Novel associations between blood DNA methylation and body mass index in middle-aged and older adults.

BACKGROUND/OBJECTIVES: There is increasing evidence of a relationship between blood DNA methylation and body mass index (BMI). We aimed to assess associations of BMI with individual methylation measures (CpGs) through a cross-sectional genome-wide DNA methylation association study and a longitudinal analysis of repeated measurements over time. SUBJECTS/METHODS: Using the Illumina Infinium HumanMethylation450 BeadChip, DNA methylation measures were determined in baseline peripheral blood samples from 5361 adults recruited to the Melbourne Collaborative Cohort Study (MCCS) and selected for nested case-control studies, 2586 because they were subsequently diagnosed with cancer (cases) and 2775 as controls. For a subset of 1088 controls, these measures were repeated using blood samples collected at wave 2 follow-up, a median of 11 years later; weight was measured at both time points. Associations between BMI and blood DNA methylation were assessed using linear mixed-effects regression models adjusted for batch effects and potential confounders. These were applied to cases and controls separately, with results combined through fixed-effects meta-analysis. RESULTS: Cross-sectional analysis identified 310 CpGs associated with BMI with P<1.0 × 10-7, 225 of which had not been reported previously. Of these 225 novel associations, 172 were replicated (P<0.05) using the Atherosclerosis Risk in Communities (ARIC) study. We also replicated using MCCS data (P<0.05) 335 of 392 associations previously reported with P<1.0 × 10-7, including 60 that had not been replicated before. Associations between change in BMI and change in methylation were observed for 34 of the 310 strongest signals in our cross-sectional analysis, including 7 that had not been replicated using the ARIC study. CONCLUSIONS: Together, these findings suggest that BMI is associated with blood DNA methylation at a large number of CpGs across the genome, several of which are located in or near genes involved in ATP-binding cassette transportation, tumour necrosis factor signalling, insulin resistance and lipid metabolism.

Nutritional predictors of chronic disease in a Central Australian Aboriginal cohort: A multi-mixture modelling analysis.

BACKGROUND AND AIMS: Chronic diseases (including diabetes, cardiovascular disease, hypertension and chronic kidney disease) are major contributors to the total burden of disease for Aboriginal people. Here we used novel epidemiological modelling to investigate nutritional profiles at a population level associated with chronic disease. METHODS AND RESULTS: Multi-mixture modelling, was used to group members of a Central Australian Aboriginal population (n = 444) based on their nutritional profile from a risk factor prevalence survey in 1995. Multi-mixture modelling assigned % membership to four classes; Class 1 (young, low adiposity and lipids, low dietary antioxidants; n = 171.7); Class 2 (older, greater adiposity and lipids; n = 22.6); Class 3 (predominantly female, greater adiposity and antioxidants, low smoking; n = 134.3) and Class 4 (predominantly male, greater lipids and adiposity, low antioxidants, high smoking prevalence; n = 115.4). For persons free of chronic disease (n = 285), incident chronic disease for classes 1, 3 and 4 was determined using follow up hospital, primary health care and death records collected in 2004/05. Fifty-four percent of Class 4 had incident chronic disease, an excess of 3355 events per 100,000 person years relative to Class 1. Incident CVD, hypertension, or CKD was highest for Class 4 and incident diabetes highest for Class 3. CONCLUSION: Multi-mixture modelling appears useful in identifying population subgroups of an Aboriginal population at risk of chronic conditions.

FGF receptor genes and breast cancer susceptibility: results from the Breast Cancer Association Consortium.

BACKGROUND: Breast cancer is one of the most common malignancies in women. Genome-wide association studies have identified FGFR2 as a breast cancer susceptibility gene. Common variation in other fibroblast growth factor (FGF) receptors might also modify risk. We tested this hypothesis by studying genotyped single-nucleotide polymorphisms (SNPs) and imputed SNPs in FGFR1, FGFR3, FGFR4 and FGFRL1 in the Breast Cancer Association Consortium. METHODS: Data were combined from 49 studies, including 53 835 cases and 50 156 controls, of which 89 050 (46 450 cases and 42 600 controls) were of European ancestry, 12 893 (6269 cases and 6624 controls) of Asian and 2048 (1116 cases and 932 controls) of African ancestry. Associations with risk of breast cancer, overall and by disease sub-type, were assessed using unconditional logistic regression. RESULTS: Little evidence of association with breast cancer risk was observed for SNPs in the FGF receptor genes. The strongest evidence in European women was for rs743682 in FGFR3; the estimated per-allele odds ratio was 1.05 (95% confidence interval=1.02-1.09, P=0.0020), which is substantially lower than that observed for SNPs in FGFR2. CONCLUSION: Our results suggest that common variants in the other FGF receptors are not associated with risk of breast cancer to the degree observed for FGFR2.

Capillary electrophoretic analysis of serine hydroxymethyltransferase in Escherichia coli fermentation broth.

Serine hydroxymethyltransferase (SHMT) expressed in Escherichia coli was analyzed in fermentation broth through the use of capillary electrophoresis (CE), a method which provided advantages over the traditional techniques of slab gel electrophoresis and chromatography. In addition, via CE the difficult resolution and quantitation of SHMT holoenzyme and apoenzyme were achieved. Using this method, a pyridoxal-5'-phosphate (PLP) cofactor/SHMT dimer molar ratio of 0.65 was estimated to be present in holoenzyme in the absence of excess PLP. This determination correlated well with results obtained by other techniques, including electrospray ionization mass spectrometry (ESI-MS). CE and ESI-MS analyses both provided evidence for significant differences between the folded conformations of SHMT holoenzyme and apoenzyme.

Inaccurate blood flow rate during rapid hemodialysis.

Simulated hemodialysis with isotonic saline was performed to compare the requested blood flow rate (BFR-r) with the actual blood flow rate (BFR-a) delivered during rapid, efficient hemodialysis. Four different blood pumps and blood lines from three different manufacturers were used for the studies. BFR-r was set on each blood pump, and a timed outflow specimen from the dialysis circuit was used to measure the BFR-a delivered. BFR-r values of 200, 350, and 500 mL/min were used; the arterial pressure was set at -50, -250, and -325 mm Hg. BFR was determined every hour for 5 hours. At an arterial pressure of -50 mm Hg, the BFR-a was slightly higher than the BFR-r, and this did not vary over the 5-hour study period. When the arterial pressure was -250 mm Hg, the initial BFR-a was 95% of the BFR-r; at the end of the 5-hour study, this had declined to an average of 87% of the BFR-r. The largest discrepancy between BFR-a and BFR-r was at an arterial pressure of -325 mm Hg; the initial actual values averaged only 90% of the requested, and by the end of the 5-hour study, this value had declined to a mean of 78% of the BFR-r. The use of whole blood with a hematocrit value of 33% and the addition of venous resistance did not significantly affect these results.(ABSTRACT TRUNCATED AT 250 WORDS)

Deferoxamine and coated charcoal hemoperfusion to remove aluminum in dialysis patients.

We studied the in vitro and in vivo characteristics of aluminum (Al) removal by coated charcoal hemoperfusion (HP) in combination with intravenous deferoxamine (DFO). DFO enhanced the clearance of Al by HP in vitro after 180 minutes of perfusion with a solution containing 403.3 +/- 14.0 ng/ml of Al at 150 ml/min. The Al clearance was 139 +/- 1.0 ml/min with DFO and 49 +/- 10.0 ml/min (P less than 0.001) without DFO. Addition of DFO enhanced in vitro Al removal from 5.5 +/- 0.9 mg to 10.0 +/- 1.2 mg (P less than 0.05). During our in vivo studies, an HP device was in series in the dialysis circuit after a Cuprophan hemodialyzer. Eight patients with Al toxicity were studied on twelve occasions. Patients received DFO (40 mg/kg) 40 hours before the study. The total Al clearance with the combined hemodialysis (HD) and HP devices was higher than that obtained by the dialyzer alone at 30 minutes (62 +/- 4.9 ml/min vs. 25 +/- 2.5 ml/min, P less than 0.02) and after 180 to 210 minutes (32 +/- 3.0 ml/min vs. 19 +/- 2.9 ml/min, P less than 0.02). After 120 minutes the Al clearance by the HP device alone was significantly lower than the initial Al clearance by HP. Combined HD plus HP removed 2.9 +/- 0.4 mg of Al, whereas the total removal of Al by HD alone was 1.5 +/- 0.3 mg (P less than 0.01).

Structure of perceptions of older adults: evidence for multiple stereotypes.

We examined the possibility that people hold multiple stereotypes of the elderly. Subjects were male and female university students. In the first phase of our study, stereotype content was sampled by asking subjects to describe the typical old person. In the second phase of the study, different subjects sorted traits from Phase 1 descriptions into one or more groups. Each group contained those traits that subjects felt could be found in one and the same older adult. Attitudes toward the stereotypes were also assessed. A distance matrix, based on the number of subjects who sorted each pair of traits into different groups, was analyzed by hierarchical cluster analysis. Evidence for multiple stereotypes was found both in the presence of contradictory traits given in Phase 1 descriptions and in the structure of the clusters. Different attitudes are identified for the cluster-defined stereotypes.