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Apolipoprotein M gene (APOM) polymorphism modifies metabolic and disease traits in type 2 diabetes.

Zhou JW, Tsui SK, Ng MC, Geng H, Li SK, So WY, Ma RC, Wang Y, Tao Q, Chen ZY, Chan JC, Ho YY - PLoS ONE (2011)

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Biochemistry, The Chinese University of Hong Kong, Hong Kong, China.

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.

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Cross-species sequence alignment and information of APOM transcripts.Transcript patterns were constructed by Ensembl browser tool. Top panel (sequence view): Fragments spanning SNPs rs707922(G+1837T) and rs707921(C+1871A) were aligned among different species including human, mouse, rat, cow and dog. Both SNPs, as indicated by arrowheads, fell within the highly conserved region (shaded in grey). Bottom panel (structure view): A schematic representation of the structure of human APOM5 transcript compared with those of the APOM1 and APOM3 with the positions of coding exons (black boxes), introns (horizontal lines) and untranslated exons (white boxes) indicated. Arrowheads followed by vertical dashed lines indicated the corresponding positions of rs707922 and rs707921 on different APOM transcripts. Also indicated by the dashed lines at the 5′ end of the gene structures was the 21-nucleotide sequence difference between APOM1 and APOM5 transcripts.
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pone-0017324-g001: Cross-species sequence alignment and information of APOM transcripts.Transcript patterns were constructed by Ensembl browser tool. Top panel (sequence view): Fragments spanning SNPs rs707922(G+1837T) and rs707921(C+1871A) were aligned among different species including human, mouse, rat, cow and dog. Both SNPs, as indicated by arrowheads, fell within the highly conserved region (shaded in grey). Bottom panel (structure view): A schematic representation of the structure of human APOM5 transcript compared with those of the APOM1 and APOM3 with the positions of coding exons (black boxes), introns (horizontal lines) and untranslated exons (white boxes) indicated. Arrowheads followed by vertical dashed lines indicated the corresponding positions of rs707922 and rs707921 on different APOM transcripts. Also indicated by the dashed lines at the 5′ end of the gene structures was the 21-nucleotide sequence difference between APOM1 and APOM5 transcripts.

Mentions: Sequence alignment analysis revealed conserved regions of the APOM gene in human, mouse, rat, cow, and dog (Supplementary Figure S3). SNPs rs707922 (G+1837T) and rs707921 (C+1871A) which associated with plasma levels of TC, LDL-C and apoM in T2D patients fell within the evolutionary conserved region. Figure 1 (top panel) illustrated the cross-species sequence conservation of the rs707922- and rs707921- flanking region. BLAST search using this conserved sequence as the template returned unique human EST clones BI757556 (human brain) and AA975560.1 (human kidney) which are likely other APOM transcripts. The Ensembl Browser also displayed three APOM transcripts (APOM1: Ensembl-ENST00000375916, APOM2: Ensembl-ENST00000375920 and APOM3: Ensembl-ENST00000375918).


Apolipoprotein M gene (APOM) polymorphism modifies metabolic and disease traits in type 2 diabetes.

Zhou JW, Tsui SK, Ng MC, Geng H, Li SK, So WY, Ma RC, Wang Y, Tao Q, Chen ZY, Chan JC, Ho YY - PLoS ONE (2011)

Cross-species sequence alignment and information of APOM transcripts.Transcript patterns were constructed by Ensembl browser tool. Top panel (sequence view): Fragments spanning SNPs rs707922(G+1837T) and rs707921(C+1871A) were aligned among different species including human, mouse, rat, cow and dog. Both SNPs, as indicated by arrowheads, fell within the highly conserved region (shaded in grey). Bottom panel (structure view): A schematic representation of the structure of human APOM5 transcript compared with those of the APOM1 and APOM3 with the positions of coding exons (black boxes), introns (horizontal lines) and untranslated exons (white boxes) indicated. Arrowheads followed by vertical dashed lines indicated the corresponding positions of rs707922 and rs707921 on different APOM transcripts. Also indicated by the dashed lines at the 5′ end of the gene structures was the 21-nucleotide sequence difference between APOM1 and APOM5 transcripts.
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Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3044746&req=5

pone-0017324-g001: Cross-species sequence alignment and information of APOM transcripts.Transcript patterns were constructed by Ensembl browser tool. Top panel (sequence view): Fragments spanning SNPs rs707922(G+1837T) and rs707921(C+1871A) were aligned among different species including human, mouse, rat, cow and dog. Both SNPs, as indicated by arrowheads, fell within the highly conserved region (shaded in grey). Bottom panel (structure view): A schematic representation of the structure of human APOM5 transcript compared with those of the APOM1 and APOM3 with the positions of coding exons (black boxes), introns (horizontal lines) and untranslated exons (white boxes) indicated. Arrowheads followed by vertical dashed lines indicated the corresponding positions of rs707922 and rs707921 on different APOM transcripts. Also indicated by the dashed lines at the 5′ end of the gene structures was the 21-nucleotide sequence difference between APOM1 and APOM5 transcripts.
Mentions: Sequence alignment analysis revealed conserved regions of the APOM gene in human, mouse, rat, cow, and dog (Supplementary Figure S3). SNPs rs707922 (G+1837T) and rs707921 (C+1871A) which associated with plasma levels of TC, LDL-C and apoM in T2D patients fell within the evolutionary conserved region. Figure 1 (top panel) illustrated the cross-species sequence conservation of the rs707922- and rs707921- flanking region. BLAST search using this conserved sequence as the template returned unique human EST clones BI757556 (human brain) and AA975560.1 (human kidney) which are likely other APOM transcripts. The Ensembl Browser also displayed three APOM transcripts (APOM1: Ensembl-ENST00000375916, APOM2: Ensembl-ENST00000375920 and APOM3: Ensembl-ENST00000375918).

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Biochemistry, The Chinese University of Hong Kong, Hong Kong, China.

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.

Show MeSH
Related in: MedlinePlus