Longitudinal lung function and gas transfer in individuals with idiopathic pulmonary fibrosis: a genome-wide association study

Oldham, Justin M.; Jenkins, David; Leavy, Olivia C.; Guillén‐Guío, Beatriz; Melbourne, Carl; Ma, Shwu‐Fan; Jou, Jonathan; Kim, John S.; Fahy, William A; Oballa, Eunice; Hubbard, Richard; Navaratnam, Vidya; Braybrooke, Rebecca; Saini, Gauri; Roach, Katy M.; Tobin, Martin D.; Hirani, Nik; Whyte, Moira K. B.; Kaminski, Naftali; Zhang, Yingze; Martínez, Fernando J.; Linderholm, A.; Adegunsoye, Ayodeji; Strek, Mary E.; Maher, Toby M.; Molyneaux, Philip L.; Flores, Carlos; Noth, Imre; Jenkins, R Gisli; Wain, Louise V.

doi:10.1016/s2213-2600(22)00251-x

Cited by 26 publications

(22 citation statements)

References 45 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Genome‐wide association studies (GWAS) involve scanning for genetic variants associated with a trait. Recent GWAS have confirmed 14 previously reported variants and revealed nine novel genetic associations with IPF risk including variants in introns of KNL1, NPRL3, STMN3 and RTEL1 , 6 as well as a variant in an antisense RNA gene for PKN2 with lung function decline 7 and PCSK6 with mortality 8 …”

Section: Pathogenesismentioning

confidence: 53%

Contemporary Concise Review 2022: Interstitial lung disease

Smith

Jenkins

2023

Respirology

View full text Add to dashboard Cite

SUMMARY OF KEY POINTS Novel genetic associations for idiopathic pulmonary fibrosis (IPF) risk have been identified. Common genetic variants associated with IPF are also associated with chronic hypersensitivity pneumonitis. The characterization of underlying mechanisms, such as pathways involved in myofibroblast differentiation, may reveal targets for future treatments. Newly identified circulating biomarkers are associated with disease progression and mortality. Deep learning and machine learning may increase accuracy in the interpretation of CT scans. Novel treatments have shown benefit in phase 2 clinical trials. Hospitalization with COVID‐19 is associated with residual lung abnormalities in a substantial number of patients. Inequalities exist in delivering and accessing interstitial lung disease specialist care.

show abstract

Section: Pathogenesismentioning

confidence: 53%

Contemporary Concise Review 2022: Interstitial lung disease

Smith

Jenkins

2023

Respirology

View full text Add to dashboard Cite

show abstract

“…In the last decade, large-scale international collaborations have been established to combine independent genomic data across thousands of patients and controls to improve the statistical power and detect novel IPF genes. This strategy has allowed the identification of at least 23 independent genetic loci associated with IPF susceptibility and has revealed novel molecular processes involved in IPF pathogenesis including host defense, cell–cell adhesion, DNA repair, airway clearance, innate immunity, profibrotic signaling pathways, mTOR signaling, and mitotic signaling ( 15 , 16 , 70 , 93 , 94 , 101 ).…”

Section: Genetics Of Ipfmentioning

confidence: 99%

“…It also suggested cell-cycle progression as another novel biological process, since KIF15 and MAD1L1 are both mitotic spindle assembly genes. Moreover, estimates of polygenic risk scores (PRS) for the first time in IPF showed that the disease is highly polygenic and there are potentially hundreds of, as yet unidentified, variants associated with IPF susceptibility ( 101 ). The first multi-ancestry meta-analysis of IPF included a total of 8,492 patients and nearly 1.36 million controls from 13 biobanks as part of the Global Biobank Meta-Analysis Initiative.…”

Section: Genetics Of Ipfmentioning

confidence: 99%

“…Despite the need for further replication of the findings in independent samples, the results of the application of the novel statistical method suggest that the association of the MUC5B variant with survival is biased and the risk allele may, in fact, be associated with decreased IPF survival ( 119 ). In this line, the existing evidence based on PRS model inferences suggest that genetic determinants of IPF susceptibility and progression may have limited overlap ( 101 , 120 ).…”

Section: Genetics Of Ipfmentioning

confidence: 99%

“…Another relevant area of study in IPF involves the identification of genetic variants associated to disease progression rather than disease risk. The first GWAS of decline in lung function in individuals diagnosed with IPF was completed by Allen et al In this study, the authors discovered a genetic locus that associated with a more rapid decline in the lung capacity, which lies in the RNA antisense gene PKN2 ( 101 ). Consistently, an inhibitor of this gene, fostamatinib, has been already suggested as a potential drug candidate in acute respiratory distress syndrome in patients with severe COVID-19 ( 122 ).…”

Section: Genetics Of Ipfmentioning

confidence: 99%

See 2 more Smart Citations

Idiopathic pulmonary fibrosis and the role of genetics in the era of precision medicine

et al. 2023

Self Cite

View full text Add to dashboard Cite

Idiopathic pulmonary fibrosis (IPF) is a chronic, rare progressive lung disease, characterized by lung scarring and the irreversible loss of lung function. Two anti-fibrotic drugs, nintedanib and pirfenidone, have been demonstrated to slow down disease progression, although IPF mortality remains a challenge and the patients die after a few years from diagnosis. Rare pathogenic variants in genes that are involved in the surfactant metabolism and telomere maintenance, among others, have a high penetrance and tend to co-segregate with the disease in families. Common recurrent variants in the population with modest effect sizes have been also associated with the disease risk and progression. Genome-wide association studies (GWAS) support at least 23 genetic risk loci, linking the disease pathogenesis with unexpected molecular pathways including cellular adhesion and signaling, wound healing, barrier function, airway clearance, and innate immunity and host defense, besides the surfactant metabolism and telomere biology. As the cost of high-throughput genomic technologies continuously decreases and new technologies and approaches arise, their widespread use by clinicians and researchers is efficiently contributing to a better understanding of the pathogenesis of progressive pulmonary fibrosis. Here we provide an overview of the genetic factors known to be involved in IPF pathogenesis and discuss how they will continue to further advance in this field. We also discuss how genomic technologies could help to further improve IPF diagnosis and prognosis as well as for assessing genetic risk in unaffected relatives. The development and validation of evidence-based guidelines for genetic-based screening of IPF will allow redefining and classifying this disease relying on molecular characteristics and contribute to the implementation of precision medicine approaches.

show abstract

Helicobacter pylori Treatment and Gastric Cancer Risk Among Individuals With High Genetic Risk for Gastric Cancer

Xu,

Han,

Liu

et al. 2024

JAMA Netw Open

View full text Add to dashboard Cite

ImportanceHelicobacter pylori treatment and nutrition supplementation may protect against gastric cancer (GC), but whether the beneficial effects only apply to potential genetic subgroups and whether high genetic risk may be counteracted by these chemoprevention strategies remains unknown.ObjectiveTo examine genetic variants associated with the progression of gastric lesions and GC risk and to assess the benefits of H pylori treatment and nutrition supplementation by levels of genetic risk.Design, Setting, and ParticipantsThis cohort study used follow-up data of the Shandong Intervention Trial (SIT, 1989-2022) and China Kadoorie Biobank (CKB, 2004-2018) in China. Based on the SIT, a longitudinal genome-wide association study was conducted to identify genetic variants for gastric lesion progression. Significant variants were examined for incident GC in a randomly sampled set of CKB participants (set 1). Polygenic risk scores (PRSs) combining independent variants were assessed for GC risk in the remaining CKB participants (set 2) and in an independent case-control study in Linqu.ExposuresH pylori treatment and nutrition supplementation.Main Outcomes and MeasuresPrimary outcomes were the progression of gastric lesions (in SIT only) and the risk of GC. The associations of H pylori treatment and nutrition supplementation with GC were evaluated among SIT participants with different levels of genetic risk.ResultsOur analyses included 2816 participants (mean [SD] age, 46.95 [9.12] years; 1429 [50.75%] women) in SIT and 100 228 participants (mean [SD] age, 53.69 [11.00] years; 57 357 [57.23%] women) in CKB, with 147 GC cases in SIT and 825 GC cases in CKB identified during follow-up. A PRS integrating 12 genomic loci associated with gastric lesion progression and incident GC risk was derived, which was associated with GC risk in CKB (highest vs lowest decile of PRS: hazard ratio [HR], 2.54; 95% CI, 1.80-3.57) and further validated in the analysis of 702 case participants and 692 control participants (mean [SD] age, 54.54 [7.66] years; 527 [37.80%] women; odds ratio, 1.83; 95% CI, 1.11-3.05). H pylori treatment was associated with reduced GC risk only for individuals with high genetic risk (top 25% of PRS: HR, 0.45; 95% CI, 0.25-0.82) but not for those with low genetic risk (HR, 0.81; 95% CI, 0.50-1.34; P for interaction = .03). Such effect modification was not found for vitamin (P for interaction = .93) or garlic (P for interaction = .41) supplementation.Conclusions and RelevanceThe findings of this cohort study indicate that a high genetic risk of GC may be counteracted by H pylori treatment, suggesting primary prevention could be tailored to genetic risk for more effective prevention.

show abstract

Longitudinal lung function and gas transfer in individuals with idiopathic pulmonary fibrosis: a genome-wide association study

Cited by 26 publications

References 45 publications

Contemporary Concise Review 2022: Interstitial lung disease

Contemporary Concise Review 2022: Interstitial lung disease

Idiopathic pulmonary fibrosis and the role of genetics in the era of precision medicine

Helicobacter pylori Treatment and Gastric Cancer Risk Among Individuals With High Genetic Risk for Gastric Cancer

Contact Info

Product

Resources

About