Снижение артериального давления и риск онкологических заболеваний: мета-анализ данных индивидуального уровня и исследования менделевской рандомизации

В статье представлен оригинальный научный анализ, основанный на современных подходах доказательной медицины. Проведён:

• Мета-анализ индивидуальных данных (IPD) из 42 рандомизированных клинических исследований (более 314 тыс. участников);
• Использована менделевская рандомизация с данными GWAS для оценки пожизненного эффекта снижения АД;
• Описаны первичные и вторичные онкологические исходы, а также отдельные локализации (рак лёгких, груди, простаты и др.);
• Подтверждена безопасность гипотензивной терапии в контексте риска развития рака.

Документ включает:

• Основной текст (11 стр., шрифт 12 пт, около 25 тыс. знаков без пробелов);
• Оформленный список литературы по ГОСТ (50 источников);
• Дополнительные материалы (методы, таблицы, рисунки, обзоры GWAS, РКИ и дополнительные 60 источников);
• Подходит для подачи в журналы из списка ВАК.

Полностью оригинальная, написана научным стилем, без заимствований. Подойдёт для аспирантов, врачей, научных сотрудников, студентов магистратуры (профили: терапия, кардиология, онкология, профилактическая медицина).

Можно использовать как курсовую, выпускную квалификационную работу (ВКР), диссертационный фрагмент или публикацию.

1. Piccirillo JF, Tierney RM, Costas I, et al. Prognostic importance of comorbidity in a hospital-based cancer registry. JAMA. 2004;291(20):2441–2447. doi:10.1001/jama.291.20.2441.

2. Copland E, Canoy D, Nazarzadeh M, et al. Antihypertensive treatment and risk of cancer: an individual participant data meta-analysis. Lancet Oncol. 2021;22(4):558–570. doi:10.1016/S1470-2045(21)00033-4.

3. Seretis A, Cividini S, Markozannes G, et al. Association between blood pressure and risk of cancer development: a systematic review and meta-analysis of observational studies. Sci Rep. 2019;9:8565. doi:10.1038/s41598-019-45014-4.

4. Christakoudi S, Kakourou A, Markozannes G, et al. Blood pressure and risk of cancer in the European Prospective Investigation Into Cancer and Nutrition. Int J Cancer. 2020;146(10):2680–2693. doi:10.1002/ijc.32576.

5. Hidayat K, Du X, Zou SY, Shi BM. Blood pressure and kidney cancer risk: meta-analysis of prospective studies. J Hypertens. 2017;35(7):1333–1344. doi:10.1097/HJH.0000000000001286.

6. Stocks T, Lukanova A, Bjоrge T, et al. Metabolic factors and the risk of colorectal cancer in 580,000 men and women in the metabolic syndrome and cancer project (Me-Can). Cancer. 2011;117(11):2398–2407. doi:10.1002/cncr.25735.

7. Han H, Guo W, Shi W, et al. Hypertension and breast cancer risk: a systematic review and meta-analysis. Sci Rep. 2017;7:44877. doi:10.1038/srep44877.

8. Scelo G, Larose TL. Epidemiology and risk factors for kidney cancer. J Clin Oncol. 2018;36:36. doi:10.1200/JCO.2018.79.1905.

9. Hiam-Galvez KJ, Allen BM, Spitzer MH. Systemic immunity in cancer. Nat Rev Cancer. 2021;21(6):345–359. doi:10.1038/s41568-021-00347-z.

10. Solak Y, Afsar B, Vaziri ND, et al. Hypertension as an autoimmune and inflammatory disease. Hypertens Res. 2016;39(8):567–573. doi:10.1038/hr.2016.35.

11. Battistoni A, Tocci G, Coluccia R, Burnier M, Ruilope LM, Volpe M. Antihypertensive drugs and the risk of cancer: a critical review of available evidence and perspective. J Hypertens. 2020;38(6):1005–1015. doi:10.1097/HJH.0000000000002339.

12. Lawlor DA, Tilling K, Davey Smith G. Triangulation in aetiological epidemiology. Int J Epidemiol. 2016;45(6):1866–1886. doi:10.1093/ije/dyw314.

13. Davies NM, Holmes MV, Davey Smith G. Reading Mendelian randomization studies: a guide, glossary, and checklist for clinicians. BMJ. 2018;362:k601. doi:10.1136/bmj.k601.

14. Rahimi K, Canoy D, Nazarzadeh M, et al. Investigating the stratified efficacy and safety of pharmacological blood pressure-lowering: an overall protocol for individual patient-level data meta-analyses of over 300 000 randomized participants in the new phase of the Blood Pressure Lowering Treatment Trialists Collaboration (BPLTTC). BMJ Open. 2019;9(5):e028698. doi:10.1136/bmjopen-2018-028698.

15. Canoy D, Copland E, Nazarzadeh M, et al. Antihypertensive drug effects on long-term blood pressure: an individual-level data meta-analysis of randomized clinical trials. Heart. 2022;108(16):1281–1289. doi:10.1136/heartjnl-2021-320171.

16. Blood Pressure Lowering Treatment Trialists Collaboration. Pharmacological blood pressure lowering for primary and secondary prevention of cardiovascular disease across different levels of blood pressure: an individual participant-level data meta-analysis. Lancet. 2021;397(10285):1625–1636. doi:10.1016/S0140-6736(21)00590-0.

17. Hommel G. A stagewise rejective multiple test procedure based on a modified Bonferroni test. Biometrika. 1988;75(2):383–386. doi:10.1093/biomet/75.2.383.

18. Wang R, Lagakos SW, Ware JH, Hunter DJ, Drazen JM. Statistics in medicine—reporting of subgroup analyses in clinical trials. N Engl J Med. 2007;357(21):2189–2194. doi:10.1056/NEJMsr077003.

19. European Medicines Agency. Multiplicity issues in clinical trials—scientific guideline. 2017. https://www.ema.europa.eu/en/multiplicity-issues-clinical-trials-scientific-guideline. Accessed April 16, 2025.

20. Smith GD, Ebrahim S. Mendelian randomization: can genetic epidemiology contribute to understanding environmental determinants of disease? Int J Epidemiol. 2003;32(1):1–22. doi:10.1093/ije/dyg070.

21. Evangelou E, Warren HR, Mosen-Ansorena D, et al. Genetic analysis of over 1 million people identifies 535 new loci associated with blood pressure traits. Nat Genet. 2018;50(10):1412–1425. doi:10.1038/s41588-018-0205-x.

22. Fortier I, Raina P, Van den Heuvel ER, et al. Maelstrom Research guidelines for rigorous retrospective data harmonization. Int J Epidemiol. 2017;46(1):103–105. doi:10.1093/ije/dyw075.

23. Hartwig FP, Davies NM, Hemani G, Davey Smith G. Two-sample Mendelian randomization: avoiding the downsides of a powerful, widely applicable but potentially fallible technique. Int J Epidemiol. 2016;45(6):1717–1726. doi:10.1093/ije/dyw028.

24. Hartwig FP, Davey Smith G, Bowden J. Robust inference in summary data Mendelian randomization via the zero modal pleiotropy assumption. Int J Epidemiol. 2017;46(6):1985–1998. doi:10.1093/ije/dyx102.

25. Hemani G, Bowden J, Davey Smith G. Evaluating the potential role of pleiotropy in Mendelian randomization studies. Hum Mol Genet. 2018;27(R2):R195–R208. doi:10.1093/hmg/ddy163.

26. Bowden J, Davey Smith G, Haycock PC, Burgess S. Consistent estimation in Mendelian randomization with some invalid instruments using a weighted median estimator. Genet Epidemiol. 2016;40(4):304–314. doi:10.1002/gepi.21965.

27. Verbanck M, Chen CY, Neale B, Do R. Detection of widespread horizontal pleiotropy in causal relationships inferred from Mendelian randomization between complex traits and diseases. Nat Genet. 2018;50(5):693–698. doi:10.1038/s41588-018-0099-7.

28. Bowden J, Davey Smith G, Burgess S. Mendelian randomization with invalid instruments: effect estimation and bias detection through Egger regression. Int J Epidemiol. 2015;44(2):512–525. doi:10.1093/ije/dyv080.

29. Zhao Q, Wang J, Hemani G, Bowden J, Small DS. Statistical inference in two-sample summary-data Mendelian randomization using robust adjusted profile score. Ann Stat. 2020;48(3):1742–1769. doi:10.1214/19-AOS1866.

30. Qi G, Chatterjee N. Mendelian randomization analysis using mixture models for robust and efficient estimation of causal effects. Nat Commun. 2019;10:1941. doi:10.1038/s41467-019-09432-2.

31. Burgess S, Bowden J, Fall T, Ingelsson E, Thompson SG. Sensitivity analyses for robust causal inference from Mendelian randomization analyses with multiple genetic variants. Epidemiology. 2017;28(1):30–42. doi:10.1097/EDE.0000000000000559.

32. Weikert S, Boeing H, Pischon T, et al. Blood pressure and risk of renal cell carcinoma in the European prospective investigation into cancer and nutrition. Am J Epidemiol. 2008;167(4):438–446. doi:10.1093/aje/kwm321.

33. Corrao G, Scotti L, Bagnardi V, Sega R. Hypertension, antihypertensive therapy and renal-cell cancer: a meta-analysis. Curr Drug Saf. 2007;2(2):125–133. doi:10.2174/157488607780598296.

34. Grossman E, Messerli FH, Boyko V, Goldbourt U. Is there an association between hypertension and cancer mortality? Am J Med. 2002;112(6):479–486. doi:10.1016/S0002-9343(02)01049-5.

35. Petrelli F, Ghidini A, Cabiddu M, et al. Effects of hypertension on cancer survival: a meta-analysis. Eur J Clin Invest. 2021;51(6):e13493. doi:10.1111/eci.13493.

36. Harding JL, Sooriyakumaran M, Anstey KJ, et al. Hypertension, antihypertensive treatment and cancer incidence and mortality: a pooled collaborative analysis of 12 Australian and New Zealand cohorts. J Hypertens. 2016;34(1):149–155. doi:10.1097/HJH.0000000000000770.

37. Clarke R, Wright N, Walters R, et al. Genetically predicted differences in systolic blood pressure and risk of cardiovascular and noncardiovascular diseases: a Mendelian randomization study in Chinese adults. Hypertension. 2023;80(3):566–576. doi:10.1161/HYPERTENSIONAHA.122.20137.

38. Chan II, Kwok MK, Schooling CM. Blood pressure and risk of cancer: a Mendelian randomization study. BMC Cancer. 2021;21:1338. doi:10.1186/s12885-021-09066-9.

39. Alcala K, Mariosa D, Smith-Byrne K, et al. The relationship between blood pressure and risk of renal cell carcinoma. Int J Epidemiol. 2022;51(4):1317–1327. doi:10.1093/ije/dyac042.

40. Bangalore S, Kumar S, Kjeldsen SE, et al. Antihypertensive drugs and risk of cancer: network meta-analyses and trial sequential analyses of 324,168 participants from randomized trials. Lancet Oncol. 2011;12(1):65–82. doi:10.1016/S1470-2045(10)70260-6.

41. Sipahi I. Risk of cancer with angiotensin-receptor blockers increases with increasing cumulative exposure: meta-regression analysis of randomized trials. PLoS One. 2022;17(3):e0263461. doi:10.1371/journal.pone.0263461.

42. Sipahi I, Debanne SM, Rowland DY, Simon DI, Fang JC. Angiotensin-receptor blockade and risk of cancer: meta-analysis of randomized controlled trials. Lancet Oncol. 2010;11(7):627–636. doi:10.1016/S1470-2045(10)70106-6.

43. Weiss W. Cigarette smoking and lung cancer trends. A light at the end of the tunnel? Chest. 1997;111(5):1414–1416. doi:10.1378/chest.111.5.1414.

44. Ference BA, Ray KK, Catapano AL, et al. Mendelian randomization study of ACLY and cardiovascular disease. N Engl J Med. 2019;380(11):1033–1042. doi:10.1056/NEJMoa1806747.

45. Gago-Dominguez M, Castelao JE, Yuan JM, Ross RK, Yu MC. Lipid peroxidation: a novel and unifying concept of the etiology of renal cell carcinoma (United States). Cancer Causes Control. 2002;13(3):287–293. doi:10.1023/A:1015044515593.

46. George AJ, Thomas WG, Hannan RD. The renin–angiotensin system and cancer: old dog, new tricks. Nat Rev Cancer. 2010;10(11):745–759. doi:10.1038/nrc2945.

47. Grant K, Loizidou M, Taylor I. Endothelin-1: a multifunctional molecule in cancer. Br J Cancer. 2003;88(2):163–166. doi:10.1038/sj.bjc.6600700.

48. Rahimi K, Emberson J, McGale P, et al. Effect of statins on atrial fibrillation: collaborative meta-analysis of published and unpublished evidence from randomized controlled trials. BMJ. 2011;342:d1250. doi:10.1136/bmj.d1250.

49. Pogue J, Walter SD, Yusuf S. Evaluating the benefit of event adjudication of cardiovascular outcomes in large simple RCTs. Clin Trials. 2009;6(3):239–251. doi:10.1177/1740774509105073.

50. Yarmolinsky J, Diez-Obrero V, Richardson TG, et al. Genetically proxied therapeutic inhibition of antihypertensive drug targets and risk of common cancers: a mendelian randomization analysis. PLoS Med. 2022;19(2):e1003897. doi:10.1371/journal.pmed.1003897.