A candidate gene for familial idiopathic pulmonary fibrosis identified

Idiopathic pulmonary fibrosis (IPF) is a chronic, late-onset disease of lung parenchyma with unknown etiology. IPF has been treated with corticosteroids and immunosuppressive agents, but the prognosis and the response to treatment have remained poor, and the estimated time of survival from the diagnosis is less than 3 years. The pathogenesis and etiology of IPF are unknown, but the reports of multiple affected family members in the same family support the influence of genetic factors.

In their previous studies researchers at the University of Helsinki and the University Hospital of Helsinki observed that the prevalence of idiopathic pulmonary fibrosis distributed unevenly in Finland. The prevalence was two times higher in eastern and southern Savo (45/100 000 inhabitants) compared to the prevalence in Finland (16-18/100 000).

The researchers identified multiplex families with IPF and noticed that familial IPF patients clustered within Savo and Carelia, the same areas with the high prevalence, suggesting that they most likely share a common disease-causing allele introduced by a common ancestor.

They performed a genome-wide scan with six multiplex families. Three regions on chromosomes 3, 4, and 13 obtained NPL scores of 1.7, 1.7, and 1.6, respectively, and on chromosomes 9 and 12 possible shared haplotypes were seen. These five loci were fine mapped with 63 markers in an extended data set.

After fine mapping the researchers did not detect the linkage to the loci on chromosomes 3, 9, 12, and 13. On chromosome 4q31.1 the NPL score increased to 2.1, and one third of the affected families (8/24) shared a 110 kb haplotype, while none of the unaffected family members carried it. The susceptibility haplotype was carried in 34 % of all the genotyped families (12/35), and in 7.7 % (11/143) of 143 controls, with an odds ratio of 6.3 (p=0.0001, 95 % CI=2.3–15.9).

The critical region harbors two novel candidate genes, ELMOD2, and LOC152586 that both are poorly characterized. An in vitro translation assay with LOC152586 failed to produce any peptide suggesting it is not a protein-coding gene. mRNA expression of ELMOD2 was decreased in lung biopsies derived from IPF patients (N=6) compared to healthy controls (N=7).

ELMOD2 is potentially involved in apoptosis, phagocytosis, cell engulfment, and cell migration. It is expressed in functionally relevant tissue, in lung and in fibroblasts, and its expression is significantly decreased in IPF lung compared to healthy lung. Therefore ELMOD2 becomes a prime candidate gene for familial IPF.