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Association of genetic variants of the incretin-related genes with quantitative traits and occurrence of type 2 diabetes in Japanese

View Article: PubMed Central - PubMed

ABSTRACT

Background: None of the high frequency variants of the incretin-related genes has been found by genome-wide association study (GWAS) for association with occurrence of type 2 diabetes in Japanese. However, low frequency and rare and/or high frequency variants affecting glucose metabolic traits remain to be investigated.

Method: We screened all exons of the incretin-related genes (GCG, GLP1R, DPP4, PCSK1, GIP, and GIPR) in 96 patients with type 2 diabetes and investigated for association of genetic variants of these genes with quantitative metabolic traits upon test meal with 38 young healthy volunteers and with the occurrence of type 2 diabetes in Japanese subjects comprising 1303 patients with type 2 diabetes and 1014 controls.

Result: Two mutations of GIPR, p.Thr3Alafsx21 and Arg183Gln, were found only in patients with type 2 diabetes, and both of them were treated with insulin. Of ten tagSNPs, we found that risk allele C of SNP393 (rs6235) of PCSK1 was nominally associated with higher fasting insulin and HOMA-R (P = 0.034 and P = 0.030), but not with proinsulin level, incretin level or BMI. The variant showed significant association with occurrence of type 2 diabetes after adjustment for age, sex, and BMI (P = 0.0043).

Conclusion: Rare variants of GIPR may contribute to the development of type 2 diabetes, possibly through insulin secretory defects. Furthermore, the genetic variant of PCSK1 might influence glucose homeostasis by altered insulin resistance independently of BMI, incretin level or proinsulin conversion, and may be associated with the occurrence of type 2 diabetes in Japanese.

No MeSH data available.


Related in: MedlinePlus

Reporter assay of the region containing SNP 232 (rs 456709) of PCSK1.C: major allele (risk allele), T: minor allele.
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f0010: Reporter assay of the region containing SNP 232 (rs 456709) of PCSK1.C: major allele (risk allele), T: minor allele.

Mentions: SNP393 (rs6235) of PCSK1 resulted in the missense mutation Ser690Thr, which has been reported not to affect its enzymatic activity [8]. Functional analysis of SNP232 (rs456709) of PCSK1 was therefore performed. Since SNP232 (rs456709) is located at intron3 of PCSK1 and is not in complete linkage disequilibrium with any of the missense mutations of PCSK1, we performed luciferase assay to determine whether or not it might affect transcriptional activity. The major C allele of SNP232 (rs456709) is conserved among human, mouse, and rat, and showed significantly lower transcriptional activity compared to that of the T allele (P < 0.05) (Fig. 2), but no transcriptional factors were detected at the region around SNPS 232 by the TF search program (www.cbrc.jp/research/db/TFSEARCH.html).


Association of genetic variants of the incretin-related genes with quantitative traits and occurrence of type 2 diabetes in Japanese
Reporter assay of the region containing SNP 232 (rs 456709) of PCSK1.C: major allele (risk allele), T: minor allele.
© Copyright Policy - CC BY-NC-ND
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC5121356&req=5

f0010: Reporter assay of the region containing SNP 232 (rs 456709) of PCSK1.C: major allele (risk allele), T: minor allele.
Mentions: SNP393 (rs6235) of PCSK1 resulted in the missense mutation Ser690Thr, which has been reported not to affect its enzymatic activity [8]. Functional analysis of SNP232 (rs456709) of PCSK1 was therefore performed. Since SNP232 (rs456709) is located at intron3 of PCSK1 and is not in complete linkage disequilibrium with any of the missense mutations of PCSK1, we performed luciferase assay to determine whether or not it might affect transcriptional activity. The major C allele of SNP232 (rs456709) is conserved among human, mouse, and rat, and showed significantly lower transcriptional activity compared to that of the T allele (P < 0.05) (Fig. 2), but no transcriptional factors were detected at the region around SNPS 232 by the TF search program (www.cbrc.jp/research/db/TFSEARCH.html).

View Article: PubMed Central - PubMed

ABSTRACT

Background: None of the high frequency variants of the incretin-related genes has been found by genome-wide association study (GWAS) for association with occurrence of type 2 diabetes in Japanese. However, low frequency and rare and/or high frequency variants affecting glucose metabolic traits remain to be investigated.

Method: We screened all exons of the incretin-related genes (GCG, GLP1R, DPP4, PCSK1, GIP, and GIPR) in 96 patients with type 2 diabetes and investigated for association of genetic variants of these genes with quantitative metabolic traits upon test meal with 38 young healthy volunteers and with the occurrence of type 2 diabetes in Japanese subjects comprising 1303 patients with type 2 diabetes and 1014 controls.

Result: Two mutations of GIPR, p.Thr3Alafsx21 and Arg183Gln, were found only in patients with type 2 diabetes, and both of them were treated with insulin. Of ten tagSNPs, we found that risk allele C of SNP393 (rs6235) of PCSK1 was nominally associated with higher fasting insulin and HOMA-R (P&nbsp;=&nbsp;0.034 and P&nbsp;=&nbsp;0.030), but not with proinsulin level, incretin level or BMI. The variant showed significant association with occurrence of type 2 diabetes after adjustment for age, sex, and BMI (P&nbsp;=&nbsp;0.0043).

Conclusion: Rare variants of GIPR may contribute to the development of type 2 diabetes, possibly through insulin secretory defects. Furthermore, the genetic variant of PCSK1 might influence glucose homeostasis by altered insulin resistance independently of BMI, incretin level or proinsulin conversion, and may be associated with the occurrence of type 2 diabetes in Japanese.

No MeSH data available.


Related in: MedlinePlus