Mendelian randomization analyses suggest a causal role for circulating GIP and IL-1RA levels in homeostatic model assessment-derived measures of β-cell function and insulin sensitivity in Africans without type 2 diabetes.
Mendelian randomization analyses suggest a causal role for circulating GIP and IL-1RA levels in homeostatic model assessment-derived measures of β-cell function and insulin sensitivity in Africans without type 2 diabetes.
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孟德尔随机分析表明，在没有2型糖尿病的非洲人中，在稳态模型评估衍生的β细胞功能和胰岛素敏感性的测量中，循环GIP和IL-1RA水平的因果作用。
DOI：
10.1186/s13073-023-01263-7
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发表时间：
2023-12-04
期刊：
影响因子：
12.3
通讯作者：
中科院分区：
文献类型：
--
作者：
体外和体内研究表明，某些细胞因子和激素可能在2型糖尿病（T2 D）的发展和进展中发挥作用。然而，关于它们在人类T2 D中的作用的研究很少。我们评估了撒哈拉以南非洲人群中11种循环细胞因子和激素与T2 D之间的关联，并使用孟德尔随机化（MR）分析测试了因果关系。我们使用logistic回归分析调整年龄、性别、体重指数和招募国家，回归11种细胞因子和激素水平（adipsin，leptin，visfatin，派-1，GIP，GLP-1，ghrelin，IL-6，IL-10，IL-1 RA）对加纳人，埃塞俄比亚人，和来自非洲美洲糖尿病研究的肯尼亚人，包括2276名T2 D个体和2790名非T2 D个体。在非T2 D个体（n = 2790）中，使用胰岛素敏感性（HOMA-S）和β细胞功能（HOMA-B）的稳态建模评估作为因变量拟合相似的线性回归模型。我们使用了35个遗传变异，以前与至少一个这11种细胞因子和激素在非T2 D个体作为工具变量在单变量和多变量MR分析。统计学显著性设定为0.0045（0.05/11细胞因子和激素）。循环GIP和IL-1 RA水平与T2 D相关。在非T2 D个体中，11种细胞因子和激素中的9种（GLP-1和IL-6除外）与HOMA-S、HOMA-B或两者相关。两阶段最小二乘MR分析为多变量分析中GIP和IL-RA对HOMA-S和HOMA-B的因果影响提供了证据（GIP ~ HOMA-S β = − 0.67，P值= 1.88 × 10−6和HOMA-B β = 0.59，P值= 1.88 × 10−5; IL-1 RA ~ HOMA-S β = − 0.51，P值= 8.49 × 10−5和HOMA-B β = 0.48，P值= 5.71 × 10−4）。IL-RA部分通过BMI（30-34%）介导，但GIP不是。逆方差加权MR分析提供了adipsin对T2 D的因果效应的证据（多变量OR = 1.83，P值= 9.79 × 10−6），尽管这些关联在所有敏感性分析中并不一致。这项综合MR分析的结果表明，循环GIP和IL-1 RA水平是胰岛素敏感性降低和β细胞功能增加的原因。GIP的作用不依赖于BMI，这表明GIP的循环水平可能是T2 D风险的有希望的早期生物标志物。我们的MR分析没有提供其他循环细胞因子在撒哈拉以南非洲人T2 D中的因果作用的确凿证据。在线版本包含补充材料，可通过10.1186/s13073-023-01263-7获得。
In vitro and in vivo studies have shown that certain cytokines and hormones may play a role in the development and progression of type 2 diabetes (T2D). However, studies on their role in T2D in humans are scarce. We evaluated associations between 11 circulating cytokines and hormones with T2D among a population of sub-Saharan Africans and tested for causal relationships using Mendelian randomization (MR) analyses. We used logistic regression analysis adjusted for age, sex, body mass index, and recruitment country to regress levels of 11 cytokines and hormones (adipsin, leptin, visfatin, PAI-1, GIP, GLP-1, ghrelin, resistin, IL-6, IL-10, IL-1RA) on T2D among Ghanaians, Nigerians, and Kenyans from the Africa America Diabetes Mellitus study including 2276 individuals with T2D and 2790 non-T2D individuals. Similar linear regression models were fitted with homeostatic modelling assessments of insulin sensitivity (HOMA-S) and β-cell function (HOMA-B) as dependent variables among non-T2D individuals (n = 2790). We used 35 genetic variants previously associated with at least one of these 11 cytokines and hormones among non-T2D individuals as instrumental variables in univariable and multivariable MR analyses. Statistical significance was set at 0.0045 (0.05/11 cytokines and hormones). Circulating GIP and IL-1RA levels were associated with T2D. Nine of the 11 cytokines and hormones (exceptions GLP-1 and IL-6) were associated with HOMA-S, HOMA-B, or both among non-T2D individuals. Two-stage least squares MR analysis provided evidence for a causal effect of GIP and IL-RA on HOMA-S and HOMA-B in multivariable analyses (GIP ~ HOMA-S β = − 0.67, P-value = 1.88 × 10−6 and HOMA-B β = 0.59, P-value = 1.88 × 10−5; IL-1RA ~ HOMA-S β = − 0.51, P-value = 8.49 × 10−5 and HOMA-B β = 0.48, P-value = 5.71 × 10−4). IL-RA was partly mediated via BMI (30-34%), but GIP was not. Inverse variance weighted MR analysis provided evidence for a causal effect of adipsin on T2D (multivariable OR = 1.83, P-value = 9.79 × 10−6), though these associations were not consistent in all sensitivity analyses. The findings of this comprehensive MR analysis indicate that circulating GIP and IL-1RA levels are causal for reduced insulin sensitivity and increased β-cell function. GIP’s effect being independent of BMI suggests that circulating levels of GIP could be a promising early biomarker for T2D risk. Our MR analyses do not provide conclusive evidence for a causal role of other circulating cytokines in T2D among sub-Saharan Africans. The online version contains supplementary material available at 10.1186/s13073-023-01263-7.
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DOI：
10.1152/ajpendo.00418.2014
发表时间：
2015-03-01
影响因子：
5.1
作者：
Chen, Shu;Okahara, Fumiaki;Shimotoyodome, Akira
通讯作者：
Shimotoyodome, Akira
影响因子：
2.1
作者：
Bowden J;Davey Smith G;Haycock PC;Burgess S
通讯作者：
Burgess S
影响因子：
3
作者：
El K;Campbell JE
通讯作者：
Campbell JE
影响因子：
12.3
作者：
Meeks KAC;Bentley AR;Gouveia MH;Chen G;Zhou J;Lei L;Adeyemo AA;Doumatey AP;Rotimi CN
通讯作者：
Rotimi CN
影响因子：
9.2
作者：
Chang CC;Chow CC;Tellier LC;Vattikuti S;Purcell SM;Lee JJ
通讯作者：
Lee JJ