Genome-wide association studies (GWAS) represent an unbiased and hypothesis-free method based on the data produced by the human HapMap Project and the fact that genetic variance at one locus can predict, with high probability, genetic variance at adjacent loci.49 As such, the human genome can be surveyed for common variants (those present in more than 5% of the population) by genotyping about 500000 accurately chosen markers, so-called tag single nucleotide polymorphisms.50 GWAS have led to the identification of thousands of loci that affect susceptibility to complex disorders, broadening understanding of the pathogenesis of many diseases.51 However, inherent drawbacks of these studies are an inability to identify sequence variants (the studies identify loci) and rare alleles, detection of non-coding variants of unknown effect, reproducibility, and, in most cases, identification of susceptibility variants that confer only a small risk of disease. In a genome-wide scan (followed by hierarchical fine mapping in a larger dataset) of six multiplex families with familial idiopathic pulmonary fibrosis from southeastern Finland, Hodgson and colleagues52 identified a shared haplotype on chromosome 4q31 that was more common in affected individuals than in healthy controls. This haplotype harboured ELMOD2, a gene expressed in alveolar macrophages and alveolar epithelium. Although ELMOD2 is a plausible candidate gene in the pathogenesis of idiopathic pulmonary fibrosis since dysfunctional ELMOD2 might potentially cause an abnormal immune response at the alveolar epithelium level,53 gene sequencing did not show any DNA variations. The first GWAS done for sporadic idiopathic pulmonary fibrosis, which examined more than 200000 SNPs in 159 Japanese patients and 934 controls,54 confirmed a previously reported association with TERT,41 substantiating the putative contribution of telomere replication and stabilisation in the pathogenesis of idiopathic pulmonary fibrosis (table). Noth and colleagues67 did a GWAS followed by two independent case-control studies in a large cohort of EuropeanAmerican patients with idiopathic pulmonary fibrosis. They identified novel genetic variants within TOLLIP (11p15.59) and SPPL2C (17q21.31) that were associated with susceptibility to idiopathic pulmonary fibrosis. Additionally, one variant within TOLLIP (rs5743890), which resulted in reduced gene expression of TOLLIP in the lungs of patients with idiopathic pulmonary fibrosis, protected against the development of fibrosis but was linked with an increased rate of disease progression and risk of mortality. TOLLIP variants seemed to confer susceptibility to idiopathic pulmonary fibrosis independently of MUC5B rs35705950, a promoter variant that significantly increases the risk of development of idiopathic pulmonary fibrosis and that resides on the same genetic locus as TOLLIP, although the two genes are separated by a recombinant hotspot.61 Whether these two genes act independently of one another has not been resolved. The role of TOLLIP in regulation of the innate immune system makes it a biologically plausible candidate in the pathogenesis of idiopathic pulmonary fibrosis. Fingerlin and colleagues68 did the largest GWAS in idiopathic pulmonary fibrosis so far. Findings of this study, which included 2492 patients with idiopathic interstitial pneumonia (most of whom had idiopathic pulmonary fibrosis) and more than 6000 controls, not only confirmed three previously known genetic associations (TERC at 3q26, TERT at 5p15, and MUC5B at 11p15) but also identified seven novel risk loci within genes involved in host defence, cellcell adhesion, and DNA repair. The association between risk of idiopathic pulmonary fibrosis and OBFC1, another gene that affects telomere length, highlights the importance of early cell senescence in the development of pulmonary fibrosis. Another gene linked to risk of pulmonary fibrosis is DSP (6p24.3), which encode desmosomes. Desmosomes are a component of adhesive intercellular junctions and are essential to preserve the integrity of tissue that undergo mechanical stress, such as the lung periphery during respiration.69 This GWAS also identified several loci with as yet unknown attributions to specific genes.
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Genetic determinants of pulmonary fibrosis: evolving concepts : The Lancet Respiratory Medicine