Apolipoprotein M Gene (APOM) Polymorphism Modifies Metabolic and Disease Traits in Type 2 Diabetes

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.

本研究旨在确证载脂蛋白M基因（apolipoprotein M gene, APOM）与2型糖尿病（type 2 diabetes, T2D）以及香港华人人群代谢性状的关联。此外，本研究还对APOM基因的功能进行了进一步表征，以阐明其在胆固醇代谢中的活性。研究人员对NCBI数据库中收录的17个APOM单核苷酸多态性（Single Nucleotide Polymorphism, SNP）进行了基因分型。在本研究由1234名T2D患者与606名对照参与者组成的队列中，共确认了5个SNP。上述5个SNP中的3个——rs707921(C+1871A)、rs707922(G+1837T)与rs805264(G+203A)——处于连锁不平衡（linkage disequilibrium, LD）状态。研究选择rs707922作为该LD区域的标签位点开展后续关联分析，并在分子层面表征了该SNP的功能。在本研究的香港华人队列中，未检测到APOM与T2D易感性存在显著关联。值得注意的是，rs805297的C等位基因与病程超过10年的T2D显著相关（比值比（odds ratio, OR）=1.245，p=0.015）。在T2D患者中，rs707922的TT基因型与血浆总胆固醇及低密度脂蛋白胆固醇水平升高显著相关（分别对应p=0.006与p=0.009）。对rs707922的分子分析发现了一种新型转录本APOM5，并揭示了该基因第5外显子的隐秘特征。通过异位表达APOM5转录本，证实了rs707922的等位基因依赖性转录本活性，该活性可在体外调控胆固醇稳态。综上，本研究结果并不支持APOM作为香港华人人群的T2D易感基因。然而，在T2D患者中，部分APOM SNP与疾病病程及代谢性状相关。进一步的分子分析证实了rs707922在APOM表达以及调控细胞胆固醇含量中的功能活性。