Mendelian randomization analysis does not support causal associations of birth weight with hypertension risk and blood pressure in adulthood

Authors: ZHENG, YAN - Fudan University; HUANG, TAO - Peking University; WANT, TIANGE - Shanghai Jiaotong University; MEI, ZHENGDONG - Fudan University; SUN, ZHONGHAN - Fudan University; ZHANG, TAO - Peking University; ELLERVIK, CHRISTINA - University Of Copenhagen; CHAI, JIN-FANG - National University Of Singapore; SIM, XUELING - National University Of Singapore; VAN DAM, ROB - National University Of Singapore; TAI, E-SHYONG - National University Of Singapore; KOH, WOON-PUAY - National University Of Singapore; DORAJOO, RAJKUMAR - Genome Institute Of Singapore; SAW, SEANG MEI - National University Of Singapore; SABANAYAGAM, CHARUMATHI - Singapore National Eye Centre; WONG, TIEN YIN - Singapore National Eye Centre; GUPTA, PREETI - Singapore National Eye Centre; ROSSING, PETER - Steno Diabetes Center Copenhagen (SDCC); AHLUWALIA, TARUNVEER - University Of Copenhagen; VINDING, REBECCA - University Of Copenhagen; BISGAARD, HANS - University Of Copenhagen; BONNELYKKE, KLAUS - University Of Copenhagen; WANG, YUJIE - University Of North Carolina; GRAFF, MARIELISA - University Of North Carolina; VOORTMAN, TRUDY - Erasmus Medical Center; VAN ROOIJ, FRANK - Erasmus Medical Center; HOFMAN, ALBERT - Erasmus Medical Center; VAN HEEMST, DIANA - Leiden University Medical Center; NOORDAM, RAYMOND - Leiden University Medical Center; ESTAMPADOR, ANGELA - Lund University; VARGA, TIBOR - Lund University; ENZENBACK, CORNELIA - University Of Leipzig; SCHOLZ, MARKUS - University Of Leipzig; THEIRY, JOACHIM - University Of Leipzig; BURKHARDT, RALPH - University Of Leipzig; ORHO-MELANDER, MARJU - Lund University; SCHULZ, CHRISTINA-ALEXA - Lund University; ERICSON, ULRIKA - Lund University; SONESTEDT, EMILY - University Of Lundt; KUBO, MICHIAKI - Riken Center For Integrative Medical Sciences; AKIYAMA, MASATO - Riken Center For Integrative Medical Sciences; ZHOU, ANG - University Of South Australia; KILPELAINEN, TUOMAS - University Of Copenhagen; HANSEN, TORBEN - University Of Copenhagen; KLEBER, MARCUS - Heidelberg University; DALGADO, GRACIELA - Heidelberg University; MCCARTHY, MARK - University Of Oxford; LEMAITRE, ROZENN - University Of Washington; FELIZ, JANINE - University Medical Center Rotterdam; JADDOE, VINCENT - University Medical Center Rotterdam; WU, YING - University Of North Carolina; MOHLKE, KAREN - University Of North Carolina; LEHTIMAKI, TERHO - University Of Tampere; WANG, CAROL - University Of Newcastle; PENNELL, CRAIG - University Of Newcastle; SCHUNKERT, HERIBERT - Technische Universitat Munchen; KESSLER, THORSTEN - Technische Universitat Munchen; ZENG, LINGYAO - Technische Universitat Munchen; WILLENBORG, CHRISTINA - University Of Lubeck; PETERS, ANNETTE - University Of Kiel; LIEB, WOLFGANG - University Of Kiel; GROTE, VEIT - Klinikum Der Universitaet; RZEHAK, PETER - Klinikum Der Universitaet; KOLETZKO, BERTHOLD - Klinikum Der Universitaet; ERDMANN, JEANETTE - University Of Lubeck; MUNZ, MATTHIAS - University Of Lubeck; WU, TANGCHUN - Huazhong University Of Science And Technology; HE, MEIAN - Huazhong University Of Science And Technology; YU, CAIZHENG - Huazhong University Of Science And Technology; LECOEUR, CECILE - Université Lille Nord De France; FROGUEL, PHILIPPE - Université Lille Nord De France; CORELLA, DOLORES - University Of Valencia; MORENO, LUIS - Centro De Investigacion Biomedica En Red (CIBER)-Epidemiología Y Salud Pública; Lai, Chao Qiang; PITKANEN, NIINA - University Of Turku; BOREHAM, COLIN - University College Dublin; RIDKER, PAUL - Brigham & Women'S Hospital; ROSENDAAL, FRITS - Leiden University Medical Center; DE MUTSERT, RENEE - Leiden University Medical Center; POWER, CHRIS - Ucl Great Ormond Street Institute Of Child Health; PATERNOSTER, LAVINIA - University Of Bristol; SORENSEN, THORKILD - University Of Copenhagen; TJONNELAND, ANNE - Danish Cancer Society Research Center; OVERVAD, KIM - Aarhus University; DJOUSSE, LUC - Brigham & Women'S Hospital; RIVADENEIRA, FERNANDO - Erasmus Medical Center; LEE, NANETTE - University Of San Carlos Guatemala; RAITAKARI, OLLI - University Of Turku; KAHONEN, MIKA - Tampere University Hospital; VIIKARI, JORMA - Turku University Hospital; LANGHENDRIES, JEAN-PAUL - Liege Chu; ESCRIBANO, JOAQUIN - University Rovira I Virgili; VERDUCI, ELVIRA - University Of Milan; DEDOUSSIS, GEORGE - Harokopio University Of Athens; COLTELL, OSCAR - University Jaume I Of Castellon; ORDOVAS, JOSE - Jean Mayer Human Nutrition Research Center On Aging At Tufts University; QI, LU - Tulane University

Submitted to: European Journal of Epidemiology
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 4/21/2020
Publication Date: 5/7/2020
Citation: Zheng, Y., Huang, T., Want, T., Mei, Z., Sun, Z., Zhang, T., Ellervik, C., Chai, J., Sim, X., Van Dam, R.M., Tai, E., Koh, W., Dorajoo, R., Saw, S., Sabanayagam, C., Wong, T., Gupta, P., Rossing, P., Ahluwalia, T.S., Vinding, R.K., Bisgaard, H., Bonnelykke, K., Wang, Y., Graff, M., Voortman, T., Van Rooij, F., Hofman, A., Van Heemst, D., Noordam, R., Estampador, A.C., Varga, T.V., Enzenback, C., Scholz, M., Theiry, J., Burkhardt, R., Orho-Melander, M., Schulz, C.A., Ericson, U., Sonestedt, E., Kubo, M., Akiyama, M., Zhou, A., Kilpelainen, T.O., Hansen, T., Kleber, M.E., Dalgado, G., McCarthy, M., Lemaitre, R., Feliz, J.F., Jaddoe, V.W., Wu, Y., Mohlke, K.L., Lehtimaki, T., Wang, C.A., Pennell, C.E., Schunkert, H., Kessler, T., Zeng, L., Willenborg, C., Peters, A., Lieb, W., Grote, V., Rzehak, P., Koletzko, B., Erdmann, J., Munz, M., Wu, T., He, M., Yu, C., Lecoeur, C., Froguel, P., Corella, D., Moreno, L., Lai, C., Pitkanen, N., Boreham, C.A., Ridker, P.M., Rosendaal, F., de Mutsert, R., Power, C., Paternoster, L., Sorensen, T.I., Tjonneland, A., Overvad, K., Djousse, L., Rivadeneira, F., Lee, N.R., Raitakari, O., Kahonen, M., Viikari, J., Langhendries, J., Escribano, J., Verduci, E., Dedoussis, G., Coltell, O., Ordovas, J.M., Qi, L. 2020. Mendelian randomization analysis does not support causal associations of birth weight with hypertension risk and blood pressure in adulthood. European Journal of Epidemiology. 35:685-697. https://doi.org/10.1007/s10654-020-00638-z.
DOI: https://doi.org/10.1007/s10654-020-00638-z

Interpretive Summary: Low birth weight has been associated with higher cardiometabolic risk factors and adiposity in children and adolescents and increases the risk of cardiovascular diseases, obesity, and early mortality later in life. However, association does not prove causality, which requires carefully designed randomized clinical intervention studies. In this specific case, such studies are not possible in humans, and alternative approaches, using novel, sophisticated statistical techniques have been developed for this purpose. In this study, a team of international scientists, including the HNRCA at Boston, evaluated the potential causal association between low birth weight with adulthood hypertension. The results show no causal relationship between low birth weight and hypertension risk in adulthood using data from almost 800,000 individuals participating in multiple well-conducted epidemiological studies and state-of-the-art statistical approaches. Therefore, the previous associations of low birth weight with a higher hypertension risk and blood pressure in adults were not supported by these analyses. These findings suggest that the reported associations of birth weight with hypertension in later life could result from other confounding factors not accounted for in previous studies.

Technical Abstract: Epidemiology studies suggested that low birthweight was associated with a higher risk of hypertension in later life. However, little is known about the causality of such associations. In our study, we evaluated the causal association of low birthweight with adulthood hypertension following a standard analytic protocol using the study-level data of 183,433 participants from 60 studies (CHARGE-BIG consortium), as well as that with blood pressure using publicly available summary-level genomewide association data from EGG consortium of 153,781 participants, ICBP consortium and UK Biobank cohort together of 757,601 participants. We used seven SNPs as the instrumental variable in the study-level analysis and 47 SNPs in the summary-level analysis. In the study-level analyses, decreased birthweight was associated with a higher risk of hypertension in adults (the odds ratio per 1 standard deviation (SD) lower birthweight, 1.22; 95% CI 1.16 to 1.28), while no association was found between genetically instrumented birthweight and hypertension risk (instrumental odds ratio for causal effect per 1 SD lower birthweight, 0.97; 95% CI 0.68 to 1.41). Such results were consistent with that from the summary-level analyses, where the genetically determined low birthweight was not associated with blood pressure measurements either. One SD lower genetically determined birthweight was not associated with systolic blood pressure (b= - 0.76, 95% CI - 2.45 to 1.08 millimeters of Hg), 0.06 millimeters of Hg lower diastolic blood pressure (b= - 0.06, 95% CI - 0.93 to 0.87 millimeters of Hg), or pulse pressure (b= - 0.65, 95% CI - 1.38 to 0.69 millimeters of Hg, all p greater than 0.05). Our findings suggest that the inverse association of birthweight with hypertension risk from observational studies was not supported by large Mendelian randomization analyses.