Zeggini Eleftheria, Damcott Coleen M, Hanson Robert L, Karim Mohammad A, Rayner N William, Groves Christopher J, Baier Leslie J, Hale Terri C, Hattersley Andrew T, Hitman Graham A, Hunt Sarah E, Knowler William C, Mitchell Braxton D, Ng Maggie C Y, O'Connell Jeffrey R, Pollin Toni I, Vaxillaire Martine, Walker Mark, Wang Xiaoqin, Whittaker Pamela, Xiang Kunsan, Jia Weiping, Chan Juliana C N, Froguel Philippe, Deloukas Panos, Shuldiner Alan R, Elbein Steven C, McCarthy Mark I
Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford OX3 7LJ, UK.
Diabetes. 2006 Sep;55(9):2541-8. doi: 10.2337/db06-0088.
The gene encoding the transcription factor upstream stimulatory factor (USF)1 influences susceptibility to familial combined hyperlipidemia (FCHL) and triglyceride levels. Phenotypic overlap between FCHL and type 2 diabetes makes USF1 a compelling positional candidate for the widely replicated type 2 diabetes linkage signal on chromosome 1q. We typed 22 variants in the F11R/USF1 region (1 per 3 kb), including those previously implicated in FCHL-susceptibility (or proxies thereof) in 3,726 samples preferentially enriched for 1q linkage. We also examined glucose- and lipid-related continuous traits in an overlapping set of 1,215 subjects of European descent. There was no convincing evidence for association with type 2 diabetes in any of seven case-control comparisons, individually or combined. Family-based association analyses in 832 Pima subjects were similarly negative. At rs3737787 (the variant most strongly associated with FCHL), the combined odds ratio, per copy of the rarer A-allele, was 1.10 (95% CI 0.97-1.24, P = 0.13). In 124 Utah subjects, rs3737787 was significantly associated (P = 0.002) with triglyceride levels, but direction of this association was opposite to previous reports, and there was no corroboration in three other samples. These data exclude USF1 as a major contributor to type 2 diabetes susceptibility and the basis for the chromosome 1q linkage. They reveal only limited evidence for replication of USF1 effects on continuous metabolic traits.
编码转录因子上游刺激因子（USF）1的基因影响家族性混合型高脂血症（FCHL）易感性和甘油三酯水平。FCHL与2型糖尿病之间的表型重叠使得USF1成为1号染色体上广泛复制的2型糖尿病连锁信号的有力位置候选基因。我们在F11R/USF1区域对22个变异体进行了分型（每3 kb一个），包括那些先前与FCHL易感性相关的变异体（或其代理变异体），样本为3726例，优先富集1号染色体连锁。我们还在一组重叠的1215名欧洲血统受试者中检查了与葡萄糖和脂质相关的连续性性状。在七项病例对照比较中的任何一项中，单独或合并分析，均未发现与2型糖尿病相关的令人信服的证据。在832名皮马受试者中进行的基于家系的关联分析结果同样为阴性。在rs3737787位点（与FCHL关联最强的变异体），每一份较罕见的A等位基因的合并比值比为1.10（95%可信区间0.97 - 1.24，P = 0.13）。在124名犹他受试者中，rs3737787与甘油三酯水平显著相关（P = 0.002），但这种关联方向与先前报道相反，且在其他三个样本中未得到证实。这些数据排除了USF1作为2型糖尿病易感性的主要贡献因素以及1号染色体连锁的基础。它们仅揭示了有限的证据支持USF1对连续性代谢性状的影响可复制。
