Department of Biochemistry, The Chinese University of Hong Kong, Hong Kong, China.
PLoS One. 2011 Feb 24;6(2):e17324. doi: 10.1371/journal.pone.0017324.
This study aimed at substantiating the associations of the apolipoproein M gene (APOM) with type 2 diabetes (T2D) as well as with metabolic traits in Hong Kong Chinese. In addition, APOM gene function was further characterized to elucidate its activity in cholesterol metabolism. Seventeen APOM SNPs documented in the NCBI database were genotyped. Five SNPs were confirmed in our study cohort of 1234 T2D and 606 control participants. Three of the five SNPs rs707921(C+1871A), rs707922(G+1837T) and rs805264(G+203A) were in linkage disequilibrium (LD). We chose rs707922 to tag this LD region for down stream association analyses and characterized the function of this SNP at molecular level. No association between APOM and T2D susceptibility was detected in our Hong Kong Chinese cohort. Interestingly, the C allele of rs805297 was significantly associated with T2D duration of longer than 10 years (OR = 1.245, p = 0.015). The rs707922 TT genotype was significantly associated with elevated plasma total- and LDL- cholesterol levels (p = 0.006 and p = 0.009, respectively) in T2D patients. Molecular analyses of rs707922 lead to the discoveries of a novel transcript APOM5 as well as the cryptic nature of exon 5 of the gene. Ectopic expression of APOM5 transcript confirmed rs707922 allele-dependent activity of the transcript in modifying cholesterol homeostasis in vitro. In conclusion, the results here did not support APOM as a T2D susceptibility gene in Hong Kong Chinese. However, in T2D patients, a subset of APOM SNPs was associated with disease duration and metabolic traits. Further molecular analysis proved the functional activity of rs707922 in APOM expression and in regulation of cellular cholesterol content.
本研究旨在证实载脂蛋白 M 基因 (APOM) 与 2 型糖尿病 (T2D) 以及与香港华人代谢特征的关联。此外，还进一步研究了 APOM 基因的功能，以阐明其在胆固醇代谢中的活性。在 NCBI 数据库中记录的 17 个 APOM SNP 进行了基因分型。在我们的 1234 名 T2D 患者和 606 名对照参与者的研究队列中，确认了 5 个 SNP。这 5 个 SNP 中的 3 个(rs707921(C+1871A)、rs707922(G+1837T)和 rs805264(G+203A))处于连锁不平衡(LD)状态。我们选择 rs707922 来标记这个 LD 区域，以便进行下游关联分析，并在分子水平上对该 SNP 的功能进行了特征描述。在我们的香港华人队列中，没有发现 APOM 与 T2D 易感性之间存在关联。有趣的是，rs805297 的 C 等位基因与 T2D 病程超过 10 年显著相关(OR = 1.245，p = 0.015)。rs707922 TT 基因型与 T2D 患者血浆总胆固醇和 LDL 胆固醇水平升高显著相关(p = 0.006 和 p = 0.009)。对 rs707922 的分子分析发现了一种新的 APOM5 转录本以及该基因外显子 5 的隐匿性质。APOM5 转录本的异位表达证实了 rs707922 等位基因依赖的活性，可在体外调节胆固醇稳态。总之，本研究结果不支持 APOM 是香港华人的 2 型糖尿病易感性基因。然而，在 T2D 患者中，一组 APOM SNP 与疾病病程和代谢特征有关。进一步的分子分析证实了 rs707922 在 APOM 表达和调节细胞胆固醇含量中的功能活性。
