Genome-Wide Association Study in Asian Populations Identifies Variants in ETS1 and WDFY4 Associated with Systemic Lupus Erythematosus

Systemic lupus erythematosus is a complex and potentially fatal autoimmune disease, characterized by autoantibody production and multi-organ damage. By a genome-wide association study (320 patients and 1,500 controls) and subsequent replication altogether involving a total of 3,300 Asian SLE patients from Hong Kong, Mainland China, and Thailand, as well as 4,200 ethnically and geographically matched controls, genetic variants in ETS1 and WDFY4 were found to be associated with SLE (ETS1: rs1128334, P = 2.33×10−11, OR = 1.29; WDFY4: rs7097397, P = 8.15×10−12, OR = 1.30). ETS1 encodes for a transcription factor known to be involved in a wide range of immune functions, including Th17 cell development and terminal differentiation of B lymphocytes. SNP rs1128334 is located in the 3′-UTR of ETS1, and allelic expression analysis from peripheral blood mononuclear cells showed significantly lower expression level from the risk allele. WDFY4 is a conserved protein with unknown function, but is predominantly expressed in primary and secondary immune tissues, and rs7097397 in WDFY4 changes an arginine residue to glutamine (R1816Q) in this protein. Our study also confirmed association of the HLA locus, STAT4, TNFSF4, BLK, BANK1, IRF5, and TNFAIP3 with SLE in Asians. These new genetic findings may help us to gain a better understanding of the disease and the functions of the genes involved

Antimicrobial resistance among migrants in Europe: a systematic review and meta-analysis

BACKGROUND: Rates of antimicrobial resistance (AMR) are rising globally and there is concern that increased migration is contributing to the burden of antibiotic resistance in Europe. However, the effect of migration on the burden of AMR in Europe has not yet been comprehensively examined. Therefore, we did a systematic review and meta-analysis to identify and synthesise data for AMR carriage or infection in migrants to Europe to examine differences in patterns of AMR across migrant groups and in different settings. METHODS: For this systematic review and meta-analysis, we searched MEDLINE, Embase, PubMed, and Scopus with no language restrictions from Jan 1, 2000, to Jan 18, 2017, for primary data from observational studies reporting antibacterial resistance in common bacterial pathogens among migrants to 21 European Union-15 and European Economic Area countries. To be eligible for inclusion, studies had to report data on carriage or infection with laboratory-confirmed antibiotic-resistant organisms in migrant populations. We extracted data from eligible studies and assessed quality using piloted, standardised forms. We did not examine drug resistance in tuberculosis and excluded articles solely reporting on this parameter. We also excluded articles in which migrant status was determined by ethnicity, country of birth of participants' parents, or was not defined, and articles in which data were not disaggregated by migrant status. Outcomes were carriage of or infection with antibiotic-resistant organisms. We used random-effects models to calculate the pooled prevalence of each outcome. The study protocol is registered with PROSPERO, number CRD42016043681. FINDINGS: We identified 2274 articles, of which 23 observational studies reporting on antibiotic resistance in 2319 migrants were included. The pooled prevalence of any AMR carriage or AMR infection in migrants was 25·4% (95% CI 19·1-31·8; I2 =98%), including meticillin-resistant Staphylococcus aureus (7·8%, 4·8-10·7; I2 =92%) and antibiotic-resistant Gram-negative bacteria (27·2%, 17·6-36·8; I2 =94%). The pooled prevalence of any AMR carriage or infection was higher in refugees and asylum seekers (33·0%, 18·3-47·6; I2 =98%) than in other migrant groups (6·6%, 1·8-11·3; I2 =92%). The pooled prevalence of antibiotic-resistant organisms was slightly higher in high-migrant community settings (33·1%, 11·1-55·1; I2 =96%) than in migrants in hospitals (24·3%, 16·1-32·6; I2 =98%). We did not find evidence of high rates of transmission of AMR from migrant to host populations. INTERPRETATION: Migrants are exposed to conditions favouring the emergence of drug resistance during transit and in host countries in Europe. Increased antibiotic resistance among refugees and asylum seekers and in high-migrant community settings (such as refugee camps and detention facilities) highlights the need for improved living conditions, access to health care, and initiatives to facilitate detection of and appropriate high-quality treatment for antibiotic-resistant infections during transit and in host countries. Protocols for the prevention and control of infection and for antibiotic surveillance need to be integrated in all aspects of health care, which should be accessible for all migrant groups, and should target determinants of AMR before, during, and after migration. FUNDING: UK National Institute for Health Research Imperial Biomedical Research Centre, Imperial College Healthcare Charity, the Wellcome Trust, and UK National Institute for Health Research Health Protection Research Unit in Healthcare-associated Infections and Antimictobial Resistance at Imperial College London

Surgical site infection after gastrointestinal surgery in high-income, middle-income, and low-income countries: a prospective, international, multicentre cohort study

Background: Surgical site infection (SSI) is one of the most common infections associated with health care, but its importance as a global health priority is not fully understood. We quantified the burden of SSI after gastrointestinal surgery in countries in all parts of the world. Methods: This international, prospective, multicentre cohort study included consecutive patients undergoing elective or emergency gastrointestinal resection within 2-week time periods at any health-care facility in any country. Countries with participating centres were stratified into high-income, middle-income, and low-income groups according to the UN's Human Development Index (HDI). Data variables from the GlobalSurg 1 study and other studies that have been found to affect the likelihood of SSI were entered into risk adjustment models. The primary outcome measure was the 30-day SSI incidence (defined by US Centers for Disease Control and Prevention criteria for superficial and deep incisional SSI). Relationships with explanatory variables were examined using Bayesian multilevel logistic regression models. This trial is registered with ClinicalTrials.gov, number NCT02662231. Findings: Between Jan 4, 2016, and July 31, 2016, 13 265 records were submitted for analysis. 12 539 patients from 343 hospitals in 66 countries were included. 7339 (58·5%) patient were from high-HDI countries (193 hospitals in 30 countries), 3918 (31·2%) patients were from middle-HDI countries (82 hospitals in 18 countries), and 1282 (10·2%) patients were from low-HDI countries (68 hospitals in 18 countries). In total, 1538 (12·3%) patients had SSI within 30 days of surgery. The incidence of SSI varied between countries with high (691 [9·4%] of 7339 patients), middle (549 [14·0%] of 3918 patients), and low (298 [23·2%] of 1282) HDI (p < 0·001). The highest SSI incidence in each HDI group was after dirty surgery (102 [17·8%] of 574 patients in high-HDI countries; 74 [31·4%] of 236 patients in middle-HDI countries; 72 [39·8%] of 181 patients in low-HDI countries). Following risk factor adjustment, patients in low-HDI countries were at greatest risk of SSI (adjusted odds ratio 1·60, 95% credible interval 1·05–2·37; p=0·030). 132 (21·6%) of 610 patients with an SSI and a microbiology culture result had an infection that was resistant to the prophylactic antibiotic used. Resistant infections were detected in 49 (16·6%) of 295 patients in high-HDI countries, in 37 (19·8%) of 187 patients in middle-HDI countries, and in 46 (35·9%) of 128 patients in low-HDI countries (p < 0·001). Interpretation: Countries with a low HDI carry a disproportionately greater burden of SSI than countries with a middle or high HDI and might have higher rates of antibiotic resistance. In view of WHO recommendations on SSI prevention that highlight the absence of high-quality interventional research, urgent, pragmatic, randomised trials based in LMICs are needed to assess measures aiming to reduce this preventable complication

Secular trends of life expectancy and disability-free life expectancy at age 65 and associated gender and area-level socioeconomic inequalities in Hong Kong: a serial cross-sectional study between 2007 and 2020.

BackgroundDespite Hong Kong's world leading longevity, little is known about its associated disability burden and social patterning. Hence, this study assessed the gender-specific secular trends and area-level inequalities in life expectancy (LE) and disability-free life expectancy (DFLE) at age 65 in Hong Kong.MethodsPopulation structure, death records, and disability data in 2007, 2013, and 2020 were retrieved from the Census and Statistics Department to estimate LE and DFLE using the Sullivan Method. District-based sociodemographic indicators were used to compare LE and DFLE across 18 districts of Hong Kong in 2013.FindingsBetween 2007 and 2020, LE at age 65 increased by 3.7 years (from 18.3 to 22.0) in men and by 2.1 years (from 22.7 to 24.8) in women. By contrast, DFLE increased more slowly, by 1.8 years (from 14.6 to 16.3) in men and by only 0.1 year (from 16.4 to 16.5) in women, leading to a substantial increase in proportion of life spent with disability. Results from multiple linear regression using district-based data in 2013 showed a similar extent of associations of education with LE and DFLE (mean year difference: 0.81 [95% CI: 0.14, 1.48] and 0.68 [0.10, 1.27], respectively, per 10% increase in average education level), while female gender was more strongly associated with LE (4.44 [3.56, 5.31]) than with DFLE (2.00 [1.18, 2.82]).InterpretationExpansion of disability burden and male-female health-survival paradox hold true in Hong Kong. Unlike Western countries with a stronger socioeconomic patterning of DFLE, the extent of area-level socioeconomic inequalities in LE and DFLE appears to be more comparable in Hong Kong.FundingHealth and Medical Research Fund (Ref. no.: 19202031) by the Health Bureau of Hong Kong

Confirmation of association of <i>HLA</i> locus, and <i>TNFSF4</i>, <i>STAT4</i>, <i>TNFAIP3</i>, <i>IRF5</i>, <i>BLK</i> with SLE.

<p>Shown are association results comparing SLE patients with controls collected in Hong Kong analyzed by Plink (−log₁₀(<i>P</i>-value) of SNPs). The best SNP in Chromosome 11 is around <i>ETS1</i> gene (rs6590330), which is in high LD with rs1128334. And the best SNP in Chromosome 10 is in <i>WDFY4</i> (rs877819).</p

Linkage disequilibrium and sequence conservation of SNPs in <i>ETS1</i>.

<p>Shown are LD for significant SNPs in and around <i>ETS1</i> detected by GWAS (A), and replicated SNPs in the 3′-UTR and downstream of the gene (B), and sequence conservation for sequences around SNP rs1128334 among different species (C).</p

Involvement of <i>ETS1</i> in Th17 cell and B lymphocyte development and autoimmunity.

<p>Involvement of <i>ETS1</i> in Th17 cell and B lymphocyte development and autoimmunity.</p

Allelic expression of <i>ETS1</i> on SNP rs1128334 in PBMC of healthy individuals.

<p>PBMC cDNA processed from 33 healthy individuals heterozygous on rs1128334 were used for allelic expression detection of <i>ETS1</i> by pyrosequencing. (A) A case example of detection on the “A” allele and the “G” allele from both DNA and cDNA samples from the same individual. (B) The ratio of G/A allelic detection for both DNA and cDNA samples. The median G/A ratio for DNA is 1.09 (95% CI: 1.08–1.11) and the median G/A ratio for cDNA expression is 1.32 (95% CI: 1.21–1.43), <i>P</i><0.0001 by paired student's <i>t</i> test.</p

Confirmation of susceptibility genes in the Hong Kong Chinese population by GWAS.

<p>A1: minor allele; F_A: minor allele frequency in cases; F_U: minor allele frequency in controls.</p

SNPs in and around <i>ETS1</i> and <i>WDFY4</i> that showed significant association with SLE in the GWAS data.

<p>SNPs in and around <i>ETS1</i> and <i>WDFY4</i> that showed significant association with SLE in the GWAS data.</p