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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

The pattern of linkage disequilibrium in the incretin-related genes examined in this study.LD color schemes are designated as follows: r2 = 0: white; 0 < r2 < 1: shades of gray; r2 = 1: black.
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f0005: The pattern of linkage disequilibrium in the incretin-related genes examined in this study.LD color schemes are designated as follows: r2 = 0: white; 0 < r2 < 1: shades of gray; r2 = 1: black.

Mentions: For association studies, we selected 10 tag-SNPs based on linkage disequilibrium (LD) pattern determined by HapMap data of 45 unrelated Japanese (http://hapmap.ncbi.nlm.nih.gov/cgi-perl/gbrowse/hapmap24_B36/#search) using Haploview (http://www.broadinstitute.org/scientific-community/science/programs/medical-and-population-genetics/haploview/haploview) (Fig. 1). We first downloaded the SNP data of the Japanese from Hapmap Data Rel 27 Phase II + III and estimated LD blocks by Haploview program, and then selected each SNP from each LD block where r2 of all possible combinations of SNPs in the database was more than 0.7. We also selected only SNPs in the neighboring regions of which there were no other SNPs, to avoid mistyping by TaqMAN assay. The ten SNPs consisted of one SNP of GCG, two SNPs of DPP4, one SNP of inter-region between GCG and DPP4, one SNP of GLP1R, two SNPs of PCSK1, one SNP of GIP, and two SNPs of GIPR. The SNP 393 (rs 6235) of PCSK1, Ser690Thr, was first reported to be associated with obesity in Caucasians [7] and the SNP394 (rs1800437) of GIPR is in strong linkage disequilibrium with the SNP rs10423928, which is reported to be associated with the plasma level of 2 h glucose and the index of insulin response during OGTT [14]. These SNPs were genotyped using Taqman SNP Genotyping Assays (Applied Biosystems, Foster City, CA) in Japanese subjects comprising 1303 patients with type 2 diabetes and 1014 controls.


Association of genetic variants of the incretin-related genes with quantitative traits and occurrence of type 2 diabetes in Japanese
The pattern of linkage disequilibrium in the incretin-related genes examined in this study.LD color schemes are designated as follows: r2 = 0: white; 0 < r2 < 1: shades of gray; r2 = 1: black.
© Copyright Policy - CC BY-NC-ND
Related In: Results  -  Collection

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

f0005: The pattern of linkage disequilibrium in the incretin-related genes examined in this study.LD color schemes are designated as follows: r2 = 0: white; 0 < r2 < 1: shades of gray; r2 = 1: black.
Mentions: For association studies, we selected 10 tag-SNPs based on linkage disequilibrium (LD) pattern determined by HapMap data of 45 unrelated Japanese (http://hapmap.ncbi.nlm.nih.gov/cgi-perl/gbrowse/hapmap24_B36/#search) using Haploview (http://www.broadinstitute.org/scientific-community/science/programs/medical-and-population-genetics/haploview/haploview) (Fig. 1). We first downloaded the SNP data of the Japanese from Hapmap Data Rel 27 Phase II + III and estimated LD blocks by Haploview program, and then selected each SNP from each LD block where r2 of all possible combinations of SNPs in the database was more than 0.7. We also selected only SNPs in the neighboring regions of which there were no other SNPs, to avoid mistyping by TaqMAN assay. The ten SNPs consisted of one SNP of GCG, two SNPs of DPP4, one SNP of inter-region between GCG and DPP4, one SNP of GLP1R, two SNPs of PCSK1, one SNP of GIP, and two SNPs of GIPR. The SNP 393 (rs 6235) of PCSK1, Ser690Thr, was first reported to be associated with obesity in Caucasians [7] and the SNP394 (rs1800437) of GIPR is in strong linkage disequilibrium with the SNP rs10423928, which is reported to be associated with the plasma level of 2 h glucose and the index of insulin response during OGTT [14]. These SNPs were genotyped using Taqman SNP Genotyping Assays (Applied Biosystems, Foster City, CA) in Japanese subjects comprising 1303 patients with type 2 diabetes and 1014 controls.

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