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 genome-wide 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 (β = - 0.76, 95% CI - 2.45 to 1.08mmHg), 0.06mmHg lower diastolic blood pressure (β = - 0.06, 95% CI - 0.93 to 0.87mmHg), or pulse pressure (β = - 0.65, 95% CI - 1.38 to 0.69mmHg, all p > 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.
Highlights
Hypertension, defined as high in systolic blood pressure, diastolic blood pressure, or both above normal levels, is a leading risk factor for mortality and morbidity
Large scale genome-wide association studies (GWAS) consortia did not suggest that the seven single-nucleotide polymorphisms (SNPs) were associated with potential hypertension risk factors, including circulating major lipids, fasting glucose and insulin, type 2 diabetes, body mass index (BMI), waist-to-hip ratio, and chronic kidney disease (Supplemental Fig. 1)
The low birthweight genetic risk score (GRS) was inversely associated with birthweight (Fig. 3a, each risk allele was associated with 0.02 standard deviation (SD) lower birthweight, and there was evidence for heterogeneity in such an association (I2 = 78%, p < 0.01)
Summary
Hypertension, defined as high in systolic blood pressure, diastolic blood pressure, or both above normal levels, is a leading risk factor for mortality and morbidity. The estimated rate of death attributable to high systolic blood pressure (140 mmHg or more) was 106.3/100,000 persons in 2015, and the number of disability-adjusted life-years was 7.8 million [2]. Epidemiology studies have provided emerging observational evidence for developmental origins for hypertension [3]. A surrogate marker of intrauterine malnutrition and developmental stressors, has emerged as a potential risk factor for cardiometabolic disorders, including hypertension in later life [4, 5]. Several lines of pathophysiological evidence have provided potential mechanisms including vascular dysfunction, reduced nephron numbers, sympathetic activation and neuroendocrine involved in the association of low birthweight with adulthood hypertension and blood pressure [6]. Traditional clinical trials are unrealistic in such cases to assess the causality of these associations, necessitating other study designs
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