Abstract
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.
Highlights
The human apolipoprotein M gene (APOM, Gene ID: 55937) is located on chromosome 6p21.33 and contains six exons spanning a region of 2.3 kb in length with gene structure conserved across species [1,2]
Plasma apoM has been positively associated with plasma total cholesterol (TC), LDL cholesterol (LDL-C), and HDL cholesterol (HDL-C) [3]
The results of this study did not support an assoiation between apolipoproein M gene (APOM) and type 2 diabetes (T2D) suseptibility in Hong Kong Chinese
Summary
The human apolipoprotein M gene (APOM, Gene ID: 55937) is located on chromosome 6p21.33 and contains six exons spanning a region of 2.3 kb in length with gene structure conserved across species [1,2]. The human apoM protein (MIM 606907) of 188 amino acids is mainly associated with HDL and to a minor degree with LDL, very low density lipoprotein, and chylomicrons [2]. APOM knockdown in mice by siRNA revealed its anti-atherosclerotic effect by participating in pre-b HDL formation and reverse cholesterol transport [4]. Recently reported the effect of cellular cholesterol accumulation on beta cell dysfunction in type 2 diabetes [5]. Such finding implies that factors (i.e., apoM) affecting the balance of cellular cholesterol content are likely to modify beta cell function and the susceptibility to or progression of type 2 diabetes
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