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Lung-function impairment underlies chronic obstructive pulmonary disease (COPD) and predicts mortality. In the largest multi-ancestry genome-wide association meta-analysis of lung function to date, comprising 588,452 participants, we identified 1,020 independent association signals implicating 559 genes supported by ≥2 criteria from a systematic variant-to-gene mapping framework. These genes were enriched in 29 pathways. Individual variants showed heterogeneity across ancestries, age and smoking groups, and collectively as a genetic risk score showed strong association with COPD across ancestry groups. We undertook phenome-wide association studies for selected associated variants as well as trait and pathway-specific genetic risk scores to infer possible consequences of intervening in pathways underlying lung function. We highlight new putative causal variants, genes, proteins and pathways, including those targeted by existing drugs. These findings bring us closer to understanding the mechanisms underlying lung function and COPD, and should inform functional genomics experiments and potentially future COPD therapies.

Although physical activity and sedentary behavior are moderately heritable, little is known about the mechanisms that influence these traits. Combining data for up to 703,901 individuals from 51 studies in a multi-ancestry meta-analysis of genome-wide association studies yields 99 loci that associate with self-reported moderate-to-vigorous intensity physical activity during leisure time (MVPA), leisure screen time (LST) and/or sedentary behavior at work. Loci associated with LST are enriched for genes whose expression in skeletal muscle is altered by resistance training. A missense variant in ACTN3makes the alpha-actinin-3 filaments more flexible, resulting in lower maximal force in isolated type IIAmuscle fibers, and possibly protection from exercise-induced muscle damage. Finally, Mendelian randomization analyses show that beneficial effects of lower LST and higher MVPA on several risk factors and diseases are mediated or confounded by body mass index (BMI). Our results provide insights into physical activity mechanisms and its role in disease prevention.

Abstract Objective To test the hypothesis that the incidence of fatal coronary heart disease and cardiovascular disease in a general population is related to serum and red cell folate and [...]

CVD is the leading cause of death worldwide, and genetic investigations into the human lipidome may provide insight into CVD risk. The aim of this study was to estimate the heritability of circulating lipid species and their genetic correlation with CVD traits. Targeted lipidomic profiling was performed on 4,492 participants from the Busselton Family Heart Study to quantify the major fatty acids of 596 lipid species from 33 classes. We estimated narrow-sense heritabilities of lipid species/classes and their genetic correlations with eight CVD traits: BMI, HDL-C, LDL-C, triglycerides, total cholesterol, waist-hip ratio, systolic blood pressure, and diastolic blood pressure. We report heritabilities and genetic correlations of new lipid species/subclasses, including acylcarnitine (AC), ubiquinone, sulfatide, and oxidized cholesteryl esters. Over 99% of lipid species were significantly heritable (h2: 0.06–0.50) and all lipid classes were significantly heritable (h2: 0.14–0.50). The monohexosylceramide and AC classes had the highest median heritabilities (h2= 0.43). The largest genetic correlation was between clinical triglycerides and total diacylglycerol (rg= 0.88). We observed novel positive genetic correlations between clinical triglycerides and phosphatidylglycerol species (rg: 0.64–0.82), and HDL-C and alkenylphosphatidylcholine species (rg: 0.45–0.74). Overall, 51% of the 4,768 lipid species-CVD trait genetic correlations were statistically significant after correction for multiple comparisons. This is the largest lipidomic study to address the heritability of lipids and their genetic correlation with CVD traits. Future work includes identifying putative causal genetic variants for lipid species and CVD using genome-wide SNP and whole-genome sequencing data.

Androgens, notably testosterone (T), have been implicated in development of several common cancers and prostate cancer; however, precise mechanisms remain unclear. This study assessed prospective associations of serum T, dihydrotestosterone (DHT) and estradiol (E2) with overall cancer (excluding skin cancer), prostate, colorectal and lung cancer risk in 1574 community-dwelling men aged 25–84 years. Sex hormones were assayed using mass spectrometry and men were followed for 20 years with outcomes ascertained using data linkage. Over 20 years, there were 289, 116, 48 and 22 men who developed any cancer, prostate cancer, colorectal cancer and lung cancer, respectively. Androgens in the lowest quartile were associated with an increased overall cancer risk (HR = 1.36, 95% CI 1.05–1.76, p= 0.020 for T; and HR = 1.30, 95% CI 1.00–1.69, p= 0.049 for DHT comparing the lowest vs other quartiles). T in the lowest quartile was associated with an increased risk of prostate cancer (HR = 1.53, 95% CI 1.02–2.29, p= 0.038 comparing the lowest vs other quartiles). The association between androgens and overall cancer risk remained similar after excluding prostate cancer outcomes; however, results were not significant. There were no associations of T, DHT or E2 with colorectal or lung cancer risk; however, LH in the highest quartile was associated with an increased risk of lung cancer (HR = 4.55, 95% CI 1.70–12.19, p= 0.003 for the highest vs other quartiles). Whether T is a biomarker of poor health in men with any cancer or prostate cancer requires further confirmation as does the nature and mechanism of the association of a high LH with future lung cancer.

We examined common variation in asthma risk by conducting a meta-analysis of worldwide asthma genome-wide association studies (23,948 asthma cases, 118,538 controls) of individuals from ethnically diverse populations. We identified five new asthma loci, found two new associations at two known asthma loci, established asthma associations at two loci previously implicated in the comorbidity of asthma plus hay fever, and confirmed nine known loci. Investigation of pleiotropy showed large overlaps in genetic variants with autoimmune and inflammatory diseases. The enrichment in enhancer marks at asthma risk loci, especially in immune cells, suggested a major role of these loci in the regulation of immunologically related mechanisms.

BackgroundGenome-wide association studies have identified numerous genetic regions that influence cross-sectional lung function. Longitudinal decline in lung function also includes a heritable component but the genetic determinants have yet to be defined.ObjectivesWe aimed to determine whether regions associated with cross-sectional lung function were also associated with longitudinal decline and to seek novel variants which influence decline.MethodsWe analysed genome-wide data from 4167 individuals from the Busselton Health Study cohort, who had undergone spirometry (12 695 observations across eight time points). A mixed model was fitted and weighted risk scores were calculated for the joint effect of 26 known regions on baseline and longitudinal changes in FEV1and FEV1/FVC. Potential additional regions of interest were identified and followed up in two independent cohorts.ResultsThe 26 regions previously associated with cross-sectional lung function jointly showed a strong effect on baseline lung function (p=4.44×10−16for FEV1/FVC) but no effect on longitudinal decline (p=0.160 for FEV1/FVC). This was replicated in an independent cohort. 39 additional regions of interest (48 variants) were identified; these associations were not replicated in two further cohorts.ConclusionsPreviously identified genetic variants jointly have a strong effect on cross-sectional lung function in adults but little or no effect on the rate of decline of lung function. It is possible that they influence COPD risk through lung development. Although no genetic variants have yet been associated with lung function decline at stringent genome-wide significance, longitudinal change in lung function is heritable suggesting that there is scope for future discoveries.

Context:Advancing age is accompanied by an accumulation of ill health and shortening of chromosomal telomeres signifying biological aging. T is metabolized to DHT by 5α-reductase (SRD5A2) and to estradiol (E2) by aromatase (CYP19A1). Telomerase preserves telomeres, and T and E2 regulate telomerase expression and activity in vitro.Objective:The objective of the study was to establish whether circulating T or its metabolites, DHT or E2, and single-nucleotide polymorphisms in SRD5A2 or CYP19A1 associate with leucocyte telomere length (LTL) in men.Participants and Methods:Early-morning serum T, DHT, and E2 were assayed using mass spectrometry, and SRD5A2 and CYP19A1 single-nucleotide polymorphisms and LTL analyzed by PCR in 980 men from the Western Australian Busselton Health Survey who participated in the study. LTL was expressed as the T/S ratio.Results:Men were aged (mean ± SD) 53.7 ± 15.6 years. LTL decreased linearly with age, from the T/S ratio of 1.89 ± 0.41 at younger than 30 years to 1.50 ± 0.49 at 70 to younger than 80 years (r = −0.225, P< .0001). After adjustment for age, DHT and E2 were positively correlated with LTL (DHT, r = 0.069, P= .030; E2, r = 0.068, P= .034). The SRD5A2 rs9282858 polymorphism was associated with serum DHT but not with LTL. Three dominant alleles of CYP19A1 were each associated with lower serum E2 and shorter LTL: rs2899470 T (E2, 59.3 vs 68.6 pmol/L, P< .0001; T/S ratio, 1.54 vs 1.62, P= .045), rs10046 C (60.5 vs 68.1 pmol/L, P= .0005, 1.54 vs 1.62, P= .035), and rs700518 A (59.9 vs 68.9 pmol/L, P< .0001, 1.54 vs 1.63, P= .020). A single-copy haplotype C/T/I/A/T rs10046/rs2899470/rs11575899/rs700518/rs17703883 (52% prevalence) was associated with both lower E2 and shorter LTL.Conclusions:In men, serum DHT and E2 correlate with LTL independently of age. Aromatase gene polymorphisms include three dominant alleles that are associated with both lower serum E2 and shorter LTL. E2 influences telomere length in vivo, thus warranting further studies to examine whether hormonal interventions might slow biological aging in men.

Context:Undercarboxylated osteocalcin (ucOC) modulates insulin secretion and sensitivity in mice, and higher ucOC is associated with lower prevalence of diabetes in men. The influence of ucOC distinct from other markers of bone turnover on incidence of cardiovascular events is unclear.Participants:Community-dwelling men aged 70–89 years resident in Perth, Western Australia.Main Outcome Measures:Serum total osteocalcin (TOC), N-terminal propeptide of type I collagen (P1NP), and collagen type I C-terminal cross-linked telopeptide (CTX) were measured by immunoassay, and ucOC by hydroxyapatite binding. The ratio ucOC/TOC was calculated. Hospital admissions and deaths from myocardial infarction (MI) and stroke were ascertained.Results:There were 3384 men followed for 7.0 years, during which 293 experienced an MI, 251 stroke, and 2840 neither. In multivariate analyses, higher ratio of ucOC/TOC (expressed as %) was associated with lower incidence of MI (quartiles Q2–4, ≥49% versus Q1,<49%, hazard ratio 0.70, 95% confidence interval = 0.54–0.91), but not of stroke (0.99, 0.73–1.34). Higher P1NP was associated with higher incidence of MI (Q2–4, ≥28.2 μg/L versus Q1, <28.2 μg/L, hazard ratio 1.45, 95% confidence interval = 1.06–1.97), but not of stroke (0.94, 0.70–1.26). CTX was not associated with incident MI or stroke.Conclusions:A reduced proportion of undercarboxylated osteocalcin or higher P1NP are associated with increased incidence of MI. UcOC/TOC ratio and P1NP predict risk of MI but not stroke, in a manner distinct from CTX. Further studies are needed to investigate potential mechanisms by which bone turnover markers related to metabolic risk and to collagen formation could modulate cardiovascular risk.

While the phenotype for heterozygous beta-thalassae-mia is straightforward, it is more difficult to confirm a causative relationship for mutations in the alpha-globin genes. The aim of this study was to generate an in vitrosystem to evaluate the pathological relevance of α-globin mutations.

We aimed to identify novel genetic variants affecting asthma risk, since these might provide novel insights into molecular mechanisms underlying the disease.

BackgroundTo investigate the prognostic importance of the metabolic syndrome (MetS) on incident cardiovascular disease (CVD).DesignProspective cohort study.MethodsThe study was based on 10-year follow-up of 3041 men and women aged 25-84 years without CVD or diabetes who participated in the 1994/1995 Busselton Health Survey. Hazards ratio (HRs) from Cox regression models were used to describe the effect of the MetS as a dichotomous classification and as the number of risk components on incident coronary heart disease (CHD), stroke and all CVD events.ResultsAll cardiovascular and metabolic risk factors studied showed a strong association with the number of MetS risk components. The age-adjusted and sex-adjusted HR for the MetS was 1.70 (95% confidence interval: 1.15-2.51) for incident CHD but this was reduced to almost unity after adjustment for cardiovascular risk factors or the homoeostasis model assessment measure of insulin resistance. However, the number of MetS risk components remained significant (P < 0.01) with those having 3+ risk components with a three-fold increase in risk compared with those with no risk components (adjusted HR: 3.59, 95% confidence interval: 1.43-8.99).ConclusionConsideration of the number of MetS risk components seems to be more informative than the (dichotomous) MetS classification when determining risk in clinical practice. Identification of people without any MetS risk components is clinically valuable, as these people seem to have a substantially reduced risk of developing CHD. Eur J Cardiovasc Prev Rehabil 16:235-241 © 2009 The European Society of Cardiology

Arterial remodelling contributes to the development of hypertension. Stromelysin-1 (MMP-3), a member of the matrix metalloproteinase family may contribute to this process. Stromelysin-1 gene expression is partly regulated by a common polymorphism in the promoter region of either five or six consecutive adenosine bases (5A/6A).

We present a descriptive analysis of the 10 case reports distributed in the Royal College of Pathologists of Australasia (RCPA) and the Australasian Association of Clinical Biochemists (AACB) Chemical Pathology Patient Report Comments Program to assess the quality of interpretative commenting in clinical biochemistry in 2001.

OBJECTIVES

PREEN, D., B. DAWSON, C. GOODMAN, S. LAWRENCE, J. BEILBY, and S. CHING. Effect of creatine loading on long-term sprint exercise performance and metabolism. Med. Sci. Sports Exerc., Vol. 33, No. 5, 2001, pp. 814–821.

Retinol (vitamin A alcohol) is an accepted adjunctive treatment in infections such as measles. There is also indirect evidence from in vitro, animal and human studies that retinol supplementation may be beneficial in severe malaria. There have, however, been no studies that have examined the pharmacokinetics of acute retinol supplementation in severe illness. To establish whether mobilization of intramuscular retinyl palmitate (RP) and its availability as retinol are adequate in complicated falciparum malaria, we administered a single dose of 400000 i.u. of RP to six Vietnamese adults with severe malaria. Another 28 patients were not given RP. All patients had blood samples taken over 96 h for RP and retinol assay using HPLC, and received conventional anti-malarial and supportive therapy. Admission serum retinol concentrations were below the lower limit of the reference range (< 1.0 µmol/l) in 74% of the 34 patients. In supplemented patients, analysis of serum RP between 0 and 96 h using a multi-compartmental model revealed a median (range) delay in mobilization of 6.9 h (0.7–15.1 h), a bioavailability of 55% (19–100%) and an elimination half-life of 13.5 h (4.2–23.7 h). The area under the serum retinol curve expressed as an absolute or percentage change from baseline was greater in supplemented than in unsupplemented patients (P < 0.05). The separation in median serum retinol concentrations in the two groups was maximal at 48 h. The model-derived retinol half-life [1.5 (0.7–15.8) h] suggested rapid uptake, metabolism and/or excretion. In conclusion, there is variable RP bioavailability in severe malaria, but a significant if delayed increase in serum retinol over that associated with recovery from the infection. In severe infections, RP supplementation appears simple, well tolerated and of potential benefit once anti-microbial and supportive therapy have been established.

We evaluated carbohydrate‐deficient transferrin (CDT) and γ‐glutarnyltranspeptidase (γ‐GT) as markers of alcohol intake and change in alcohol intake in white Australian men aged 20 to 63 years who regularly drank 20 to 60 g of alcohol/day (2 to 6 standard drinks), either as weekend (n = 14) or daily drinkers (n = 41). After 4 weeks of familiarization on usual alcohol intake, men were provided with low alcohol beer (24 times 375 ml cans, 0.9%, v/v, two‐weekly), and, for 4 weeks, consumed as much or as little as they wished with no additional alcohol permitted. In an alternate 4‐week period, the same amount of full‐strength beer (4.9%, v/v) was provided, whereas subjects continued their usual amount and pattern of alcohol consumption. The order of experimental conditions was randomized. Retrospective 7‐day diaries documented weekly alcohol intake during 4 weeks of familiarization and 8 weeks of intervention. Mean alcohol intake was 345 g/week of alcohol (SD 97) during familiarization. During the last 4 weeks of intervention (study weeks 8 to 12), mean alcohol intake either increased by 360 g/week (SD 138) with the switch from low to high alcohol or decreased by 328 g/week (SD 120) with the reverse. During familiarization (study weeks 1 to 4), alcohol intake was significantly related independently (R2= 0.21) to mean corpuscular volume (ρ= 0.008) and uric acid (ρ= 0.003), but not to γ‐GT (ρ= 0.22) nor CDT (p = 0.94). Change in alcohol intake was predicted independently (R2= 0.60) by change in CDT (ρ < 0.0001) and γ‐GT (ρ= 0.0003), but not by change in uric acid or mean corpuscular volume. A 10% change in CDT gave 70% sensitivity and 80% specificity to detect a change of at least 2 standard drinks/day; respective values were 68% and 0 for 10% change in γ‐GT. Results were not related to drinking pattern, smoking, age, or weight CDT, particularly when used as a continuous variable, may have a place in monitoring alcohol consumption, even in men whose alcohol intake is in the 20 to 60 g/day range.

Direct testing for the CAG repeat sequence in the Huntington's disease gene is quick, accurate and more acceptable to individuals at risk thank previous methods Objective: To develop an accurate presymptomatic test for Huntington's disease. Method: An improved polymerase chain reaction method was used to investigate the pattern of expansions of a CAG repeat sequence located in the 5' region of a gene recently found to produce the protein called Huntingtin. We documented the range of trinucleotide repeat expansions in the responsible gene in 82 affected individuals compared with SO control subjects from a Western Australian population. Results: The number of expanded repeats ranged from 40 to 73 in affected individuals and from 13 to 38 in normal controls. Conclusion: Polymerase chain reaction analysis of a CAG repeat sequence in the Huntington's disease gene clearly differentiated between normal and mutated alleles, providing an accurate diagnostic test for the disorder in individuals at risk. This predictive test has met with greater acceptance and demand than methods using family based linkage studies.

Cardiac troponin I (cTnI) has been reported to be a highly specific marker for cardiac injury. We investigated the performance of this assay in patients admitted to a coronary care unit for suspected acute myocardial infarction (AMI), patients with extensive skeletal muscle damage, marathon runners and as a routine diagnostic test over a four week period. cTnI proved to be as sensitive a marker for AMI as creatine kinase/MB isoenzyme (CKMB) in patients admitted to the coronary care unit. In 10 patients with a proven AMI, the cTnI remained elevated from 69 to 183 h with a median time of 127 h. Cardiac troponin I had superior specificity to CKMB in patients with skeletal muscle damage. It was very useful in these patients to confirm or exclude concurrent myocardial damage. In routine diagnostic use, cTnI had greater efficiency than CKMB to classify patients as having an AMI. Consequently cTnI should replace CKMB as a marker for AMI.

Former blue asbestos workers known to be at high risk of asbestos-related diseases, particularly malignant mesothelioma and lung cancer, were enrolled in a chemo-prevention program using vitamin A. Our aims were to compare rates of disease and death in subjects randomly assigned to β-carotene or retinol. Subjects were assigned randomly to take 30 mg/day β-carotene (512 subjects) or 25,000 IU/day retinol (512 subjects) and followed up through death and cancer registries from the start of the study in June 1990 till May 1995. Comparison between groups was by Cox regression in both intention-to-treat analyses and efficacy analyses based on treatment actually taken. Median follow-up time was 232 weeks. Four cases of lung cancer and 3 cases of mesothelioma were observed in subjects randomised to retinol and 6 cases of lung cancer and 12 cases of mesothelioma in subjects randomised to β-carotene. The relative rate of mesothelioma (the most common single cause of death in our study) for those on retinol compared with those on β-carotene was 0.24 (95% CI 0.07–0.86). In the retinol group, there was also a significantly lower rate for death from all causes but a higher rate of ischaemic heart disease mortality. Similar results were found with efficacy analyses. Our results confirm other findings of a lack of any benefit from administration of large doses of synthetic β-carotene. The finding of significantly lower rates of mesothelioma among subjects assigned to retinol requires further investigation. Int. J. Cancer 75:362–367, 1998. © 1998 Wiley-Liss, Inc.

Our aim was to describe a vitamin A-based cancer prevention program for former asbestos workers and to check for possible harmful effects by comparing rates of disease and death in study subjects with subjects who chose not to join. All subjects had been occupationally exposed to crocidolite at Wittenoom Gorge between 1943 and 1966; 1,677 subjects indicated interest in the program and 1,203 joined between June 1990 and May 1995. Comparison subjects consisted of 996 former workers known to be alive in Western Australia in 1990 who did not join the program. Program subjects were provided with annual supplies of vitamin A (either synthetic β-carotene or retinol), help in quitting smoking and dietary advice. The comparison group received only mail contact. Both groups were followed up to December 1994 for vital status and cancer information, and rates of cancer and death from various causes were compared. Mortality in both groups was higher than expected (standardised mortality ratio 1.23 in program subjects and 1.67 in comparison subjects). After adjustment for age, smoking and asbestos exposure, the relative rates in participants compared with non-participants was below 1 for all examined cancers and causes of death. For mesothelioma and lung cancer, group differences increased with time from entry, whereas other differences dissipated with time. No significant side effects were reported. In conclusion, program participants had significantly lower mortality than non-participants, but the rates of the 2 groups converged with time. Int. J. Cancer 75:355–361, 1998. © 1998 Wiley-Liss, Inc.

The effect of oral creatine (Cr) supplementation on maximal 2500m rowing ergometer performance (MREP) in trained oarspeople was examined in this study. Twenty subjects were tested on two occasions. Baseline measures of timed performance, VO2.peak, VO2 total and HR were taken during the initial MREP exercise task. Capillary blood drawn pre‐ and post exercise was assayed for pH and [La−]. Subjects were then matched in two equal groups. One group of subjects was administered a Cr supplement while the other group received a placebo (Pl) these were taken 4 times a day for 5 days, in double blind fashion. The supplement dose was based on the result of a pilot study indicating that a dose of 60 mg·kg−1body mass of CrH2O provided at least a 2 hour plasma Cr concentration above a threshold accepted as that required for the absorption of Cr from blood into skeletal muscle. Subjects were then re‐tested using the same experimental protocol as in the initial testing session. A significant difference in MREP between the two groups (p ≤ 0.05) was observed following supplementation. A group mean (±sd) improvement in performance time of 3.46 ± 4.00 seconds was observed in the Cr group while the Pl group was 3.19 ± 6.08 seconds slower in the second trial, however no significant within group change in performance was identified. Of the 10 matched pairs 8 had a change indicating improved performance following Cr supplementation. The change in post exercise blood pH following supplementation was significantly (p ≤ 0.05) better for the Cr group, however, there was no significant within group change. No significant change occurred in VO2, body mass, HRmax or [La−] pre‐ and post exercise due to the ingestion of Cr supplement. It was concluded that Cr supplementation is potentially of benefit to rowing ergometer performance. Further research is required to investigate the trend towards performance improvement identified in this study.

Hunt, Clive C. J., Jodi E. Burley, Caroline M. L. Chapman, and John P. Beilby.A high-throughput MS-PCR method on MADGE gels for ANG II type-1 receptor A1166C polymorphism. Physiol. Genomics1: 71–73, 1999.—We have developed a highly accurate, low-cost, single-step, mutagenically separated polymerase chain reaction (MS-PCR) method for the determination of angiotensin II type-1 receptor (AT1) A1166C gene polymorphism. The genotypes are determined using the microtiter array diagonal gel electrophoresis (MADGE) system. We have compared the MS-PCR method with allele-specific oligonucleotide hybridization and DdeI digestion techniques for determining the AT1A1166C genotype. The combination of MS-PCR and MADGE serves as a model for high-throughput single-nucleotide polymorphism genotyping in large population studies.

Alpha-thalassaemia is often caused by deletion of alpha (α) globin gene/s on chromosome 16p. Non-deletional mutations (αT), detected on a globin gene sequencing, are uncommon. Rarely, these two types of mutations co-exist.