Controversial association results for INSIG2 on body mass index may be explained by interactions with age and with MC4R
Controversial association results for INSIG2 on body mass index may be explained by interactions with age and with MC4R
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INSIG2 与体重指数的有争议的关联结果可以通过与年龄和 MC4R 的相互作用来解释
DOI：
10.1038/ejhg.2014.3
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发表时间：
2014
影响因子：
5.2
通讯作者：
Bickeböller H
中科院分区：
文献类型：
--
作者：
Malzahn D;Müller-Nurasyid M;Heid IM;Wichmann H;the KORA study group;Bickeböller H
在先前报道的与体重指数(BMI)和肥胖相关的单核苷酸多态(SNPs)中，我们重点关注胰岛素诱导基因2(INSIG2)基因上游常见的风险变量rs7566605和黑素皮质素-4受体(MC4R)基因上罕见的保护性变量rs2229616。INSIG2参与脂肪形成，MC4R影响荷尔蒙食欲控制脂肪组织的数量。Rs2229616(MC4R)对BMI和肥胖的影响已被反复证实，并提供了对潜在机制的见解。然而，由于关联的复制不一致，rs7566605(INSIG2)的一个主要作用仍在争论中。Rs7566605与AGE的相互作用可能提供了一种解释。SNP-AGE和SNP-SNP交互作用模型在来自三个基于人群的纵向队列的独立个体上进行了测试，将分析限制在25-74岁的观察年龄。分析了KORA S3/F3、KORA S4/F4(德国奥格斯堡，1994-2005年、1999-2008年)和弗雷明翰-后代数据(美国弗雷明翰，1971-2001年)，在联合分析中总样本量为N=6926。Rs7566605和年龄之间的交互作用对BMI和肥胖状态的影响是显著的，并且在研究中是一致的。这一关于rs7566605(INSIG2)的新证据补充了先前的研究。此外，还观察了rs7566605与MC4R变异体rs2229616对体重指数的交互作用。这一效应大小是先前报道的rs2229616的单基因座主效应的三倍。这导致了这样的结论：如果不加解释，SNP-AGE或SNP-SNP的相互作用可以掩盖复杂疾病的遗传效应。
Among the single-nucleotide polymorphisms (SNPs) previously reported to be associated with body mass index (BMI) and obesity, we focus on a common risk variant rs7566605 upstream of the insulin-induced gene 2 (INSIG2) gene and a rare protective variant rs2229616 on the melanocortin-4 receptor (MC4R) gene. INSIG2 is involved in adipogenesis and MC4R effects hormonal appetite control in response to the amount of adipose tissue. The influence of rs2229616 (MC4R) on BMI and obesity has been confirmed repeatedly and insight into the underlying mechanism provided. However, a main effect of rs7566605 (INSIG2) is under debate because of inconsistent replications of association. Interaction of rs7566605 with age may offer an explanation. SNP–age and SNP–SNP interaction models were tested on independent individuals from three population-based longitudinal cohorts, restricting the analysis to an observed age of 25–74 years. KORA S3/F3, KORA S4/F4 (Augsburg, Germany, 1994–2005, 1999–2008), and Framingham-Offspring data (Framingham, USA, 1971–2001) were analysed, with a total sample size of N= 6926 in the joint analysis. The effect of interaction between rs7566605 and age on BMI and obesity status is significant and consistent across studies. This new evidence for rs7566605 (INSIG2) complements previous research. In addition, the interaction effect of rs7566605 with the MC4R variant rs2229616 on BMI was observed. This effect size was three times larger than that in a previously reported single-locus main effect of rs2229616. This leads to the conclusion that SNP–age or SNP–SNP interactions can mask genetic effects for complex diseases if left unaccounted for.
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影响因子：
4
作者：
Heid, IM;Vollmert, C;Kronenberg, F
通讯作者：
Kronenberg, F
影响因子：
4.9
作者：
Smith, A. J. P.;Cooper, J. A.;Humphries, S. E.
通讯作者：
Humphries, S. E.
影响因子：
9.8
作者：
Lasky-Su, Jessica;Lyon, Helen N.;Lange, Christoph
通讯作者：
Lange, Christoph
影响因子：
9.8
作者：
Deng, HW;Deng, HY;Recker, RR
通讯作者：
Recker, RR
影响因子：
9.8
作者：
Fornage, Myriam;Papanicolaou, George;Lewis, Cora E.;Boerwinkle, Eric;Siscovick, David S.
通讯作者：
Siscovick, David S.