A novel polygenic risk score improves prognostic prediction of heart failure with preserved ejection fraction in the Chinese Han population

Abstract

Aims Mortality risk assessment in patients with heart failure (HF) with preserved ejection fraction (HFpEF) presents a major challenge. We sought to construct a polygenic risk score (PRS) to accurately predict the mortality risk of HFpEF. Methods and results We first carried out a microarray analysis of 50 HFpEF patients who died and 50 matched controls who survived during 1-year follow-up for candidate gene selection. The HF-PRS was developed using the independent common (MAF > 0.05) genetic variants that showed significant associations with 1-year all-cause death (P < 0.05) in 1442 HFpEF patients. Internal cross-validation and subgroup analyses were performed to evaluate the discrimination ability of the HF-PRS. In 209 genes identified by microarray analysis, 69 independent variants (r < 0.1) were selected to develop the HF-PRS model. This model yielded the best discrimination capability for 1-year all-cause mortality with an area under the curve (AUC) of 0.852 (95% CI 0.827–0.877), which outperformed the clinical risk score consisting of 10 significant traditional risk factors for 1-year all-cause mortality (AUC 0.696, 95% CI 0.658–0.734, P = 4 × 10−11), with net reclassification improvement (NRI) of 0.741 (95% CI 0.605–0.877; P < 0.001) and integrated discrimination improvement (IDI) of 0.181 (95% CI 0.145–0.218; P < 0.001). Individuals in the medium and the highest tertile of the HF-PRS had nearly a five-fold (HR = 5.3, 95% CI 2.4–11.9; P = 5.6 × 10−5) and 30-fold (HR = 29.8, 95% CI 14.0–63.5; P = 1.4 × 10−18) increased risk of mortality compared to those in the lowest tertile, respectively. The discrimination ability of the HF-PRS was excellent in cross validation and throughout the subgroups regardless of comorbidities, gender, and patients with or without a history of heart failure. Conclusion The HF-PRS comprising 69 genetic variants provided an improvement of prognostic power over the contemporary risk scores and NT-proBNP in HFpEF patients.

Prognostic Value of a Multi-mRNA Signature for 1-Year All-Cause Death in Hospitalized Patients With Heart Failure With a Preserved Ejection Fraction

“…25 The SNP rs2340584 at the CCNE2 locus was reported to be significantly associated with 1-year all-cause death in patients with HFpEF. 27 Cox6b2 encodes a subunit of cytochrome c oxidase (complex IV). Recently, Mia et al 28 reported that mitochondrial genes such as cox6b2 were influenced by BMAL1 (basic helix-loop-helix ARNT like 1) deletion; while previous study have found that cardiomyocyte-specific BMAL1-knockout mice exhibited abnormalities in cardiac mitochondrial function.…”

Influence of genetic characteristics of patients on systolic and diastolic function after acute myocardial infarction: a literature review

“…Авторы еще одного крупного исследования [32] оценили риск смертности у пациентов с СН с со-храненной ФВ. В 209 генах, идентифицированных с помощью микрочипового анализа, было отобрано 69 независимых вариантов для разработки модели ПШР СН.…”

“…У лиц со средним и высшим терцилем ПШР СН было почти 5-кратное (отношение рисков (ОР) 5,3, 95% ДИ: 2,4-11,9; P=5,6×10 -5 ) и 30-кратное (ОР 29,8, 95% ДИ: 14,0-63,5; P=1,4×10 -18 ) повышение риска смерти по сравнению с низшим терцилем, соответственно. ПШР СН хорошо себя показала во всех подгруппах, независимо от наличия сопутствующих заболеваний, пола пациентов, СН в анамнезе [32]. В то же время Tsao NL, et al [33] не удалось улучшить точность прогноза моделей СН с традиционными факторами риска, добавляя генетические маркеры.…”

Using Omics to Identify Novel Therapeutic Targets in Heart Failure

“…12 Additionally, a prognostic PRS comprised 69 variants outperformed a clinical risk score in predicting 1-year mortality in a cohort of patients with HFpEF. 23 Patients in the highest PRS risk tertile had a 30-fold increased risk of 1-year mortality compared with those in the lowest tertile. While the promise remains to be seen, PRS may improve our understanding of the key biological pathways involved in HF development and progression, providing another method to identify potential therapeutic targets implicated in HF.…”