Thematic Review Series 2007

Genetic Predisposition to Respiratory Diseases: Infiltrative Lung Diseases
Mark P. Steele^a, Kevin K. Brown<sup>b

a</sup>Division of Pulmonary, Allergy, and Critical Care Medicine, Duke University Medical Center, Durham, N.C., and
^bDepartment of Medicine, Division of Pulmonary and Critical Care, National Jewish Medical and Research Center, Denver, Colo., USA

Address of Corresponding Author

Respiration 2007;74:601-608 (DOI: 10.1159/000110204)

  Key Words

• Sarcoidosis
• Candidate gene studies
• Linkage analysis
• Interstitial pneumonia, familial
• Interstitial pneumonia, idiopathic

  Abstract

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.

Copyright © 2007 S. Karger AG, Basel

  Author Contacts

Mark P. Steele, MD
Division of Pulmonary, Allergy, and Critical Care Medicine
350 Bell Building, Box 3171, Duke University Medical Center
Durham, NC 27710 (USA)
Tel. +1 919 684 6140, Fax +1 919 684 3067, E-Mail Steel002@mc.duke.edu

  Article Information

Previous articles in this series: 1. Contopoulos-Ioannidis DG, Kouri IN, Ioannidis JPA: Genetic predisposition to asthma and atopy. Respiration 2007;74:8-12. 2. Sztrymf B, Yaïci A, Girerd B, Humbert M: Genes and pulmonary arterial hypertension. Respiration 2007;74:123-132. 3. Southern KW: Cystic fibrosis and formes frustes of CFTR-related disease. Respiration 2007;74:241-251. 4. Morillas HN, Zariwala M, Knowles MR: Genetic causes of bronchiectasis: primary ciliary dyskinesia. Respiration 2007;74:252-263. 5. Notarangelo LD, Plebani A, Mazzolari E, Soresina A, Bondioni MP: Genetic causes of bronchiectasis: primary immune deficiencies and the lung. Respiration 2007;74:264-275. 6. Cottin V, Dupuis-Girod S, Lesca G, Cordier J-F: Pulmonary vascular manifestations of hereditary hemorrhagic telangiectasia (Rendu-Osler disease). Respiration 2007;74:361-378. 7. Wood AM, Stockley RA: Alpha one antitrypsin deficiency: from gene to treatment. Respiration 2007;74:481-492.

Number of Print Pages : 8
Number of Figures : 0, Number of Tables : 2, Number of References : 90