Comprehensive Analysis of Established Dyslipidemia-Associated Loci in the Diabetes Prevention Program.
Comprehensive Analysis of Established Dyslipidemia-Associated Loci in the Diabetes Prevention Program.
复制标题
糖尿病预防计划中已建立的血脂异常相关位点的综合分析。
DOI：
10.1161/circgenetics.116.001457
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发表时间：
2016
期刊：
影响因子：
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通讯作者：
Franks,PaulW
中科院分区：
文献类型：
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作者：
Varga,TiborV;Winters,AlexandraH;Jablonski,KathleenA;Horton,EdwardS;Khare-Ranade,Prajakta;Knowler,WilliamC;Marcovina,SanticaM;Renström,Frida;Watson,KarolE;Goldberg,Ronald;Florez,JoséC;Pollin,ToniI;Franks,PaulW
背景我们在糖尿病预防计划随机对照试验中评估了 234 个已确定的血脂异常相关位点是否改变二甲双胍治疗和生活方式干预（与安慰剂对照）对脂质和脂质亚组分水平的影响。方法和结果我们测试了与基线调整的后续血脂浓度（高密度脂蛋白 [HDL] 和低密度脂蛋白胆固醇、总胆固醇和甘油三酯）和脂蛋白亚组分颗粒相关的基因治疗相互作用。 2993 名糖尿病前期参与者的浓度和大小。在之前报道的单核苷酸多态性关联中，32.5% 的重复率与基线脂质性状的 P<0.05。除 2 个性状外，性状特异性遗传风险评分与其各自的基线性状密切相关 (3×10–4>P>1.1×10–16)。生活方式改变了遗传风险评分对大HDL颗粒数量的影响，使得遗传风险评分的每个风险等位基因在生活方式组的随访中与较低浓度的大HDL颗粒相关（每个遗传风险评分风险等位基因β=−0.11 µmol/L；95%置信区间，−0.188至−0.033；生活方式与安慰剂相比，P=5×10–3；Pinteraction=1×10–3），但在生活方式组中则不然。二甲双胍或安慰剂组（P>0.05）。在生活方式组中，与遗传风险较低的参与者相比，在 20 个特征中的 17 个特征中，具有高遗传风险的参与者在 1 年时具有更有利或相似的特征水平。 结论 生活方式带来的大 HDL 颗粒浓度的改善可能会因遗传因素而减弱。然而，生活方式干预成功地抵消了大多数脂质性状的不利基因负荷。临床试验注册网址：https://www.clinicaltrials.gov。唯一标识符：NCT00004992。
BackgroundWe assessed whether 234 established dyslipidemia-associated loci modify the effects of metformin treatment and lifestyle intervention (versus placebo control) on lipid and lipid subfraction levels in the Diabetes Prevention Program randomized controlled trial.Methods and ResultsWe tested gene treatment interactions in relation to baseline-adjusted follow-up blood lipid concentrations (high-density lipoprotein [HDL] and low-density lipoprotein-cholesterol, total cholesterol, and triglycerides) and lipoprotein subfraction particle concentrations and size in 2993 participants with pre–diabetes. Of the previously reported single-nucleotide polymorphism associations, 32.5% replicated atP<0.05 with baseline lipid traits. Trait-specific genetic risk scores were robustly associated (3×10–4>P>1.1×10–16) with their respective baseline traits for all but 2 traits. Lifestyle modified the effect of the genetic risk score for large HDL particle numbers, such that each risk allele of the genetic risk scores was associated with lower concentrations of large HDL particles at follow-up in the lifestyle arm (β=−0.11 µmol/L per genetic risk scores risk allele; 95% confidence interval, −0.188 to −0.033;P=5×10–3;Pinteraction=1×10–3for lifestyle versus placebo), but not in the metformin or placebo arms (P>0.05). In the lifestyle arm, participants with high genetic risk had more favorable or similar trait levels at 1-year compared with participants at lower genetic risk at baseline for 17 of the 20 traits.ConclusionsImprovements in large HDL particle concentrations conferred by lifestyle may be diminished by genetic factors. Lifestyle intervention, however, was successful in offsetting unfavorable genetic loading for most lipid traits.Clinical Trial RegistrationURL: https://www.clinicaltrials.gov. Unique Identifier: NCT00004992.