Common Variants at 10 Genomic Loci Influence Hemoglobin A(1C) Levels via Glycemic and Nonglycemic Pathways

OBJECTIVE Glycated hemoglobin (HbA1c), used to monitor and diagnose diabetes, is influenced by average glycemia over a 2- to 3-month period. Genetic factors affecting expression, turnover, and abnormal glycation of hemoglobin could also be associated with increased levels of HbA1c. We aimed to identify such genetic factors and investigate the extent to which they influence diabetes classification based on HbA1c levels. RESEARCH DESIGN AND METHODS We studied associations with HbA1c in up to 46,368 nondiabetic adults of European descent from 23 genome-wide association studies (GWAS) and 8 cohorts with de novo genotyped single nucleotide polymorphisms (SNPs). We combined studies using inverse-variance meta-analysis and tested mediation by glycemia using conditional analyses. We estimated the global effect of HbA1c loci using a multilocus risk score, and used net reclassification to estimate genetic effects on diabetes screening. RESULTS Ten loci reached genome-wide significant association with HbA1c, including six new loci near FN3K (lead SNP/P value, rs1046896/P = 1.6 × 10−26), HFE (rs1800562/P = 2.6 × 10−20), TMPRSS6 (rs855791/P = 2.7 × 10−14), ANK1 (rs4737009/P = 6.1 × 10−12), SPTA1 (rs2779116/P = 2.8 × 10−9) and ATP11A/TUBGCP3 (rs7998202/P = 5.2 × 10−9), and four known HbA1c loci: HK1 (rs16926246/P = 3.1 × 10−54), MTNR1B (rs1387153/P = 4.0 × 10−11), GCK (rs1799884/P = 1.5 × 10−20) and G6PC2/ABCB11 (rs552976/P = 8.2 × 10−18). We show that associations with HbA1c are partly a function of hyperglycemia associated with 3 of the 10 loci (GCK, G6PC2 and MTNR1B). The seven nonglycemic loci accounted for a 0.19 (% HbA1c) difference between the extreme 10% tails of the risk score, and would reclassify ∼2% of a general white population screened for diabetes with HbA1c. CONCLUSIONS GWAS identified 10 genetic loci reproducibly associated with HbA1c. Six are novel and seven map to loci where rarer variants cause hereditary anemias and iron storage disorders. Common variants at these loci likely influence HbA1c levels via erythrocyte biology, and confer a small but detectable reclassification of diabetes diagnosis by HbA1c

Body mass index as a predictor of healthy and disease-free life expectancy between ages 50 and 75 : a multicohort study

BACKGROUND: While many studies have shown associations between obesity and increased risk of morbidity and mortality, little comparable information is available on how body mass index (BMI) impacts health expectancy. We examined associations of BMI with healthy and chronic disease-free life expectancy in four European cohort studies. METHODS: Data were drawn from repeated waves of cohort studies in England, Finland, France and Sweden. BMI was categorized into four groups from normal weight (18.5-24.9 kg m(-2)) to obesity class II (>= 35 kg m(-2)). Health expectancy was estimated with two health indicators: sub-optimal self-rated health and having a chronic disease (cardiovascular disease, cancer, respiratory disease and diabetes). Multistate life table models were used to estimate sex-specific healthy life expectancy and chronic disease-free life expectancy from ages 50 to 75 years for each BMI category. RESULTS: The proportion of life spent in good perceived health between ages 50 and 75 progressively decreased with increasing BMI from 81% in normal weight men and women to 53% in men and women with class II obesity which corresponds to an average 7-year difference in absolute terms. The proportion of life between ages 50 and 75 years without chronic diseases decreased from 62 and 65% in normal weight men and women and to 29 and 36% in men and women with class II obesity, respectively. This corresponds to an average 9 more years without chronic diseases in normal weight men and 7 more years in normal weight women between ages 50 and 75 years compared to class II obese men and women. No consistent differences were observed between cohorts. CONCLUSIONS: Excess BMI is associated with substantially shorter healthy and chronic disease-free life expectancy, suggesting that tackling obesity would increase years lived in good health in populations.Peer reviewe

Onset of Workplace Bullying and Risk of Weight Gain: A Multicohort Longitudinal Study

OBJECTIVE: This study aimed to examine the onset of workplace bullying as a risk factor for BMI increase. METHODS: Repeated biennial survey data from three Nordic cohort studies were used, totaling 46,148 participants (67,337 participant observations) aged between 18 and 65 who did not have obesity and who were not bullied at the baseline. Multinomial logistic regression was applied for the analysis under the framework of generalized estimating equations. RESULTS: Five percent reported onset of workplace bullying within 2 years from the baseline. In confounder-adjusted models, onset of workplace bullying was associated with a higher risk of weight gain of ≥ 1 BMI unit (odds ratio = 1.09; 95% CI: 1.01-1.19) and of ≥ 2.5 BMI units (odds ratio = 1.24; 95% CI: 1.06-1.45). A dose-response pattern was observed, and those exposed to workplace bullying more frequently showed a higher risk (Ptrend  = 0.04). The association was robust to adjustments, restrictions, stratifications, and use of relative/absolute scales for BMI change. CONCLUSIONS: Participants with exposure to the onset of workplace bullying were more likely to gain weight, a possible pathway linking workplace bullying to increased long-term risk of type 2 diabetes

Sleep Duration and Sleep Disturbances as Predictors of Healthy and Chronic Disease-Free Life Expectancy between Ages 50 and 75: A Pooled Analysis of Three Cohorts

The aim of this study was to examine the associations of sleep duration and sleep disturbances with healthy and chronic disease-free life expectancy (LE) between ages 50 and 75.\nData were drawn from repeated waves of three occupational cohort studies in England, Finland and Sweden (n=55,494) and the follow-up ranged from 6 to 18 years. Self-reported sleep duration was categorized into Persons who slept 7-8.5 hours could expect to live 19.1 (95% CI 19.0-19.3) years in good health and 13.5 (95% CI 13.2-13.7) years without chronic diseases between ages 50 and 75. Healthy and disease-free years were 1-3 years shorter for those who slept less than 7 hours or slept 9 hours or more. Persons who did not have sleep disturbances could expect to live 20.4 (95% CI 20.3-20.6) years in good health and 14.3 (95% CI 14.1-14.5) years without chronic diseases between ages 50 and 75. Healthy and disease-free years were 6-3 years shorter for those who reported severe sleep disturbances.Sleeping 7-8.5 hours and having no sleep disturbances between ages 50 to 75 are associated with longer healthy and chronic disease-free LE

Long working hours and risk of 50 health conditions and mortality outcomes: a multicohort study in four European countries

Background: Studies on the association between long working hours and health have captured only a narrow range of outcomes (mainly cardiometabolic diseases and depression) and no outcome-wide studies on this topic are available. To achieve wider scope of potential harm, we examined long working hours as a risk factor for a wide range of disease and mortality endpoints. / Methods: The data of this multicohort study were from two population cohorts from Finland (primary analysis, n=59 599) and nine cohorts (replication analysis, n=44 262) from Sweden, Denmark, and the UK, all part of the Individual-participant Meta-analysis in Working Populations (IPD-Work) consortium. Baseline-assessed long working hours (≥55 hours per week) were compared to standard working hours (35-40 h). Outcome measures with follow-up until age 65 years were 46 diseases that required hospital treatment or continuous pharmacotherapy, all-cause, and three cause-specific mortality endpoints, ascertained via linkage to national health and mortality registers. / Findings: 2747 (4·6%) participants in the primary cohorts and 3027 (6·8%) in the replication cohorts worked long hours. After adjustment for age, sex, and socioeconomic status, working long hours was associated with increased risk of cardiovascular death (hazard ratio 1·68; 95% confidence interval 1·08-2·61 in primary analysis and 1·52; 0·90-2·58 in replication analysis), infections (1·37; 1·13-1·67 and 1·45; 1·13-1·87), diabetes (1·18; 1·01-1·38 and 1·41; 0·98-2·02), injuries (1·22; 1·00-1·50 and 1·18; 0·98-1·18) and musculoskeletal disorders (1·15; 1·06-1·26 and 1·13; 1·00-1·27). Working long hours was not associated with all-cause mortality. / Interpretation: Follow-up of 50 health outcomes in four European countries suggests that working long hours is associated with an elevated risk of early cardiovascular death and hospital-treated infections before age 65. Associations, albeit weak, were also observed with diabetes, musculoskeletal disorders and injuries. In these data working long hours was not related to elevated overall mortality. Funding: NordForsk, the Medical Research Council, the National Institute on Aging, the Wellcome Trust, Academy of Finland, and Finnish Work Environment Fund

Workplace bullying and workplace violence as risk factors for cardiovascular disease: a multi-cohort study

Aims To assess the associations between bullying and violence at work and cardiovascular disease (CVD).Methods and results Participants were 79 201 working men and women, aged 18–65 years and free of CVD and were sourced from three cohort studies from Sweden and Denmark. Exposure to workplace bullying and violence was measured at baseline using self-reports. Participants were linked to nationwide health and death registers to ascertain incident CVD, including coronary heart disease and cerebrovascular disease. Study-specific results were estimated by marginal structural Cox regression and were combined using fixed-effect meta-analysis. Nine percent reported being bullied at work and 13% recorded exposure to workplace violence during the past year. We recorded 3229 incident CVD cases with a mean follow-up of 12.4 years (765 in the first 4 years). After adjustment for age, sex, country of birth, marital status, and educational level, being bullied at work vs. not was associated with a hazard ratio (HR) of 1.59 [95% confidence interval (CI) 1.28–1.98] for CVD. Experiencing workplace violence vs. not was associated with a HR of 1.25 (95% CI 1.12–1.40) for CVD. The population attributable risk was 5.0% for workplace bullying and 3.1% for workplace violence. The excess risk remained similar in analyses with different follow-up lengths, cardiovascular risk stratifications, and after additional adjustments. Dose–response relations were observed for both workplace bullying and violence (Ptrend Conclusion Bullying and violence are common at workplaces and those exposed to these stressors are at higher risk of CVD.</p

Human papillomavirus, high-grade intraepithelial neoplasia and killer immunoglogulin-like receptors: a Western Australian cohort study

Background: Human papillomavirus (HPV) is the causative agent in cervical cancer and HPV genotypes 16 and 18 cause the majority of these cancers. Natural killer (NK) cells destroy virally infected and tumour cells via killer immunoglobulin-like receptors (KIR) that recognize decreased MHC class I expression. These NK cells may contribute to clearance of HPV infected and/or dysplastic cells, however since KIR controls NK cell activity, KIR gene variation may determine outcome of infection.Methods: KIR gene frequencies were compared between 147 patients with a history of high-grade cervical intraepithelial neoplasia (CIN) and a control population of 187, to determine if any KIR genes are associated with high-grade CIN. In addition a comparison was also made between cases of high grade CIN derived from 30 patients infected with HPV 16/18 and 29 patients infected with non-16/18 HPV to determine if KIR variation contributes to the disproportional carcinogenesis derived from HPV 16/18 infection.Results: High-grade CIN was weakly associated with the absence of KIR2DL2 and KIR2DS2 (p = 0.046 and 0.049 respectively, OR 0.6; 95% CI 0.4 – 0.9) but this association was lost after correction for multi-gene statistical analysis.No difference in KIR gene frequencies was found between high-grade CIN caused by HPV 16/18 and non-16/18.Conclusion: No strong association between KIR genes, high-grade CIN and HPV genotype was found in the Western Australian population