Association between Diet Quality Indices and Incidence of Type 2 Diabetes in the Melbourne Collaborative Cohort Study

Type 2 diabetes mellitus is a common condition whose incidence is increasing worldwide, and for which obesity and diet are important risk factors. The aim of this study was to assess the association of three diet quality scores with diabetes risk and how much of the association was mediated through body size. The Melbourne Collaborative Cohort Study recruited 41,513 men and women aged 40–69 years during 1990–94. At baseline, data were collected on lifestyle and diet, anthropometric measures were performed. Incident diabetes was assessed by self-report at follow-up surveys in 1994–98 and 2003–07. The associations between the dietary inflammatory index (DII®), Mediterranean Diet Score (MDS) and the Alternative Healthy Eating Index—2010 and incident diabetes were assessed using Poisson regression, adjusting for age, sex, physical activity, smoking, alcohol consumption, socio-economic status (area based) and family history of diabetes. Data from 39,185 participants were included in the analysis and 1989 cases of diabetes were identified. Both DII and AHEI-2010 were associated with diabetes incidence, but MDS was not. In the top quintile of DII (most pro-inflammatory) vs. the least inflammatory quintile IRR was 1.49 95% CI (1.30, 1.72), p trend across quintiles <0.001. For AHEI-2010 the IRR was 0.67 (0.58, 0.78), p trend <0.001 for the healthiest vs. the least healthy quintile. Mediation analysis indicated that body size (body mass index/waist to hip ratio) mediated 35–48% of the association with incident diabetes for the AHEI and DII. Healthier diets may reduce risk of diabetes both by reducing weight gain and other mechanisms such as reducing inflammation.

Association of markers of inflammation, the kynurenine pathway and B vitamins with age and mortality, and a signature of inflammaging

Background Inflammation is a key feature of aging. We aimed to i) investigate the association of 34 blood markers potentially involved in inflammatory processes with age and mortality, ii) develop a signature of ‘inflammaging’. Methods Thirty-four blood markers relating to inflammation, B vitamin status and the kynurenine pathway were measured in 976 participants in the Melbourne Collaborative Cohort Study at baseline (median age=59 years) and follow-up (median age=70 years). Associations with age and mortality were assessed using linear and Cox regression, respectively. A parsimonious signature of inflammaging was developed and its association with mortality was compared with two marker scores calculated across all markers associated with age and mortality, respectively. Results The majority of markers (30/34) were associated with age, with stronger associations observed for neopterin, cystatin C, IL-6, TNF-α, several markers of the kynurenine pathway and derived indices KTR (kynurenine/tryptophan ratio), PAr index (ratio of 4-pyridoxic acid and the sum of pyridoxal 5´-phosphate and pyridoxal), and HK:XA (3-hydroxykynurenine/xanthurenic acid ratio). Many markers (17/34) showed an association with mortality, in particular IL-6, neopterin, CRP, quinolinic acid, PAr index, and KTR. The inflammaging signature included ten markers and was strongly associated of mortality (HR per SD=1.40, 95%CI:1.24-1.57, P=2x10 -8), similar to scores based on all age-associated (HR=1.38, 95%CI:1.23-1.55, P=4x10 -8) and mortality-associated markers (HR=1.43, 95%CI:1.28-1.60, P=1x10 -10), respectively. Strong evidence of replication of the inflammaging signature association with mortality was found in the Hordaland Health Study. Conclusion Our study highlights the key role of the kynurenine pathway and vitamin B6 catabolism in aging, along with other well-established inflammation-related markers. A signature of inflammaging based on ten markers was strongly associated with mortality.

Diet scores and prediction of general and abdominal obesity in the Melbourne Collaborative Cohort Study.

Objective To ascertain which of the Alternative Healthy Eating Index 2010 (AHEI), Dietary Inflammatory Index (DII®) and Mediterranean Diet Score (MDS) best predicted body mass index (BMI) and waist-to-hip circumference ratio (WHR). Design Body size was measured at baseline (1990-94) and in 2003-7. Diet was assessed at baseline using a food frequency questionnaire, along with age, sex, socioeconomic status, smoking, alcohol drinking, physical activity, and country of birth. Regression coefficients and 95% confidence intervals for the association of baseline dietary scores with follow-up BMI and WHR were generated using multivariable linear regression, adjusting for baseline body-size, confounders and energy intake. Setting Population-based cohort in Melbourne, Australia. Participants Included were data from 11,030 men and 16,774 women aged 40 to 69 years at baseline. Results Median (IQR) follow up was 11.6 (10.7 – 12.8) years. BMI and WHR at follow-up were associated with baseline DII® (Q5 vs Q1 (BMI 0.41 95%CI (0.21, 0.61) and WHR 0.009 95%CI (0.006, 0.013)), and AHEI (Q5 vs Q1 (BMI -0.51 95%CI (-0.68, -0.35) and WHR -0.011 95%CI (-0.013, -0.008)). WHR, but not BMI, at follow-up was associated with baseline MDS (Group 3 most Mediterranean vs G1 (BMI -0.05 95%CI (-0.23, 0.13) and WHR -0.004 95%CI (-0.007, -0.001)). Based on Akaike’s Information Criterion and Bayesian Information Criterion statistics, AHEI was a stronger predictor of body size than the other diet scores. Conclusion Poor quality or pro-inflammatory diets predicted overall and central obesity. The AHEI may provide the best way to assess the obesogenic potential of diet.

Smoking methylation marks for prediction of urothelial cancer risk

BackgroundSelf-reported information may not accurately capture smoking exposure. We aimed to evaluate whether smoking-associated DNA methylation markers improve urothelial cell carcinoma (UCC) risk prediction.MethodsConditional logistic regression was used to assess associations between blood-based methylation and UCC risk using two matched case-control samples, N=404 pairs from the Melbourne Collaborative Cohort Study (MCCS) and N=440 pairs from the Women’s Health Initiative (WHI) cohort, respectively. Results were pooled using fixed-effects meta-analysis. We developed methylation-based predictors of UCC and evaluated their prediction accuracy on two replication datasets using the area under the curve (AUC).ResultsThe meta-analysis identified associations (P<4.7×10−5) for 29 of 1,061 smoking-associated methylation sites, but these were substantially attenuated after adjustment for self-reported smoking. Nominally significant associations (P<0.05) were found for 387 (36%) and 86 (8%) of smoking-associated markers without/with adjustment for self-reported smoking, respectively, with same direction of association as with smoking for 387 (100%) and 79 (92%) markers. A Lasso-based predictor was associated with UCC risk in one replication dataset in MCCS (N=134, odds ratio per SD [OR]=1.37, 95%CI=1.00-1.90) after confounder adjustment; AUC=0.66, compared with AUC=0.64 without methylation information. Limited evidence of replication was found in the second testing dataset in WHI (N=440, OR=1.09, 95%CI=0.91-1.30).ConclusionsCombination of smoking-associated methylation marks may provide some improvement to UCC risk prediction. Our findings need further evaluation using larger datasets.ImpactDNA methylation may be associated with UCC risk beyond traditional smoking assessment and could contribute to some improvements in stratification of UCC risk in the general population.

Obesity defined by body mass index and waist circumference and risk of total knee arthroplasty for osteoarthritis: A prospective cohort study

Objective To examine the risk of total knee arthroplasty (TKA) due to osteoarthritis associated with obesity defined by body mass index (BMI) or waist circumference (WC) and whether there is discordance between these measures in assessing this risk. Methods 36,784 participants from the Melbourne Collaborative Cohort Study with BMI and WC measured at 1990–1994 were included. Obesity was defined by BMI (≥30 kg/m2) or WC (men ≥102cm, women ≥88cm). The incidence of TKA between January 2001 and December 2018 was determined by linking participant records to the National Joint Replacement Registry. Results Over 15.4±4.8 years, 2,683 participants underwent TKA. There were 20.4% participants with BMI-defined obesity, 20.8% with WC-defined obesity, and 73.6% without obesity defined by either BMI or WC. Obesity was classified as non-obese (misclassified obesity) in 11.7% of participants if BMI or WC alone was used to define obesity. BMI-defined obesity (HR 2.69, 95%CI 2.48–2.92), WC-defined obesity (HR 2.28, 95%CI 2.10–2.48), and obesity defined by either BMI or WC (HR 2.53, 95%CI 2.33–2.74) were associated with an increased risk of TKA. Compared with those without obesity, participants with misclassified obesity had an increased risk of TKA (HR 2.06, 95%CI 1.85–2.30). 22.7% of TKA in the community can be attributable to BMI-defined obesity, and a further 3.3% of TKA can be identified if WC was also used to define obesity. Conclusions Both BMI and WC should be used to identify obese individuals who are at risk of TKA for osteoarthritis and should be targeted for prevention and treatment.

Body Mass Index- and Waist Circumference-Defined Obesity with the risk of Total Knee Arthroplasty for Osteoarthritis: A prospective cohort study

Background: There is a discordance in classification of obesity when defined by body mass index (BMI) or waist circumference (WC). We aimed to examine whether categories of BMI- and WC-defined obesity are differentially associated with the risk of total knee arthroplasty for osteoarthritis.Methods: 38,924 participants from the Melbourne Collaborative Cohort Study with BMI and WC measured at baseline (1990-1994) were included. Obesity status was defined as: not obese (non-obese BMI and non-obese WC); WC-defined obesity only (non-obese BMI and obese WC); BMI-defined obesity only (non-obese WC and obese BMI); and BMI- and WC-defined obesity. The incidence of total knee arthroplasty for osteoarthritis between January 2001 and December 2013 was determined by linking participant records to the National Joint Replacement Registry. Results: Over 11.5±3.1 years follow-up, 1,875 participants underwent total knee arthroplasty for osteoarthritis. Participants with WC-defined obesity only (HR=1.79, 95%CI 1.51-2.53), BMI-defined obesity only (HR=2.39, 95%CI 2.02-2.84), and BMI- and WC-defined obesity (HR=3.14, 95%CI 2.82-3.49) had an increased risk of total knee arthroplasty compared with those who were not obese. Conclusions: Individuals with either BMI- or WC-defined obesity should be targeted for prevention of knee osteoarthritis as both are significant predictors for severe osteoarthritis requiring a total knee arthroplasty.

Body Mass Index- and Waist Circumference-Defined Obesity with the risk of Total Knee Arthroplasty for Osteoarthritis: A prospective cohort study

Background There is a discordance in classification of obesity when defined by body mass index (BMI) or waist circumference (WC). We aimed to examine whether categories of BMI- and WC-defined obesity are differentially associated with the risk of total knee arthroplasty for osteoarthritis. Methods 38,924 participants from the Melbourne Collaborative Cohort Study with BMI and WC measured at baseline (1990-1994) were included. Obesity status was defined as: not obese (non-obese BMI and non-obese WC); WC-defined obesity only (non-obese BMI and obese WC); BMI-defined obesity only (non-obese WC and obese BMI); and BMI- and WC-defined obesity. The incidence of total knee arthroplasty for osteoarthritis between January 2001 and December 2013 was determined by linking participant records to the National Joint Replacement Registry. Results Over 11.5±3.1 years follow-up, 1,875 participants underwent total knee arthroplasty for osteoarthritis. Participants with WC-defined obesity only (HR=1.79, 95%CI 1.51-2.53), BMI-defined obesity only (HR=2.39, 95%CI 2.02-2.84), and BMI- and WC-defined obesity (HR=3.14, 95%CI 2.82-3.49) had an increased risk of total knee arthroplasty compared with those who were not obese. Conclusions Individuals with either BMI- or WC-defined obesity should be targeted for prevention of knee osteoarthritis as both are significant predictors for severe osteoarthritis requiring a total knee arthroplasty.

Analysis of retrotransposon subfamily DNA methylation reveals novel early epigenetic changes in chronic lymphocytic leukemia

Retrotransposons such as LINE-1 and Alu comprise >25% of the human genome. While global hypomethylation of these elements has been widely reported in solid tumours, their epigenetic dysregulation is yet to be characterised in chronic lymphocytic leukaemia, and there has been scant consideration of their evolutionary history that mediates sensitivity to hypomethylation. Here, we developed an approach for locus- and evolutionary subfamily-specific analysis of retrotransposons using the Illumina Infinium Human Methylation 450K microarray platform, which we applied to publicly-available datasets from chronic lymphocytic leukaemia and other haematological malignancies. We identified 9,797 microarray probes mapping to 117 LINE-1 subfamilies and 13,130 mapping to 37 Alu subfamilies. Of these, 10,782 were differentially methylated (PFDR<0.05) in chronic lymphocytic leukaemia patients (n=139) compared with healthy individuals (n=14), with enrichment at enhancers (p=0.002). Differential methylation was associated with evolutionary age of LINE-1 (r2=0.31, p=0.003) and Alu (r2=0.74, p=0.002) elements, with greater hypomethylation of older subfamilies (L1M, AluJ). Locus-specific hypomethylation was associated with differential expression of proximal genes, including DCLK2, HK1, ILRUN, TANK, TBCD, TNFRSF1B and TXNRD2, with higher expression of DCLK2 and TNFRSF1B associated with reduced patient survival. Hypomethylation at nine loci was highly frequent in chronic lymphocytic leukaemia (>90% patients) but not observed in healthy individuals or other leukaemias, and was detectable in blood samples taken prior to chronic lymphocytic leukaemia diagnosis in 9 of 82 individuals from the Melbourne Collaborative Cohort Study. Our results demonstrate differential methylation of retrotransposons in chronic lymphocytic leukaemia by their evolutionary heritage that modulates expression of proximal genes.