity assay at baseline and the 13-year follow up. Cross-sectional and longitudinal associations of loge-CRP and lung function were examined using multivariable linear mixed models. In the cross-sectional analysis, 1-standard-deviation increase in baseline loge-CRP (about 3-fold higher CRP on the original milligrams per liter scale) was associated with a −86.3 mL (95% confidence interval: −93.9, −78.6) reduction in FEV1. In longitudinal analysis, a 1-standard-deviation increase in loge-CRP over 13 years was also associated with a −64.0 mL (95% confidence interval: −72.1, −55.8) decline in FEV1 over the same period. The associations were similar for FVC and persisted among lifetime never-smokers. Baseline CRP levels were not predictive of the rate of change in FEV1 or FVC over time. In the present study, we found longitudinal observational evidence that suggested that increases in systemic inflammation are associated with declines in lung function.
doi:10.1093/aje/kwt208
PMCID: PMC3864708  PMID: 24064740
aging; chronic obstructive pulmonary disease; C-reactive protein; inflammation; longitudinal study; lung function

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