TY - JOUR
T1 - Pulmonary fibrosis in the era of stratified medicine
AU - Mathai, Susan K.
AU - Newton, Chad A.
AU - Schwartz, David A.
AU - Garcia, Christine Kim
N1 - Funding Information:
The U.S. Department of Veterans Affairs (grant no. Merit Award 1I01BX001534 (DAS)) and the National Institutes of Health (grant nos. P01- HL092870 (DAS), R01-HL097163 (DAS), R01HL093096 (CKG), R25-ES025476 (DAS), R33-HL120770 (DAS), T32HL098040 (CAN), UL1TR001105 (CAN) and UH2- HL123442 (DAS)).
PY - 2016/12/1
Y1 - 2016/12/1
N2 - Both common and rare variants contribute to the genetic architecture of pulmonary fibrosis. Genome-wide association studies have identified common variants, or those with a minor allele frequency of <5%, that are linked to pulmonary fibrosis. The most widely replicated variant (rs35705950) is located in the promoter region of the MUC5B gene and has been strongly associated with idiopathic pulmonary fibrosis (IPF) and familial interstitial pneumonia (FIP) across multiple different cohorts. However, many more common variants have been identified with disease risk and in aggregate account for approximately one-third of the risk of IPF. Moreover, several of these common variants appear to have prognostic potential. Next generation sequencing technologies have facilitated the identification of rare variants. Recent whole exome sequencing studies have linked pathogenic rare variants in multiple new genes to FIP. Compared with common variants, rare variants have lower population allele frequencies and higher effect sizes. Pulmonary fibrosis rare variants genes can be subdivided into two pathways: telomere maintenance and surfactant metabolism. Heterozygous rare variants in telomere-related genes co-segregate with adult-onset pulmonary fibrosis with incomplete penetrance, lead to reduced protein function, and are associated with short telomere lengths. Despite poor genotype-phenotype correlations, lung fibrosis associated with pathogenic rare variants in different telomere genes is progressive and displays similar survival characteristics. In contrast, many of the heterozygous rare variants in the surfactant genes predict a gain of toxic function from protein misfolding and increased endoplasmic reticulum (ER) stress. Evidence of both telomere shortening and increased ER stress have been found in sporadic IPF patients, suggesting that the mechanisms identified from rare variant genetic studies in unique individuals and families are applicable to a wider spectrum of patients. The ability to sequence large cohorts of individuals rapidly has the potential to further our understanding of the relative contributions of common and rare variants in the pathogenesis of pulmonary fibrosis. The UK 100,000 Genomes Project will provide opportunities to interrogate both common and rare variants and to investigate how these biological signals provide diagnostic and prognostic information in the era of stratified medicine.
AB - Both common and rare variants contribute to the genetic architecture of pulmonary fibrosis. Genome-wide association studies have identified common variants, or those with a minor allele frequency of <5%, that are linked to pulmonary fibrosis. The most widely replicated variant (rs35705950) is located in the promoter region of the MUC5B gene and has been strongly associated with idiopathic pulmonary fibrosis (IPF) and familial interstitial pneumonia (FIP) across multiple different cohorts. However, many more common variants have been identified with disease risk and in aggregate account for approximately one-third of the risk of IPF. Moreover, several of these common variants appear to have prognostic potential. Next generation sequencing technologies have facilitated the identification of rare variants. Recent whole exome sequencing studies have linked pathogenic rare variants in multiple new genes to FIP. Compared with common variants, rare variants have lower population allele frequencies and higher effect sizes. Pulmonary fibrosis rare variants genes can be subdivided into two pathways: telomere maintenance and surfactant metabolism. Heterozygous rare variants in telomere-related genes co-segregate with adult-onset pulmonary fibrosis with incomplete penetrance, lead to reduced protein function, and are associated with short telomere lengths. Despite poor genotype-phenotype correlations, lung fibrosis associated with pathogenic rare variants in different telomere genes is progressive and displays similar survival characteristics. In contrast, many of the heterozygous rare variants in the surfactant genes predict a gain of toxic function from protein misfolding and increased endoplasmic reticulum (ER) stress. Evidence of both telomere shortening and increased ER stress have been found in sporadic IPF patients, suggesting that the mechanisms identified from rare variant genetic studies in unique individuals and families are applicable to a wider spectrum of patients. The ability to sequence large cohorts of individuals rapidly has the potential to further our understanding of the relative contributions of common and rare variants in the pathogenesis of pulmonary fibrosis. The UK 100,000 Genomes Project will provide opportunities to interrogate both common and rare variants and to investigate how these biological signals provide diagnostic and prognostic information in the era of stratified medicine.
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U2 - 10.1136/thoraxjnl-2016-209172
DO - 10.1136/thoraxjnl-2016-209172
M3 - Review article
C2 - 27799632
AN - SCOPUS:84994894900
SN - 0040-6376
VL - 71
SP - 1154
EP - 1160
JO - Thorax
JF - Thorax
IS - 12
ER -