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Common variants in CDKAL1, CDKN2A/B, IGF2BP2, SLC30A8, and HHEX/IDE genes are associated with type 2 diabetes and impaired fasting glucose in a Chinese Han population.

Wu Y, Li H, Loos RJ, Yu Z, Ye X, Chen L, Pan A, Hu FB, Lin X - Diabetes (2008)

Bottom Line: We genotyped 17 single nucleotide polymorhisms (SNPs) in 3,210 unrelated Chinese Hans, including 424 participants with type 2 diabetes, 878 with impaired fasting glucose (IFG), and 1,908 with normal fasting glucose.None of the SNPs in EXT2 or LOC387761 exhibited significant association with type 2 diabetes or IFG.Our results indicate that in Chinese Hans, common variants in CDKAL1, CDKN2A/B, IGF2BP2, and SLC30A8 loci independently or additively contribute to type 2 diabetes risk, likely mediated through beta-cell dysfunction.

View Article: PubMed Central - PubMed

Affiliation: Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences and Graduate School of the Chinese Academy of Sciences, Shanghai, China.

ABSTRACT

Objective: Genome-wide association studies have identified common variants in CDKAL1, CDKN2A/B, IGF2BP2, SLC30A8, HHEX/IDE, EXT2, and LOC387761 loci that significantly increase the risk of type 2 diabetes. We aimed to replicate these observations in a population-based cohort of Chinese Hans and examine the associations of these variants with type 2 diabetes and diabetes-related phenotypes.

Research design and methods: We genotyped 17 single nucleotide polymorhisms (SNPs) in 3,210 unrelated Chinese Hans, including 424 participants with type 2 diabetes, 878 with impaired fasting glucose (IFG), and 1,908 with normal fasting glucose.

Results: We confirmed the associations between type 2 diabetes and variants near CDKAL1 (odds ratio 1.49 [95% CI 1.27-1.75]; P = 8.91 x 10(-7)) and CDKN2A/B (1.31 [1.12-1.54]; P = 1.0 x 10(-3)). We observed significant association of SNPs in IGF2BP2 (1.17 [1.03-1.32]; P = 0.014) and SLC30A8 (1.12 [1.01-1.25]; P = 0.033) with combined IFG/type 2 diabetes. The SNPs in CDKAL1, IGF2BP2, and SLC30A8 were also associated with impaired beta-cell function estimated by homeostasis model assessment of beta-cell function. When combined, each additional risk allele from CDKAL1-rs9465871, CDKN2A/B-rs10811661, IGF2BP2-rs4402960, and SLC30A8-rs13266634 increased the risk for type 2 diabetes by 1.24-fold (P = 2.85 x 10(-7)) or for combined IFG/type 2 diabetes by 1.21-fold (P = 6.31 x 10(-11)). None of the SNPs in EXT2 or LOC387761 exhibited significant association with type 2 diabetes or IFG. Significant association was observed between the HHEX/IDE SNPs and type 2 diabetes in individuals from Shanghai only (P < 0.013) but not in those from Beijing (P > 0.33).

Conclusions: Our results indicate that in Chinese Hans, common variants in CDKAL1, CDKN2A/B, IGF2BP2, and SLC30A8 loci independently or additively contribute to type 2 diabetes risk, likely mediated through beta-cell dysfunction.

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Combined effects of increasing numbers of the risk alleles from CDKAL1-rs9465871, CDKN2A/B-rs10811661, IGF2BP2-rs4402960, and SLC30A8-rs13266634. A: The risk allele distribution in the participants with NFG and participants with type 2 diabetes. □, control; ▪, type 2 diabetes. Each additional risk allele increased the risk of type 2 diabetes by 1.24-fold (P = 2.85 × 10−7) (B) and of IFG and diabetes combined by 1.21-fold (P = 6.31 × 10−11) (C). B: Participants harboring seven or all eight risk alleles had a 4.44-fold increased risk for type 2 diabetes (P = 5 × 10−4) compared with the reference group. Consistently, participants with increasing numbers of risk alleles tended to have increased fasting levels of plasma glucose (P = 0.013) (D) and A1C (P = 0.07) (E), as well as decreased HOMA-B values (P = 3.34 × 10−7) (F) and lower BMI (P = 5.3 × 10−3) (H), but showed no association with plasma insulin (P = 0.13) (G).
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f1: Combined effects of increasing numbers of the risk alleles from CDKAL1-rs9465871, CDKN2A/B-rs10811661, IGF2BP2-rs4402960, and SLC30A8-rs13266634. A: The risk allele distribution in the participants with NFG and participants with type 2 diabetes. □, control; ▪, type 2 diabetes. Each additional risk allele increased the risk of type 2 diabetes by 1.24-fold (P = 2.85 × 10−7) (B) and of IFG and diabetes combined by 1.21-fold (P = 6.31 × 10−11) (C). B: Participants harboring seven or all eight risk alleles had a 4.44-fold increased risk for type 2 diabetes (P = 5 × 10−4) compared with the reference group. Consistently, participants with increasing numbers of risk alleles tended to have increased fasting levels of plasma glucose (P = 0.013) (D) and A1C (P = 0.07) (E), as well as decreased HOMA-B values (P = 3.34 × 10−7) (F) and lower BMI (P = 5.3 × 10−3) (H), but showed no association with plasma insulin (P = 0.13) (G).

Mentions: We found no evidence of multiplicative gene-gene interactions among the main SNPs (rs9465871, rs10811661, rs4402960, and rs13266634) in each of the CDKAL1, CDKN2A/B, IGF2BP2, and SLC30A8 genes. A significantly higher proportion of participants with type 2 diabetes carry increasing numbers of risk alleles, compared with participants with NFG (Fig. 1A). In combined analysis, each additional risk allele increased the risk of type 2 diabetes by 1.24-fold (P = 2.85 × 10−7) (Fig. 1B) and combined IFG/type 2 diabetes by 1.21-fold (P = 6.31 × 10−11) (Fig. 1C). Participants harboring seven or all eight risk alleles had a 4.44-fold increased risk for type 2 diabetes (P = 5 × 10−4) compared with those with one or no risk alleles (Fig. 1B). Consistently, participants with increasing numbers of risk alleles tended to have increased fasting levels of plasma glucose (P = 0.013) (Fig. 1D) and A1C (P = 0.07) (Fig. 1E), as well as decreased HOMA-B values (P = 3.34 × 10−7) (Fig. 1F). Of note, participants with increasing numbers of risk alleles tended to have significantly lower BMI (P = 5.3 × 10−3) (Fig. 1F), which is consistent with previous results found for the CDKAL1 and SLC30A8 polymorphisms (Table 3).


Common variants in CDKAL1, CDKN2A/B, IGF2BP2, SLC30A8, and HHEX/IDE genes are associated with type 2 diabetes and impaired fasting glucose in a Chinese Han population.

Wu Y, Li H, Loos RJ, Yu Z, Ye X, Chen L, Pan A, Hu FB, Lin X - Diabetes (2008)

Combined effects of increasing numbers of the risk alleles from CDKAL1-rs9465871, CDKN2A/B-rs10811661, IGF2BP2-rs4402960, and SLC30A8-rs13266634. A: The risk allele distribution in the participants with NFG and participants with type 2 diabetes. □, control; ▪, type 2 diabetes. Each additional risk allele increased the risk of type 2 diabetes by 1.24-fold (P = 2.85 × 10−7) (B) and of IFG and diabetes combined by 1.21-fold (P = 6.31 × 10−11) (C). B: Participants harboring seven or all eight risk alleles had a 4.44-fold increased risk for type 2 diabetes (P = 5 × 10−4) compared with the reference group. Consistently, participants with increasing numbers of risk alleles tended to have increased fasting levels of plasma glucose (P = 0.013) (D) and A1C (P = 0.07) (E), as well as decreased HOMA-B values (P = 3.34 × 10−7) (F) and lower BMI (P = 5.3 × 10−3) (H), but showed no association with plasma insulin (P = 0.13) (G).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2551696&req=5

f1: Combined effects of increasing numbers of the risk alleles from CDKAL1-rs9465871, CDKN2A/B-rs10811661, IGF2BP2-rs4402960, and SLC30A8-rs13266634. A: The risk allele distribution in the participants with NFG and participants with type 2 diabetes. □, control; ▪, type 2 diabetes. Each additional risk allele increased the risk of type 2 diabetes by 1.24-fold (P = 2.85 × 10−7) (B) and of IFG and diabetes combined by 1.21-fold (P = 6.31 × 10−11) (C). B: Participants harboring seven or all eight risk alleles had a 4.44-fold increased risk for type 2 diabetes (P = 5 × 10−4) compared with the reference group. Consistently, participants with increasing numbers of risk alleles tended to have increased fasting levels of plasma glucose (P = 0.013) (D) and A1C (P = 0.07) (E), as well as decreased HOMA-B values (P = 3.34 × 10−7) (F) and lower BMI (P = 5.3 × 10−3) (H), but showed no association with plasma insulin (P = 0.13) (G).
Mentions: We found no evidence of multiplicative gene-gene interactions among the main SNPs (rs9465871, rs10811661, rs4402960, and rs13266634) in each of the CDKAL1, CDKN2A/B, IGF2BP2, and SLC30A8 genes. A significantly higher proportion of participants with type 2 diabetes carry increasing numbers of risk alleles, compared with participants with NFG (Fig. 1A). In combined analysis, each additional risk allele increased the risk of type 2 diabetes by 1.24-fold (P = 2.85 × 10−7) (Fig. 1B) and combined IFG/type 2 diabetes by 1.21-fold (P = 6.31 × 10−11) (Fig. 1C). Participants harboring seven or all eight risk alleles had a 4.44-fold increased risk for type 2 diabetes (P = 5 × 10−4) compared with those with one or no risk alleles (Fig. 1B). Consistently, participants with increasing numbers of risk alleles tended to have increased fasting levels of plasma glucose (P = 0.013) (Fig. 1D) and A1C (P = 0.07) (Fig. 1E), as well as decreased HOMA-B values (P = 3.34 × 10−7) (Fig. 1F). Of note, participants with increasing numbers of risk alleles tended to have significantly lower BMI (P = 5.3 × 10−3) (Fig. 1F), which is consistent with previous results found for the CDKAL1 and SLC30A8 polymorphisms (Table 3).

Bottom Line: We genotyped 17 single nucleotide polymorhisms (SNPs) in 3,210 unrelated Chinese Hans, including 424 participants with type 2 diabetes, 878 with impaired fasting glucose (IFG), and 1,908 with normal fasting glucose.None of the SNPs in EXT2 or LOC387761 exhibited significant association with type 2 diabetes or IFG.Our results indicate that in Chinese Hans, common variants in CDKAL1, CDKN2A/B, IGF2BP2, and SLC30A8 loci independently or additively contribute to type 2 diabetes risk, likely mediated through beta-cell dysfunction.

View Article: PubMed Central - PubMed

Affiliation: Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences and Graduate School of the Chinese Academy of Sciences, Shanghai, China.

ABSTRACT

Objective: Genome-wide association studies have identified common variants in CDKAL1, CDKN2A/B, IGF2BP2, SLC30A8, HHEX/IDE, EXT2, and LOC387761 loci that significantly increase the risk of type 2 diabetes. We aimed to replicate these observations in a population-based cohort of Chinese Hans and examine the associations of these variants with type 2 diabetes and diabetes-related phenotypes.

Research design and methods: We genotyped 17 single nucleotide polymorhisms (SNPs) in 3,210 unrelated Chinese Hans, including 424 participants with type 2 diabetes, 878 with impaired fasting glucose (IFG), and 1,908 with normal fasting glucose.

Results: We confirmed the associations between type 2 diabetes and variants near CDKAL1 (odds ratio 1.49 [95% CI 1.27-1.75]; P = 8.91 x 10(-7)) and CDKN2A/B (1.31 [1.12-1.54]; P = 1.0 x 10(-3)). We observed significant association of SNPs in IGF2BP2 (1.17 [1.03-1.32]; P = 0.014) and SLC30A8 (1.12 [1.01-1.25]; P = 0.033) with combined IFG/type 2 diabetes. The SNPs in CDKAL1, IGF2BP2, and SLC30A8 were also associated with impaired beta-cell function estimated by homeostasis model assessment of beta-cell function. When combined, each additional risk allele from CDKAL1-rs9465871, CDKN2A/B-rs10811661, IGF2BP2-rs4402960, and SLC30A8-rs13266634 increased the risk for type 2 diabetes by 1.24-fold (P = 2.85 x 10(-7)) or for combined IFG/type 2 diabetes by 1.21-fold (P = 6.31 x 10(-11)). None of the SNPs in EXT2 or LOC387761 exhibited significant association with type 2 diabetes or IFG. Significant association was observed between the HHEX/IDE SNPs and type 2 diabetes in individuals from Shanghai only (P < 0.013) but not in those from Beijing (P > 0.33).

Conclusions: Our results indicate that in Chinese Hans, common variants in CDKAL1, CDKN2A/B, IGF2BP2, and SLC30A8 loci independently or additively contribute to type 2 diabetes risk, likely mediated through beta-cell dysfunction.

Show MeSH
Related in: MedlinePlus