Hermansky-Pudlak syndrome

Idiopathic pulmonary fibrosis (IPF) by definition is of unknown etiology. The condition is highly heterogeneous, is likely to be initiated by multiple types of lung injury, and has variable histologic features of inflammation and fibroproliferation. As with other complex disorders, a number of genetic factors contribute to the disease phenotype of IPF. The best evidence for an important genetic component to pulmonary fibrosis derives from murine models. Some strains such as C57BL/6 are fibrosis prone, and others such as Balb/c are fibrosis resistant after irradiation (1) or overexpression of transforming growth factor-[beta]1 (2). Further evidence derives from the existence of rare familial forms of IPF and also of syndromes, such as the Hermansky-Pudlak syndrome, that include an IPF-like pulmonary fibrosis among additional features that are not shared by sporadic IPF patients (3).

There are no data on the heritability of IPF in the general population, and the vast majority of cases appear to be sporadic. Thus, studies of genetic predisposition to IPF have been limited to assessment of candidate genes. In most complex human diseases, the combination of multiple genes of modest individual effect, gene-gene and gene-environment interactions, and population heterogeneity will make both detection and replication of disease associations very difficult (4). Particular problems in IPF include the relative rarity of the condition (so that no studies to date have been adequately powered to refute association with the candidate gene or genes studied) and the complexity of the disease phenotype, with the added possibility that IPF is the "end stage" of a number of different environmental insults impacting on a range of genetic loci. Published studies have focused on genes involved in host defense and inflammation, particularly polymorphisms that may regulate the functions of upstream cytokines, especially interleukin-1[beta] and tumor necrosis factor-[alpha], which also cause a degree of pulmonary librosis (5). Although none of the reported findings have yet been independently replicated, studies have implicated polymorphisms within the interleukin-1 cluster on chromosome 2 (6) and in the tumor necrosis factor-[alpha]/HLA region on chromosome 6 (6, 7). In addition, polymorphisms in these regions have been implicated in diseases associated with pulmonary fibrosis, such as scleroderma and sarcoidosis (8).

Transforming growth factor-[beta]1 is a critical mediator of fibrogenesis, with both immunologic actions and direct effects on structural cells that stimulate production of extracellular matrix, fibroblast proliferation, and induction of a myofibroblast phenotype (9). Multiple studies in animals and humans support a direct role for transforming growth factor-[beta] in fibrogenesis in vivo (2, 5, 9). The biology of transforming growth factor-[beta] is very complex, with three protein isoforms, of which transforming growth factor-[beta]1 is the most abundant and widely studied in fibrosis (9, 10). There is evidence that the circulating concentration of transforming growth factor-[beta]1 is predominantly under genetic control (10), implying that genetic variation at the TGFB1 locus might influence diseases, including IPF, where transforming growth factor-[beta]1 is implicated.

Against this background, Xaubet and colleagues (11) in this issue of AJRCCM (pp. 431-435) have assessed polymorphisms in the TGFB1 gene in 128 patients with IPF. They studied two exon 1 polymorphisms, at positions +869 and +915, that result in a leucine to proline amino acid substitution at codon 10 and an arginine to proline substitution at codon 25. The authors found no association of either polymorphism with susceptibility to IPF. Interestingly, however, in 110 patients with follow-up data of a mean of 30 months, there was evidence that the codon 10 Pro allele was associated with a more rapid deterioration in lung function, with a significant increase in the alveolar-arterial oxygen tension gradient, indicating worsening of gas exchange, together with nonsignificant reductions in FVC and diffusing capacity.

Clearly, a single study will be subject to bias arising from relatively small numbers of patients and only modest effects on lung function. Moreover, transforming growth factor-[beta]1 in scrum was not measured, and there are conflicting data on the functional effect of codon 10 Pro, with both higher (12) and lower (13) serum levels of transforming growth factor-[beta]1 reported that may not, in any case, reflect the levels within the lung. The codon 10 Pro allele has been associated with hepatitis C-induced hepatic fibrosis (14) and with graft versus host disease after cardiac transplantation (15). In contrast, the codon 10 Leu allele was associated with accelerated decline of lung function in patients with cystic fibrosis (16).

Nonetheless, the study of Xaubet and coworkers (11) provides the first evidence for the TGFB1 gene as a potential determinant of disease progression in IPF. As the authors stated, there is a need for further studies to confirm the association in other, larger cohorts of patients with IPF and to assess other markers of disease progression, ideally correlating these with histologic features (such as predominance of usual interstitial pneumonia) and measurements of levels of transforming growth factor-[beta]1.

The challenges of case-association studies in IPF are multiple, but two considerations must be paramount. First, there can be little doubt that much larger studies are required to detect or confirm genetic association, particularly for polymorphisms with a lower heterozygosity index in the study population (4). Second, the onus is on investigators to intensively characterize the phenotype of patients with IPF. Most pulmonary physicians recognize highly variable patterns of disease progression, inflammatory activation, and possible environmental triggers. Ideally, the disease phenotype would include all known environmental, occupational, and drug exposures, together with agreed indices of disease severity, progression, and histology. A large group of well characterized patients might then allow the identification of genes within specific subpopulations which influence disease susceptibility, progression, and the pharmacogenetics of treatment response. Collecting this large IPF cohort will require large-scale collaborations of interested researchers.

The study performed by Xaubet and colleagues (11) illustrates the potential value as well as the limitations of candidate gene studies in IPF. If their results are confirmed, it would add weight to the development of anti-transforming growth factor-[beta]1 strategies for the treatment of IPF. The use of genetic marker(s) for disease progression would permit identification of a subset of patients with more rapidly progressive disease that should be more closely monitored, potentially targeted for anticytokine treatment, and considered for early transplantation.

References

1. Ward WF, Sharplin J, Franko AJ, Hinz JM. Radiation-induced pulmonary endothelial dysfunction and hydroxyproline accumulation in four strains of mice. Radiat Res 1989;120:113-120.

2. Kolb M, Bonniaud P, Galt T, Sime PJ, Kelly MM, Margetts PJ, Gauldie J. Differences in the fibrogenic response after transfer of active transforming growth factor-[beta]1 gene to lungs of "fibrosis-prone" and "fibrosis-resistant" mouse strains. Am J Respir Cell Mol Biol 2002;27:141-150.

3. Crystal RG, Bitterman PB, Mossman B, Schwarz MI, Sheppard D, Almasy L, Chapman HA, Friedman SL, King TE Jr, Leinwand LA, et al. Future research directions in idiopathic pulmonary fibrosis: summary of a National Heart, Lung, and Blood Institute working group. Am J Respir Crit Care Med 2002;166:236-246.

4. Cardon LR, Palmer LJ. Population stratification and spurious allelic association. Lancet 2003;361:598-604.

5. Kelly M, Kolb M, Bonniaud P, Gauldie J. Re-evaluation of fibrogenic cytokines in lung fibrosis. Curr Pharm Das 2003;9:39-49.

6. Whyte M, Hubbard R, Meliconi R, Whidborne M, Eaton V, Bingle C, Timms J, Duff G, Facchini A, Pacilli A, et al. Increased risk of fibrosing alveolitis associated with interleukin-1 receptor antagonist and tumor necrosis factor-[alpha] gene polymorphisms. Am J Respir Crit Care Med 2000;162:755-758.

7. Pantelidis P, Fanning GC, Wells AU, Welsh KI, Du Bois RM. Analysis of tumor necrosis factor-[alpha], lymphotoxin-[alpha], tumor necrosis factor receptor II, and interleukin-6 polymorphisms in patients with idiopathic pulmonary fibrosis. Am J Respir Crit Care Med 2001;163:1432-1436.

8. Du Bois RM. The genetic predisposition to interstitial lung disease. Chest 2002;121:14S-20S.

9. Sime PJ, O'Reilly MJ. Fibrosis of the lung and other tissues: new concepts in pathogenesis and treatment. Clin Immunol 2001;99:308-319.

10. Grainger DJ, Heathcote K, Chiano M, Snieder H, Kemp PR, Metcalfe JC, Carter ND, Spector TD. Genetic control of the circulating concentration of transforming growth factor type [beta]1. Hum Mol Genet 1999;8:93-97.

11. Xaubet A, Marin-Arguedas A, Lario S, Ancochea J, Morell F. Ruiz-Manzano J, Rodriguez-Becerra E, Rodriguez-Arias JM, Inigo P, Sanz S, et al. TGF-[beta] 1 gene polymorphisms are associated to disease progression in idiopathic pulmonary fibrosis. Am J Respir Crit Care Med 2003;168:431-435.

12. Perrey C, Pravica V, Sinnott PJ, Hutchinson IV. Genotyping for polymorphisms in interferon-gamma, interleukin-10, transforming growth factor-beta 1 and tumour necrosis factor-alpha genes: a technical report. Transpl Immunol 1998;6:193-197.

13. Yamada Y. Association of a Leu10 to Pro polymorphism of the transforming growth faclor-[beta]1 with genetic susceptibility to osteoporosis and spinal osteoarthritis. Mech Ageing Dev 2000;116:113-123.

14. Gewaltig J, Mangasser-Stephan K, Gartung C, Biesterfeld S, Gressner AM. Association of polymorphisms of the transforming growth factor-[beta]1 gene with the rate of progression of HCV-induced liver fibrosis. Clin Chim Acta 2002;316:83-94.

15. Holweg CT, Baan CC, Balk AH, Niesters HG, Maat AP, Mulder PM, Weimar W. The transforming growth factor-beta1 codon 10 gene polymorphism and accelerated graft vascular disease after clinical heart transplantation. Transplantation 2001;71:1463-1467.

16. Arkwright PD, Laurie S, Super M, Pravica V, Schwarz MJ, Webb AK, Hutchinson IV. TGF-[beta]1 genotype and accelerated decline in lung function of patients with cystic fibrosis. Thorax 2000;55:459-462.

DOI: 10.1164/rccm.2306003

MOIRA K.B. WHYTE, PH.D.

University of Sheffield

Sheffield, United Kingdom

Conflict of Interest Statement: M.K.B.W. is a minor shareholder (well below the $10,000 threshold) in Interleukin Genetics, Inc. Interleukin Genetics has patents issued and pending on cytokine genetic markers and susceptibility to various diseases and the use of those genetic factors for diagnostic and therapeutic purposes.

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