Mendelian randomisation studies: principle and selected examples from cardiovascular medicine


Authors: Jaroslav A. Hubáček 1,2
Authors‘ workplace: Centrum experimentální medicíny, IKEM, Praha 1;  III. interní klinika – klinika endokrinologie a metabolismu 1. LF UK a VFN v Praze 2
Published in: AtheroRev 2020; 5(3): 176-180
Category:

Overview

Mendelian randomizations (MR) are studies that have been experiencing an unprecedented boom in last decade, although the principle is known for almost half of century. The sequencing of human genome and GWAs studies help us to understood the genetic mosaic of human diseases and has identified a hundreds of variants associated with cardiovascular disease. The fundament of mendelian randomization is to use a genetic marker to investigate, if there is a causal relationship between a biomarker and risk of disease. The principle is that, if genetic marker is associated with level of the biomarker, it needs to be in similar extent associated also with the disease risk and the causal relationship is confirmed. If the biomarker is genotype-associated but not disease-related, then the causality “parameter → disease” does not apply. For example, causality between plasma triglycerides and CVD risk or between statin therapy and an increased risk of T2DM has been proved by MR. In contrast, HDL-cholesterol levels or CRP levels have not been proven causal for CVD development. The myth of the protective effect of alcohol consumption on CVD risk was disproved. These findings may have a major impact on treatment – pharmacotherapy of non-causal factors will fails and can be even dangerous for the patients.

Keywords:

genetic – prediction – CVD – genome wide association studies (GWAS) – mendelian randomization


Sources
  1. Roth GA, Huffman MD, Moran AE et al. Global and regional patterns in cardiovascular mortality from 1990 to 2013. Circulation 2015; 132(17): 1667–1678. Dostupné z DOI: <http://dx.doi.org/10.1161/CIRCULATIONAHA.114.008720>.
  2. Hopkins PN, Williams RR. A survey of 246 suggested coronary risk factors. Atherosclerosis 1981; 40(1): 1–52. Dostupné z DOI: <http://dx.doi.org/10.1016/0021–9150(81)90122–2>.
  3. Rogers J. The finished genome sequence of Homo sapiens. Cold Spring Harb Symp Quant Biol 2003; 68: 1–11. Dostupné z DOI: <http://dx.doi.org/10.1101/sqb.2003.68.1>.
  4. Hubáček JA. Genetické testování pro včasnou predikci kardiovaskulárních onemocnění. Celogenomové asociační studie a polygenní skóre. AtheroRev 2020; 5(2): 88–92.
  5. Dehghan A. Genome-wide association studies. Methods Mol Biol 2018; 1793: 37–49. Dostupné z DOI: <http://dx.doi.org/10.1007/978–1-4939–7868–7_4>.
  6. Nikpay M, Goel A, Won HH et al. A comprehensive 1,000 Genomes-based genome-wide association meta-analysis of coronary artery disease. Nat Genet 2015; 47(10): 1121–1130. Dostupné z DOI: <http://dx.doi.org/10.1038/ng.3396>.
  7. Katan MB. Apolipoprotein E isoforms, serum cholesterol, and cancer. Lancet 1986; 1(8479): 507–508. Dostupné z DOI: <http://dx.doi.org/10.1016/s0140–6736(86)92972–7>.
  8. Mendel G. Versuche über Pflanzen-Hybriden. Verhandlungen des naturforschenden Vereins in Brünn. IV. Band. Abhandlungen 1865, Brünn, 1866. Im Verlage des Vere ins, S. 3–47.
  9. Dlouhá D, Hubáček JA. Gen pro FTO a jeho role v genetické determinaci obezity. Vnitř Lék 2012; 58(3): 208–215.
  10. Novotný L, Bencko V. Asociace genotypu s nemocí a odhalování jejich prostředím ovlivnitelných příčin: využití principu mendelovské randomizace. Čas Lék Česk 2007; 146(4): 343–350.
  11. Holmes MV, Ala-Korpela M, Smith GD. Mendelian randomization in cardiometabolic disease: challenges in evaluating causality. Nat Rev Cardiol 2017; 14(10): 577–590. Dostupné z DOI: <http://dx.doi.org/10.1038/nrcardio.2017.78>.
  12. Nikpay M, Goel A, Won HH et al. A comprehensive 1,000 Genomes-based genome-wide association meta-analysis of coronary artery disease. Nat Genet 2015; 47(10): 1121–1130. Dostupné z DOI: <http://dx.doi.org/10.1038/ng.3396>.
  13. Davies NM, Holmes MV, Davey Smith G. Reading mendelian randomisation studies: a guide, glossary, and checklist for clinicians. BMJ 2018; 362: k601. Dostupné z DOI: <http://dx.doi.org/10.1136/bmj.k601>.
  14. Sattar N, Preiss D. Reverse causality in cardiovascular epidemiological research: more common than imagined? Circulation 2017; 135(24): 2369–2372. Dostupné z DOI: <http://dx.doi.org/10.1161/CIRCULATIONAHA.117.028307>.
  15. Hubáček JA. Apolipoprotein AV a triglyceridémie. Čas Lék Česk 2004; 143(12): 799–803.
  16. Sarwar N, Sandhu MS, Ricketts SL et al. [Triglyceride Coronary Disease Genetics Consortium and Emerging Risk Factors Collaboration]. Triglyceride-mediated pathways and coronary disease: collaborative analysis of 101 studies. Lancet 2010; 375(9726): 1634–1639. Dostupné z DOI: <http://dx.doi.org/10.1016/S0140–6736(10)60545–4>. Erratum in: Lancet 2010; 376(9735): 90.
  17. Wu Z, Lou Y, Qiu X et al. Association of cholesteryl ester transfer protein (CETP) gene polymorphism, high density lipoprotein cholesterol and risk of coronary artery disease: a meta-analysis using a Mendelian randomization approach. BMC Med Genet 2014; 15: 118. Dostupné z DOI: <http://dx.doi.org/10.1186/s12881–014–0118–1>.
  18. Haase CL, Tybjærg-Hansen A, Qayyum AA et al. LCAT, HDL cholesterol and ischemic cardiovascular disease: a Mendelian randomization study of HDL cholesterol in 54,500 individuals. J Clin Endocrinol Metab 2012; 97(2): E248-E256. Dostupné z DOI: <http://dx.doi.org/10.1210/jc.2011–1846>.
  19. Chiva-Blanch G, Arranz S, Lamuela-Raventos RM et al. Effects of wine, alcohol and polyphenols on cardiovascular disease risk factors: evidences from human studies. Alcohol Alcoholism 2013; 48(3): 270–277. Dostupné z DOI: <http://dx.doi.org/10.1093/alcalc/agt007>.
  20. Holmes MV, Dale CE, Zuccolo L et al. Association between alcohol and cardiovascular disease: Mendelian randomisation analysis based on individual participant data. BMJ 2014; 349: g4164. Dostupné z DOI: <http://dx.doi.org/10.1136/bmj.g4164>.
  21. Hooper L, Al-Khudairy L, Abdelhamid AS et al. Omega-6 fats for the primary and secondary prevention of cardiovascular disease. Cochrane Database Syst Rev 2018; 7(7): CD011094. Dostupné z DOI: <http://dx.doi.org/10.1002/14651858.CD011094.pub3>.
  22. Liao LZ, Li WD, Liu Y et al. Exploring the causal pathway from omega-6 levels to coronary heart disease: A network Mendelian randomization study. Nutr Metab Cardiovasc Dis 2020; 30(2): 233–240. Dostupné z DOI: <http://dx.doi.org/10.1016/j.numecd.2019.09.013>.
  23. Li Y, Zhong X, Cheng G et al. Hs-CRP and all-cause, cardiovascular, and cancer mortality risk: A meta-analysis. Atherosclerosis 2017; 259: 75–82. Dostupné z DOI: <http://dx.doi.org/10.1016/j.atherosclerosis.2017.02.003>.
  24. Wensley F, Gao P, Burgess S et al. [C Reactive Protein Coronary Heart Disease Genetics Collaboration (CCGC)]. Association between C reactive protein and coronary heart disease: mendelian randomisation analysis based on individual participant data. BMJ 2011; 342: d548. Dostupné z DOI: <http://dx.doi.org/10.1136/bmj.d548>.
  25. Nordestgaard BG, Zacho J. Lipids, atherosclerosis and CVD risk: Is CRP an innocent bystander? Nutr Metab Cardiovasc Dis 2009; 19: 521–524. Dostupné z DOI: <http://dx.doi.org/10.1016/j.numecd.2009.07.005>.
  26. Katsiki N, Athyros VG, Karagiannis A et al. Statins and type 2 diabetes mellitus: an update after 1 year. Curr Pharm Des 2016; 22(18): 2723–2725. Dostupné z DOI: <http://dx.doi.org/10.2174/1381612822666160125114626>.
  27. Swerdlow DI, Preiss D, Kuchenbaecker KB, et al. HMG-coenzyme A reductase inhibition, type 2 diabetes, and bodyweight: evidence from genetic analysis and randomised trials. Lancet 2015; 385(9965): 351–61. Dostupné z DOI: <http://dx.doi.org/10.1016/S0140–6736(14)61183–1>.
  28. Lotta LA, Sharp SJ, Burgess S et al. Association between low-density lipoprotein cholesterol-lowering genetic variants and risk of type 2 diabetes: A Meta-analysis. JAMA 2016; 316(13): 1383–1391. Dostupné z DOI: <http://dx.doi.org/10.1001/jama.2016.14568>.
  29. Afzal S, Brøndum-Jacobsen P, Bojesen SE et al. Vitamin D concentration, obesity, and risk of diabetes: a mendelian randomisation study. Lancet Diabetes Endocrinol 2014; 2(4): 298–306. Dostupné z DOI: <http://dx.doi.org/10.1016/S2213–8587(13)70200–6>.
  30. Ong JS, Gharahkhani P, An J et al. Vitamin D and overall cancer risk and cancer mortality: a Mendelian randomization study. Hum Mol Genet 2018; 27(24): 4315–4322. Dostupné z DOI: <http://dx.doi.org/10.1093/hmg/ddy307>.
  31. Benn M, Nordestgaard BG, Tybjærg-Hansen A et al. Impact of glucose on risk of dementia: Mendelian randomisation studies in 115,875 individuals. Diabetologia 2020; 63(6): 1151–1161. Dostupné z DOI: <http://dx.doi.org/10.1007/s00125–020–05124–5>.
  32. Wootton RE, Richmond RC, Stuijfzand BG et al. Evidence for causal effects of lifetime smoking on risk for depression and schizophrenia: a Mendelian randomisation study. Psychol Med 2019; 1–9. Dostupné z DOI: <http://dx.doi.org/10.1017/S0033291719002678>.
Labels
Angiology Diabetology Internal medicine Cardiology General practitioner for adults

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