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BackgroundCertain infectious agents are recognised causes of cancer and potentially other chronic diseases. Identifying associations and understanding pathological mechanisms involving infectious agents and subsequent chronic disease risk will be possible through measuring exposure to multiple infectious agents in large-scale prospective cohorts such as UK Biobank.MethodsFollowing expert consensus we designed a Multiplex Serology platform capable of simultaneously measuring quantitative antibody responses against 45 antigens from 20 infectious agents implicated in non-communicable diseases, including human herpes, hepatitis, polyoma, papilloma, and retroviruses, as well asChlamydia trachomatis, Helicobacter pyloriandToxoplasma gondii. This panel was assayed in a random subset of UK Biobank participants (n=9,695) to test associations between infectious agents and recognised demographic and genetic risk factors and disease outcomes.FindingsSeroprevalence estimates for each infectious agent were consistent with those expected from the literature. The data confirmed epidemiological associations of infectious agent antibody responses with sociodemographic characteristics (e.g. lifetime sexual partners withC, trachomatis;P=1·8×10−149), genetic variants (e.g. rs6927022 with Epstein-Barr virus (EBV) EBNA1 antibodies,P=9·5×10−91) and disease outcomes including human papillomavirus-16 seropositivity and cervical intraepithelial neoplasia (odds ratio 2·28, 95% confidence interval 1·38-3·63), and quantitative EBV viral capsid antigen responses and multiple sclerosis through genetic correlation (MHC rG=0·30,P=0·01).InterpretationThis dataset, intended as a pilot study to demonstrate applicability of Multiplex Serology in epidemiological studies, is itself one of the largest studies to date covering diverse infectious agents in a prospective UK cohort including those traditionally under-represented in population cohorts such as human immunodeficiency virus-1 andC. trachomatis. Our results emphasise the validity of our Multiplex Serology approach in large-scale epidemiological studies opening up opportunities for improving our understanding of host-pathogen-disease relationships. These data are available to researchers interested in examining the relationship between infectious agents and human health.

Background: Estimates of the burden of cardio-metabolic risk factors in Latin America and the Caribbean (LAC) rely on relative risks (RRs) from non-LAC countries. Whether these RRs apply to LAC remains unknown. Methods: We pooled LAC cohorts. We estimated RRs per unit of exposure to body mass index (BMI), systolic blood pressure (SBP), fasting plasma glucose (FPG), total cholesterol (TC) and non-HDL cholesterol on fatal (31 cohorts, n=168,287) and non-fatal (13 cohorts, n=27,554) cardiovascular diseases, adjusting for regression dilution bias. We used these RRs and national data on mean risk factor levels to estimate the number of cardiovascular deaths attributable to non-optimal levels of each risk factor. Results: Our RRs for SBP, FPG and TC were like those observed in cohorts conducted in high-income countries; however, for BMI, our RRs were consistently smaller in people below 75 years of age. Across risk factors, we observed smaller RRs among older ages. Non-optimal SBP was responsible for the largest number of attributable cardiovascular deaths ranging from 38 per 100,000 women and 54 men in Peru, to 261 (Dominica, women) and 282 (Guyana, men). For non-HDL cholesterol, the lowest attributable rate was for women in Peru (21) and men in Guatemala (25), and the largest in men (158) and women (142) from Guyana. Interpretation: RRs for BMI from studies conducted in high-income countries may overestimate disease burden metrics in LAC; conversely, RRs for SBP, FPG and TC from LAC cohorts are similar to those estimated from cohorts in high-income countries. Funding: Wellcome Trust (214185/Z/18/Z)

Background The association of HLA-B*27 with AS is amongst the strongest of any known association of a common variant with any human disease. Nonetheless, there is strong evidence indicating that other HLA-B alleles are involved in the disease. European ethnicity studies have demonstrated risk associations with HLA-B*40 and multiple other HLA-B, HLA-A, and HLA class II alleles, and demonstrated that in that ethnic group, the amino acid sequence at position 97 in HLA-B is the key determinant of HLA associations with AS. A recent study in Korean AS cases and controls additionally identified association at HLA-C*15:02. In the current study, we examined the MHC associations of AS in an expanded East Asian cohort. Methods A total of 1637 Chinese, Taiwanese, and Korean AS cases meeting the modified New York Criteria for AS, and 1589 ethnically matched controls, were genotyped with the Illumina Immunochip, including a dense coverage of the MHC region. HLA genotypes and amino acid composition were imputed using the SNP2HLA programme using the Han-MHC reference panel based on the data of Han Chinese subjects (n = 9689), and association tested using logistic regression controlling for population stratification effects. Results A strong association was seen with HLA-B*27 (odds ratio (OR) = 205.3, P = 5.76 × 10−244). Controlling for this association, the strongest risk association is seen with HLA-C*15 at genome-wide significant level (OR = 7.62, P = 9.30 × 10−19), and confirmed association is also seen with HLA-B*40 at suggestive level (OR = 1.65, P = 2.54 × 10−4). At amino acid level, the strongest association seen in uncontrolled analysis was with histidine at position 114 in HLA-B (P = 7.24 × 10−241), but conditional analyses suggest that the primary amino acid associations are with lysine at position 70 and asparagine at position 97. Restriction of the ERAP1 association with HLA-B27-positive AS, previously reported in European subjects, was confirmed in East Asians. Conclusions This study confirms in East Asians that the HLA associations of AS are multiple, including previously reported associations at HLA-B*27, HLA-B*40, and HLA-C*15, as well as novel association with HLA-DQB1*04. The HLA-B associations are driven by the amino acids at positions 70 and 97, in the B pocket of HLA-B.

Objective: Although history of preeclampsia increases a woman′s risk of developing hypertension (HTN) in adulthood, it remains unclear whether a heart-healthy post-pregnancy diet could ameliorate some of this risk. Therefore, we evaluated whether adherence to dietary patterns is related with HTN among women with prior preeclampsia Methods: At baseline, 4,781 women without HTN reported at least one pregnancy with preeclampsia in the 2008 Mexican Teachers’ Cohort follow-up cycle. From the baseline food frequency questionnaire (FFQ) we derived diet scores based on the American Heart Association (AHA) 2020 Goals and the Dietary Approaches to Stop Hypertension (DASH). The AHA score has 5 items: fruits and vegetables, fish, whole grain, sugar-sweetened beverages and sodium, whereas the DASH diet has 8: low-fat dairy, nuts/legumes, fruits, vegetables, whole grain, red and processed meats, sugar-sweetened beverages, and sodium. Incident HTN reported in 2011, was defined as high blood pressure diagnosed by a medical doctor or currently taking antihypertensive treatment. We estimated the relative risk (RR) and 95% confidence intervals (95%CI) of HTN by comparing women in the lowest score quintile to women in the highest score quintile, using log-binomial regression after adjusting for common risk factors for HTN as well as health care provider, demographic regions and indigenous heritage. Results: The mean age (SD) of women affected by preeclampsia was 41(7) years and BMI of 28(5) kg/m 2 . Over the 3-year study period, 555(12%) women developed incident HTN, which was higher that the incidence of HTN among women with normotensive pregnancies (6%). Women with the highest AHA scores had 0.82(95% CI 0.68,1.06) times the risk of developing HTN than women with lowest scores (p-trend=0.04). Similarly, highest adherence to the DASH diet had 0.74(95% CI 0.57,0.96) times the risk of developing HTN than women with the lowest score(p-trend=0.03). When individual components of the diet were separately evaluated, only sodium intake was associated with HTN. Specifically, women who consumed ≥2,500 mg/day of sodium had 1.18(0.92,1.52) times the risk of HTN compared to women who consumed Conclusion: Greater adherence to AHA and DASH diet patterns were inversely related to risk of HTN among Mexican women with a history of preeclampsia and even though lower sodium intake was also related to HTN, the FFQ underestimates absolute sodium intake. Nevertheless, post-partum recommendations on diet quality in this high-risk group may provide one strategy to prevent long-term risk of HTN.

OBJECTIVES: To examine the relation between breakfast frequency and incidence of diabetes in middle-aged women. METHODS: The Mexican Teacher´s Cohort is a prospective study in women. We included 71,373 participants at baseline (2006–2008). Participants were classified according to breakfast frequency 0, 1–3, 4–6, or 7 d/wk; and meal frequency 1–2, 3–4, or ≥5 meals/d. Diabetes was self-reported. We used Cox proportional hazards models to calculate hazard ratios (HR) and 95% confidence intervals (CI) to estimate the association between breakfast frequency and diabetes incidence. Models were adjusted for sociodemographic and lifestyle confounders that are associated with breakfast consumption and are risk factors for diabetes. Stratified analyses were performed for age, birth weight, indigenous background, and physical activity. RESULTS: We identified 3,613 new diabetes cases during a median of 2.2 years of follow-up. Prevalence of daily breakfast consumers was 25%. After adjustment for known risk factors for diabetes, compared to 0 d/wk, women who eat daily breakfast had 12% lower rate of diabetes (HR = 0.88; 95% CI 0.78, 0.99; p-trend = 0.0018). One day additional per week having breakfast decreased the risk of diabetes (HR = 0.98; CI 0.97, 0.99). In stratified analysis, women with indigenous background who consumed breakfast 4–6 d/wk and 7 d/wk vs. 0 d/wk shown lower risk (HR = 0.68; 95% CI 0.47, 0.98) and HR = 0.76; 95% CI 0.76 (0.51, 1.15) respectively; p-interaction = 0.197). CONCLUSIONS: Daily breakfast was associated with a lower incidence of diabetes, independently of dietary and lifestyle factors. Likely effect modifiers as ethnicity warrants more research. Daily breakfast consumption is a potential component of diabetes prevention. FUNDING SOURCES: This work is supported by the American Institute for Cancer Research (05B047) and Consejo Nacional de Ciencia y Tecnología (CONACyT) grant S0008-2009-1: 000000000115312.

Why was the cohort set up? Latin America and the Caribbean (LAC) are characterized by much diversity in terms of socio-economic status, ecology, environment, access to health care,1,2 as well as the frequency of risk factors for and prevalence or incidence of non-communicable diseases;3–7 importantly, these differences are observed both between and within countries in LAC.8,9 LAC countries share a large burden of non-communicable (e.g. diabetes and hypertension) and cardiovascular (e.g. ischaemic heart disease) diseases, with these conditions standing as the leading causes of morbidity, disability and mortality in most of LAC.10–12 These epidemiological estimates—e.g. morbidity—cannot inform about risk factors or risk prediction, which are relevant to identify prevention avenues. Cohort studies, on the other hand, could provide this evidence. Pooled analysis, using data from multiple cohort studies, have additional strengths such as increased statistical power and decreased statistical uncertainty.13 LAC cohort studies have been under-represented,14 or not included at all,15–17 in international efforts aimed at pooling data from multiple cohort studies. We therefore set out to pool data from LAC cohorts to address research questions that individual cohort studies would not be able to answer. Drawing from previous successful regional enterprises (e.g. Asia Pacific Cohort Studies Collaboration),18,19 we established the Cohorts Consortium of Latin America and the Caribbean (CC-LAC). The main aim of the CC-LAC is to start a collaborative cohort data pooling in LAC to examine the association between cardio-metabolic risk factors (e.g. blood pressure, glucose and lipids) and non-fatal and fatal cardiovascular outcomes (e.g. stroke or myocardial infarction). In so doing, we aim to provide regional risk estimates to inform disease burden metrics, as well as other ambitious projects including a cardiovascular risk score to strengthen cardiovascular prevention in LAC. Initial funding has been provided by a fellowship from the Wellcome Trust Centre for Global Health Research at Imperial College London (Strategic Award, Wellcome Trust–Imperial College Centre for Global Health Research, 100693/Z/12/Z). Additional funding is being provided by an International Training Fellowship from the Wellcome Trust (214185/Z/18/Z). At the time of writing, the daily operations and pooled database are hosted at Imperial College London, though a mid-term goal is to transfer this expertise and operations to LAC. The collaboration relies fundamentally on a strong regional network of health researchers and practitioners

To the Editor, As Zhou and Reveille note,1 MICA is a functionally enticing candidate gene for ankylosingspondylitis (AS). It is however challenging to study because of the technical difficulty of direct genotyping studies of the locus, its proximity and strong linkage disequilibrium with HLA-B , and the fact that it is subject to major population stratification effects. We recently performed an association study of common MICA alleles with AS susceptibility and observed no evidence of association in either HLA-B*27 positive or negative stratified analyses.2 In this study, …

Background Among the 100 genes associated with ankylosing spondylitis (AS), RUNX3 a transcription factor (TF) involved in diverse immunological processes has a very robust (10−15) association.1 The biggest challenge following association studies remain to understand the mechanism behind this association and get insights of the disease. We have recently demonstrated that the association between AS and the single nucleotide polymorphism (SNP) rs4648889 located in a 2 kb regulatory locus upstream the promoter of RUNX3 can be explained by allele-specific effects on TF recruitment that alter gene expression, specifically in CD8 +T cells.2 In addition, another closely adjacent SNP, rs4265380 shows functional effects (i.e. TF recruitment, histone marks enrichment and cell count) on CD14 +monocytes.3 Objectives The main objectives of this work are: 1) to dissect the functional effects of the different SNPs at the RUNX3 locus, acting in different cell types (especially CD8 +T cells and monocytes); 2) to identify the different interacting partners (i.e. TFs) binding at the RUNX3 locus in the presence of the AS-associated alleles. Methods We used publicly available dataset to define the epigenetic landscape of the RUNX3 locus. In vitro functional studies were performed to characterise the effects of these specific genetic variants, providing critical functional evidence for their role in AS. Results (1) Roadmap data revealed a robust peak for open chromatin and specific histone modifications associated with regulatory elements. Hi-C data showed the interaction of RUNX3 with different genomic loci within chromosome 1, in GM12878 lymphoblastoid cell line, CD8 +T cells and monocytes; (2) ChIP-qPCR experiments on monocytes and CD8 +T cells from AS patients revealed the enrichment for several histone modifications (i.e. H3K79Me2 and H3K4Me1) at the RUNX3 locus overlapping the SNPs of interest; (3) preliminary DNA pull-down experiments, followed by Mass Spectrometry, started to identify the whole range of proteins and TFs (DNA/protein ‘interactome’) that bind at the RUNX3 locus in the presence of the AS-associated alleles, evaluated in both CD8 +T cells and monocytes; (4) initial pathway enrichment analysis highlighted the distinct contribution of proteins involved in the transcriptional machinery (AS-risk VS protective alleles). Conclusions We provide first evidence that the 2 kb region upstream the RUNX3 gene has a plausible functional role in AS. These new observations are critically important not only in identifying specific cell types that play a pathogenic role in AS, but also in defining dysregulated pathways and potential therapeutic drug targets. References [1] ] IGAS, et al. Nat Genet2013Jul;45(7):730–8. [2] Vecellio M, et al. Ann Rheum Dis2016Aug;75(8):1534–40. [3] Vecellio M, et al. RMD Open2018. Disclosure of Interest None declared

A small percentage of women with cervical HPV infection progress to cervical neoplasia, and the risk factors determining progression are incompletely understood. We sought to define the genetic loci involved in cervical neoplasia and to assess its heritability using unbiased unrelated case/control statistical approaches. We demonstrated strong association of cervical neoplasia with risk and protective HLA haplotypes that are determined by the amino-acids carried at positions 13 and 71 in pocket 4 of HLA-DRB1 and position 156 in HLA-B. Furthermore, 36% (standard error 2.4%) of liability of HPV-associated cervical pre-cancer and cancer is determined by common genetic variants. Women in the highest 10% of genetic risk scores have approximately >7.1% risk, and those in the highest 5% have approximately >21.6% risk, of developing cervical neoplasia. Future studies should examine genetic risk prediction in assessing the risk of cervical neoplasia further, in combination with other screening methods., Author summary Around 1% of women with cervical human papillomavirus (HPV) infection progress to cervical cancer. Previous studies had indicated that a person’s genetic makeup could predispose to HPV-associated cervical cancer, and that some of the genes likely to be involved include the immune-related human leukocyte antigen (HLA) genes among the major histocompatibility complex (MHC). However, it has been difficult to determine which alleles might be associated with cervical pre-cancer or cancer due to the complex and high level of co-inheritance of MHC alleles. Here, we performed a genome-wide association study that assessed the correlation of genetic variants among those with cervical cancer and healthy controls. We show that host genetics is a major determinant of HPV-associated cervical cancer, with 36% of liability due to common genetic variants in the population, and identify both risk and protective HLA alleles. Our study was also sufficiently powerful to identify particular residue variants on a number of the immune-related proteins that provide risk or protection, providing further insight into the biological basis for cervical cancer development. Our findings could lay the foundation for screening for people at increased risk of developing cancer following HPV infection, and aid in the treatment and prognosis of cervical cancer.

Objectives To explore the functions of RUNX3 single nucleotide polymorphisms (SNPs) associated with ankylosing spondylitis (AS). Methods Individual SNP associations were evaluated in 4230 UK cases. Their effects on transcription factor (TF) binding, transcription regulation, chromatin modifications, gene expression and gene interactions were tested by database interrogation, luciferase reporter assays, electrophoretic mobility gel shifts, chromatin immunoprecipitation and real-time PCR. Results We confirmed the independent association of AS with rs4265380 , which was robust (P=4.7×10 −6 ) to conditioning on another nearby AS-associated RUNX3 SNP ( rs4648889 ). A RUNX3 haplotype incorporating both SNPs was strongly associated with AS (OR 6.2; 95% CI 3.1 to 13.2, P=1.4×10 −8 ). In a large UK cohort, rs4265380 is associated with leucocyte counts (including monocytes). RUNX3 expression is lower in AS peripheral blood mononuclear cells than healthy controls (P rs4265380 genotype. Enhancer function for this RUNX3 region was suggested by increased luciferase activity (approximately tenfold; P=0.005) for reporter constructs containing rs4265380 . In monocytes, there was differential allelic binding of nuclear protein extracts to a 50 bp DNA probe containing rs4265380 that was strongly augmented by lipopolysaccharide activation. TF binding also included the histone modifier p300. There was enrichment for histone modifications associated with active enhancer elements (H3K27Ac and H3K79Me2) that may be allele dependent. Hi-C database interrogation showed chromosome interactions of RUNX3 bait with the nearby RP4-799D16.1 lincRNA. Conclusions The association of AS with this RUNX3 regulatory region involves at least two SNPs apparently operating in different cell types. Monocytes may be potential therapeutic targets in AS.

Free to read Objective To use high-density genotyping to investigate the genetic associations of acute anterior uveitis (AAU) in patients with and those without ankylosing spondylitis (AS). Methods We genotyped samples from 1,711 patients with AAU (either primary or combined with AS), 2,339 AS patients without AAU, and 10,000 control subjects on an Illumina Immunochip Infinium microarray. We also used data for AS patients from previous genome-wide association studies to investigate the AS risk locus ANTXR2 for its putative effect in AAU. ANTXR2 expression in mouse eyes was investigated by real-time quantitative reverse transcription–polymerase chain reaction. Results A comparison between all patients with AAU and healthy control subjects showed strong association over HLA–B, corresponding to the HLA–B27 tag single-nucleotide polymorphism rs116488202. The association of 3 non–major histocompatibility complex loci, IL23R, the intergenic region 2p15, and ERAP1, reached genome-wide significance (P < 5 × 10−8). Five loci harboring the immune-related genes IL10–IL19, IL18R1–IL1R1, IL6R, the chromosome 1q32 locus harboring KIF21B, as well as the eye-related gene EYS, were also associated, reaching a suggestive level of significance (P < 5 × 10−6). Several previously confirmed AS associations demonstrated significant differences in effect size between AS patients with AAU and AS patients without AAU. ANTXR2 expression varied across eye compartments. Conclusion These findings of both novel AAU-specific associations and associations shared with AS demonstrate overlapping but also distinct genetic susceptibility loci for AAU and AS. The associations in IL10 and IL18R1 are shared with inflammatory bowel disease, suggesting common etiologic pathways.

Ankylosing spondylitis (AS) susceptibility is strongly correlated with genetic variation within the major histocompatibility complex (MHC), and the class I HLA-B*27 allele confers the major genetic risk factor to AS. Furthermore, strong evidence for additional alleles in the MHC has been observed which affect susceptibility independently from the HLA-B*27 allele, either by direct genotyping in candidate gene studies or through large-scale imputation-driven association studies. We have previously identified variants in both class I and II which affect susceptibility to AS through imputation of classical HLA alleles...

Free to read Objective Ankylosing spondylitis (AS) is a highly heritable common inflammatory arthritis that targets the spine and sacroiliac joints of the pelvis, causing pain and stiffness and leading eventually to joint fusion. Although previous studies have shown a strong association of IL23R with AS in white Europeans, similar studies in East Asian populations have shown no association with common variants of IL23R, suggesting either that IL23R variants have no role or that rare genetic variants contribute. The present study was undertaken to screen IL23R to identify rare variants associated with AS in Han Chinese. Methods A 170-kb region containing IL23R and its flanking regions was sequenced in 50 patients with AS and 50 ethnically matched healthy control subjects from a Han Chinese population. In addition, the 30-kb region of peak association in white Europeans was sequenced in 650 patients with AS and 1,300 healthy controls. Validation genotyping was undertaken in 846 patients with AS and 1,308 healthy controls. Results We identified 1,047 variants, of which 729 were not found in the dbSNP genomic build 130. Several potentially functional rare variants in IL23R were identified, including one nonsynonomous single-nucleotide polymorphism (nsSNP), Gly149Arg (position 67421184 GA on chromosome 1). Validation genotyping showed that the Gly149Arg variant was associated with AS (odds ratio 0.61, P = 0.0054). Conclusion This is the first study to implicate rare IL23R variants in the pathogenesis of AS. The results identified a low-frequency nsSNP with predicted loss-of-function effects that was protectively associated with AS in Han Chinese, suggesting that decreased function of the interleukin-23 (IL-23) receptor protects against AS. These findings further support the notion that IL-23 signaling has an important role in the pathogenesis of AS.

Genetic discovery from the multitude of phenotypes extractable from routine healthcare data has the ability to radically transform our understanding of the human phenome, thereby accelerating progress towards precision medicine. However, a critical question when analysing high-dimensional and heterogeneous data is how to interrogate increasingly specific subphenotypes whilst retaining statistical power to detect genetic associations. Here we develop and employ a novel Bayesian analysis framework that exploits the hierarchical structure of diagnosis classifications to jointly analyse genetic variants against UK Biobank healthcare phenotypes. Our method displays a more than 20% increase in power to detect genetic effects over other approaches, such that we uncover the broader burden of genetic variation: we identify associations with over 2,000 diagnostic terms. We find novel associations with common immune-mediated diseases (IMD), we reveal the extent of genetic sharing between specific IMDs, and we expose differences in disease perception or diagnosis with potential clinical implications.

The association of endoplasmic reticulum aminopeptidase 2 (ERAP2) with ankylosing spondylitis (AS) was recently described in the large International Genetics of AS Consortium Immunochip study. Variants in ERAP2 have also been associated with inflammatory bowel disease, psoriasis, acute anterior uveitis and birdshot chorioretinopathy. Subsequent investigation demonstrated an association of ERAP2 with AS which was present when one conditioned on one of the two independent haplotypes of ERAP1 associated with AS or when HLA-B27-negative patients were analysed separately. These two analyses provide analogous evidence for the association of ERAP2 with AS in HLA-B27-negative cases because of the genetic interaction between HLA-B27 and the AS-associated ERAP1 variants in AS cases. ERAP1 and ERAP2 are located on chromosome 5q15 in the opposite orientation. The locus is challenging to analyse because of the strong linkage disequilibrium (LD) across the locus and the epistasis between ERAP1 and HLA-B alleles associated with AS. We therefore sought to investigate the association of ERAP2 with AS in HLA-B27-positive patients. This is of clinical importance because functional studies have demonstrated that the strongly AS-protective variant rs2248374 causes a functional ERAP2 protein knockout, because its G allele causes a loss of ERAP2 protein expression. There is also a variant of ERAP2 which changes its enzyme catalytic activity and specificity (rs2549782, K392A). Because this is in almost complete LD with rs2248374 (1000 Genomes D′=1.00, r2=0.90), it is almost never translated in vivo. Further, the very strong LD between these markers means that analysis of rs2549782 for association would yield results almost identical to the results for rs2248374 presented below. Therefore, it is of relevance to determine whether the association of ERAP2 with HLA-B27-negative disease is also found in HLA-B27-positive cases, since ERAP inhibition may offer a novel therapeutic for AS...

ObjectiveTo identify genetic associations with severity of radiographic damage in ankylosing spondylitis (AS).MethodWe studied 1537 AS cases of European descent; all fulfilled the modified New York Criteria. Radiographic severity was assessed from digitised lateral radiographs of the cervical and lumbar spine using the modified Stoke Ankylosing Spondylitis Spinal Score (mSASSS). A two-phase genotyping design was used. In phase 1, 498 single nucleotide polymorphisms (SNPs) were genotyped in 688 cases; these were selected to capture >90% of the common haplotypic variation in the exons, exon–intron boundaries, and 5 kb flanking DNA in the 5′ and 3′ UTR of 74 genes involved in anabolic or catabolic bone pathways. In phase 2, 15 SNPs exhibiting pResultsExperiment-wise association was observed with the SNP rs8092336 (combined OR 0.32, p=1.2×10−5), which lies within RANK (receptor activator of NFκB), a gene involved in osteoclastogenesis, and in the interaction between T cells and dendritic cells. Association was also found with the SNP rs1236913 in PTGS1 (prostaglandin-endoperoxide synthase 1, cyclooxygenase 1), giving an OR of 0.53 (p=2.6×10−3). There was no observed association between radiographic severity and HLA-B*27.ConclusionsThese findings support roles for bone resorption and prostaglandins pathways in the osteoproliferative changes in AS.

Objective.Smoking contributes to progression of ankylosing spondylitis (AS). Because smoking is also a risk factor for incident rheumatoid arthritis (RA) and psoriatic arthritis, our aim was to test whether smoking habits are associated with incident AS.Methods.Using data from the HUNT health study of the entire adult population of Nord-Trøndelag, Norway, participants in HUNT2 (1995–1997) and HUNT3 (2006–2008) were identified who reported a diagnosis of AS in HUNT3 but not in HUNT2 (n = 107). Incident AS cases were compared with AS-unaffected individuals (n = 35,278) in a case-control design. Participants with RA were excluded.Results.Present smoking was significantly associated with incident self-reported AS in logistic regression adjusted for potential confounders (OR 1.99, 95% CI 1.28–3.11, p = 0.002). Previous smoking (OR 1.15, 95% CI 0.66–2.02, p = 0.62) or total pack-years at HUNT2 (OR 1.01, 95% CI 0.99–1.04, p = 0.21) were not significant. The association with present smoking remained significant in various sensitivity analyses: including only cases with high probability of true AS diagnosis (OR 1.82, 95% CI 1.03–3.19, p = 0.04); including only cases with AS reported more than 3–5 years after HUNT2 (OR 2.34, 95% CI 1.09–5.03, p = 0.029), or including only participants genotyped for HLA-B27 (94 cases and 859 controls) adjusting for genotype (OR 1.79, 95% CI 1.04–2.85, p = 0.033). Hypertension was also significantly associated with incident AS (OR from 1.65 to 2.81).Conclusion.In the HUNT population-based study, incident AS was associated with current smoking and hypertension. If verified in further studies, this suggests that smoking should be discouraged in those at a higher AS risk, e.g., with a family history or carrying HLA-B27.

of genetic risk factors, including these 14 novel loci, were common to both European and non-European IBD. However, the amount of phenotypic variance explained by these loci between populations was clearly heterogeneous, driven by a combination of differences in effect size and allele frequency. Phenotype data was available for 3,986 non-European and 47,799 European patients. There was a male predominance for Crohn’s disease (69% vs 45%), more ileocolonic disease (54% vs. 39%) and lower colectomy rates in UC (4% vs 18%) in nonEuropean than European populations. Conclusions: In this largest study to date of genetic risk factors underlying non-European IBD, we identified 14 novel IBD loci increasing the total number of IBD loci to 177. There is pervasive sharing of genetic risk factors between different ethnicities; Despite shared genetics, the relative contributions for individual genes to the variance explained differ between ethnicities. Overall the clinical characteristics are remarkably similar between different ethnicities. The presented similarities and dissimilarities between populations add to the heterogeneity of IBD.

Background and Objectives Ankylosing spondylitis (AS), a common inflammatory arthritis affecting primarily the spine and pelvis, is a highly heritable disease. In addition to HLA-B*27, 25 loci were associated with AS in populations of European ancestry in a recent international collaborative study, using the “Immunochip”. There is, however, well-known heterogeneity of allele frequencies across populations. We therefore re-examined this large dataset (10,619 patients and 15,145 controls) and focused on the Portuguese sample, asking whether alleles might be distinctly associated with AS in Portugal. Materials and Methods We extracted the data subset corresponding to 184 AS patients (according to the modified New York criteria) and 161 controls, all from mainland Portugal. Written informed consent was obtained from all subjects. Removal of outliers with Eigenstrat and quality control of genotyping data left 325 subjects (174 cases / 151 controls) genotyped with 119768 SNPs. Association analysis was performed using PLINK (v1.07). Results Apart from the MHC, there was no significant association at the genome-wide level (5 x 10 -8 ). However, 14 SNPs in 12 loci were associated with a nominal P -4 . The top-ranking SNP was in the inducible T-cell co-stimulator ligand (ICOSLG) gene (P = 7.56 x 10 -7 , OR = 5.014), previously associated in the whole consortium dataset. Other listed loci include USP34, an ubiquitin hydrolase that acts as regulator of the Wnt signalling pathway, CLEC16A, a member of the C-lectin type domain family, and several transcription factors or DNA-binding proteins. Conclusions Association of ICOSLG points to a potential alteration of the T-cell costimulation pathway in AS pathogenesis and warrants functional studies. Failure to replicate some of the loci associated in the whole consortium dataset likely results from our relatively small sample size. Conversely, new association findings will need confirmation in independent samples and may lead to population-specific genomic variants predisposing to AS.