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Association of common genetic variants in the MAP4K4 locus with prediabetic traits in humans.

Sartorius T, Staiger H, Ketterer C, Heni M, Machicao F, Guilherme A, Grallert H, Schulze MB, Boeing H, Stefan N, Fritsche A, Czech MP, Häring HU - PLoS ONE (2012)

Bottom Line: Three SNPs (rs6543087, rs17801985, rs1003376) revealed nominal and two SNPs (rs11674694, rs11678405) significant associations with 2-hour glucose levels.SNPs rs6543087 and rs11674694 were also nominally associated with decreased insulin sensitivity.SNP rs11674694 was significantly associated with type 2 diabetes.

View Article: PubMed Central - PubMed

Affiliation: Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Centre Munich at the University of Tübingen, Tübingen, Germany.

ABSTRACT
Mitogen-activated protein kinase kinase kinase kinase 4 (MAP4K4) is expressed in all diabetes-relevant tissues and mediates cytokine-induced insulin resistance. We investigated whether common single nucleotide polymorphisms (SNPs) in the MAP4K4 locus associate with glucose intolerance, insulin resistance, impaired insulin release, or elevated plasma cytokines. The best hit was tested for association with type 2 diabetes. Subjects (N = 1,769) were recruited from the Tübingen Family (TÜF) study for type 2 diabetes and genotyped for tagging SNPs. In a subgroup, cytokines were measured. Association with type 2 diabetes was tested in a prospective case-cohort study (N = 2,971) derived from the EPIC-Potsdam study. Three SNPs (rs6543087, rs17801985, rs1003376) revealed nominal and two SNPs (rs11674694, rs11678405) significant associations with 2-hour glucose levels. SNPs rs6543087 and rs11674694 were also nominally associated with decreased insulin sensitivity. Another two SNPs (rs2236936, rs2236935) showed associations with reduced insulin release, driven by effects in lean subjects only. Three SNPs (rs11674694, rs13003883, rs2236936) revealed nominal associations with IL-6 levels. SNP rs11674694 was significantly associated with type 2 diabetes. In conclusion, common variation in MAP4K4 is associated with insulin resistance and β-cell dysfunction, possibly via this gene's role in inflammatory signalling. This variation's impact on insulin sensitivity may be more important since its effect on insulin release vanishes with increasing BMI.

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Association of single nucleotide polymorphisms (SNPs) rs2236936 and rs2236935 with insulin release in lean subjects.Subjects were stratified into lean (BMI<25kg/m2), overweight (25 kg/m2≤BMI<30 kg/m2), and obese (BMI≥30 kg/m2) subgroups. Insulin release was estimated from the oral glucose tolerance test by calculating the index AUCIns 0–30/AUCGlc 0–30 (for calculation, see Materials and Methods). Insulin release was adjusted for gender, age, and insulin sensitivity. Adjusted loge-transformed data derived from multiple linear regression models ±SE are shown.
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pone-0047647-g002: Association of single nucleotide polymorphisms (SNPs) rs2236936 and rs2236935 with insulin release in lean subjects.Subjects were stratified into lean (BMI<25kg/m2), overweight (25 kg/m2≤BMI<30 kg/m2), and obese (BMI≥30 kg/m2) subgroups. Insulin release was estimated from the oral glucose tolerance test by calculating the index AUCIns 0–30/AUCGlc 0–30 (for calculation, see Materials and Methods). Insulin release was adjusted for gender, age, and insulin sensitivity. Adjusted loge-transformed data derived from multiple linear regression models ±SE are shown.

Mentions: Two SNPs not associated with 2-hour glycaemia (rs2236936, rs2236935) showed nominal associations (0.04194≤p≤0.0461) with lower insulin release (AUCIns 0–30/AUCGlc 0–30, Table 3). The other SNPs did not reveal associations with insulin release (p≥0.15, all, Table 3 and Table S3). To assess whether the two nominally associated SNPs affect insulin release depending on genotype interactions with age, gender, BMI, or 2-hour glucose, we performed ANCOVAs. SNP rs2236935 revealed significant (p = 0.0096) and SNP rs2236936 nominal (p = 0.0489) interaction with BMI. All other interaction tests were negative (p≥0.08). Therefore, we stratified our overall population in lean (BMI<25 kg/m2), overweight (25 kg/m2≤BMI<30 kg/m2), and obese (BMI≥30 kg/m2) subjects and assessed these SNPs’ effects on insulin release in these strata. SNP rs2236935 was significantly (p = 0.0043) and SNP rs2236936 nominally (p = 0.0272) associated with reduced insulin release in lean subjects, whereas no such associations were seen in the other strata (p≥0.1, Figure 2).


Association of common genetic variants in the MAP4K4 locus with prediabetic traits in humans.

Sartorius T, Staiger H, Ketterer C, Heni M, Machicao F, Guilherme A, Grallert H, Schulze MB, Boeing H, Stefan N, Fritsche A, Czech MP, Häring HU - PLoS ONE (2012)

Association of single nucleotide polymorphisms (SNPs) rs2236936 and rs2236935 with insulin release in lean subjects.Subjects were stratified into lean (BMI<25kg/m2), overweight (25 kg/m2≤BMI<30 kg/m2), and obese (BMI≥30 kg/m2) subgroups. Insulin release was estimated from the oral glucose tolerance test by calculating the index AUCIns 0–30/AUCGlc 0–30 (for calculation, see Materials and Methods). Insulin release was adjusted for gender, age, and insulin sensitivity. Adjusted loge-transformed data derived from multiple linear regression models ±SE are shown.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3475716&req=5

pone-0047647-g002: Association of single nucleotide polymorphisms (SNPs) rs2236936 and rs2236935 with insulin release in lean subjects.Subjects were stratified into lean (BMI<25kg/m2), overweight (25 kg/m2≤BMI<30 kg/m2), and obese (BMI≥30 kg/m2) subgroups. Insulin release was estimated from the oral glucose tolerance test by calculating the index AUCIns 0–30/AUCGlc 0–30 (for calculation, see Materials and Methods). Insulin release was adjusted for gender, age, and insulin sensitivity. Adjusted loge-transformed data derived from multiple linear regression models ±SE are shown.
Mentions: Two SNPs not associated with 2-hour glycaemia (rs2236936, rs2236935) showed nominal associations (0.04194≤p≤0.0461) with lower insulin release (AUCIns 0–30/AUCGlc 0–30, Table 3). The other SNPs did not reveal associations with insulin release (p≥0.15, all, Table 3 and Table S3). To assess whether the two nominally associated SNPs affect insulin release depending on genotype interactions with age, gender, BMI, or 2-hour glucose, we performed ANCOVAs. SNP rs2236935 revealed significant (p = 0.0096) and SNP rs2236936 nominal (p = 0.0489) interaction with BMI. All other interaction tests were negative (p≥0.08). Therefore, we stratified our overall population in lean (BMI<25 kg/m2), overweight (25 kg/m2≤BMI<30 kg/m2), and obese (BMI≥30 kg/m2) subjects and assessed these SNPs’ effects on insulin release in these strata. SNP rs2236935 was significantly (p = 0.0043) and SNP rs2236936 nominally (p = 0.0272) associated with reduced insulin release in lean subjects, whereas no such associations were seen in the other strata (p≥0.1, Figure 2).

Bottom Line: Three SNPs (rs6543087, rs17801985, rs1003376) revealed nominal and two SNPs (rs11674694, rs11678405) significant associations with 2-hour glucose levels.SNPs rs6543087 and rs11674694 were also nominally associated with decreased insulin sensitivity.SNP rs11674694 was significantly associated with type 2 diabetes.

View Article: PubMed Central - PubMed

Affiliation: Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Centre Munich at the University of Tübingen, Tübingen, Germany.

ABSTRACT
Mitogen-activated protein kinase kinase kinase kinase 4 (MAP4K4) is expressed in all diabetes-relevant tissues and mediates cytokine-induced insulin resistance. We investigated whether common single nucleotide polymorphisms (SNPs) in the MAP4K4 locus associate with glucose intolerance, insulin resistance, impaired insulin release, or elevated plasma cytokines. The best hit was tested for association with type 2 diabetes. Subjects (N = 1,769) were recruited from the Tübingen Family (TÜF) study for type 2 diabetes and genotyped for tagging SNPs. In a subgroup, cytokines were measured. Association with type 2 diabetes was tested in a prospective case-cohort study (N = 2,971) derived from the EPIC-Potsdam study. Three SNPs (rs6543087, rs17801985, rs1003376) revealed nominal and two SNPs (rs11674694, rs11678405) significant associations with 2-hour glucose levels. SNPs rs6543087 and rs11674694 were also nominally associated with decreased insulin sensitivity. Another two SNPs (rs2236936, rs2236935) showed associations with reduced insulin release, driven by effects in lean subjects only. Three SNPs (rs11674694, rs13003883, rs2236936) revealed nominal associations with IL-6 levels. SNP rs11674694 was significantly associated with type 2 diabetes. In conclusion, common variation in MAP4K4 is associated with insulin resistance and β-cell dysfunction, possibly via this gene's role in inflammatory signalling. This variation's impact on insulin sensitivity may be more important since its effect on insulin release vanishes with increasing BMI.

Show MeSH
Related in: MedlinePlus