Bill Musk

Identification of IL6R and chromosome 11q13.5 as risk loci for asthma

BACKGROUND We aimed to identify novel genetic variants affecting asthma risk, since these might provide novel insights into molecular mechanisms underlying the disease. METHODS We did a genome-wide association study (GWAS) in 2669 physician-diagnosed asthmatics and 4528 controls from Australia. Seven loci were prioritised for replication after combining our results with those from the GABRIEL consortium (n=26,475), and these were tested in an additional 25,358 independent samples from four in-silico cohorts. Quantitative multi-marker scores of genetic load were constructed on the basis of results from the GABRIEL study and tested for association with asthma in our Australian GWAS dataset. FINDINGS Two loci were confirmed to associate with asthma risk in the replication cohorts and reached genome-wide significance in the combined analysis of all available studies (n=57,800): rs4129267 (OR 1·09, combined p=2·4×10(-8)) in the interleukin-6 receptor (IL6R) gene and rs7130588 (OR 1·09, p=1·8×10(-8)) on chromosome 11q13.5 near the leucine-rich repeat containing 32 gene (LRRC32, also known as GARP). The 11q13.5 locus was significantly associated with atopic status among asthmatics (OR 1·33, p=7×10(-4)), suggesting that it is a risk factor for allergic but not non-allergic asthma. Multi-marker association results are consistent with a highly polygenic contribution to asthma risk, including loci with weak effects that might be shared with other immune-related diseases, such as NDFIP1, HLA-B, LPP, and BACH2. INTERPRETATION The IL6R association further supports the hypothesis that cytokine signalling dysregulation affects asthma risk, and raises the possibility that an IL6R antagonist (tocilizumab) may be effective to treat the disease, perhaps in a genotype-dependent manner. Results for the 11q13.5 locus suggest that it directly increases the risk of allergic sensitisation which, in turn, increases the risk of subsequent development of asthma. Larger or more functionally focused studies are needed to characterise the many loci with modest effects that remain to be identified for asthma. FUNDING National Health and Medical Research Council of Australia. A full list of funding sources is provided in the webappendix.

Genome-wide association analysis identifies 11 risk variants associated with the asthma with hay fever phenotype.

BACKGROUND To date, no genome-wide association study (GWAS) has considered the combined phenotype of asthma with hay fever. Previous analyses of family data from the Tasmanian Longitudinal Health Study provide evidence that this phenotype has a stronger genetic cause than asthma without hay fever. OBJECTIVE We sought to perform a GWAS of asthma with hay fever to identify variants associated with having both diseases. METHODS We performed a meta-analysis of GWASs comparing persons with both physician-diagnosed asthma and hay fever (n = 6,685) with persons with neither disease (n = 14,091). RESULTS At genome-wide significance, we identified 11 independent variants associated with the risk of having asthma with hay fever, including 2 associations reaching this level of significance with allergic disease for the first time: ZBTB10 (rs7009110; odds ratio [OR], 1.14; P = 4 × 10(-9)) and CLEC16A (rs62026376; OR, 1.17; P = 1 × 10(-8)). The rs62026376:C allele associated with increased asthma with hay fever risk has been found to be associated also with decreased expression of the nearby DEXI gene in monocytes. The 11 variants were associated with the risk of asthma and hay fever separately, but the estimated associations with the individual phenotypes were weaker than with the combined asthma with hay fever phenotype. A variant near LRRC32 was a stronger risk factor for hay fever than for asthma, whereas the reverse was observed for variants in/near GSDMA and TSLP. Single nucleotide polymorphisms with suggestive evidence for association with asthma with hay fever risk included rs41295115 near IL2RA (OR, 1.28; P = 5 × 10(-7)) and rs76043829 in TNS1 (OR, 1.23; P = 2 × 10(-6)). CONCLUSION By focusing on the combined phenotype of asthma with hay fever, variants associated with the risk of allergic disease can be identified with greater efficiency.

Increasing incidence of malignant mesothelioma after exposure to asbestos during home maintenance and renovation.

Objective: To determine trends in incidence of malignant mesothelioma (MM) caused by exposure to asbestos during home maintenance and renovation.

Fruit, vegetable, vitamin A intakes, and prostate cancer risk

Prostate cancer risk was examined in relation to intakes of fruit, vegetables, β-carotene and retinol. Subjects were a cohort of 1985 men previously to asbestos who participated in a cancer prevention programme of β-carotene and retinol supplements that commenced in July 1990. Diet was assessed at entry to the programme. Ninety-seven cases of prostate cancer were identified during follow-up until the end of 2004. A decreased prostate cancer risk was observed with increasing intakes of vitamin C-rich vegetables, including bell peppers and broccoli. Fruit, other vegetables and vitamin A intakes did not appear to be strong factors in the development of prostate cancer in this study.

Large-Scale Genome-Wide Association Studies and Meta-Analyses of Longitudinal Change in Adult Lung Function

Background Genome-wide association studies (GWAS) have identified numerous loci influencing cross-sectional lung function, but less is known about genes influencing longitudinal change in lung function. Methods We performed GWAS of the rate of change in forced expiratory volume in the first second (FEV1) in 14 longitudinal, population-based cohort studies comprising 27,249 adults of European ancestry using linear mixed effects model and combined cohort-specific results using fixed effect meta-analysis to identify novel genetic loci associated with longitudinal change in lung function. Gene expression analyses were subsequently performed for identified genetic loci. As a secondary aim, we estimated the mean rate of decline in FEV1 by smoking pattern, irrespective of genotypes, across these 14 studies using meta-analysis. Results The overall meta-analysis produced suggestive evidence for association at the novel IL16/STARD5/TMC3 locus on chromosome 15 (P  =  5.71 × 10-7). In addition, meta-analysis using the five cohorts with ≥3 FEV1 measurements per participant identified the novel ME3 locus on chromosome 11 (P  =  2.18 × 10-8) at genome-wide significance. Neither locus was associated with FEV1 decline in two additional cohort studies. We confirmed gene expression of IL16, STARD5, and ME3 in multiple lung tissues. Publicly available microarray data confirmed differential expression of all three genes in lung samples from COPD patients compared with controls. Irrespective of genotypes, the combined estimate for FEV1 decline was 26.9, 29.2 and 35.7 mL/year in never, former, and persistent smokers, respectively. Conclusions In this large-scale GWAS, we identified two novel genetic loci in association with the rate of change in FEV1 that harbor candidate genes with biologically plausible functional links to lung function.

Cancer incidence among women and girls environmentally and occupationally exposed to blue asbestos at Wittenoom, Western Australia.

The impact of crocidolite exposure on the health of former Wittenoom miners and millers (largely male) has been well documented. Less is known about the health outcomes of the 2,968 women and girls who lived (N = 2,552) and worked (N = 416) in the blue asbestos milling and mining town of Wittenoom between 1943 and 1992. Quantitative exposure measurements were derived from dust studies undertaken over the lifetime of the mine and mill and the township. Incident cancers were obtained from the Western Australian (WA) Cancer Registry and the National Cancer Clearing House. Standardized incidence ratios (SIRS) compared Wittenoom females with the WA female population. Exposure‐response relationships were examined using a matched case‐control study design. There were (47) mesothelioma and (55) lung cancer cases among the 437 cancers in the Wittenoom females over the period 1960–2005. When compared to the WA female population, Wittenoom women and girls had higher rates of mesothelioma and possibly lung cancer. Mesothelioma incidence rates are increasing with the incidence rate of 193 per 100,000 in the period 2000–2005 being more than double that for the period 1995–1999 at 84 per 100,000. A significant exposure‐response relationship was present for mesothelioma, but not for lung cancer. Forty years after the asbestos mine and mill at Wittenoom were closed, there is a high toll from cancer among the former female residents of the town and company workers.

Aerodigestive and gastrointestinal tract cancers and exposure to crocidolite (blue asbestos): Incidence and mortality among former crocidolite workers

The objective of this article was to assess the association between the incidence and mortality from aerodigestive cancers and exposure to crocidolite (blue asbestos). Our study is a cohort study of former workers of the now‐defunct crocidolite mining and milling operation at Wittenoom, Western Australia, who have been followed up since 1979 and on whom asbestos exposure and smoking information was known. Standardised mortality and incidence rates were used to compare former workers with the Western Australian male population. Cases were matched with up to 10 randomly assigned controls, and conditional logistic regression was used to examine the relationship between asbestos exposure, smoking status and cancer incidence. There were 129 incident cases from all cancers of interest and 57 deaths. Former workers had a significantly higher risk of mortality from upper aerodigestive cancers than the Western Australian male population. The incidence of upper and lower aerodigestive cancers was higher in the Wittenoom cohort but not significantly so. Cumulative exposure to asbestos did not appear to be associated with the incidence of stomach cancer, colorectal cancer or upper aerodigestive cancers. Smoking status was strongly associated with the incidence of upper aerodigestive cancers, with current smokers experiencing the greatest risk. Our study with longer and more complete follow‐up, smoking information and a stronger study design does not show an association between cumulative asbestos exposure and stomach cancer or other gastrointestinal cancers. The excess mortality from upper aerodigestive cancers seen in this cohort of former asbestos workers compared to the Western Australian male population does not appear to be associated with exposure to crocidolite.

Retinol supplementation and mesothelioma incidence in workers earlier exposed to blue asbestos (Crocidolite) at Wittenoom, Western Australia

Owing to the high rates of malignant mesothelioma in workers exposed to crocidolite earlier at Wittenoom and evidence of protection against cancer by vitamin A, a population-based cancer prevention programme providing retinol supplements (25 000 IU/day) was commenced in 1990. The former workers at Wittenoom known to be alive and living in Western Australia in June 1990 constitute the study population. The participants were classified into two groups: those who received supplemental retinol (intervention group) and those who received none (comparison group). The relative rate of mesothelioma for those receiving retinol was estimated using Cox regression, adjusting for cumulative asbestos exposure and age at first exposure to asbestos. Nine hundred and twenty-eight former Wittenoom workers received retinol at some stage of the programme, whereas 1471 workers never received retinol (comparison group). Those who received retinol were younger, had a greater exposure to asbestos and smoked less than the comparison group. There were 65 cases of mesothelioma in the retinol group and 88 in the comparison group. After adjustment, the hazard ratio was 0.99 (95% confidence interval=0.70–1.41). This result did not alter when the participants who received only retinol once or those who received β-carotene earlier were excluded from the analysis. In conclusion, this study provides little support for possible preventive effects of retinol against mesothelioma in workers exposed to blue asbestos.

Autoimmune antibodies and asbestos exposure: Evidence from Wittenoom, Western Australia

BACKGROUND Studies comparing different forms of asbestos are rare, and limited by the failure to compare results with unexposed populations. We compare autoimmune responses among former workers and residents of the crocidolite mining and milling town of Wittenoom, Western Australia, with an unexposed population. METHODS ANA testing using indirect immunofluorescence was performed on randomly selected serum samples from Wittenoom workers or residents and compared with those from participants of another unexposed cohort study. RESULTS ANA scores were higher in the Wittenoom participants compared with Busselton and the odds of being ANA positive was fivefold greater among Wittenoom participants than Busselton (OR 5.5, 95%CI 2.3-13.0). CONCLUSIONS This study is the first to report increased ANA positivity among persons exposed exclusively to crocidolite. This finding of a high frequency of positive ANA tests among crocidolite-exposed subjects may be an indicator for an increased risk of systemic autoimmune diseases and needs further scrutiny.

0424 Risk of mesothelioma and risk of exposure to asbestos in people supposedly unexposed to asbestos

Objectives Malignant mesothelioma (MM) is a rare and generally fatal cancer, usually caused by asbestos, although about 5%–10% of cases report no asbestos exposure. This study aimed to identify sources whereby people in Western Australia (WA) may be unknowingly exposed to asbestos or to other exposures which may cause MM. Methods Cases with no known asbestos exposure were selected from the WA Mesothelioma Register. Matched controls were selected from hospital patients admitted for conditions unrelated to asbestos. Occupational histories were coded by an industrial hygienist. Data were analysed using conditional logistic regression. Results Eligible cases were far fewer than anticipated. After 9 years there were 38 MM cases (from a total of more than 400 reported cases of MM over the same time period), 65 other cancer controls and 69 medical controls recruited. Odds ratios did not differ by type of control so both sets of controls were combined. Thirty-eight MM participants and 134 controls were recruited. Risk of MM was increased (OR=3.1, 95% CI 1.0–9.6) after no known, but likely, exposure to asbestos at work. Conclusions Because of its widespread use, very few people in WA have never been exposed to asbestos and careful elucidation of occupational and environmental histories usually uncovers likely exposures sufficient to cause MM. This study suggests that most cases of MM in people with apparently no known exposure to asbestos occur, at a low rate, among the large numbers of people who have had small amounts of incidental asbestos exposure.