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G-allele of intronic rs10830963 in MTNR1B confers increased risk of impaired fasting glycemia and type 2 diabetes through an impaired glucose-stimulated insulin release: studies involving 19,605 Europeans.

Sparsø T, Bonnefond A, Andersson E, Bouatia-Naji N, Holmkvist J, Wegner L, Grarup N, Gjesing AP, Banasik K, Cavalcanti-Proença C, Marchand M, Vaxillaire M, Charpentier G, Jarvelin MR, Tichet J, Balkau B, Marre M, Lévy-Marchal C, Faerch K, Borch-Johnsen K, Jørgensen T, Madsbad S, Poulsen P, Vaag A, Dina C, Hansen T, Pedersen O, Froguel P - Diabetes (2009)

Bottom Line: The G-allele was associated with a decreased insulin release after oral and intravenous glucose challenges (P < 0.01) but not after injection of tolbutamide.In elderly twins, the G-allele associated with hepatic insulin resistance (P = 0.017).The same allele associates with estimates of beta-cell dysfunction and hepatic insulin resistance.

View Article: PubMed Central - PubMed

Affiliation: Steno Diabetes Center, Gentofte, Denmark. tspr@steno.dk.

ABSTRACT

Objective: Genome-wide association studies have identified several variants within the MTNR1B locus that are associated with fasting plasma glucose (FPG) and type 2 diabetes. We refined the association signal by direct genotyping and examined for associations of the variant displaying the most independent effect on FPG with isolated impaired fasting glycemia (i-IFG), isolated impaired glucose tolerance (i-IGT), type 2 diabetes, and measures of insulin release and peripheral and hepatic insulin sensitivity.

Research design and methods: We examined European-descent participants in the Inter99 study (n = 5,553), in a sample of young healthy Danes (n = 372), in Danish twins (n = 77 elderly and n = 97 young), in additional Danish type 2 diabetic patients (n = 1,626) and control subjects (n = 505), in the Data from the Epidemiological Study on the Insulin Resistance Syndrome (DESIR) study (n = 4,656), in the North Finland Birth Cohort 86 (n = 5,258), and in the Haguenau study (n = 1,461).

Results: The MTNR1B intronic variant, rs10830963, carried most of the effect on FPG and showed the strongest association with FPG (combined P = 5.3 x 10(-31)) and type 2 diabetes. The rs10830963 G-allele increased the risk of i-IFG (odds ratio [OR] 1.64, P = 5.5 x 10(-11)) but not i-IGT. The G-allele was associated with a decreased insulin release after oral and intravenous glucose challenges (P < 0.01) but not after injection of tolbutamide. In elderly twins, the G-allele associated with hepatic insulin resistance (P = 0.017).

Conclusions: The G-allele of MTNR1B rs10830963 increases risk of type 2 diabetes through a state of i-IFG and not through i-IGT. The same allele associates with estimates of beta-cell dysfunction and hepatic insulin resistance.

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Genomic context and recombination rate of the eight associated SNPs at the MTNR1B locus with FPG. The upper panel shows the LD structure of the 621-kb LD block in the CEU population from HapMap phase II using the Haploview software. The lower panel shows the association magnitude (−log P value) with FPG of the eight SNPs and the recombination rate (%) at the MTNR1B locus.
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Figure 1: Genomic context and recombination rate of the eight associated SNPs at the MTNR1B locus with FPG. The upper panel shows the LD structure of the 621-kb LD block in the CEU population from HapMap phase II using the Haploview software. The lower panel shows the association magnitude (−log P value) with FPG of the eight SNPs and the recombination rate (%) at the MTNR1B locus.

Mentions: The recombination rate based on HapMap data defines a region that includes MTNR1B and its 5′ region flanked by two recombination hot spots (Fig. 1). In DESIR, NFBC86, and Haguenau, we genotyped all common SNPs (HapMap data, n = 7) in high LD (r2 > 0.70) with rs1387153: six are located in the 5′ region of MTNR1B (rs7112766 [LD with rs1387153 r2 = 0.86], rs11523890 [r2 = 0.82], rs10830956 [r2 = 1.0], rs10765573 [r2 = 0.82], rs7936247 [r2 = 0.84], and rs11020124 [r2 = 0.94]) and one SNP rs10830963 (r2 = 0.70) is located in the only intron of MTNR1B (Fig. 1). Genotyping of all SNPs was performed using Taqman allelic discrimination. Inter99, the young Danish sample set and twin populations were genotyped for rs10830963. Genotype success rate was at least 96%, and no deviation (P≥ 0.05) from Hardy-Weinberg equilibrium was observed in any of the examined populations.


G-allele of intronic rs10830963 in MTNR1B confers increased risk of impaired fasting glycemia and type 2 diabetes through an impaired glucose-stimulated insulin release: studies involving 19,605 Europeans.

Sparsø T, Bonnefond A, Andersson E, Bouatia-Naji N, Holmkvist J, Wegner L, Grarup N, Gjesing AP, Banasik K, Cavalcanti-Proença C, Marchand M, Vaxillaire M, Charpentier G, Jarvelin MR, Tichet J, Balkau B, Marre M, Lévy-Marchal C, Faerch K, Borch-Johnsen K, Jørgensen T, Madsbad S, Poulsen P, Vaag A, Dina C, Hansen T, Pedersen O, Froguel P - Diabetes (2009)

Genomic context and recombination rate of the eight associated SNPs at the MTNR1B locus with FPG. The upper panel shows the LD structure of the 621-kb LD block in the CEU population from HapMap phase II using the Haploview software. The lower panel shows the association magnitude (−log P value) with FPG of the eight SNPs and the recombination rate (%) at the MTNR1B locus.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2682679&req=5

Figure 1: Genomic context and recombination rate of the eight associated SNPs at the MTNR1B locus with FPG. The upper panel shows the LD structure of the 621-kb LD block in the CEU population from HapMap phase II using the Haploview software. The lower panel shows the association magnitude (−log P value) with FPG of the eight SNPs and the recombination rate (%) at the MTNR1B locus.
Mentions: The recombination rate based on HapMap data defines a region that includes MTNR1B and its 5′ region flanked by two recombination hot spots (Fig. 1). In DESIR, NFBC86, and Haguenau, we genotyped all common SNPs (HapMap data, n = 7) in high LD (r2 > 0.70) with rs1387153: six are located in the 5′ region of MTNR1B (rs7112766 [LD with rs1387153 r2 = 0.86], rs11523890 [r2 = 0.82], rs10830956 [r2 = 1.0], rs10765573 [r2 = 0.82], rs7936247 [r2 = 0.84], and rs11020124 [r2 = 0.94]) and one SNP rs10830963 (r2 = 0.70) is located in the only intron of MTNR1B (Fig. 1). Genotyping of all SNPs was performed using Taqman allelic discrimination. Inter99, the young Danish sample set and twin populations were genotyped for rs10830963. Genotype success rate was at least 96%, and no deviation (P≥ 0.05) from Hardy-Weinberg equilibrium was observed in any of the examined populations.

Bottom Line: The G-allele was associated with a decreased insulin release after oral and intravenous glucose challenges (P < 0.01) but not after injection of tolbutamide.In elderly twins, the G-allele associated with hepatic insulin resistance (P = 0.017).The same allele associates with estimates of beta-cell dysfunction and hepatic insulin resistance.

View Article: PubMed Central - PubMed

Affiliation: Steno Diabetes Center, Gentofte, Denmark. tspr@steno.dk.

ABSTRACT

Objective: Genome-wide association studies have identified several variants within the MTNR1B locus that are associated with fasting plasma glucose (FPG) and type 2 diabetes. We refined the association signal by direct genotyping and examined for associations of the variant displaying the most independent effect on FPG with isolated impaired fasting glycemia (i-IFG), isolated impaired glucose tolerance (i-IGT), type 2 diabetes, and measures of insulin release and peripheral and hepatic insulin sensitivity.

Research design and methods: We examined European-descent participants in the Inter99 study (n = 5,553), in a sample of young healthy Danes (n = 372), in Danish twins (n = 77 elderly and n = 97 young), in additional Danish type 2 diabetic patients (n = 1,626) and control subjects (n = 505), in the Data from the Epidemiological Study on the Insulin Resistance Syndrome (DESIR) study (n = 4,656), in the North Finland Birth Cohort 86 (n = 5,258), and in the Haguenau study (n = 1,461).

Results: The MTNR1B intronic variant, rs10830963, carried most of the effect on FPG and showed the strongest association with FPG (combined P = 5.3 x 10(-31)) and type 2 diabetes. The rs10830963 G-allele increased the risk of i-IFG (odds ratio [OR] 1.64, P = 5.5 x 10(-11)) but not i-IGT. The G-allele was associated with a decreased insulin release after oral and intravenous glucose challenges (P < 0.01) but not after injection of tolbutamide. In elderly twins, the G-allele associated with hepatic insulin resistance (P = 0.017).

Conclusions: The G-allele of MTNR1B rs10830963 increases risk of type 2 diabetes through a state of i-IFG and not through i-IGT. The same allele associates with estimates of beta-cell dysfunction and hepatic insulin resistance.

Show MeSH
Related in: MedlinePlus