Abstract
Background: China has high stroke rates despite the population being relatively lean. Uncertainty persists about the relevance of adiposity to risk of stroke types. We aimed to assess the associations of adiposity with incidence of stroke types and effect mediation by blood pressure in Chinese men and women. Methods: The China Kadoorie Biobank enrolled 512 891 adults aged 30–79 years from ten areas (five urban and five rural) during 2004–08. During a median 9 years (IQR 8–10) of follow-up, 32 448 strokes (about 90% confirmed by neuroimaging) were recorded among 489 301 participants without previous cardiovascular disease. Cox regression analysis was used to produce adjusted hazard ratios (HRs) for ischaemic stroke (n=25 210) and intracerebral haemorrhage (n=5380) associated with adiposity. Findings: Mean baseline body-mass index (BMI) was 23·6 kg/m2 (SD 3·2), and 331 723 (67·8%) participants had a BMI of less than 25 kg/m2. Throughout the range examined (mean 17·1 kg/m2 [SD 0·9] to 31·7 kg/m2 [2·0]), each 5 kg/m2 higher BMI was associated with 8·3 mm Hg (SE 0·04) higher systolic blood pressure. BMI was positively associated with ischaemic stroke, with an HR of 1·30 (95% CI 1·28–1·33 per 5 kg/m2 higher BMI), which was generally consistent with that predicted by equivalent differences in systolic blood pressure (1·25 [1·24–1·26]). The HR for intracerebral haemorrhage (1·11 [1·07–1·16] per 5 kg/m2 higher BMI) was less extreme, and much weaker than that predicted by the corresponding difference in systolic blood pressure (1·48 [1·46–1·50]). Other adiposity measures showed similar associations with stroke types. After adjustment for usual systolic blood pressure, the positive associations with ischaemic stroke were attenuated (1·05 [1·03–1·07] per 5 kg/m2 higher BMI); for intracerebral haemorrhage, they were reversed (0·73 [0·70–0·77]). High adiposity (BMI >23 kg/m2) accounted for 14·7% of total stroke (16·5% of ischaemic stroke and 6·7% of intracerebral haemorrhage). Interpretation: In Chinese adults, adiposity was strongly positively associated with ischaemic stroke, chiefly through its effect on blood pressure. For intracerebral haemorrhage, leanness, either per se or through some other factor (or factors), might increase risk, offsetting the protective effects of lower blood pressure. Funding: UK Wellcome Trust, UK Medical Research Council, British Heart Foundation, Cancer Research UK, Kadoorie Charitable Foundation, Chinese Ministry of Science and Technology, Chinese National Natural Science Foundation.
| Original language | English |
|---|---|
| Pages (from-to) | e630-e640 |
| Number of pages | 11 |
| Journal | The Lancet Global Health |
| Volume | 6 |
| Issue number | 6 |
| DOIs | |
| Publication status | Published - 1 Jun 2018 |
Bibliographical note
Publisher Copyright:© 2018 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license
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This large prospective study showed that, among relatively lean but healthy Chinese adults, adiposity was strongly positively associated with systolic blood pressure, and that systolic blood pressure was strongly positively related to stroke incidence, particularly intracerebral haemorrhage, without evidence of any threshold throughout the range studied. However, despite these two continuous and apparently causal relationships, adiposity showed an expected strong positive association only with ischaemic stroke, but not with intracerebral haemorrhage. Several large prospective studies, and meta-analyses of such studies, have consistently reported positive associations between BMI and risks of ischaemic stroke and total stroke. 5,6,8,11–13,15–17 In a meta-analysis of 16 large prospective studies, including eight from east Asia, the pooled relative risk (RR) for ischaemic stroke was greater in east Asian than in high-income populations (1·35 vs 1·22, per 5 kg/m 2 higher BMI), 17 but varied greatly across different studies both within and between east Asian and high-income populations. Our RR estimate for ischaemic stroke (1·30 per 5 kg/m 2 BMI) was similar to that observed in previous east Asian studies. Likewise, a meta-analysis of 97 prospective studies, including 33 from Asia, which examined the associations of BMI with total stroke only, reported pooled RR in Asian cohorts that were similar to those reported in the present study (1·29 vs 1·27 per 5 kg/m 2 higher BMI), but stronger than those in high-income populations (1·14). 16 For total stroke, our study estimated that high BMI (defined as >23 kg/m 2 ) accounted for 15% of total stroke, which was less than the 20% previously estimated for China in a recent Global Burden of Disease report 10 that used the same BMI cut points. Moreover, our study also demonstrated that the RRs for ischaemic stroke were substantially greater at younger than older ages, although the absolute excess risks were greater at older ages. Previous studies showed that, given BMI levels, men tend to have greater insulin resistance, ectopic fat levels in the liver and elsewhere, and higher risks of type 2 diabetes and cardiovascular disease. 9,33 In our study, the RRs were also higher in men than in women, which was due mainly to the stronger associations in men between systolic blood pressure and stroke. Consistent with previous studies, 6,16 the observed association of BMI with ischaemic stroke was mediated mainly through blood pressure in this Chinese population. Most previous studies have focused mainly on haemorrhagic stroke rather than intracerebral haemorrhage specifically, and the results have been inconsistent, partly because of the relatively small number of cases studied and the strong possibility of misclassification of stroke types in studies without widespread use of brain imaging. In the most recent meta-analysis, which included more than 17 000 haemorrhagic stroke cases, 17 the overall association between BMI and risk of haemorrhagic stroke differed substantially between high-income and east Asian cohorts (RR 0·91 vs 1·16, per 5 kg/m 2 higher BMI). In the high-income cohorts, more than 80% of the haemorrhagic stroke cases were from one UK study, which used self-reported BMI and had a disproportionally large number of subarachnoid haemorrhage cases compared with intracerebral haemorrhage cases (3062 vs 2790). Moreover, this UK study reported no increased risk of intracerebral haemorrhage even among those who were obese, nor a positive association with risk of ischaemic stroke at BMI levels of less than 27·5 kg/m 2 , in contrast with the findings of this and many other previous studies. 5,6,11–13,16 Consistent with our study, several large prospective studies in east Asian populations have reported little or no clear positive associations between BMI and risk of haemorrhagic stroke at a BMI of less than 25 kg/m 2 . 5,8,11,12 However, none of the previous studies included sufficient numbers of well characterised intracerebral haemorrhage cases as in this study, or attempted to quantify the associations in the context of the association between adiposity and systolic blood pressure and between systolic blood pressure and stroke risk. Among the two-thirds of CKB participants with a BMI of less than 25 kg/m 2 , there was no association between adiposity and intracerebral haemorrhage. Given the strong positive associations observed between adiposity and systolic blood pressure and between systolic blood pressure and intracerebral haemorrhage, the lack of any apparent association with intracerebral haemorrhage below BMI 25 kg/m 2 was unexpected and unexplained. There was a mean difference of at least 11/5 mm Hg in systolic/diastolic blood pressure across the BMI range below 25 kg/m 2 , and this difference should, other things being equal, correspond to an HR of 1·6 for intracerebral haemorrhage, but it was totally flat. The disparities are too extreme to be accounted for by chance, by known confounding factors, or by reverse causality, although one cannot exclude the possibility that some other unmeasured or unknown risk factors associated with low BMI might offset the protective effects of lower blood pressure. Future Mendelian randomisation studies are needed to establish the causal relevance of adiposity for intracerebral haemorrhage. 34 Few prospective cohort studies have examined the associations between stroke types and measures of adiposity other than BMI, such as waist circumference, waist-to-hip ratio, and body fat percentage. 6,24,25 Compared with raised BMI, measures of central adiposity, such as waist circumference and waist-to-hip ratio, might be better indicators of accumulation of visceral fat and an adverse metabolic profile. 35–37 However, in the Emerging Risk Factors Collaboration meta-analysis of 21 studies involving about 2400 ischaemic stroke cases, 6 BMI, waist circumference, and waist-to-hip ratio each showed a similar strength of association with ischaemic stroke risk. This study included a ten times greater number of ischaemic stroke cases than did the latter meta-analysis and confirmed the similar associations between ischaemic stroke and different measures of adiposity. These associations are consistent with the fact that most of the adiposity measures (eg, BMI and waist circumference) were highly correlated with each other. Moreover, this study also provided a new assessment of the relevance of central adiposity and other measures of adiposity (eg, BMI at age 25 years and body fat percentage) for intracerebral haemorrhage. Our study had several strengths, including a very large study population, availability of different measures of adiposity, completeness of follow-up, and a high proportion of stroke types reliably diagnosed by neuroimaging. Moreover, this study explored the effects of mediators (eg, systolic blood pressure) on the associations of adiposity with stroke types both directly and indirectly. However, the study also had several limitations. First, despite the widespread use of neuroimaging, the study was not able to examine the associations between adiposity and different subtypes of ischaemic stroke (eg, lacunar vs non-lacunar ischaemic stroke) or of intracerebral haemorrhage (eg, lobar vs non-lobar intracerebral haemorrhage). Second, information collected on diet was limited and did not include salt intake, so residual confounding might still persist, even though adjustment for fresh fruit and meat consumption did not alter the associations. Third, it was not possible to fully explore the mediating effects of lipids and other blood-related factors, although examination of a subset of data indicated that further adjustment for lipids had little additional impact over and above blood pressure. In summary, our study shows that, among relatively lean but healthy Chinese adults, adiposity was strongly and positively associated with ischaemic stroke, mainly through its effect on blood pressure. However, there was no association between adiposity and intracerebral haemorrhage across the normal range (ie, BMI <25 kg/m 2 ), suggesting that leanness, either per se or through some other factor (or factors), might increase risk, thereby offsetting the protective effects associated with lower blood pressure. Since ischaemic stroke constitutes the majority of total stroke cases, the findings on intracerebral haemorrhage should not diminish the fundamental importance of high adiposity as a major modifiable determinant of overall stroke. In view of the substantial risks associated with high blood pressure, this study highlights the importance of controlling blood pressure (and other intermediate risk factors) for prevention of both ischaemic stroke and intracerebral haemorrhage, irrespective of levels of adiposity. Contributors All authors were involved in study design, conduct, long-term follow-up, analysis of data, interpretation, or writing of the report. Declaration of interests We declare no competing interests. Acknowledgments The chief acknowledgment is to the participants, the project staff, and the China National Centre for Disease Control and Prevention and its regional offices for access to death and disease registries. The Chinese National Health Insurance scheme provides electronic linkage to all hospital admission data. The baseline survey and the first re-survey were supported by a research grant from the Kadoorie Charitable Foundation in Hong Kong. The long-term continuation of the project is supported by programme grants from the UK Wellcome Trust (088158/Z/09/Z, 104085/Z/14/Z, 088158/Z/09/Z), the Chinese Ministry of Science and Technology (2011BAI09B01, 2012-14), the Chinese National Natural Science Foundation (81390540/81390541/81390544, 2013-18), and the National Key Research and Development Program of China (2016YFC0900500/2016YFC0900501/2016YFC0900504/2016YFC1303904, 2016-2021). The British Heart Foundation (BHF), UK Medical Research Council, and Cancer Research UK provide core funding to the Oxford Clinical Trial Service Unit and Epidemiological Studies Unit. FB acknowledges support from the BHF Centre of Research Excellence, Oxford.
ASJC Scopus subject areas
- General Medicine
