Genetic evidence of a causal effect of insulin resistance on branched-chain amino acid levels
Genetic evidence of a causal effect of insulin resistance on branched-chain amino acid levels
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DOI：
10.1007/s00125-017-4222-6
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发表时间：
2017-05-01
期刊：
影响因子：
8.2
通讯作者：
Hansen, Torben
中科院分区：
文献类型：
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作者：
Mahendran, Yuvaraj;Jonsson, Anna;Hansen, Torben
空腹血浆支链氨基酸（BCAA）水平与胰岛素抵抗有关，但目前尚不清楚两者之间是否存在因果关系。我们的目的是通过孟德尔随机化研究来解开因果关系，使用与循环BCAA水平和胰岛素抵抗相关的遗传变异作为工具变量。我们通过NMR光谱法测量了来自ADDITION-PRO队列的1，321名个体的血浆中循环BCAA水平。我们通过使用先前发表的葡萄糖和胰岛素相关性状联合会（MAGIC）荟萃分析（n = 46，186）和血清BCAA水平GWAS（n = 24，925）的全基因组关联研究（GWAS）结果来补充我们的分析。我们使用了遗传风险评分（GRS），使用10个已建立的空腹血清胰岛素相关变异计算，作为胰岛素抵抗的工具变量。增加循环BCAA水平的三种变异的GRS被用作循环BCAA水平的工具变量。在ADDITION-PRO中，空腹血浆BCAA水平与较高的HOMA-IR相关（β 0.137 [95%CI 0.08，0.19] p = 6 x 10（-7））。然而，在ADDITION-PRO研究中，循环BCAA水平的GRS与空腹胰岛素水平或HOMA-IR无关。（β-0.011 [95% CI-0.053，0.032] p = 0.6和β-0.011 [95% CI-0.054，0.031] p = 0.6，或MAGIC的HOMA-IR的GWAS结果（缬氨酸增加GRS的β为-0.012 [95%CI-0.069，0.045] p = 0.7）。相比之下，胰岛素抵抗增加的GRS与ADDITION-PRO中BCAA水平的增加显著相关。（β 0.027 [95% CI 0.005，0.048] p = 0.01）和血清BCAA水平的GWAS结果（对于异亮氨酸、亮氨酸和缬氨酸水平，β 1.22 [95% CI 0.71，1.73] p = 4 x 10（-6），β 0.96 [95% CI 0.45，1.47] p = 3 x 10（-4）和β 0.67 [95% CI 0.16，1.18] p = 0.01，ADDITION-PRO中的工具变量分析表明HOMA-IR与较高的循环空腹BCAA水平存在因果关系（β 0.73 [95% CI 0.26，1.19] p = 0.002）我们的研究结果表明，较高的支链氨基酸水平对胰岛素抵抗没有因果关系，而胰岛素抵抗的增加会导致较高的循环空腹支链氨基酸水平。
Fasting plasma levels of branched-chain amino acids (BCAAs) are associated with insulin resistance, but it remains unclear whether there is a causal relation between the two. We aimed to disentangle the causal relations by performing a Mendelian randomisation study using genetic variants associated with circulating BCAA levels and insulin resistance as instrumental variables.We measured circulating BCAA levels in blood plasma by NMR spectroscopy in 1,321 individuals from the ADDITION-PRO cohort. We complemented our analyses by using previously published genome-wide association study (GWAS) results from the Meta-Analyses of Glucose and Insulin-related traits Consortium (MAGIC) (n = 46,186) and from a GWAS of serum BCAA levels (n = 24,925). We used a genetic risk score (GRS), calculated using ten established fasting serum insulin associated variants, as an instrumental variable for insulin resistance. A GRS of three variants increasing circulating BCAA levels was used as an instrumental variable for circulating BCAA levels.Fasting plasma BCAA levels were associated with higher HOMA-IR in ADDITION-PRO (beta 0.137 [95% CI 0.08, 0.19] p = 6 x 10(-7)). However, the GRS for circulating BCAA levels was not associated with fasting insulin levels or HOMA-IR in ADDITION-PRO (beta -0.011 [95% CI -0.053, 0.032] p = 0.6 and beta -0.011 [95% CI -0.054, 0.031] p = 0.6, respectively) or in GWAS results for HOMA-IR from MAGIC (beta for valine-increasing GRS -0.012 [95% CI -0.069, 0.045] p = 0.7). By contrast, the insulin-resistance-increasing GRS was significantly associated with increased BCAA levels in ADDITION-PRO (beta 0.027 [95% CI 0.005, 0.048] p = 0.01) and in GWAS results for serum BCAA levels (beta 1.22 [95% CI 0.71, 1.73] p = 4 x 10(-6), beta 0.96 [95% CI 0.45, 1.47] p = 3 x 10(-4), and beta 0.67 [95% CI 0.16, 1.18] p = 0.01 for isoleucine, leucine and valine levels, respectively) and instrumental variable analyses in ADDITION-PRO indicated that HOMA-IR is causally related to higher circulating fasting BCAA levels (beta 0.73 [95% CI 0.26, 1.19] p = 0.002).Our results suggest that higher BCAA levels do not have a causal effect on insulin resistance while increased insulin resistance drives higher circulating fasting BCAA levels.