Genetic predisposition to respiratory diseases: infiltrative lung diseases

The availability of high-throughput genotyping and large collaborative clinical networks creating well-characterized patient populations with DNA repositories has facilitated genome-wide scans and candidate gene studies to identify susceptibility alleles for the development of interstitial lung disease. The association of pulmonary fibrosis with rare inherited disorders, and the variable susceptibility of inbred mouse strains to this disease indicate that pulmonary fibrosis is determined by genetic factors. Sarcoidosis represents a complex disease with racial and ethnic differences in disease prevalence, and evidence of familial clustering. Familial aggregation of sarcoidosis from 'A Case-Control Etiologic Study of Sarcoidosis' (ACCESS) reveals a familial odds ratio (OR) of sarcoidosis of 5.8 (95% CI 2.1-15.9) for sibs and 3.8 (95% CI 1.2-11.3) for parents. Several HLA class II alleles have been associated with either increased or decreased risk of sarcoidosis, and results vary depending on study populations of different ethnicity. Genome-wide screening has conclusively identified linkage to chromosome 5q11and the development of sarcoidosis, and HLA genes and BTNL2 are susceptibility genes located in this region. Familial aggregation of idiopathic interstitial pneumonia (IIP) has been established by several groups, and a large US-based study suggests autosomal dominant inheritance with reduced penetrance; furthermore, cigarette smoking was associated with affection status among siblings (OR = 3.6, 95% CI 1.3-9.8, p = 0.01). Families demonstrate more than one type of IIP, suggesting various subtypes of IIP may share a common pathogenesis. Genome-wide linkage scans in familial interstitial pneumonia demonstrate linkage to chromosomes 4, 5 and 11. Candidate gene studies indicate that surfactant protein C and telomerase are susceptibility genes for the development of pulmonary fibrosis. Future challenges include determining how multiple susceptibility alleles interact with each other and environmental factors resulting in disease risk and multiple phenotypes, and determining the mechanism of action and cellular pathways involving susceptibility alleles. Further insight into these areas may lead to new therapeutic interventions.