目的:本研究的目的是评估降脂药[HMG-CoA还原酶抑制剂,前蛋白转化酶枯草杆菌蛋白酶/kexin9型抑制剂,和Niemann-PickC1-Like1(NPC1L1)抑制剂]通过孟德尔随机研究对成年型糖尿病的新型亚型。
方法:我们首先推断脂质相关性状之间的因果关联[包括高密度脂蛋白胆固醇,低密度脂蛋白胆固醇(LDL-C),甘油三酯(TG),载脂蛋白A-I,和载脂蛋白B]和成人发病糖尿病的新亚型。三类降脂药物的药物靶基因表达数量性状位点,以及与LDL-C相关的药物靶基因内或附近的遗传变异,然后被用作降脂药物暴露的代理。使用LDL-C全基因组关联研究的汇总数据进行孟德尔随机化分析,严重的自身免疫性糖尿病,严重的胰岛素缺乏型糖尿病(SIDD),严重的胰岛素抵抗糖尿病(SIRD),轻度肥胖相关糖尿病(MOD),和轻度与年龄有关的糖尿病。
结果:HMGCR介导的LDL-C与SIRD的风险之间存在关联[比值比(OR)=0.305,95%置信区间(CI)=0.129-0.723;p=0.007],PCSK9介导的LDL-C与SIDD(OR=0.253,95%CI=0.120-0.532;p<0.001)和MOD(OR=0.345,95%CI=0.171-0.696;p=0.003)的风险相关。此外,NPC1L1介导的LDL-C(OR=0.109,95%CI=0.019-0.613;p=0.012)和NPC1L1基因在血液中的表达增加(OR=0.727,95%CI=0.541-0.977;p=0.034)均与SIRD显着相关。这些结果通过敏感性分析进一步证实。
结论:总之,不同的降脂药物对成年型糖尿病不同新型亚型的风险增加有特定的影响.
OBJECTIVE: The aims of the present study were to assess the effects of lipid-lowering drugs [HMG-CoA reductase inhibitors, proprotein convertase subtilisin/kexin type 9 inhibitors, and Niemann-Pick C1-Like 1 (NPC1L1) inhibitors] on novel subtypes of adult-onset diabetes through a Mendelian randomisation study.
METHODS: We first inferred causal associations between lipid-related traits [including high-density lipoprotein cholesterol, low-density lipoprotein cholesterol (LDL-C), triglycerides (TG), apolipoproteins A-I, and apolipoproteins B] and novel subtypes of adult-onset diabetes. The expression quantitative trait loci of drug target genes for three classes of lipid-lowering drugs, as well as genetic variants within or nearby drug target genes associated with LDL-C, were then utilised as proxies for the exposure of lipid-lowering drugs. Mendelian randomisation analysis was performed using summary data from genome-wide association studies of LDL-C, severe autoimmune diabetes, severe insulin-deficient diabetes (SIDD), severe insulin-resistant diabetes (SIRD), mild obesity-related diabetes (MOD), and mild age-related diabetes.
RESULTS: There was an association between HMGCR-mediated LDL-C and the risk of SIRD [odds ratio (OR) = 0.305, 95% confidence interval (CI) = 0.129-0.723; p = 0.007], and there was an association of PCSK9-mediated LDL-C with the risk of SIDD (OR = 0.253, 95% CI = 0.120-0.532; p < 0.001) and MOD (OR = 0.345, 95% CI = 0.171-0.696; p = 0.003). Moreover, NPC1L1-mediated LDL-C (OR = 0.109, 95% CI = 0.019-0.613; p = 0.012) and the increased expression of NPC1L1 gene in blood (OR = 0.727, 95% CI = 0.541-0.977; p = 0.034) both showed a significant association with SIRD. These results were further confirmed by sensitivity analyses.
CONCLUSIONS: In summary, the different lipid-lowering medications have a specific effect on the increased risk of different novel subtypes of adult-onset diabetes.