A genome-wide association study of inflammatory biomarker changes in response to fenofibrate treatment in the Genetics of Lipid Lowering Drug and Diet Network.
A genome-wide association study of inflammatory biomarker changes in response to fenofibrate treatment in the Genetics of Lipid Lowering Drug and Diet Network.
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DOI：
10.1097/fpc.0b013e32834fdd41
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发表时间：
2012-03
影响因子：
2.6
通讯作者：
Arnett DK
中科院分区：
文献类型：
--
作者：
Aslibekyan S;Kabagambe EK;Irvin MR;Straka RJ;Borecki IB;Tiwari HK;Tsai MY;Hopkins PN;Shen J;Lai CQ;Ordovas JM;Arnett DK
尽管有证据支持非诺贝特的抗炎和降低甘油三酯作用，但对观察到的治疗反应异质性的遗传决定因素知之甚少。这项研究首次对非诺贝特对全身炎症的影响进行了全基因组检查。对参加降脂药物遗传学和饮食网络(GOLDN，n=1092)的参与者在每天服用160 mg非诺贝特治疗3周之前和之后检测炎症的生物标志物。通过主成分分析得到两种炎症模式(hsCRP-IL6和MCP1-肿瘤坏死因子-α)。使用混合线性模型评估Affymetrix 6.0芯片上单核苷酸多态与表型的相关性，将年龄、性别、研究中心和血统调整为固定效应，家系作为随机效应。在非诺贝特治疗前，观察到IL2RA基因附近或内部的多态性与hsCRP-IL6模式有最强的相关性(rs7911500，P=5×10−9和rs12722605，P=5×10−8)。在非诺贝特治疗前，MCP1-肿瘤坏死因子-α模式与几个生物学上可信的基因(CYP4F8(Rs3764563)、APB1IP(Rs1775246)、COL13A1(Rs2683572)和COMMD10(Rs1396485))的关联接近全基因组意义(P分别为3×10−7、5×10−7、6×10−7和7×10−7)。经非诺贝特治疗后，IL2RA的rs12722605基因座也与MCP1-肿瘤坏死因子-α模式相关(P=3×10−7)。个体生物标记物对非诺贝特的反应分析没有得到全基因组的显著结果，但靠近免疫相关的IFNAR2基因的rs6517147基因座可能与IL6相关(P=7×10−7)。我们已经确定了在非诺贝特治疗前后与全身炎症相关的几个新的生物学基因。
Despite evidence in support of anti-inflammatory and triglyceride-lowering effects of fenofibrate, little is known about genetic determinants of the observed heterogeneity in treatment response. This study provides the first genome-wide examination of fenofibrate effects on systemic inflammation. Biomarkers of inflammation were measured in participants of the Genetics of Lipid Lowering Drugs and Diet Network (GOLDN, n=1092) before and after a 3-week daily treatment with 160 mg of fenofibrate. Two inflammatory patterns (hsCRP-IL6 and MCP1-TNF-α) were derived using principal component analysis. Associations between single nucleotide polymorphisms on the Affymetrix 6.0 chip and phenotypes were assessed using mixed linear models, adjusted for age, sex, study center, and ancestry as fixed effects and pedigree as a random effect. Before fenofibrate treatment, the strongest evidence for association was observed for polymorphisms near or within the IL2RA gene with the hsCRP-IL6 pattern (rs7911500, P=5×10−9 and rs12722605, P=5×10−8). Associations of the MCP1-TNF-α pattern with loci in several biologically plausible genes (CYP4F8 (rs3764563), APBB1IP (rs1775246), COL13A1 (rs2683572), and COMMD10 (rs1396485)) approached genome-wide significance (P=3×10−7, 5×10−7, 6×10−7, and 7×10−7 respectively) before fenofibrate treatment. After fenofibrate treatment, the rs12722605 locus in IL2RA was also associated with the MCP1-TNF-α pattern (P=3×10−7). The analyses of individual biomarker response to fenofibrate did not yield genome-wide significant results, but the rs6517147 locus near the immunologically relevant IFNAR2 gene was suggestively associated with IL6 (P=7×10−7). We have identified several novel biologically relevant loci associated with systemic inflammation before and after fenofibrate treatment.