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1.  Influence of the ABCG2 gout risk 141 K allele on urate metabolism during a fructose challenge 
Introduction
Both genetic variation in ATP-binding cassette sub-family G member 2 (ABCG2) and intake of fructose-containing beverages are major risk factors for hyperuricemia and gout. This study aimed to test the hypothesis that the ABCG2 gout risk allele 141 K promotes the hyperuricaemic response to fructose loading.
Methods
Healthy volunteers (n = 74) provided serum and urine samples immediately before and 30, 60, 120 and 180 minutes after ingesting a 64 g fructose solution. Data were analyzed based on the presence or absence of the ABCG2 141 K gout risk allele.
Results
The 141 K risk allele was present in 23 participants (31%). Overall, serum urate (SU) concentrations during the fructose load were similar in those with and without the 141 K allele (PSNP = 0.15). However, the 141 K allele was associated with a smaller increase in SU following fructose intake (PSNP <0.0001). Those with the 141 K allele also had a smaller increase in serum glucose following the fructose load (PSNP = 0.002). Higher fractional excretion of uric acid (FEUA) at baseline and throughout the fructose load was observed in those with the 141 K risk allele (PSNP <0.0001). However, the change in FEUA in response to fructose was not different in those with and without the 141 K risk allele (PSNP = 0.39). The 141 K allele effects on serum urate and glucose were more pronounced in Polynesian participants and in those with a body mass index ≥25 kg/m2.
Conclusions
In contrast to the predicted responses for a hyperuricemia/gout risk allele, the 141 K allele is associated with smaller increases in SU and higher FEUA following a fructose load. The results suggest that ABCG2 interacts with extra-renal metabolic pathways in a complex manner to regulate SU and gout risk.
Clinical Trials Registration
The study was registered by the Australian Clinical Trials Registry (ACTRN12610001036000).
doi:10.1186/ar4463
PMCID: PMC3978630  PMID: 24476385
2.  Lack of change in urate deposition by dual-energy computed tomography among clinically stable patients with long-standing tophaceous gout: a prospective longitudinal study 
Arthritis Research & Therapy  2013;15(5):R160.
Introduction
Dual-energy computed tomography (DECT) has potential for monitoring urate deposition in patients with gout. The aim of this prospective longitudinal study was to analyse measurement error of DECT urate volume measurement in clinically stable patients with tophaceous gout.
Methods
Seventy-three patients with tophaceous gout on stable therapy attended study visits at baseline and twelve months. All patients had a comprehensive clinical assessment including serum urate testing and DECT scanning of both feet. Two readers analysed the DECT scans for the total urate volume in both feet. Analysis included inter-reader intraclass correlation coefficients (ICCs) and limits of agreement, and calculation of the smallest detectable change.
Results
Mean (standard deviation) serum urate concentration over the study period was 0.38 (0.09) mmol/L. Urate-lowering therapy was prescribed in 70 (96%) patients. The median (interquartile range) baseline DECT urate volume was 0.49 (0.16, 2.18) cm3, and change in DECT urate volume was -0.01 (-0.40, 0.28) cm3. Inter-reader ICCs were 1.00 for baseline DECT volumes and 0.93 for change values. Inter-reader bias (standard deviation) for baseline volumes was -0.18 (0.63) cm3 and for change was -0.10 (0.93) cm3. The smallest detectable change was 0.91 cm3. There were 47 (64%) patients with baseline DECT urate volumes <0.91 cm3. Higher serum urate concentrations were observed in patients with increased DECT urate volumes above the smallest detectable change (P = 0.006). However, a relationship between changes in DECT urate volumes and serum urate concentrations was not observed in the entire group.
Conclusions
In patients with tophaceous gout on stable conventional urate-lowering therapy the measurement error for DECT urate volume assessment is substantially greater than the median baseline DECT volume. Analysis of patients commencing or intensifying urate-lowering therapy should clarify the optimal use of DECT as a potential outcome measure in studies of chronic gout.
doi:10.1186/ar4343
PMCID: PMC3978645  PMID: 24286500
3.  Treatment with a copper-selective chelator causes substantive improvement in cardiac function of diabetic rats with left-ventricular impairment 
Background
Defective copper regulation is implicated as a causative mechanism of organ damage in diabetes. Treatment with trientine, a divalent-copper-selective chelator, improves arterial and renal structure/function in diabetes, wherein it also ameliorates left-ventricular (LV) hypertrophy. However, direct in vivo evidence that trientine can improve cardiac function in heart failure has hitherto been lacking.
Methods
To determine whether trientine treatment could improve in vivo outcome, we measured cardiac function in groups of trientine-treated diabetic (TETA-DIA), non-drug-treated diabetic (DIA) and sham-treated control (SHAM) rats, by using in vivo high-field cardiac magnetic-resonance imaging (cMRI) and an ex vivo isolated-perfused working heart method. Forty age-matched animals underwent a cMRI scan after which 12 were randomized to the SHAM group and 28 underwent streptozotocin-injection; of these, 25 developed stable diabetes, and 12 were then randomized to receive no treatment for 16 weeks (DIA) and the other 13 to undergo 8-weeks’ untreated diabetes followed by 8-weeks’ drug treatment (TETA-DIA). Animals were studied again by cMRI at 8 and 16 weeks following disease induction, and finally by measurement of ex vivo cardiac function.
Results
After eight weeks diabetes, rats (DIA/TETA-DIA) had developed significant impairment of LV function, as judged by impairment of ejection fraction (LVEF), cardiac output (CO), and LV mass (LVM)/body-mass (all P < 0.001), as well as other functional indexes. LVEF, CO (both P < 0.001) and the other indexes deteriorated further at 16 weeks in DIA, whereas trientine (TETA-DIA) improved cardiac function by elevating LVEF and CO (both P < 0.001), and also partially reversed the increase in LVM/body-mass (P < 0.05). In ex vivo hearts from DIA, the CO response to increasing preload pressure was deficient compared with SHAM (P < 0.001) whereas the preload-CO relationship was significantly improved in TETA-DIA animals (P < 0.001).
Conclusions
Trientine treatment significantly improved cardiac function in diabetic rats with substantive LV impairment. These results implicate impaired copper regulation in the pathogenesis of impaired cardiac function caused by diabetic cardiomyopathy, and support ongoing studies of trientine treatment in patients with heart failure.
doi:10.1186/1475-2840-12-28
PMCID: PMC3602174  PMID: 23368770
Heart failure; Cardiovascular disease; Cardiac output; Complications of diabetes; Diabetic cardiomyopathy; Diastolic function; Cardiac magnetic resonance imaging; Left-ventricular ejection fraction; Left-ventricular end systolic volume; Left-ventricular end diastolic volume; Selective copper chelation; Systolic function; Experimental therapeutics
4.  GSTM1 null genotype in COPD and lung cancer: evidence of a modifier or confounding effect? 
Background
Studies over the past two decades have reported associations between GSTM1 (glutathione S-transferase mu 1) null genotype and chronic obstructive pulmonary disease (COPD) or lung cancer. However, a modifier or confounding effect from COPD mediating the GSTM1 association with lung cancer has not been previously explored.
Aim and methods
This variant was examined in a case-control study of current or former smokers with COPD (n = 669), lung cancer (n = 454), or normal lung function (n = 488). Sex, age, and smoking history were comparable between groups.
Results
The GSTM1 null genotype was found to be more frequent in smokers with COPD alone (odds ratio [OR] 1.30, 95% confidence interval [CI] 1.02–1.66, P = 0.031) and lung cancer (OR 1.26, 95% CI 0.96–1.65, P = 0.083) than in matched smokers with normal lung function (62%, 61%, and 56%, respectively). However, when smokers with lung cancer were subgrouped according to the presence of COPD, then the association with all COPD subjects (OR 1.34, 95% CI 1.07–1.70, P = 0.010) and with COPD and lung cancer (OR 1.50, 95% CI 1.06–2.12, P = 0.018) continued to be significant while that with lung cancer only was reduced (OR 1.11, 95% CI 0.78–1.56, P = 0.55). These associations were independent of age, sex, height, lung function, and smoking history.
Conclusion
Findings suggest that COPD is an important subphenotype of lung cancer and may underlie previously reported associations with the GSTM1 null genotype.
doi:10.2147/TACG.S21517
PMCID: PMC3681185  PMID: 23776374
lung cancer; chronic obstructive pulmonary disease; GSTM1; association study; polymorphism; copy number variant
5.  Genetic evidence linking lung cancer and COPD: a new perspective 
Epidemiological studies indicate that tobacco smoke exposure accounts for nearly 90% of cases of chronic obstructive pulmonary disease (COPD) and lung cancer. However, genetic factors may explain why 10%–30% of smokers develop these complications. This perspective reviews the evidence suggesting that COPD is closely linked to susceptibility to lung cancer and outlines the potential relevance of this observation. Epidemiological studies show that COPD is the single most important risk factor for lung cancer among smokers and predates lung cancer in up to 80% of cases. Genome-wide association studies of lung cancer, lung function, and COPD have identified a number of overlapping “susceptibility” loci. With stringent phenotyping, it has recently been shown that several of these overlapping loci are independently associated with both COPD and lung cancer. These loci implicate genes underlying pulmonary inflammation and apoptotic processes mediated by the bronchial epithelium, and link COPD with lung cancer at a molecular genetic level. It is currently possible to derive risk models for lung cancer that incorporate lung cancer-specific genetic variants, recently identified “COPD-related” genetic variants, and clinical variables. Early studies suggest that single nucleotide polymorphism-based risk stratification of smokers might help better target novel prevention and early diagnostic strategies in lung cancer.
doi:10.2147/TACG.S20083
PMCID: PMC3681182  PMID: 23776371
lung cancer; chronic obstructive pulmonary disease; association study; single nucleotide polymorphism; risk model
6.  Authors’ reply 
BMJ : British Medical Journal  2008;336(7641):404.
doi:10.1136/bmj.39495.575289.BE
PMCID: PMC2249642
7.  FAM13A locus in COPD is independently associated with lung cancer – evidence of a molecular genetic link between COPD and lung cancer 
Recent genome-wide association studies have reported a FAM13A variant on chromosome 4q22.1 is associated with lung function and COPD. We examined this variant in a case-control study of current or former smokers with chronic obstructive pulmonary disease (COPD, n = 458), lung cancer (n = 454), or normal lung function (n = 488). Sex, age, and smoking history were comparable between groups. We confirmed the FAM13A variant (rs7671167) confers a protective effect on smoking-related COPD alone (C allele odds ratio [OR] = 0.79, P = 0.013, and CC genotype OR = 0.71, P = 0.024) and those with COPD, both with and without lung cancer (C allele OR = 0.80, P = 0.008, and CC genotype OR = 0.70, P = 0.007). The FAM13A variant also confers a protective effect on lung cancer overall (C allele OR = 0.75, P = 0.002, and CC genotype OR = 0.64, P = 0.003) even after excluding those with co-existing COPD (C allele OR = 0.67, P = 0.0007, and CC genotype OR = 0.58, P = 0.006). This was independent of age, sex, height, lung function, and smoking history. This protective effect was confined to those with nonsmall cell lung cancer (C allele OR = 0.72, P = 0.0009, and CC genotype OR = 0.61, P = 0.003). This study suggests that genetic predisposition to COPD is shared with lung cancer through shared pathogenetic factors such as the 4q22.1 locus implicating the Rho-kinase pathway.
doi:10.2147/TACG.S15758
PMCID: PMC3681173  PMID: 23776362
lung cancer; chronic obstructive pulmonary disease; FAM13A; association study; polymorphism; GTPase
8.  Lung Cancer Susceptibility Model Based on Age, Family History and Genetic Variants 
PLoS ONE  2009;4(4):e5302.
Background
Epidemiological and pedigree studies suggest that lung cancer results from the combined effects of age, smoking, impaired lung function and genetic factors. In a case control association study of healthy smokers and lung cancer cases, we identified genetic markers associated with either susceptibility or protection to lung cancer.
Methodology/Principal Findings
We screened 157 candidate single nucleotide polymorphisms (SNP) in a discovery cohort of 439 subjects (200 controls and 239 lung cancer cases) and identified 30 SNPs associated with either the healthy smokers (protective) or lung cancer (susceptibility) phenotype. After genotyping this 30 SNP panel in a validation cohort of 491 subjects (248 controls and 207 lung cancers) and, using the same protective and susceptibility genotypes from our discovery cohort, a 20 SNP panel was selected based on replication of SNP associations in the validation cohort. Following multivariate logistic regression analyses, including the selected SNPs from runs 1 and 2, we found age and family history of lung cancer to be significantly and independently associated with lung cancer. Numeric scores were assigned to both the SNP and demographic data, and combined to form a simple algorithm of risk.
Conclusions/Significance
Significant differences in the distribution of the lung cancer susceptibility score was found between normal controls and lung cancer cases, which remained after accounting for differences in lung function. Validation in other case-control and prospective cohorts are underway to further define the potential clinical utility of this model.
doi:10.1371/journal.pone.0005302
PMCID: PMC2668761  PMID: 19390575
9.  Vascular events in healthy older women receiving calcium supplementation: randomised controlled trial 
BMJ : British Medical Journal  2008;336(7638):262-266.
Objective To determine the effect of calcium supplementation on myocardial infarction, stroke, and sudden death in healthy postmenopausal women.
Design Randomised, placebo controlled trial.
Setting Academic medical centre in an urban setting in New Zealand.
Participants 1471 postmenopausal women (mean age 74): 732 were randomised to calcium supplementation and 739 to placebo.
Main outcome measures Adverse cardiovascular events over five years: death, sudden death, myocardial infarction, angina, other chest pain, stroke, transient ischaemic attack, and a composite end point of myocardial infarction, stroke, or sudden death.
Results Myocardial infarction was more commonly reported in the calcium group than in the placebo group (45 events in 31 women v 19 events in 14 women, P=0.01). The composite end point of myocardial infarction, stroke, or sudden death was also more common in the calcium group (101 events in 69 women v 54 events in 42 women, P=0.008). After adjudication myocardial infarction remained more common in the calcium group (24 events in 21 women v 10 events in 10 women, relative risk 2.12, 95% confidence interval 1.01 to 4.47). For the composite end point 61 events were verified in 51 women in the calcium group and 36 events in 35 women in the placebo group (relative risk 1.47, 0.97 to 2.23). When unreported events were added from the national database of hospital admissions in New Zealand the relative risk of myocardial infarction was 1.49 (0.86 to 2.57) and that of the composite end point was 1.21 (0.84 to 1.74). The respective rate ratios were 1.67 (95% confidence intervals 0.98 to 2.87) and 1.43 (1.01 to 2.04); event rates: placebo 16.3/1000 person years, calcium 23.3/1000 person years. For stroke (including unreported events) the relative risk was 1.37 (0.83 to 2.28) and the rate ratio was 1.45 (0.88 to 2.49).
Conclusion Calcium supplementation in healthy postmenopausal women is associated with upward trends in cardiovascular event rates. This potentially detrimental effect should be balanced against the likely benefits of calcium on bone.
Trial registration Australian Clinical Trials Registry ACTRN 012605000242628.
doi:10.1136/bmj.39440.525752.BE
PMCID: PMC2222999  PMID: 18198394
10.  Individual and Cumulative Effects of GWAS Susceptibility Loci in Lung Cancer: Associations after Sub-Phenotyping for COPD 
PLoS ONE  2011;6(2):e16476.
Epidemiological studies show that approximately 20–30% of chronic smokers develop chronic obstructive pulmonary disease (COPD) while 10–15% develop lung cancer. COPD pre-exists lung cancer in 50–90% of cases and has a heritability of 40–77%, much greater than for lung cancer with heritability of 15–25%. These data suggest that smokers susceptible to COPD may also be susceptible to lung cancer. This study examines the association of several overlapping chromosomal loci, recently implicated by GWA studies in COPD, lung function and lung cancer, in (n = 1400) subjects sub-phenotyped for the presence of COPD and matched for smoking exposure. Using this approach we show; the 15q25 locus confers susceptibility to lung cancer and COPD, the 4q31 and 4q22 loci both confer a reduced risk to both COPD and lung cancer, the 6p21 locus confers susceptibility to lung cancer in smokers with pre-existing COPD, the 5p15 and 1q23 loci both confer susceptibility to lung cancer in those with no pre-existing COPD. We also show the 5q33 locus, previously associated with reduced FEV1, appears to confer susceptibility to both COPD and lung cancer. The 6p21 locus previously linked to reduced FEV1 is associated with COPD only. Larger studies will be needed to distinguish whether these COPD-related effects may reflect, in part, associations specific to different lung cancer histology. We demonstrate that when the “risk genotypes” derived from the univariate analysis are incorporated into an algorithm with clinical variables, independently associated with lung cancer in multivariate analysis, modest discrimination is possible on receiver operator curve analysis (AUC = 0.70). We suggest that genetic susceptibility to lung cancer includes genes conferring susceptibility to COPD and that sub-phenotyping with spirometry is critical to identifying genes underlying the development of lung cancer.
doi:10.1371/journal.pone.0016476
PMCID: PMC3033394  PMID: 21304900

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