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1.  Parity and the risk of developing rheumatoid arthritis: results from the Swedish EIRA study 
Annals of the rheumatic diseases  2013;73(4):752-755.
Objective
To study the impact of parity history on the risk of ACPA- (antibodies to citrullinated peptides antigens) positive/-negative rheumatoid arthritis (RA), in different age-groups.
Method
Data from a population-based case-control study of female incident RA cases were analysed (2035 cases, 2911 controls, aged 18-70). Parity history was assessed through questionnaire. Parous women were compared with nulliparous, by calculating odds ratios (OR) with 95% confidence interval (CI).
Results
Parity was associated with an increased risk of ACPA-negative RA in the age-group 18-44 (OR=2.1, 95% CI 1.4-3.2), but not in the age-group 45-70 (OR=0.9, 95% CI 0.7-1.3). Among young women, an increased risk of ACPA-negative RA was found in those with delivery during the year of symptom onset (OR=2.6, 95% CI 1.4-4.8) and at young age at first birth (<23) (OR=2.5, 95% CI 1.5-4.1).Parity and the postpartum period were not associated with ACPA-positive RA, but older age at first birth was weakly associated with a decreased risk.
Conclusions
The increased risk of ACPA-negative RA in parous women of reproductive age seemed to be conferred to an increased postpartum risk and to young age at first birth. Further research is needed to explore the biological mechanisms behind our findings.
doi:10.1136/annrheumdis-2013-203567
PMCID: PMC4086877  PMID: 23887288
Rheumatoid arthritis; Parity; Postpartum period; Antibodies to citrullinated peptides (ACPA); Epidemiology
2.  Ambient air pollution exposures and risk of rheumatoid arthritis in the Nurses’ Health Study 
Arthritis care & research  2013;65(7):1190-1196.
Objective
Environmental factors may play a role in the development of rheumatoid arthritis (RA), and we have previously observed increased RA risk among women living closer to major roads (a source of air pollution). We examined whether long-term exposures to specific air pollutants were associated with RA risk among women in the Nurses’ Health Study.
Methods
The Nurses’ Health Study (NHS) is a large cohort of U.S. female nurses followed prospectively every two years since 1976. We studied 111,425 NHS participants with information on air pollution exposures as well as data concerning other lifestyle and behavioral exposures and disease outcomes. Outdoor levels of different size fractions of particulate matter (PM10 and PM2.5) and gaseous pollutants (SO2 and NO2) were predicted for all available residential addresses using monitoring data from the USEPA. We examined the association of time-varying exposures, 6 and 10 years before each questionnaire cycle, and cumulative average exposure with the risks of RA, seronegative (rheumatoid factor [RF] and anti–citrullinated peptide antibodies [ACPA]) RA, and seropositive RA.
Results
Over the 3,019,424 years of follow-up, 858 incident RA cases were validated by medical record review by two board-certified rheumatologists. Overall, we found no evidence of increased risks of RA, seronegative or seropositive RA, with exposure to the different pollutants, and little evidence of effect modification by socioeconomic status or smoking status, geographic region, or calendar period.
Conclusion
In this group of socioeconomically-advantaged middle-aged and elderly women, adult exposures to air pollution were not associated with an increased RA risk.
doi:10.1002/acr.21975
PMCID: PMC3659202  PMID: 23401426
3.  Association of Environmental and Genetic Factors and Gene-Environment Interactions with Risk of Developing Rheumatoid Arthritis 
Arthritis care & research  2013;65(7):1147-1156.
Background
We developed RA risk models based on validated environmental factors (E), genetic risk scores (GRS), and gene-environment interactions (GEI) to identify factors that can improve accuracy and reclassification.
Methods
Models including E, GRS, GEI were developed among 317 Caucasian seropositive RA cases and 551 controls from Nurses’ Health Studies (NHS) and validated in 987 Caucasian ACPA positive cases and 958 controls from the Swedish Epidemiologic Investigation of RA (EIRA), stratified by gender. Primary analyses included age, smoking, alcohol, parity, weighted GRS using 31 non-HLA alleles, 8 HLA-DRB1 alleles and HLA X smoking interaction. Expanded models included reproductive, geographic, and occupational factors, and additional GEI terms. Hierarchical models were compared for discriminative accuracy using AUC and reclassification using Integrated Discrimination Improvement (IDI) and continuous Net Reclassification Index.
Results
Mean (SD) age of RA diagnosis was 57 in NHS and 50 in EIRA. Primary models produced an AUC of 0.716 in NHS, 0.728 in EIRA women and 0.756 in EIRA men. Expanded models produced improvements in discrimination with AUCs of 0.738 in NHS, 0.728 in EIRA women and 0.769 in EIRA men. Models including G or G + GEI improved reclassification over E models; the full E+G+GEI model provided the optimal predictive ability by IDI analyses.
Conclusions
We have developed comprehensive RA risk models incorporating epidemiologic and genetic factors and gene-environment interactions that have improved discriminative accuracy for RA. Further work developing and assessing highly specific prediction models in prospective cohorts is still needed to inform primary RA prevention trials.
doi:10.1002/acr.22005
PMCID: PMC3740546  PMID: 23495093
4.  AMBIENT AIR POLLUTION EXPOSURES AND RISK OF RHEUMATOID ARTHRITIS: RESULTS FROM THE SWEDISH EIRA CASE-CONTROL STUDY 
Annals of the rheumatic diseases  2012;72(6):888-894.
Objective
Environmental factors may play a role in the development of rheumatoid arthritis (RA). We examined whether long-term exposures to air pollution were associated with risk of RA in the Swedish Epidemiological Investigation of Rheumatoid Arthritis (EIRA) Study.
Methods
We studied 1,497 incident RA cases and 2,536 controls. Local levels of particulate matter (PM10) and gaseous pollutants (SO2 and NO2,) from traffic and home heating were predicted for all residential addresses. We examined the association of an interquartile range increase (2μg/m3 for PM10, 8μg/m3 for SO2, and 9μg/m3 for NO2) in each pollutant at different time points prior to symptom onset and average exposure with the risk of all RA and the risk of the rheumatoid factor (RF) and anti-citrullinated protein antibody (ACPA) RA phenotypes.
Results
There was no evidence of an increased risk of RA with PM10. Total RA risks were modestly elevated for the gaseous pollutants, but were not statistically significant after adjustment for smoking and education (odds ratio (OR)=1.18 [95%confidence interval (CI): 0.97–1.43] and OR=1.09 [95%CI: 0.99–1.19] for SO2 and NO2 in the 10th year before onset). Stronger elevated risks were observed for individuals with less than a university education and with the ACPA- RA phenotype.
Conclusion
No consistent overall associations between air pollution in the Stockholm area and risk for RA were observed. However, there was a suggestion of increased risks of RA incidence with increases in NO2 from local traffic and SO2 from home heating sources with stronger associations for the ACPA- phenotype.
doi:10.1136/annrheumdis-2012-201587
PMCID: PMC3654032  PMID: 22833374
air pollution; rheumatoid arthritis; traffic pollution; home heating pollution
5.  Analysis of immune-related loci identifies 48 new susceptibility variants for multiple sclerosis 
Beecham, Ashley H | Patsopoulos, Nikolaos A | Xifara, Dionysia K | Davis, Mary F | Kemppinen, Anu | Cotsapas, Chris | Shahi, Tejas S | Spencer, Chris | Booth, David | Goris, An | Oturai, Annette | Saarela, Janna | Fontaine, Bertrand | Hemmer, Bernhard | Martin, Claes | Zipp, Frauke | D’alfonso, Sandra | Martinelli-Boneschi, Filippo | Taylor, Bruce | Harbo, Hanne F | Kockum, Ingrid | Hillert, Jan | Olsson, Tomas | Ban, Maria | Oksenberg, Jorge R | Hintzen, Rogier | Barcellos, Lisa F | Agliardi, Cristina | Alfredsson, Lars | Alizadeh, Mehdi | Anderson, Carl | Andrews, Robert | Søndergaard, Helle Bach | Baker, Amie | Band, Gavin | Baranzini, Sergio E | Barizzone, Nadia | Barrett, Jeffrey | Bellenguez, Céline | Bergamaschi, Laura | Bernardinelli, Luisa | Berthele, Achim | Biberacher, Viola | Binder, Thomas M C | Blackburn, Hannah | Bomfim, Izaura L | Brambilla, Paola | Broadley, Simon | Brochet, Bruno | Brundin, Lou | Buck, Dorothea | Butzkueven, Helmut | Caillier, Stacy J | Camu, William | Carpentier, Wassila | Cavalla, Paola | Celius, Elisabeth G | Coman, Irène | Comi, Giancarlo | Corrado, Lucia | Cosemans, Leentje | Cournu-Rebeix, Isabelle | Cree, Bruce A C | Cusi, Daniele | Damotte, Vincent | Defer, Gilles | Delgado, Silvia R | Deloukas, Panos | di Sapio, Alessia | Dilthey, Alexander T | Donnelly, Peter | Dubois, Bénédicte | Duddy, Martin | Edkins, Sarah | Elovaara, Irina | Esposito, Federica | Evangelou, Nikos | Fiddes, Barnaby | Field, Judith | Franke, Andre | Freeman, Colin | Frohlich, Irene Y | Galimberti, Daniela | Gieger, Christian | Gourraud, Pierre-Antoine | Graetz, Christiane | Graham, Andrew | Grummel, Verena | Guaschino, Clara | Hadjixenofontos, Athena | Hakonarson, Hakon | Halfpenny, Christopher | Hall, Gillian | Hall, Per | Hamsten, Anders | Harley, James | Harrower, Timothy | Hawkins, Clive | Hellenthal, Garrett | Hillier, Charles | Hobart, Jeremy | Hoshi, Muni | Hunt, Sarah E | Jagodic, Maja | Jelčić, Ilijas | Jochim, Angela | Kendall, Brian | Kermode, Allan | Kilpatrick, Trevor | Koivisto, Keijo | Konidari, Ioanna | Korn, Thomas | Kronsbein, Helena | Langford, Cordelia | Larsson, Malin | Lathrop, Mark | Lebrun-Frenay, Christine | Lechner-Scott, Jeannette | Lee, Michelle H | Leone, Maurizio A | Leppä, Virpi | Liberatore, Giuseppe | Lie, Benedicte A | Lill, Christina M | Lindén, Magdalena | Link, Jenny | Luessi, Felix | Lycke, Jan | Macciardi, Fabio | Männistö, Satu | Manrique, Clara P | Martin, Roland | Martinelli, Vittorio | Mason, Deborah | Mazibrada, Gordon | McCabe, Cristin | Mero, Inger-Lise | Mescheriakova, Julia | Moutsianas, Loukas | Myhr, Kjell-Morten | Nagels, Guy | Nicholas, Richard | Nilsson, Petra | Piehl, Fredrik | Pirinen, Matti | Price, Siân E | Quach, Hong | Reunanen, Mauri | Robberecht, Wim | Robertson, Neil P | Rodegher, Mariaemma | Rog, David | Salvetti, Marco | Schnetz-Boutaud, Nathalie C | Sellebjerg, Finn | Selter, Rebecca C | Schaefer, Catherine | Shaunak, Sandip | Shen, Ling | Shields, Simon | Siffrin, Volker | Slee, Mark | Sorensen, Per Soelberg | Sorosina, Melissa | Sospedra, Mireia | Spurkland, Anne | Strange, Amy | Sundqvist, Emilie | Thijs, Vincent | Thorpe, John | Ticca, Anna | Tienari, Pentti | van Duijn, Cornelia | Visser, Elizabeth M | Vucic, Steve | Westerlind, Helga | Wiley, James S | Wilkins, Alastair | Wilson, James F | Winkelmann, Juliane | Zajicek, John | Zindler, Eva | Haines, Jonathan L | Pericak-Vance, Margaret A | Ivinson, Adrian J | Stewart, Graeme | Hafler, David | Hauser, Stephen L | Compston, Alastair | McVean, Gil | De Jager, Philip | Sawcer, Stephen | McCauley, Jacob L
Nature genetics  2013;45(11):10.1038/ng.2770.
Using the ImmunoChip custom genotyping array, we analysed 14,498 multiple sclerosis subjects and 24,091 healthy controls for 161,311 autosomal variants and identified 135 potentially associated regions (p-value < 1.0 × 10-4). In a replication phase, we combined these data with previous genome-wide association study (GWAS) data from an independent 14,802 multiple sclerosis subjects and 26,703 healthy controls. In these 80,094 individuals of European ancestry we identified 48 new susceptibility variants (p-value < 5.0 × 10-8); three found after conditioning on previously identified variants. Thus, there are now 110 established multiple sclerosis risk variants in 103 discrete loci outside of the Major Histocompatibility Complex. With high resolution Bayesian fine-mapping, we identified five regions where one variant accounted for more than 50% of the posterior probability of association. This study enhances the catalogue of multiple sclerosis risk variants and illustrates the value of fine-mapping in the resolution of GWAS signals.
doi:10.1038/ng.2770
PMCID: PMC3832895  PMID: 24076602
6.  JC Polyomavirus Infection Is Strongly Controlled by Human Leucocyte Antigen Class II Variants 
PLoS Pathogens  2014;10(4):e1004084.
JC polyomavirus (JCV) carriers with a compromised immune system, such as in HIV, or subjects on immune-modulating therapies, such as anti VLA-4 therapy may develop progressive multifocal leukoencephalopathy (PML) which is a lytic infection of oligodendrocytes in the brain. Serum antibodies to JCV mark infection occur only in 50–60% of infected individuals, and high JCV-antibody titers seem to increase the risk of developing PML. We here investigated the role of human leukocyte antigen (HLA), instrumental in immune defense in JCV antibody response. Anti-JCV antibody status, as a surrogate for JCV infection, were compared to HLA class I and II alleles in 1621 Scandinavian persons with MS and 1064 population-based Swedish controls and associations were replicated in 718 German persons with MS. HLA-alleles were determined by SNP imputation, sequence specific (SSP) kits and a reverse PCR sequence-specific oligonucleotide (PCR-SSO) method. An initial GWAS screen displayed a strong HLA class II region signal. The HLA-DRB1*15 haplotype was strongly negatively associated to JCV sero-status in Scandinavian MS cases (OR = 0.42, p = 7×10−15) and controls (OR = 0.53, p = 2×10−5). In contrast, the DQB1*06:03 haplotype was positively associated with JCV sero-status, in Scandinavian MS cases (OR = 1.63, p = 0.006), and controls (OR = 2.69, p = 1×10−5). The German dataset confirmed these findings (OR = 0.54, p = 1×10−4 and OR = 1.58, p = 0.03 respectively for these haplotypes). HLA class II restricted immune responses, and hence CD4+ T cell immunity is pivotal for JCV infection control. Alleles within the HLA-DR1*15 haplotype are associated with a protective effect on JCV infection. Alleles within the DQB1*06:03 haplotype show an opposite association. These associations between JC virus antibody response and human leucocyte antigens supports the notion that CD4+ T cells are crucial in the immune defence to JCV and lays the ground for risk stratification for PML and development of therapy and prevention.
Author Summary
JC virus infection can lead to progressive multifocal leukoencephalopathy in individuals with a compromised immune system, such as during HIV infections or when treated with immunosuppressive or immunomodulating therapies. Progressive multifocal leukoencephalopathy is a rare but potentially fatal disease characterized by progressive damage of the brain white matter at multiple locations. It is therefore of importance to understand the host genetic control of response to JC virus in order to identify patients that can be treated with immunomodulating therapies, common treatments for autoimmune diseases, without increased risk for progressive multifocal leukoencephalopathy. This may also lead to development of preventative or curative anti-JC virus therapies. We here identify genetic variants being associated with JC virus antibody development; a negative association with the human leucocyte antigen DRB1*15-DQA1*01:02-DQB1*06:02 haplotype and a positive association with the DRB1*13-DQA1*01:03-DQB1*06:03 haplotype among controls and patients with multiple sclerosis from Scandinavia. We confirmed the associations in patients with multiple sclerosis from Germany. These associations between JC virus antibody response and human leucocyte antigens imply that CD4+ T cells are crucial in the immune defence and lay the ground for development of therapy and prevention.
doi:10.1371/journal.ppat.1004084
PMCID: PMC3999271  PMID: 24763718
7.  Regional differences regarding risk of developing Rheumatoid Arthritis in Stockholm County, Sweden 
Scandinavian journal of rheumatology  2013;42(5):10.3109/03009742.2013.769062.
Objectives
Rheumatoid arthritis (RA) is a complex disease that is associated with genetic and environmental factors. We have investigated geospatial variation in risk of developing RA within Stockholm County, with respect to established environmental risk factors for RA, as well as serologically-defined subgroups of RA.
Methods
Information regarding geographical location for 1432 cases and 2529 controls from the Epidemiological Investigation of Rheumatoid Arthritis (EIRA) study, living in Stockholm County at RA symptom onset, or matched date for controls, was used to estimate geospatial variation in risk. We used Generalized Additive Models (GAM) to create a risk surface, calculate odds ratios and adjust for potential confounding by smoking, educational level and RA within family. We performed a stratified analysis based on presence/absence of antibodies to citrullinated peptides (ACPA).
Results
We found significant spatial variation in the odds of developing RA in Stockholm County. After adjustment for smoking, educational level and family history of RA, this geospatial variation remained. The stratified analysis showed areas with higher odds ratios for ACPA-positive RA and ACPA-negative RA, after adjusting for smoking, educational level and having a family history of RA. Living in the city of Stockholm was associated with decreased risk of RA.
Conclusion
The risk of developing RA in Stockholm County is not evenly distributed and there are areas of increased risk that could not be explained by known factors. Further investigations of local exposures or social factors are warranted.
doi:10.3109/03009742.2013.769062
PMCID: PMC3815679  PMID: 23611369
Rheumatoid Arthritis; Epidemiologic methods; Antibodies; Geography; Risk; Smoking; ACPA; Stockholm
8.  Interaction between adolescent obesity and HLA risk genes in the etiology of multiple sclerosis 
Neurology  2014;82(10):865-872.
Objective:
We investigated potential interactions between human leukocyte antigen (HLA) genotype and body mass index (BMI) status in relation to the risk of developing multiple sclerosis (MS).
Methods:
We used 2 case-control studies, one with incident cases (1,510 cases, 2,017 controls) and one with prevalent cases (937 cases, 609 controls). Subjects with different genotypes and BMI were compared with regard to incidence of MS by calculating odds ratios (ORs) with 95% confidence intervals (CIs) employing logistic regression. Potential interactions between genotypes and BMI were evaluated by calculating the attributable proportion due to interaction.
Results:
In both cohorts, a significant interaction was observed between HLA-DRB1*15 and obesity, regardless of HLA-A*02 status. Similarly, there was a significant interaction between absence of A*02 and obesity, regardless of DRB1*15 status. In the incident cohort, obese subjects with the most susceptible genotype (carriage of DRB1*15 and absence of A*02) had an OR of 16.2 (95% CI 7.5–35.2) compared to nonobese subjects without the genetic risk factors. The corresponding OR in the prevalent study was 13.8 (95% CI 4.1–46.8).
Conclusions:
We observed striking interactions between BMI status and HLA genotype with regard to MS risk. Hypothetically, a low-grade inflammatory response inherent to obesity synergizes with the adaptive, HLA molecule–restricted arm of the immune system, causing MS. Prevention of adolescent obesity may thus lower the risk of developing MS, predominantly among people with a genetic susceptibility to the disease.
doi:10.1212/WNL.0000000000000203
PMCID: PMC3959752  PMID: 24500647
9.  Study protocol for examining job strain as a risk factor for severe unipolar depression in an individual participant meta-analysis of 14 European cohorts 
F1000Research  2014;2:233.
Background: Previous studies have shown that gainfully employed individuals with high work demands and low control at work (denoted “job strain”) are at increased risk of common mental disorders, including depression. Most existing studies have, however, measured depression using self-rated symptom scales that do not necessarily correspond to clinically diagnosed depression. In addition, a meta-analysis from 2008 indicated publication bias in the field.
 
Methods: This study protocol describes the planned design and analyses of an individual participant data meta-analysis, to examine whether job strain is associated with an increased risk of clinically diagnosed unipolar depression based on hospital treatment registers.  The study will be based on data from approximately 120,000 individuals who participated in 14 studies on work environment and health in 4 European countries. The self-reported working conditions data will be merged with national registers on psychiatric hospital treatment, primarily hospital admissions. Study-specific risk estimates for the association between job strain and depression will be calculated using Cox regressions. The study-specific risk estimates will be pooled using random effects meta-analysis.
 
Discussion: The planned analyses will help clarify whether job strain is associated with an increased risk of clinically diagnosed unipolar depression. As the analysis is based on pre-planned study protocols and an individual participant data meta-analysis, the pooled risk estimates will not be influenced by selective reporting and publication bias. However, the results of the planned study may only pertain to severe cases of unipolar depression, because of the outcome measure applied.
doi:10.12688/f1000research.2-233.v2
PMCID: PMC3938244  PMID: 24627793
10.  Job Strain and the Risk of Inflammatory Bowel Diseases: Individual-Participant Meta-Analysis of 95 000 Men and Women 
PLoS ONE  2014;9(2):e88711.
Background and Aims
Many clinicians, patients and patient advocacy groups believe stress to have a causal role in inflammatory bowel diseases, such as Crohn's disease and ulcerative colitis. However, this is not corroborated by clear epidemiological research evidence. We investigated the association between work-related stress and incident Crohn's disease and ulcerative colitis using individual-level data from 95 000 European adults.
Methods
We conducted individual-participant data meta-analyses in a set of pooled data from 11 prospective European studies. All studies are a part of the IPD-Work Consortium. Work-related psychosocial stress was operationalised as job strain (a combination of high demands and low control at work) and was self-reported at baseline. Crohn's disease and ulcerative colitis were ascertained from national hospitalisation and drug reimbursement registers. The associations between job strain and inflammatory bowel disease outcomes were modelled using Cox proportional hazards regression. The study-specific results were combined in random effects meta-analyses.
Results
Of the 95 379 participants who were free of inflammatory bowel disease at baseline, 111 men and women developed Crohn's disease and 414 developed ulcerative colitis during follow-up. Job strain at baseline was not associated with incident Crohn's disease (multivariable-adjusted random effects hazard ratio: 0.83, 95% confidence interval: 0.48, 1.43) or ulcerative colitis (hazard ratio: 1.06, 95% CI: 0.76, 1.48). There was negligible heterogeneity among the study-specific associations.
Conclusions
Our findings suggest that job strain, an indicator of work-related stress, is not a major risk factor for Crohn's disease or ulcerative colitis.
doi:10.1371/journal.pone.0088711
PMCID: PMC3928274  PMID: 24558416
11.  A genome-wide association study of anorexia nervosa 
Boraska, Vesna | Franklin, Christopher S | Floyd, James AB | Thornton, Laura M | Huckins, Laura M | Southam, Lorraine | Rayner, N William | Tachmazidou, Ioanna | Klump, Kelly L | Treasure, Janet | Lewis, Cathryn M | Schmidt, Ulrike | Tozzi, Federica | Kiezebrink, Kirsty | Hebebrand, Johannes | Gorwood, Philip | Adan, Roger AH | Kas, Martien JH | Favaro, Angela | Santonastaso, Paolo | Fernández-Aranda, Fernando | Gratacos, Monica | Rybakowski, Filip | Dmitrzak-Weglarz, Monika | Kaprio, Jaakko | Keski-Rahkonen, Anna | Raevuori, Anu | Van Furth, Eric F | Slof-Op t Landt, Margarita CT | Hudson, James I | Reichborn-Kjennerud, Ted | Knudsen, Gun Peggy S | Monteleone, Palmiero | Kaplan, Allan S | Karwautz, Andreas | Hakonarson, Hakon | Berrettini, Wade H | Guo, Yiran | Li, Dong | Schork, Nicholas J. | Komaki, Gen | Ando, Tetsuya | Inoko, Hidetoshi | Esko, Tõnu | Fischer, Krista | Männik, Katrin | Metspalu, Andres | Baker, Jessica H | Cone, Roger D | Dackor, Jennifer | DeSocio, Janiece E | Hilliard, Christopher E | O’Toole, Julie K | Pantel, Jacques | Szatkiewicz, Jin P | Taico, Chrysecolla | Zerwas, Stephanie | Trace, Sara E | Davis, Oliver SP | Helder, Sietske | Bühren, Katharina | Burghardt, Roland | de Zwaan, Martina | Egberts, Karin | Ehrlich, Stefan | Herpertz-Dahlmann, Beate | Herzog, Wolfgang | Imgart, Hartmut | Scherag, André | Scherag, Susann | Zipfel, Stephan | Boni, Claudette | Ramoz, Nicolas | Versini, Audrey | Brandys, Marek K | Danner, Unna N | de Kovel, Carolien | Hendriks, Judith | Koeleman, Bobby PC | Ophoff, Roel A | Strengman, Eric | van Elburg, Annemarie A | Bruson, Alice | Clementi, Maurizio | Degortes, Daniela | Forzan, Monica | Tenconi, Elena | Docampo, Elisa | Escaramís, Geòrgia | Jiménez-Murcia, Susana | Lissowska, Jolanta | Rajewski, Andrzej | Szeszenia-Dabrowska, Neonila | Slopien, Agnieszka | Hauser, Joanna | Karhunen, Leila | Meulenbelt, Ingrid | Slagboom, P Eline | Tortorella, Alfonso | Maj, Mario | Dedoussis, George | Dikeos, Dimitris | Gonidakis, Fragiskos | Tziouvas, Konstantinos | Tsitsika, Artemis | Papezova, Hana | Slachtova, Lenka | Martaskova, Debora | Kennedy, James L. | Levitan, Robert D. | Yilmaz, Zeynep | Huemer, Julia | Koubek, Doris | Merl, Elisabeth | Wagner, Gudrun | Lichtenstein, Paul | Breen, Gerome | Cohen-Woods, Sarah | Farmer, Anne | McGuffin, Peter | Cichon, Sven | Giegling, Ina | Herms, Stefan | Rujescu, Dan | Schreiber, Stefan | Wichmann, H-Erich | Dina, Christian | Sladek, Rob | Gambaro, Giovanni | Soranzo, Nicole | Julia, Antonio | Marsal, Sara | Rabionet, Raquel | Gaborieau, Valerie | Dick, Danielle M | Palotie, Aarno | Ripatti, Samuli | Widén, Elisabeth | Andreassen, Ole A | Espeseth, Thomas | Lundervold, Astri | Reinvang, Ivar | Steen, Vidar M | Le Hellard, Stephanie | Mattingsdal, Morten | Ntalla, Ioanna | Bencko, Vladimir | Foretova, Lenka | Janout, Vladimir | Navratilova, Marie | Gallinger, Steven | Pinto, Dalila | Scherer, Stephen | Aschauer, Harald | Carlberg, Laura | Schosser, Alexandra | Alfredsson, Lars | Ding, Bo | Klareskog, Lars | Padyukov, Leonid | Finan, Chris | Kalsi, Gursharan | Roberts, Marion | Logan, Darren W | Peltonen, Leena | Ritchie, Graham RS | Barrett, Jeffrey C | Estivill, Xavier | Hinney, Anke | Sullivan, Patrick F | Collier, David A | Zeggini, Eleftheria | Bulik, Cynthia M
Molecular psychiatry  2010;16(9):10.1038/mp.2010.107.
Anorexia nervosa (AN) is a complex and heritable eating disorder characterized by dangerously low body weight. Neither candidate gene studies nor an initial genome wide association study (GWAS) have yielded significant and replicated results. We performed a GWAS in 2,907 cases with AN from 14 countries (15 sites) and 14,860 ancestrally matched controls as part of the Genetic Consortium for AN (GCAN) and the Wellcome Trust Case Control Consortium 3 (WTCCC3). Individual association analyses were conducted in each stratum and meta-analyzed across all 15 discovery datasets. Seventy-six (72 independent) SNPs were taken forward for in silico (two datasets) or de novo (13 datasets) replication genotyping in 2,677 independent AN cases and 8,629 European ancestry controls along with 458 AN cases and 421 controls from Japan. The final global meta-analysis across discovery and replication datasets comprised 5,551 AN cases and 21,080 controls. AN subtype analyses (1,606 AN restricting; 1,445 AN binge-purge) were performed. No findings reached genome-wide significance. Two intronic variants were suggestively associated: rs9839776 (P=3.01×10−7) in SOX2OT and rs17030795 (P=5.84×10−6) in PPP3CA. Two additional signals were specific to Europeans: rs1523921 (P=5.76×10−6) between CUL3 and FAM124B and rs1886797 (P=8.05×10−6) near SPATA13. Comparing discovery to replication results, 76% of the effects were in the same direction, an observation highly unlikely to be due to chance (P= 4×10−6), strongly suggesting that true findings exist but that our sample, the largest yet reported, was underpowered for their detection. The accrual of large genotyped AN case-control samples should be an immediate priority for the field.
doi:10.1038/mp.2010.107
PMCID: PMC3859494  PMID: 21079607
anorexia nervosa; eating disorders; GWAS; genome-wide association study; body mass index; metabolic
12.  Epidemiology of Environmental Exposures and Human Autoimmune Diseases: Findings from a National Institute of Environmental Health Sciences Expert Panel Workshop 
Journal of autoimmunity  2012;39(4):259-271.
Autoimmune diseases (AID) are a collection of many complex disorders of unknown etiology resulting in immune responses to self-antigens and are thought to result from interactions between genetic and environmental factors. Here we review the epidemiologic evidence for the role of environmental factors in the development of human AID, the conclusions that can be drawn from the existing data, critical knowledge gaps, and research needed to fill these gaps and to resolve uncertainties. We specifically summarize the state of knowledge and our levels of confidence in the role of specific agents in the development of autoimmune diseases, and we define the areas of greatest impact for future investigations. Among our consensus findings we are confident that: 1) crystalline silica exposure can contribute to the development of several AID; 2) solvent exposure can contribute to the development of systemic sclerosis; 3) smoking can contribute to the development of seropositive rheumatoid arthritis; and 4) an inverse association exists between ultraviolet radiation exposure and the risk of development of multiple sclerosis. We suggest that more studies of phenotypes, genotypes, and multiple exposures are needed. Additional knowledge gaps needing investigation include: defining important windows in the timing of exposures and latencies relating to age, developmental state, and hormonal changes; understanding dose-response relationships; and elucidating mechanisms for disease development. Addressing these essential issues will require more resources to support research, particularly of rare AID, but knowledge of the risks conferred by environmental factors in specific genetic contexts could pave the way for prevention of AID in the future.
doi:10.1016/j.jaut.2012.05.002
PMCID: PMC3496812  PMID: 22739348
autoimmune disease; environmental risk factors; biologic agents; chemical agents; physical factors; research priorities
13.  Study protocol for examining job strain as a risk factor for severe unipolar depression in an individual participant meta-analysis of 14 European cohorts 
F1000Research  2013;2:233.
Background: Previous studies have shown that gainfully employed individuals with high work demands and low control at work (denoted “job strain”) are at increased risk of common mental disorders, including depression. Most existing studies have, however, measured depression using self-rated symptom scales that do not necessarily correspond to clinically diagnosed depression. In addition, a meta-analysis from 2008 indicated publication bias in the field.
 
Methods: This study protocol describes the planned design and analyses of an individual participant data meta-analysis, to examine whether job strain is associated with an increased risk of clinically diagnosed unipolar depression based on hospital treatment registers.  The study will be based on data from approximately 120,000 individuals who participated in 14 studies on work environment and health in 4 European countries. The self-reported working conditions data will be merged with national registers on psychiatric hospital treatment, primarily hospital admissions. Study-specific risk estimates for the association between job strain and depression will be calculated using Cox regressions. The study-specific risk estimates will be pooled using random effects meta-analysis.
 
Discussion: The planned analyses will help clarify whether job strain is associated with an increased risk of clinically diagnosed unipolar depression. As the analysis is based on pre-planned study protocols and an individual participant data meta-analysis, the pooled risk estimates will not be influenced by selective reporting and publication bias. However, the results of the planned study may only pertain to severe cases of unipolar depression, because of the outcome measure applied.
doi:10.12688/f1000research.2-233.v1
PMCID: PMC3938244  PMID: 24627793
14.  Smoking and multiple sclerosis susceptibility 
Smoking is one of the most established risk factors for multiple sclerosis (MS). The aim of this study was to investigate how age at smoking debut, duration, intensity and cumulative dose of smoking, and smoking cessation influence the association between smoking and MS risk. In two Swedish population-based case–control studies (7,883 cases, 9,264 controls), subjects with different smoking habits were compared regarding MS risk, by calculating odds ratios with 95 % confidence intervals. We observed a clear dose response association between cumulative dose of smoking and MS risk (p value for trend <10−35). Both duration and intensity of smoking contributed independently to the increased risk of MS. However, the detrimental effect of smoking abates a decade after smoking cessation regardless of the cumulative dose of smoking. Age at smoking debut did not affect the association between smoking and MS. Smoking increases the risk of MS in a dose response manner. However, in contrary to several other risk factors for MS that seem to affect the risk only if the exposure takes place during a specific period in life, smoking affects MS risk regardless of age at exposure, and the detrimental effect slowly abates after smoking cessation.
Electronic supplementary material
The online version of this article (doi:10.1007/s10654-013-9853-4) contains supplementary material, which is available to authorized users.
doi:10.1007/s10654-013-9853-4
PMCID: PMC3898140  PMID: 24146047
Multiple sclerosis; Smoking; Case–control study
15.  Epigenome-wide association data implicate DNA methylation as an intermediary of genetic risk in Rheumatoid Arthritis 
Nature biotechnology  2013;31(2):142-147.
Epigenetic mechanisms integrate genetic and environmental causes of disease. Comprehensive genome-wide analyses of epigenetic modifications have not demonstrated robust association with common diseases. Using Illumina HumanMethylation450 arrays on 354 ACPA positive rheumatoid arthritis (RA) cases and 337 controls, we identified two clusters within the MHC region whose differential methylation potentially mediates genetic risk for RA. To reduce confounding hampering previous epigenome-wide studies, we corrected for cellular heterogeneity by estimating and adjusting for cell-type proportions and used mediation analysis to filter out associations likely consequential to disease. Four CpGs also showed association between genotype and variance of methylation in addition to mean. The associations for both clusters replicated at least one CpG (p<0.01), with the rest showing suggestive association, in monocytes in an independent 12 cases and 12 controls. Thus, DNA methylation is a potential mediator of genetic risk.
doi:10.1038/nbt.2487
PMCID: PMC3598632  PMID: 23334450
16.  Job Strain and Cardiovascular Disease Risk Factors: Meta-Analysis of Individual-Participant Data from 47,000 Men and Women 
PLoS ONE  2013;8(6):e67323.
Background
Job strain is associated with an increased coronary heart disease risk, but few large-scale studies have examined the relationship of this psychosocial characteristic with the biological risk factors that potentially mediate the job strain – heart disease association.
Methodology and Principal Findings
We pooled cross-sectional, individual-level data from eight studies comprising 47,045 participants to investigate the association between job strain and the following cardiovascular disease risk factors: diabetes, blood pressure, pulse pressure, lipid fractions, smoking, alcohol consumption, physical inactivity, obesity, and overall cardiovascular disease risk as indexed by the Framingham Risk Score. In age-, sex-, and socioeconomic status-adjusted analyses, compared to those without job strain, people with job strain were more likely to have diabetes (odds ratio 1.29; 95% CI: 1.11–1.51), to smoke (1.14; 1.08–1.20), to be physically inactive (1.34; 1.26–1.41), and to be obese (1.12; 1.04–1.20). The association between job strain and elevated Framingham risk score (1.13; 1.03–1.25) was attributable to the higher prevalence of diabetes, smoking and physical inactivity among those reporting job strain.
Conclusions
In this meta-analysis of work-related stress and cardiovascular disease risk factors, job strain was linked to adverse lifestyle and diabetes. No association was observed between job strain, clinic blood pressure or blood lipids.
doi:10.1371/journal.pone.0067323
PMCID: PMC3688665  PMID: 23840664
17.  Associations of job strain and lifestyle risk factors with risk of coronary artery disease: a meta-analysis of individual participant data 
Background:
It is unclear whether a healthy lifestyle mitigates the adverse effects of job strain on coronary artery disease. We examined the associations of job strain and lifestyle risk factors with the risk of coronary artery disease.
Methods:
We pooled individual-level data from 7 cohort studies comprising 102 128 men and women who were free of existing coronary artery disease at baseline (1985–2000). Questionnaires were used to measure job strain (yes v. no) and 4 lifestyle risk factors: current smoking, physical inactivity, heavy drinking and obesity. We grouped participants into 3 lifestyle categories: healthy (no lifestyle risk factors), moderately unhealthy (1 risk factor) and unhealthy (2–4 risk factors). The primary outcome was incident coronary artery disease (defined as first nonfatal myocardial infarction or cardiac-related death).
Results:
There were 1086 incident events in 743 948 person-years at risk during a mean follow-up of 7.3 years. The risk of coronary artery disease among people who had an unhealthy lifestyle compared with those who had a healthy lifestyle (hazard ratio [HR] 2.55, 95% confidence interval [CI] 2.18–2.98; population attributable risk 26.4%) was higher than the risk among participants who had job strain compared with those who had no job strain (HR 1.25, 95% CI 1.06–1.47; population attributable risk 3.8%). The 10-year incidence of coronary artery disease among participants with job strain and a healthy lifestyle (14.7 per 1000) was 53% lower than the incidence among those with job strain and an unhealthy lifestyle (31.2 per 1000).
Interpretation:
The risk of coronary artery disease was highest among participants who reported job strain and an unhealthy lifestyle; those with job strain and a healthy lifestyle had half the rate of disease. A healthy lifestyle may substantially reduce disease risk among people with job strain.
doi:10.1503/cmaj.121735
PMCID: PMC3680555  PMID: 23670152
18.  High density genetic mapping identifies new susceptibility loci for rheumatoid arthritis 
Nature genetics  2012;44(12):1336-1340.
Summary
Using the Immunochip custom single nucleotide polymorphism (SNP) array, designed for dense genotyping of 186 genome wide association study (GWAS) confirmed loci we analysed 11,475 rheumatoid arthritis cases of European ancestry and 15,870 controls for 129,464 markers. The data were combined in meta-analysis with GWAS data from additional independent cases (n=2,363) and controls (n=17,872). We identified fourteen novel loci; nine were associated with rheumatoid arthritis overall and 5 specifically in anti-citrillunated peptide antibody positive disease, bringing the number of confirmed European ancestry rheumatoid arthritis loci to 46. We refined the peak of association to a single gene for 19 loci, identified secondary independent effects at six loci and association to low frequency variants (minor allele frequency <0.05) at 4 loci. Bioinformatic analysis of the data generated strong hypotheses for the causal SNP at seven loci. This study illustrates the advantages of dense SNP mapping analysis to inform subsequent functional investigations.
doi:10.1038/ng.2462
PMCID: PMC3605761  PMID: 23143596
19.  Short and Long Term Mortality after Coronary Artery Bypass Grafting (CABG) Is Influenced by Socioeconomic Position but Not by Migration Status in Sweden, 1995–2007 
PLoS ONE  2013;8(5):e63877.
Background
There are no nationwide studies on mortality after coronary artery bypass grafting (CABG) among foreign-born populations that include detailed information about country of birth and information about socioeconomic position. The objective was to investigate the risk of mortality after CABG considering socioeconomic position, sex and country of birth.
Material and Methods
We included all 72 333 patients undergoing a first isolated CABG in Sweden, during 1995 - 2007 of whom 12.7% were foreign-born. The patients were classified according to educational level, sex, and country of birth and were followed up to December 2007. We estimated the risk of short and long term mortality after CABG in a multivariable model adjusted for age, calendar year of surgery, diabetes, educational level, and waiting time for surgery. Hazard ratios (HR) with 95% confidence intervals (CI) were calculated based on the Cox proportional hazard model.
Findings
There were 15,284 deaths during the follow-up, 10.4% of whom were foreign-born. The foreign-born patients were 3 to 4 years younger than Sweden-born patients at the time of CABG surgery. There were no significant differences in overall early or late mortality between foreign-born and Sweden-born men and women after CABG. All-cause mortality differed in between regions and was highest in foreign-born men from Eastern Africa (HR 3.80, 95% CI 1.58–9.17), China (HR 3.61, 95% CI 1.50–8.69), and in Chile (HR 2.12, 95% CI 1.01–4.47). Patients with low level of education had worse survival compared to those with longer than 12 years of education irrespective of sex and country of birth. This difference was more pronounced among foreign-born women (HR 1.50, 95% CI 1.00–2.33).
Conclusion
This national study showed higher CABG mortality in patients from lower socioeconomic position. Early and late mortality did not differ after isolated CABG in foreign-born and Sweden-born patients.
doi:10.1371/journal.pone.0063877
PMCID: PMC3661557  PMID: 23717501
20.  Rheumatoid Arthritis Risk Allele PTPRC Is Also Associated With Response to Anti–Tumor Necrosis Factor α Therapy 
Arthritis and rheumatism  2010;62(7):1849-1861.
Objective
Anti–tumor necrosis factor α (anti-TNF) therapy is a mainstay of treatment in rheumatoid arthritis (RA). The aim of the present study was to test established RA genetic risk factors to determine whether the same alleles also influence the response to anti-TNF therapy.
Methods
A total of 1,283 RA patients receiving etanercept, infliximab, or adalimumab therapy were studied from among an international collaborative consortium of 9 different RA cohorts. The primary end point compared RA patients with a good treatment response according to the European League Against Rheumatism (EULAR) response criteria (n = 505) with RA patients considered to be nonresponders (n = 316). The secondary end point was the change from baseline in the level of disease activity according to the Disease Activity Score in 28 joints (ΔDAS28). Clinical factors such as age, sex, and concomitant medications were tested as possible correlates of treatment response. Thirty-one single-nucleotide polymorphisms (SNPs) associated with the risk of RA were genotyped and tested for any association with treatment response, using univariate and multivariate logistic regression models.
Results
Of the 31 RA-associated risk alleles, a SNP at the PTPRC (also known as CD45) gene locus (rs10919563) was associated with the primary end point, a EULAR good response versus no response (odds ratio [OR] 0.55, P = 0.0001 in the multivariate model). Similar results were obtained using the secondary end point, the ΔDAS28 (P = 0.0002). There was suggestive evidence of a stronger association in autoantibody-positive patients with RA (OR 0.55, 95% confidence interval [95% CI] 0.39–0.76) as compared with autoantibody-negative patients (OR 0.90, 95% CI 0.41–1.99).
Conclusion
Statistically significant associations were observed between the response to anti-TNF therapy and an RA risk allele at the PTPRC gene locus. Additional studies will be required to replicate this finding in additional patient collections.
doi:10.1002/art.27457
PMCID: PMC3652476  PMID: 20309874
21.  Likelihood of Treatment in a Coronary Care Unit for a First-Time Myocardial Infarction in Relation to Sex, Country of Birth and Socioeconomic Position in Sweden 
PLoS ONE  2013;8(4):e62316.
Objective
To examine the relationship between sex, country of birth, level of education as an indicator of socioeconomic position, and the likelihood of treatment in a coronary care unit (CCU) for a first-time myocardial infarction.
Design
Nationwide register based study.
Setting
Sweden.
Patients
199 906 patients (114 387 men and 85,519 women) of all ages who were admitted to hospital for first-time myocardial infarction between 2001 and 2009.
Main outcome measures
Admission to a coronary care unit due to myocardial infarction.
Results
Despite the observed increasing access to coronary care units over time, the proportion of women treated in a coronary care unit was 13% less than for men. As compared with men, the multivariable adjusted odds ratio among women was 0.80 (95% confidence interval 0.77 to 0.82). This lower proportion of women treated in a CCU varied by age and year of diagnosis and country of birth. Overall, there was no evidence of a difference in likelihood of treatment in a coronary care unit between Sweden-born and foreign-born patients. As compared with patients with high education, the adjusted odds ratio among patients with a low level of education was 0.93 (95% confidence interval 0.89 to 0.96).
Conclusions
Foreign-born and Sweden-born first-time myocardial infarction patients had equal opportunity of being treated in a coronary care unit in Sweden; this is in contrast to the situation in many other countries with large immigrant populations. However, the apparent lower rate of coronary care unit admission after first-time myocardial infarction among women and patients with low socioeconomic position warrants further investigation.
doi:10.1371/journal.pone.0062316
PMCID: PMC3636189  PMID: 23638036
22.  Cigarette smoking and smoking cessation in relation to risk of rheumatoid arthritis in women 
Introduction
Whereas the overall association between smoking and rheumatoid arthritis (RA) must be regarded as established, considerably less is known about how much smoking is needed to increase the risk of RA, that is, the effect of smoking intensity, duration and cessation.
Methods
The Swedish Mammography Cohort, including 34,101 women aged 54 to 89 years, was followed up from January 1, 2003 through December 31, 2010 (219 RA cases identified). Relative risks (RR) and their 95% confidence intervals (CI) were estimated as rate ratios using Cox proportional hazards model.
Results
There was a statistically significant association between smoking intensity (RR comparing 1 to 7 cigarettes/day vs never smoking 2.31 (95% CI: 1.59, 3.36)) as well as duration of smoking (comparing 1 to 25 years vs never smoking RR = 1.60 (95% CI: 1.07, 2.38)) and risk of RA. Compared to never smokers, the risk was still significantly elevated 15 years after smoking cessation (RR = 1.99 (95% CI: 1.23, 3.20)). However, among former smokers, the risk of RA seemed to be decreasing over time since stopping smoking: women who stopped smoking 15 years before the start of the follow-up had 30% lower risk of RA compared to those who stopped only a year before start of the follow-up (RR = 0.70 (95% CI: 0.24,2.02)).
Conclusions
This prospective study highlights that even light cigarette smoking is associated with increased risk of RA in women and that smoking cessation may reduce, though not remove, this risk.
doi:10.1186/ar4218
PMCID: PMC3672738  PMID: 23607815
23.  Oligoclonal Band Status in Scandinavian Multiple Sclerosis Patients Is Associated with Specific Genetic Risk Alleles 
PLoS ONE  2013;8(3):e58352.
The presence of oligoclonal bands (OCB) in cerebrospinal fluid (CSF) is a typical finding in multiple sclerosis (MS). We applied data from Norwegian, Swedish and Danish (i.e. Scandinavian) MS patients from a genome-wide association study (GWAS) to search for genetic differences in MS relating to OCB status. GWAS data was compared in 1367 OCB positive and 161 OCB negative Scandinavian MS patients, and nine of the most associated SNPs were genotyped for replication in 3403 Scandinavian MS patients. HLA-DRB1 genotypes were analyzed in a subset of the OCB positive (n = 2781) and OCB negative (n = 292) MS patients and compared to 890 healthy controls. Results from the genome-wide analyses showed that single nucleotide polymorphisms (SNPs) from the HLA complex and six other loci were associated to OCB status. In SNPs selected for replication, combined analyses showed genome-wide significant association for two SNPs in the HLA complex; rs3129871 (p = 5.7×10−15) and rs3817963 (p = 5.7×10−10) correlating with the HLA-DRB1*15 and the HLA-DRB1*04 alleles, respectively. We also found suggestive association to one SNP in the Calsyntenin-2 gene (p = 8.83×10−7). In HLA-DRB1 analyses HLA-DRB1*15∶01 was a stronger risk factor for OCB positive than OCB negative MS, whereas HLA-DRB1*04∶04 was associated with increased risk of OCB negative MS and reduced risk of OCB positive MS. Protective effects of HLA-DRB1*01∶01 and HLA-DRB1*07∶01 were detected in both groups. The groups were different with regard to age at onset (AAO), MS outcome measures and gender. This study confirms both shared and distinct genetic risk for MS subtypes in the Scandinavian population defined by OCB status and indicates different clinical characteristics between the groups. This suggests differences in disease mechanisms between OCB negative and OCB positive MS with implications for patient management, which need to be further studied.
doi:10.1371/journal.pone.0058352
PMCID: PMC3589422  PMID: 23472185
24.  Polymorphisms in peptidylarginine deiminase associate with rheumatoid arthritis in diverse Asian populations: evidence from MyEIRA study and meta-analysis 
Arthritis Research & Therapy  2012;14(6):R250.
Introduction
The majority of our knowledge regarding disease-related mechanisms of uncontrolled citrullination and anti-citrullinated protein antibody development in rheumatoid arthritis (RA) was investigated in Caucasian populations. However, peptidylarginine deiminase (PADI) type 4 gene polymorphisms are associated with RA in East Asian populations and weak or no association was found in Caucasian populations. This study explores the association between the PADI4 polymorphisms and RA risk in a multiethnic population residing in South East Asia with the goal of elucidating generalizability of association in non-Caucasian populations.
Methods
A total of 320 SNPs from the PADI locus (including PADI1, PADI2, PADI3, PADI4 and PADI6 genes) were genotyped in 1,238 RA cases and 1,571 control subjects from the Malaysian Epidemiological Investigation of Rheumatoid Arthritis (MyEIRA) case-control study. Additionally, we conducted meta-analysis of our data together with the previously published studies of RA from East Asian populations.
Results
The overall odds ratio (ORoverall) for the PADI4 (rs2240340) allelic model was 1.11 (95% confidence interval (CI) = 1.00 to 1.23, P = 0.04) and for the genotypic model was 1.20 (95% CI = 1.01 to 1.44, P = 0.04). Haplotype analysis for four selected PADI4 SNPs revealed a significant association of one with susceptibility (P = 0.001) and of another with a protective effect (P = 0.02). The RA susceptibility was further confirmed when combined meta-analysis was performed using these data together with data from five previously published studies from Asia comprising 5,192 RA cases and 4,317 control subjects (ORoverall = 1.23 (95% CI = 1.16 to 1.31, Pheterogeneity = 0.08) and 1.31 (95% CI = 1.20 to 1.44, Pheterogeneity = 0.32) in allele and genotype-based models, respectively). In addition, we also detected a novel association of PADI2 genetic variant rs1005753 with RA (ORoverall = 0.87 (95% CI = 0.77 to 0.99)).
Conclusion
Our study demonstrates an association between PADI4 and RA in the multiethnic population from South East Asia and suggests additional association with a PADI2 gene. The study thus provides further support for the notion that polymorphisms in genes for enzymes responsible for citrullination contribute to RA development in multiple populations of Asian descent.
doi:10.1186/ar4093
PMCID: PMC3674620  PMID: 23164236
25.  Job Strain as a Risk Factor for Leisure-Time Physical Inactivity: An Individual-Participant Meta-Analysis of Up to 170,000 Men and Women 
American Journal of Epidemiology  2012;176(12):1078-1089.
Unfavorable work characteristics, such as low job control and too high or too low job demands, have been suggested to increase the likelihood of physical inactivity during leisure time, but this has not been verified in large-scale studies. The authors combined individual-level data from 14 European cohort studies (baseline years from 1985–1988 to 2006–2008) to examine the association between unfavorable work characteristics and leisure-time physical inactivity in a total of 170,162 employees (50% women; mean age, 43.5 years). Of these employees, 56,735 were reexamined after 2–9 years. In cross-sectional analyses, the odds for physical inactivity were 26% higher (odds ratio = 1.26, 95% confidence interval: 1.15, 1.38) for employees with high-strain jobs (low control/high demands) and 21% higher (odds ratio = 1.21, 95% confidence interval: 1.11, 1.31) for those with passive jobs (low control/low demands) compared with employees in low-strain jobs (high control/low demands). In prospective analyses restricted to physically active participants, the odds of becoming physically inactive during follow-up were 21% and 20% higher for those with high-strain (odds ratio = 1.21, 95% confidence interval: 1.11, 1.32) and passive (odds ratio = 1.20, 95% confidence interval: 1.11, 1.30) jobs at baseline. These data suggest that unfavorable work characteristics may have a spillover effect on leisure-time physical activity.
doi:10.1093/aje/kws336
PMCID: PMC3521479  PMID: 23144364
cohort studies; exercise; physical activity; psychosocial factors; working population

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