Raised blood pressure remains the leading cause of death globally, high systolic blood pressure accounted for 10·8 million deaths in 2019 (1). Unfortunately, hypertension has high prevalence but low rate of control. It is estimated that 1 in 4 men and 1 in 5 women (1.13 billion people), living with hypertension in 2015, but less than 1/5 have their blood pressure under control (2).

In the worldwide, a large number of people suffer from higher body mass index (BMI), including overweight and obesity. In 2016, a total of 39% adults are overweight, with a BMI ≥ 25 kg/m², and 13% are obese (BMI ≥ 30 kg/m²) (3). Higher BMI is a major risk factor of hypertension. In the original Framingham cohort, Wilson et al. (4) found overweight and obese status were associated with increased risk of hypertension: the multi-adjusted risk ratios (RRs) among the overweight was 1.48 in men and 1.70 in women, while among the obese was 2.23 in men and 2.63 in women. In another Framingham study, weight loss led to a 21%~29% reduction in long-term hypertension risk (5). Mendelian randomization (MR) analysis, using genetic variants as the instrumental variable, has also demonstrated the causality between obesity and hypertension (6).

Genetic and early-life environmental factors, including shared fetal environment, childhood socioeconomic situation and adolescent environment, might have long-term effects on the subsequent risk of obesity (7–9) and hypertension (10–12). However, due to the limitations of general population-based study, their roles in the obesity-hypertension association are uncertain. Co-twin case-control analysis could address part of this difficulty, by controlling for genetic background and key shared familial environmental factors associated with obesity and hypertension. Twins are generally raised together, so they share their early-life environmental factors. They also share the same genetic predisposition and intrauterine environments. Therefore, as naturally matched pairs, co-twin case-control analyses provide an opportunity to explore the role of genetic and early-life environmental factors in the association between overweight or obesity and hypertension (13, 14).

The purpose of this study was to examine the association between overweight or obesity and hypertension, and to explore whether the association could be explained by genetic and common environmental factors shared within a twin pair, based on information from the Chinese National Twin Registry (CNTR).

In this large-scale, nationwide Chinese twin study, we found that both overweight and obesity were significantly associated with increased hypertension risk. And the associations were different between unmatched and matched analyses, and even non-significant in the co-twin analysis of MZ twins, indicating genetic or both genetic and environmental factors shared between co-twins are likely to contribute to the association. Furthermore, we found a positive correlation between BMI and hypertension, which was explained by a genetic correlation, providing evidence for the contribution of overlap genetic factors on their association.

Consistent with our findings, a growing number of studies have reported that overweight and obesity were independently associated with increased risk of hypertension. Using 5209 participants aged 30 to 62 years from the original Framingham cohort, Wilson et al. (4) found overweight and obese status were positively associated with hypertension: compared with those with normal weight, overweight increased a 48% (95% CI: 1.24~1.75) and 70% (95% CI: 1.48~1.94) risk of hypertension in the men and women, respectively; the age-adjusted RRs were 2.23 (95% CI: 1.75~2.84), and 2.63 (95% CI: 2.20~3.15) in male and female obese individuals, respectively. After 6.38-year follow-up, Qi et al. (28) reported a positive association between BMI and hypertension in the Chines: the RR was 3.13 (95% CI: 2.84~3.45) for the obesity. In the Framingham Study, Moore et al. (5) found weight loss ≥ 6.8 kg led to a 28% (RR=0.72, 95% CI: 0.49~1.05) and a 37% (RR=0.63, 95% CI: 0.42~0.95) reduction in hypertension risk for middle-aged and older adults, respectively; And sustained weight loss also reduced the hypertension risk: 22% and 26% for middle-aged and older adults, respectively. These studies provided evidence that overweight and obesity were independently associated with hypertension risk.

The mechanisms underlying the overweight (obesity)-hypertension association are complex and not completely understood. Obesity can directly produce a variety of structural and functional changes of the cardiovascular system, including lower cardiac output, poorer left ventricular systolic function, higher peripheral resistance, increased left ventricular mass, left ventricular wall thickness and internal dimension (29). In addition, obesity is associated with mechanisms that could increase sympathetic nervous system (SNS) activity, which is believed to play an important role in the development of hypertension. Angiotensin II could increase SNS activity, while angiotensinogen is expressed in visceral adipocytes (30, 31). In the obesity, the inhibitory of arterial baroreflex on SNS activity is reduced, contributing to the increased SNS activity to muscle and kidney (32, 33). And the dysregulation of the hypothalamic-pituitary-adrenal axis, characterized by obesity, seems to be important to the activation of the SNS in obese humans (34).

The co-twin case-control analysis could explore associations, under the control of genetic and unmeasured early-life environmental factors. In the current study, we found the overweight-hypertension association was attenuated in the matched study, and even disappeared in the co-twin analysis of MZ twins, indicating that the observed association was fully explained by genetic and familiar factors shared within a twin pair. Our results indicate these with family history of obesity may have high hypertension risk, which showed the important to prevent hypertension in these population. However, not consistent with our findings, MR analysis has demonstrated the causal effect of obesity on hypertension. Including 119,859 participants from UK Biobank, Lee et al. (6) showed a positive association between genetically instrumented higher BMI and hypertension risk (OR= 1.64, 95% CI: 1.48~1.83). In a Korea cohort study, using genetic risk scores (GRS), created by 6 single-nucleotide polymorphisms associated with BMI, researchers found a causal effect of BMI on hypertension (OR: 1.13~1.26) (35). In addition, a large number of studies have investigated the biological mechanisms underlying obesity-hypertension association. Therefore, our findings based on statistics analysis should be interpreted with caution. More large studies from Chinese population are warranted to verify our results.

Furthermore, using bivariate twin model, we further found the positive BMI-hypertension association was explained by a genetic correlation between them, providing evidence for the contribution of overlap genes on their relationship. Including a total of 913 subjects from 179 families, Li et al. (36) found waist circumference (WC) was genetically correlated with systolic blood pressure (r _A=0.27), but found no significant genetic correlations between BMI and blood pressure. Although we found no study exploring the genetic link between overweight (obesity) and hypertension, numerous studies provide evidences for the pleiotropy between obesity and hypertension. FTO (fat mass and obesity-associated) gene, the first identified gene for obesity, is the strongest BMI related genetic factors (37, 38). Meta-analysis has demonstrated the associations between FTO SNPs and obesity risk (39, 40). It is reported that FTO gene is highly expressed in the hypothalamic nuclei (41, 42), involving in the control of energy homeostasis (43) and regulation of blood pressure (44). To date, several studies have investigated the association between FTO variants and risk of hypertension. Although the results are inconsistent, many large studies showed some of FTO genotypes significantly increased risks of hypertension (45). Many other genes, such as MC4R (46–48), TNF-α (49–51), LEP (LEPR) (52–56) and β2AR (57, 58), were all associated with both obesity and hypertension. However, because of the lack of comparable co-twin studies, the roles of shared genetic factors in the relationship between overweight or obesity and hypertension are still needed to be explored.

Although our co-twin analysis reported that early-life environment might contribute to the overweight-hypertension association, the common environmental correlation was not significant in the twin model. Not consistent with our results, as important parts of early-life environments, a growing body of studies described that poor fetal and early postnatal growth were associated with subsequent risk of obesity and hypertension. The majority of epidemiological studies utilize birth weight and gestational age as proxy markers for suboptimal utero growth. Abundant evidences suggested that high birth weight (HBW) and large for gestational age were associated with an increased risk of obesity later in life (59–61). In a meta-analysis, including 14 cohort studies, HBW (≥4000g) was associated with higher risk of obesity (OR=1.43, 95% CI: 1.25~1.64), but not low birth weight (LBW) (<2500 g) (60). Furthermore, low birth weight (LBW) was associated with higher hypertension risk (62–65). In the Shanghai Women’s Health Study and the Shanghai Men’s Health Study, an excess risk of hypertension was observed for LBW, hazard ratio (HR) was 1.20 (95% CI: 1.11~1.30) (63). In the Swedish twin study on the fetal origins of hypertension, Bergvall et al. (65) provided evidence that LBW was associated with increased hypertension risk. Although early-life environmental factors are associated with both obesity and hypertension, whether those factors confound the overweight (obesity)-hypertension association is unknown.

Some limitations of this study need to be mentioned. First, we calculated BMI from self-reported height and weight, which could have led to an underestimation of the overweight. Besides, we collected disease information from self-reported questionnaires without measuring the blood pressure. Because of the higher proportion of patients who were not aware of their hypertension (12.3%~24.7%) in the Chinese adults (66, 67), individuals with undiagnosed hypertension might have been misclassified as hypertension-free. Both of those could have led to biased estimation for the overweight-hypertension association. Finally, despite the large sample sizes, the number of cases for stratification analyses was small, especially for the co-twin control analysis. Specifically, we obtained a borderline significant association between obesity and hypertension, due to the limited sample sizes. Thus, further investigations are needed to assess whether the genetics and early-life environmental factors account for this association.

Nonetheless, the current study has several strengths. First, the large nationwide twin cohort allowed us to explore the effects of overweight and obesity on hypertension, and simultaneously estimate the potential influence of genetic and early-life environmental factors in their relationship with sufficient power. We used GEE models, controlling for the clustering of twins within a pair, to provide evidence for the overweight-hypertension association. And further assessing the roles of genetic and familiar factors on the given association, via co-twin case-control design. Second, we only included twins who were diagnosed with hypertension during the follow-up, making the temporality clear and thus minimize the possibility of reverse causality. Third, due to DZ twins only share 50% of their genetic predisposition, co-twin matched case-control analyses including both MZ and DZ twins do not completely control for genetic factors. Therefore, we further repeated co-twin design in MZ and DZ twins separately, which verified our results.

In conclusion, with the current study, we add evidence to the positive link between overweight (obesity) and hypertension, and show the importance of genetic and family environmental factors for their association. That is, due to the common genetic predisposition, individuals with higher BMI seem to be more likely to develop into hypertension. A next step would be to verify our findings in more prospective studies, and find more genes and environments responsible for the overweight (obesity)-hypertension association.

The original contributions presented in the study are included in the article/ Supplementary Material . Further inquiries can be directed to the corresponding authors.

The studies involving human participants were reviewed and approved by the Ethics Committee at Peking University Health Science Center (IRB00001052-11029/14021). The patients/participants provided their written informed consent to participate in this study.

WC and WG contributed to the study design and supervise the whole project. ZP, MY, HW, XPW, ZD, FW, GJ, XJW, YL, JD, and LL contributed to conduct field study and collect the data. KZ, JL, CY, SW, TH, DS, CL, and YP contributed to the results interpretation and provided critical comments. LML helped to design and supervise the whole study and obtain funding. YX analyzed data and drafted the manuscript. All authors contributed to the article and approved the submitted version.

This study was funded by National Natural Science Foundation of China (82073633, 81973126, 81711530051, 81573223, 81473041), and Special Fund for Health Scientific Research in the Public Welfare (201502006, 201002007). The funders had no role in study design and conduct, data collection, analysis and interpretation, preparation of the manuscript, or the decision to publication.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

The reviewer XT declared a shared affiliation, with no collaboration, with ZP to the handling editor at the time of review.

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