What can genetics tell us about the cause of fixed airflow obstruction?

Chronic obstructive pulmonary disease (COPD) is a major cause of chronic morbidity and mortality worldwide with smoking being the most important risk factor of the disease. However, lung function and COPD are known to also have a genetic component and a deeper knowledge of the genetic architecture of the disease could lead to further understanding of predisposition to COPD and also to development of new therapeutic interventions. Genetic linkage studies and candidate gene association studies have not provided evidence to convincingly identify the genes underlying lung function or COPD. However, recent large genome-wide association studies (GWAS) including tens of thousands of individuals have identified 26 variants at different loci in the human genome that show robust association with quantitative lung function measures in the general population. A growing number of these variants are being shown to be associated with COPD. Following the identification of these new lung function loci, the challenge now lies in refining the signals to identify the causative variants underlying the association signals and relating these signals to the molecular pathways that underlie lung function.

Genome-wide association study to identify genetic determinants of severe asthma.

BACKGROUND: The genetic basis for developing asthma has been extensively studied. However, association studies to date have mostly focused on mild to moderate disease and genetic risk factors for severe asthma remain unclear. OBJECTIVE: To identify common genetic variants affecting susceptibility to severe asthma. METHODS: A genome-wide association study was undertaken in 933 European ancestry individuals with severe asthma based on Global Initiative for Asthma (GINA) criteria 3 or above and 3346 clean controls. After standard quality control measures, the association of 480 889 genotyped single nucleotide polymorphisms (SNPs) was tested. To improve the resolution of the association signals identified, non-genotyped SNPs were imputed in these regions using a dense reference panel of SNP genotypes from the 1000 Genomes Project. Then replication of SNPs of interest was undertaken in a further 231 cases and 1345 controls and a meta-analysis was performed to combine the results across studies. RESULTS: An association was confirmed in subjects with severe asthma of loci previously identified for association with mild to moderate asthma. The strongest evidence was seen for the ORMDL3/GSDMB locus on chromosome 17q12-21 (rs4794820, p=1.03×10((-8)) following meta-analysis) meeting genome-wide significance. Strong evidence was also found for the IL1RL1/IL18R1 locus on 2q12 (rs9807989, p=5.59×10((-8)) following meta-analysis) just below this threshold. No novel loci for susceptibility to severe asthma met strict criteria for genome-wide significance. CONCLUSIONS: The largest genome-wide association study of severe asthma to date was carried out and strong evidence found for the association of two previously identified asthma susceptibility loci in patients with severe disease. A number of novel regions with suggestive evidence were also identified warranting further study.

South Asian ethnicity and risk of childhood accidents: an ecological study at enumeration district level in Leicester.

BACKGROUND: Surveys of 'self-reported' accidents suggest that South Asian children in the United Kingdom may have lower rates of childhood accidents, but little is known about their susceptibility to severe accidents compared with white children. METHODS: We conducted an ecological study at the level of Census enumeration districts to compare hospital utilization as a result of childhood accidents according to White, South Asian, Black or 'Other' ethnic grouping and Townsend deprivation score in Leicester. Enumeration districts were assigned to postcoded data for fracture clinic attendances between 1997 and 1999 and in-patient admissions and in-patient stays of longer than 3 days as a result of accidents between 1995 and 1999 in children under 16 years. RESULTS: South Asian children were less likely than white children to attend fracture clinic, be admitted or to have a prolonged stay as a result of an accident. Having adjusted for deprivation score, for a 10 per cent increase in the proportion of South Asian residents in an enumeration district, the odds ratio for an in-patient stay of longer than 3 days was 0.95 (95 per cent confidence interval (CI) 0.91-1.00, p = 0.035), for an accident admission the odds ratio was 0.93 (95 per cent CI 0.92-0.94, p < 0.001) and for attendance at fracture clinic the odds ratio was 0.94 (95 per cent CI 0.92-0.96, p < 0.001). For a district with 70 per cent of its children from South Asian groups (as observed in one-fifth of Leicester's enumeration districts), this represents a 40 per cent lower rate of accident admissions. CONCLUSIONS: South Asian children were significantly less likely to utilize hospital services as a result of an accident. This may well be explained by differential exposure to accident hazards across ethnic groups, rather than by different thresholds of hospital attendance, given that hospital utilization was also lower for serious accidents in South Asian children.

Can primary care groups learn how to manage demand from fundholders? A study of fundholders in Nottingham.

BACKGROUND: Primary care groups (PCGs) will commission care for their patients and may be increasingly required to manage clearly defined resources. Existing general practice fundholders already operate in this environment, but can PCGs learn from the experience of fundholders in managing demand? AIM: To explore how general practice fundholders manage demand for hospital and community health services, and for prescribing. METHOD: A general practitioner (GP), and a fundholding manager from each of 26 practices were invited to take part. Questionnaires were developed, with structured and semi-structured components, and piloted in three practices. Interviews were conducted between October 1996 and February 1997 by the same interviewer (MDT). RESULTS: All practices stated that they were monitoring their waiting lists and giving priority to patients whose problems had become worse, but eight of the 23 GPs felt that they were unable to manage demand. Eight of the 15 fundholders who had developed in-house services actively managed the waiting list for these clinics. All fundholders had identified areas of unmet demand. Widely differing methods for increasing supply to meet demand were identified, and are described. Formularies were used by 12 out of the 23 fundholders. Guidelines were only considered useful by eight of the 23 practices; fundholders from later waves were less likely to find guidelines useful than fundholders from earlier waves (odds ratio [OR] = 0.11; 95% confidence interval [CI] = 0 to 0.96). Private specialist surgery was less likely to be accessed by later wave fundholders using the fund than by early wave fundholders (OR = 0.10; 95% CI = 0.09 to 0.97). CONCLUSION: Fundholders in Nottingham had not developed consistent approaches to managing demand within limited resources. Given the apparent diversity of attitudes and practices, the larger PCGs will require strong support to develop the intended commissioning function.