Objective Pro-inflammatory interleukin 6 (IL6) trans-signalling is associated with increased risk of cardiovascular events (CVEs). Whether this association exists for both sexes is, however, uncertain. Hence, we analysed the risk of CVE associated with IL6 trans-signalling in men and women and investigated if potential interaction between IL6 trans-signalling and sex affects the risk. Methods In a prospective cohort of 60-year-old men and women without cardiovascular disease (men=2039, women=2193), subjects were followed for 20 years. To assess the IL6 trans-signalling activity, the proportion between the active binary and inactive ternary IL6 complexes, the binary/ternary ratio (B/T ratio), was estimated. CVE (myocardial infarction, angina pectoris and ischaemic stroke, n=629) risk was analysed with Cox regression, presented as HRs with 95% CIs. B/T ratio was dichotomised, with levels >median representing IL6 trans-signalling. Interaction was analysed on the additive scale and expressed as the synergy index (S). Analyses were adjusted for cardiovascular risk factors. Results B/T ratio >median was associated with increased CVE risk in men (HR 1.63; 95% CI 1.32 to 2.01), but not in women (HR 1.21; 95% CI 0.93 to 1.57). There was a significant synergistic interaction (S=1.98; 95% CI 1.15 to 3.42) between the B/T ratio and male sex, the combination increasing the risk by 88%. Conclusions Our results suggest differential susceptibility to inflammation mediated by IL6 trans-signalling and subsequent CVE in men and women. The B/T ratio could be considered as a novel biomarker for cardiovascular risk in men, but not in women. Data are available on reasonable request. Data are stored at Karolinska Institutet. Due to legal restrictions imposed by the Swedish Secrecy Act, requests for access individual data can be sent to BG (bruna.gigante@ki.se).

中文翻译：

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白细胞介素 6 信号转导与男性和女性未来发生心血管事件的风险

目的促炎性白细胞介素 6 (IL6) 转信号与心血管事件 (CVE) 风险增加有关。然而，这种关联是否对两性都存在尚不确定。因此，我们分析了男性和女性中与 IL6 转信号相关的 CVE 风险，并调查了 IL6 转信号与性别之间的潜在相互作用是否会影响风险。方法 在一个由 60 岁无心血管疾病的男性和女性（男性 = 2039，女性 = 2193）组成的前瞻性队列中，对受试者进行了 20 年的随访。为了评估 IL6 转信号活性，估计了活性二元和无活性三元 IL6 复合物之间的比例，即二元/三元比率（B/T 比率）。使用 Cox 回归分析 CVE（心肌梗塞、心绞痛和缺血性中风，n = 629）风险，以 95% CI 的 HR 表示。B/T 比率被二分，水平 > 中值代表 IL6 反式信号转导。在加性尺度上分析相互作用并表示为协同指数（S）。对心血管危险因素的分析进行了调整。结果 B/T 比 > 中位数与男性 CVE 风险增加相关（HR 1.63；95% CI 1.32 至 2.01），但与女性无关（HR 1.21；95% CI 0.93 至 1.57）。B/T 比率和男性之间存在显着的协同相互作用（S=1.98；95% CI 1.15 至 3.42），这种组合使风险增加了 88%。结论我们的结果表明男性和女性对由 IL6 反式信号传导和随后的 CVE 介导的炎症的易感性不同。B/T 比值可以被视为男性心血管风险的新生物标志物，但不是女性。可应合理要求提供数据。数据存储在卡罗林斯卡医学院。由于瑞典保密法施加的法律限制，访问个人数据的请求可以发送到 BG (bruna.gigante@ki.se)。