Cardiometabolic effects of genetic upregulation of the interleukin 1 receptor antagonist: a Mendelian randomisation analysis.
Cardiometabolic effects of genetic upregulation of the interleukin 1 receptor antagonist: a Mendelian randomisation analysis.
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DOI：
10.1016/s2213-8587(15)00034-0
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发表时间：
2015-04
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通讯作者：
Interleukin 1 Genetics Consortium
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作者：
Interleukin 1 Genetics Consortium
为了研究长期药理学白细胞介素1（IL-1）抑制的潜在心血管和其他影响，我们研究了产生IL-1抑制的遗传变异，IL-1是炎症的主要调节因子。我们创建了一个遗传评分，结合了位于IL-1受体拮抗剂（IL-1 Ra; IL-1α和IL-1β的内源性抑制剂）编码基因IL-1 RN上游的两种常见变体（rs6743376和rs 1542176）的等位基因的影响;两种等位基因均增加可溶性IL-1 Ra蛋白浓度。我们比较了这种遗传评分与阿那白滞素（IL-1 Ra的重组形式）对炎症生物标志物的影响，阿那白滞素以前曾在类风湿性关节炎和其他炎症性疾病的随机试验中进行过研究。在主要分析中，我们调查了与类风湿性关节炎和四种心脏代谢疾病（2型糖尿病、冠心病、缺血性卒中和腹主动脉瘤;共453411例参与者）相关的评分。 在探索性分析中，我们研究了得分与许多疾病特征和其他24种与IL-1信号传导相关的疾病（共746 171名参与者）的关系。 对于每个遗传的IL 1 RN次要等位基因，血清IL-1 Ra浓度增加0.22 SD（95% CI 0.18 - 0.25; 12.5%; p= 9.3 × 10−33），白细胞介素6浓度降低0.02 SD（− 0.04至− 0.01; − 1.7%; p= 3.5 × 10−3），C反应蛋白浓度降低0.03 SD（− 0.04至− 0.02; − 3.4%; p= 7.7 × 10−14）。 我们注意到遗传评分对这些炎症生物标志物的影响与阿那白滞素的影响方向一致。遗传评分的等位基因计数与IL-1 Ra浓度和冠心病风险呈大致对数线性、剂量依赖性相关。携带4个IL-1 Ra升高等位基因的人与不携带IL-1 Ra升高等位基因的人相比，患冠心病的比值比为1.15（1.08 ~ 1.22; p= 1.8 × 10−6）;每个等位基因患冠心病的比值比为1.03（1.02 ~ 1.04; p= 3.9 × 10−10）。 类风湿性关节炎、2型糖尿病、缺血性卒中和腹主动脉瘤的每等位基因优势比分别为0.97（0.95 - 0.99; p= 9.9 ×10−4）、0.99（0.97 - 1.01; p= 0.47）、1.00（0.98 - 1.02; p= 0.92）和1.08（1.04 - 1.12; p= 1.8 ×10−5）。 在探索性分析中，我们观察到每个等位基因的致动脉粥样硬化脂质（包括LDL-胆固醇）浓度增加，但没有明确的证据表明与血压、血脂特征或所研究的24种其他疾病相关。模型表明，观察到的LDL胆固醇增加可以解释遗传评分与冠状动脉风险增加之间观察到的相关性的约三分之一。人类遗传数据表明，长期双重IL-1α/β抑制可增加心血管风险，相反，可降低类风湿性关节炎的发生风险。心血管风险可能部分通过致动脉粥样硬化脂质浓度的增加介导。英国医学研究理事会、英国心脏基金会、英国国家健康研究所、国家健康研究所剑桥生物医学研究中心、欧洲研究理事会和欧盟委员会框架计划7。
To investigate potential cardiovascular and other effects of long-term pharmacological interleukin 1 (IL-1) inhibition, we studied genetic variants that produce inhibition of IL-1, a master regulator of inflammation. We created a genetic score combining the effects of alleles of two common variants (rs6743376 and rs1542176) that are located upstream of IL1RN, the gene encoding the IL-1 receptor antagonist (IL-1Ra; an endogenous inhibitor of both IL-1α and IL-1β); both alleles increase soluble IL-1Ra protein concentration. We compared effects on inflammation biomarkers of this genetic score with those of anakinra, the recombinant form of IL-1Ra, which has previously been studied in randomised trials of rheumatoid arthritis and other inflammatory disorders. In primary analyses, we investigated the score in relation to rheumatoid arthritis and four cardiometabolic diseases (type 2 diabetes, coronary heart disease, ischaemic stroke, and abdominal aortic aneurysm; 453 411 total participants). In exploratory analyses, we studied the relation of the score to many disease traits and to 24 other disorders of proposed relevance to IL-1 signalling (746 171 total participants). For each IL1RN minor allele inherited, serum concentrations of IL-1Ra increased by 0·22 SD (95% CI 0·18–0·25; 12·5%; p=9·3 × 10−33), concentrations of interleukin 6 decreased by 0·02 SD (−0·04 to −0·01; −1·7%; p=3·5 × 10−3), and concentrations of C-reactive protein decreased by 0·03 SD (−0·04 to −0·02; −3·4%; p=7·7 × 10−14). We noted the effects of the genetic score on these inflammation biomarkers to be directionally concordant with those of anakinra. The allele count of the genetic score had roughly log-linear, dose-dependent associations with both IL-1Ra concentration and risk of coronary heart disease. For people who carried four IL-1Ra-raising alleles, the odds ratio for coronary heart disease was 1·15 (1·08–1·22; p=1·8 × 10−6) compared with people who carried no IL-1Ra-raising alleles; the per-allele odds ratio for coronary heart disease was 1·03 (1·02–1·04; p=3·9 × 10−10). Per-allele odds ratios were 0·97 (0·95–0·99; p=9·9 × 10−4) for rheumatoid arthritis, 0·99 (0·97–1·01; p=0·47) for type 2 diabetes, 1·00 (0·98–1·02; p=0·92) for ischaemic stroke, and 1·08 (1·04–1·12; p=1·8 × 10−5) for abdominal aortic aneurysm. In exploratory analyses, we observed per-allele increases in concentrations of proatherogenic lipids, including LDL-cholesterol, but no clear evidence of association for blood pressure, glycaemic traits, or any of the 24 other disorders studied. Modelling suggested that the observed increase in LDL-cholesterol could account for about a third of the association observed between the genetic score and increased coronary risk. Human genetic data suggest that long-term dual IL-1α/β inhibition could increase cardiovascular risk and, conversely, reduce the risk of development of rheumatoid arthritis. The cardiovascular risk might, in part, be mediated through an increase in proatherogenic lipid concentrations. UK Medical Research Council, British Heart Foundation, UK National Institute for Health Research, National Institute for Health Research Cambridge Biomedical Research Centre, European Research Council, and European Commission Framework Programme 7.