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Acute exacerbations (AE) contribute significantly to morbidity and mortality, and account for a substantial proportion of the direct costs associated with chronic obstructive pulmonary disease (COPD).1 Although AE frequency generally increases with worsening spirometric airflow obstruction on the population level, considerable variation in the number of exacerbations experienced by individuals exists. Epidemiological studies support the existence of an ‘intrinsic susceptibility’ towards AE which is independent of the degree of impairment in forced expiratory volume in 1 s (FEV1) on spirometry.2 This has fuelled the search for genetic variants which may contribute to differential susceptibility towards AEs.
An overview of studies investigating associations between genetic sequence variants and AE risk in COPD is shown in table 1. The vast majority of studies published to date have used the ‘candidate gene’ approach, whereby a limited number of variants in genes felt to be plausible contributors to exacerbation susceptibility are examined. Unfortunately, the body of knowledge arising from these investigations is often inconsistent. Non-replication or conflicting reports of association between studies are common, even when identical variants are interrogated (as exemplified by studies on the adrenoreceptor beta 2 gene, ARDB2). This is likely due, at least in part, to chance findings, limited power from small study sizes and inadequate statistical rigour. Recent advances in genotyping, computing power and statistical methodologies have facilitated the widespread application of ‘hypothesis-free’ genomics-based studies of complex diseases and traits, yet studies of AE risk in COPD using this approach have been conspicuously absent from the literature.
A major limitation of hypothesis-free approaches, which …
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