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J. linked to development of IPF (Table 1) (43). To assess the role of common genetic variation in IPF, several genome-wide association studies (GWAS) have now been performed (44C46), resulting in identification of SNPs at 17 different loci that associate with development of IPF, most notably in the promoter region of the Mucin 5B gene, (47). This SNP (rs35705950), which has now been confirmed in multiple studies, is located adjacent to a FOXA2 binding site in a region of the promoter that is differentially methylated in IPF (48). The minor (T) allele is present in ~18% of the Caucasian populace, compared to 60C70% of IPF patients of European ancestry and is associated with increased mRNA expression in normal (although not IPF) lungs (47). Although minor allele carriers of rs35705950 have increased risk of developing disease, IPF patients who carry the risk allele appear to have slower disease progression than noncarriers (49). rs35705950 is much rarer among IPF patients of Asian ancestry (49a), underscoring a need for further study of genetic risk for IPF in ethnically diverse populations. Animal studies have suggested that regulates airway host defense (50); however, the mechanisms by which altered expression influences fibrotic remodeling remain uncertain. Table 1. Genetic variants linked to IPF by GWAS and Next-Generation Sequencing Studies Ipratropium bromide and being the most common (43). Rare genetic variants in the surfactant protein pathway are much less common in FIP, accounting for no more than 1C2% of cases. Patients with telomerase pathway rare variants have very short telomeres as measured in white blood cells, more rapid disease progression, and often other manifestations of the short-telomere syndrome, including liver and bone marrow disease (51, 52, 67, 68). The degree of similarity in the genetic underpinnings of familial and sporadic IPF has been an unresolved question in the field. The prevalence of the SNP minor allele appears to be similar in patients with familial and sporadic IPF (47), suggesting that common genetic variants are shared in both forms of the disease. For rare genetic variants, prior studies have shown that mutations in the surfactant protein pathway are uncommon in sporadic IPF (69). In contrast, recent data indicate that rare variants in the telomerase pathway occur at a relatively high frequency in patients with sporadic IPF. A recent Ipratropium bromide study using whole-exome sequencing data from 262 subjects with sporadic IPF and unaffected controls found that rare variants in were overrepresented in sporadic IPF cases (70). We recently reported data from whole-genome sequencing of 1 1,510 patients with sporadic IPF and exhibited that rare variants in were present in ~8.5% of IPF patients, significantly higher than the percentage of control populations (71). In addition, this study identified an conversation between rare variants in and the promoter SNP. These findings showed that the risk allele was substantially less Ipratropium bromide common in IPF patients who harbored a rare variant than in IPF patients without a telomerase mutation, thus suggesting that this polymorphism and rare variants may be separable, independent risk pathways for development of IPF. Rabbit Polyclonal to MARCH2 The finding that rare genetic variants in telomerase pathway genes occur frequently in sporadic IPF points to a potential role for genetic testing. We recently Ipratropium bromide published recommendations for genetic testing in Ipratropium bromide familial IPF (72), and ongoing discussions regarding the role.

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