Association of NPPB rs198389 and NPPA rs5068 single-nucleotide polymorphisms with natriuretic peptide levels and heart failure progression risks in patients with atrial fibrillation

Natriuretic peptides (NUPs) are the strongest predictors of poor prognosis in patients with heart failure (HF). Single-nucleotide polymorphisms (SNPs) rs198389 of the NPPB gene and rs5068 of the NPPA gene are associated with altered levels of NUP. The role of candidate gene polymorphisms in the activity of the NUP system and the association of NPPA/ NPPB SNPs with the risk of cardiovascular disease (CVD) in individuals with HF and atrial fibrillation (AF) is not well understood.

The study aims to evaluate the allele and genotype frequencies of NPPA rs5068 and NPPB rs198389 SNPs in a selective sample of the Belarusian population, to determine the relationship of these SNPs with NUP concentrations, and to assess the prognostic significance of these SNPs on the risk of HF hospitalization in patients with HF and permanent AF.

The study involved 187 patients. The main group included 152 patients with HF with left ventricular ejection fraction (LVEF) < 50 %. Group 1 included 48 patients with HF and AF; group 2 – 51 patients with HF and sinus rhythm (SR) and 35 patients in the control group. The levels of atrial and brain natriuretic peptides (ANP and BNP) and the N-terminal fragment of the brain natriuretic peptide (NT-proBNP) were determined. A genetic testing of polymorphic loci of the rs5068 NPPA gene and the rs198389 NPPB gene was performed. The primary endpoint of the study was hospitalization due to HF progression.

The average observation period was 12.1 [from 9 to 14] months. The distribution of the genotype and allele frequencies of rs198389 NPPB and rs5068 NPPA in HF patients with LVEF < 50 % is comparable to that in individuals without CVD. In patients with HF and persistent AF, the minor allele C rs198389 NPPB is associated with higher BNP levels compared to patients with HF and SR (542 [333.7; 909.4] pg/ml versus 247.3 [244; 365.2] pg/ml; p < 0.05), but it has no relationship with the NT-proBNP level. In patients with HF and permanent AF, the ANP levels are not associated with rs5068 NPPA.

The frequency of the T allele rs198389 NPPB in hospitalized patients was significantly lower compared to patients who were not hospitalized (22 patients (44 %) versus 83 patients (62 %); p = 0.04). The presence of the C allele rs198389 NPPB was associated with a higher risk of HF progression in patients with HF and AF, the odds ratio (OR) = 2.071 [95 % CI from 1.072 to 4.001], p < 0.05.

1. Geelhoed B., Börschel C. S., Niiranen T., Palosaari T., Havulinna A. S., Fouodo C. J. K. [et al.]. Assessment of causality of natriuretic peptides and atrial fibrillation and heart failure: a Mendelian randomization study in the FINRISK cohort. Europace, 2020, vol. 22, no. 10, pp. 1463–1469. https://doi.org/10.1093/europace/euaa158

2. Kristensen S. L., Jhund P. S., Mogensen U. M., Rørth R., Abraham W. T., Desai A. [et al.]. Prognostic Value of N-Terminal Pro-B-Type Natriuretic Peptide Levels in Heart Failure Patients with and Without Atrial Fibrillation. Circulation: Heart Failure, 2017, vol. 10, no. 10, p. e004409. https://doi.org/10.1161/CIRCHEARTFAILURE.117.004409

3. Sramko M., Melenovsky V., Wichterle D.., Franekova J., Clemens M., Kautzner J. Impact of Atrial Fibrillation on Natriuretic Peptides: An Invasive Atrial Hemodynamic Study. JACC: Clinical Electrophysiology, 2018, vol. 4, no. 1, pp. 153–154. https://doi.org/10.1016/j.jacep.2017.05.008

4. Cannone V., Scott C. G., Decker P. A., Larson N. B., Palmas W., Taylor K. D., Wang T. J., Gupta D. K., Bielinski S. J., Burnett J. C. Jr. A favorable cardiometabolic profile is associated with the G allele of the genetic variant rs5068 in African Americans: The Multi-Ethnic Study of Atherosclerosis (MESA). PLoS ONE, 2017, vol. 12, no. 12, p. e0189858. https://doi. org/10.1371/journal.pone.0189858

5. Ellis K. L., Newton-Cheh C., Wang T. J., Frampton C. M., Doughty R. N., Whalley G. A. [et al.] Association of genetic variation in the natriuretic peptide system with cardiovascular outcomes. Journal of Molecular and Cellular Cardiology, 2011, vol. 50, no. 4, pp. 695–701. https://doi.org/10.1016/j.yjmcc.2011.01.010

6. Pfister R., Luben R. N., Khaw K.-T., Wareham N. J. Common genetic variants of the natriuretic peptide gene locus are not associated with heart failure risk in participants in the EPIC-Norfolk study. European Journal of Heart Failure, 2013, vol. 15, no. 6, pp. 624–627. https://doi.org/10.1093/eurjhf/hft007

7. Seidelmann S. B., Vardeny O., Claggett B., Yu B., Shah A. M., Ballantyne C. M., Selvin E., MacRae C. A., Boerwinkle E., Solomon S. D. An NPPB promoter polymorphism associated with elevated N-terminal pro-B-type natriuretic peptide and lower blood pressure, hypertension, and mortality. Journal of the American Heart Association, 2017, vol. 6, no. 4, p. e005257. https://doi.org/10.1161/JAHA.116.005257

8. Cannone V., Cefalu’ A. B., Noto D., Scott C. G., Bailey K. R., Cavera G., Pagano M., Sapienza M., Averna M. R., Burnett J. C. Jr. The atrial natriuretic peptide genetic variant rs5068 is associated with a favorable cardiometabolic phenotype in a Mediterranean population. Diabetes Care, 2013, vol. 36, no. 9, pp. 2850–2856. https://doi.org/10.2337/dc12-2337

9. Cannone V., Boerrigter G., Cataliotti A., Costello-Boerrigter L. C., Olson T. M., McKie P. M. [et al.]. A genetic variant of the atrial natriuretic peptide gene is associated with cardiometabolic protection in the general community. Journal of the American College of Cardiology, 2011, vol. 58, no. 6, pp. 629–636. https://doi.org/10.1016/j.jacc.2011.05.011

10. Hahn M., Stamer U. M., Luedi M. M., Book M., Rieder H. U., Stüber F. ASA status, NPPA/NPPB haplotype and coronary artery disease have an impact on BNP/NT-proBNP plasma levels. Cells, 2022, vol. 11, no. 5, art. 766. https://doi. org/10.3390/cells11050766

11. Lanfear D. E., Stolker J. M., Marsh S., Rich M. W., McLeod H. L. Genetic variation in the B-type natiuretic peptide pathway affects BNP levels. Cardiovascular Drugs and Therapy, 2007, vol. 21, no. 1, pp. 55–62. https://doi.org/10.1007/s10557- 007-6007-5

12. Takeishi Y., Toriyama S., Takabatake N., Shibata Y., Konta T., Emi M., Kato T., Kawata S., Kubota I. Linkage disequilibrium analyses of natriuretic peptide precursor B locus reveal risk haplotype conferring high plasma BNP levels. Biochemical and Biophysical Research Communications, 2007, vol. 362, no. 2, pp. 480–484. https://doi.org/10.1016/j.bbrc. 2007.08.028

13. Meirhaeghe A., Sandhu M. S., McCarthy M. I., de Groote P., Cottel D., Arveiler D. [et al.]. Association between the T-381C polymorphism of the brain natriuretic peptide gene and risk of type 2 diabetes in human populations. Human Molecular Genetics, 2007, vol. 16, no. 11, pp. 1343–1350. https://doi.org/10.1093/hmg/ddm084

14. Zakirpva G. A., Kamilova U. K. Association of rs198389 NPPB gene polymorphism with chronic heart failure. American Journal of Medicine and Medical Sciences, 2021, vol. 11, no. 8, pp. 553–556. https://doi.org/10.5923/j.ajmms.20211108.01

15. Cannone V., Ledwidge M., Watson C., McKie P. M., Burnett J. C. Jr, McDonald K. STOP-HF Trial: higher endogenous BNP and cardiovascular protection in subjects at risk for heart failure. JACC: Basic to Translational Science, 2021, vol. 6, no. 6, pp. 497–504. https://doi.org/10.1016/j.jacbts.2021.05.001

16. Bachmann K. N., Gupta D. K., Xu M., Brittain E., Farber-Eger E., Arora P., Collins S., Wells Q. S., Wang T. J. Unexpectedly low natriuretic peptide levels in patients with heart failure. JACC: Heart Failure, 2021, vol. 9, no. 3, pp. 192–200. https://doi.org/10.1016/j.jchf.2020.10.008

17. Benmachiche M., Marques-Vidal P., Waeber G., Méan M. In-hospital mortality is associated with high NT-proBNP level. PLoS ONE, 2018, vol. 13, no. 11, p. e0207118. https://doi.org/10.1371/journal.pone.0207118

18. Zile M. R., Desai A. S., Agarwal R., Bharmi R., Dalal N., Adamson P. B., Maisel A. S. Prognostic value of brain natriuretic peptide vs history of heart failure hospitalization in a large real-world population. Clinical Cardiology, 2020, vol. 43, no. 12, pp. 1501–1510. https://doi.org/10.1002/clc.23468

19. Chen H. H. Heart failure: a state of brain natriuretic peptide deficiency or resistance or both! Journal of the American College of Cardiology, 2007, vol. 49, no. 10, pp. 1089–1091. https://doi.org/10.1016/j.jacc.2006.12.013

20. Hawkridge A. M., Heublein D. M., Bergen H. R. 3rd, Cataliotti A., Burnett J. C., Jr., Muddiman D. C. Quantitative mass spectral evidence for the absence of circulating brain natriuretic peptide (BNP-32) in severe human heart failure. Proceedings of the National Academy of Sciences of the United States of America, 2005, vol. 102, no. 48, pp. 17442–17447. https:// doi.org/10.1073/pnas.0508782102

21. Borodulin K., Tolonen H., Jousilahti P., Jula A., Juolevi A., Koskinen S. [et al.]. Cohort Profile: The National FINRISK Study. International Journal of Epidemiology, 2018, vol. 47, no. 3, pp. 696–696i. https://doi.org/10.1093/ije/dyx239

22. Ardashev A. V., Belenkov Yu. N., Matyukevich M. Ch., Snezhitskii V. A. Atrial Fibrillation and Mortality: Prognostic Factors and Direction of Prevention. Kardiologiya [Cardiology], 2021, vol. 61, no. 2, pp. 91–98 (in Russian).