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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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Related in: MedlinePlus

Genomic region of human chromosome 2q11.2-q12 harbouring the MAP4K4 gene and HapMap linkage disequilibrium data of common (minor allele frequency >0.05) informative single nucleotide polymorphisms (SNPs) within this region.The MAP4K4 gene consists of 30 exons and 29 introns and spans 196.66 kb from nucleotide position 101,680,920 to nucleotide position 101,877,583. The analysed region additionally included 5 kb of the 5′-flanking region and 3 kb of the 3′-flanking region. This genomic region did not overlap with other known gene loci. The locations of the 14 tagging SNPs (highlighted by flags) are indicated by arrows. Linkage disequilibrium data based on r2 values are given by shadings (white diamonds – low linkage; black diamonds – high linkage; grey diamonds – in between).
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pone-0047647-g001: Genomic region of human chromosome 2q11.2-q12 harbouring the MAP4K4 gene and HapMap linkage disequilibrium data of common (minor allele frequency >0.05) informative single nucleotide polymorphisms (SNPs) within this region.The MAP4K4 gene consists of 30 exons and 29 introns and spans 196.66 kb from nucleotide position 101,680,920 to nucleotide position 101,877,583. The analysed region additionally included 5 kb of the 5′-flanking region and 3 kb of the 3′-flanking region. This genomic region did not overlap with other known gene loci. The locations of the 14 tagging SNPs (highlighted by flags) are indicated by arrows. Linkage disequilibrium data based on r2 values are given by shadings (white diamonds – low linkage; black diamonds – high linkage; grey diamonds – in between).

Mentions: Based on publicly available phase III data of the International HapMap Project derived from Utah residents with Central European (CEU) ancestry (release #28 August 2010, http://hapmap.ncbi.nlm.nih.gov/index.html.en), we screened in silico the complete MAP4K4 gene spanning 196.66 kb (30 exons, 29 introns) on human chromosome 2q11.2-q12 as well as 5 and 3kb of its 5′- and 3′-flanking regions, respectively (Figure 1). Within this locus, 215 informative HapMap SNPs were present with 106 displaying MAFs >0.05. The HapMap linkage disequilibrium (r2) data of the 106 common SNPs are schematically presented in Figure 1. These SNPs reside in non-coding, i.e., intronic or flanking, regions of the gene with one exception: rs1139583 in exon 13 results in the synonymous amino acid exchange Glu418Glu. Among these common HapMap SNPs, 14 SNPs were selected tagging all the other common SNPs within this locus with an r2 >0.8 (100% coverage) by Tagger analysis using Haploview software (http://www.broadinstitute.org/scientific-community/science/programs/medical-and-population-genetics/haploview/haploview). The 14 tagging SNPs were rs12465765 (G/A), rs6543087 (A/T), rs11674694 (C/T), rs11894820 (C/T), rs13003883 (T/A), rs17205284 (C/T), rs4851502 (G/A), rs2236936 (C/G), rs2236935 (A/G), rs17801985 (A/G), rs972372 (G/A), rs3771904 (A/T), rs11678405 (T/C), and rs1003376 (G/C).


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)

Genomic region of human chromosome 2q11.2-q12 harbouring the MAP4K4 gene and HapMap linkage disequilibrium data of common (minor allele frequency >0.05) informative single nucleotide polymorphisms (SNPs) within this region.The MAP4K4 gene consists of 30 exons and 29 introns and spans 196.66 kb from nucleotide position 101,680,920 to nucleotide position 101,877,583. The analysed region additionally included 5 kb of the 5′-flanking region and 3 kb of the 3′-flanking region. This genomic region did not overlap with other known gene loci. The locations of the 14 tagging SNPs (highlighted by flags) are indicated by arrows. Linkage disequilibrium data based on r2 values are given by shadings (white diamonds – low linkage; black diamonds – high linkage; grey diamonds – in between).
© Copyright Policy
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC3475716&req=5

pone-0047647-g001: Genomic region of human chromosome 2q11.2-q12 harbouring the MAP4K4 gene and HapMap linkage disequilibrium data of common (minor allele frequency >0.05) informative single nucleotide polymorphisms (SNPs) within this region.The MAP4K4 gene consists of 30 exons and 29 introns and spans 196.66 kb from nucleotide position 101,680,920 to nucleotide position 101,877,583. The analysed region additionally included 5 kb of the 5′-flanking region and 3 kb of the 3′-flanking region. This genomic region did not overlap with other known gene loci. The locations of the 14 tagging SNPs (highlighted by flags) are indicated by arrows. Linkage disequilibrium data based on r2 values are given by shadings (white diamonds – low linkage; black diamonds – high linkage; grey diamonds – in between).
Mentions: Based on publicly available phase III data of the International HapMap Project derived from Utah residents with Central European (CEU) ancestry (release #28 August 2010, http://hapmap.ncbi.nlm.nih.gov/index.html.en), we screened in silico the complete MAP4K4 gene spanning 196.66 kb (30 exons, 29 introns) on human chromosome 2q11.2-q12 as well as 5 and 3kb of its 5′- and 3′-flanking regions, respectively (Figure 1). Within this locus, 215 informative HapMap SNPs were present with 106 displaying MAFs >0.05. The HapMap linkage disequilibrium (r2) data of the 106 common SNPs are schematically presented in Figure 1. These SNPs reside in non-coding, i.e., intronic or flanking, regions of the gene with one exception: rs1139583 in exon 13 results in the synonymous amino acid exchange Glu418Glu. Among these common HapMap SNPs, 14 SNPs were selected tagging all the other common SNPs within this locus with an r2 >0.8 (100% coverage) by Tagger analysis using Haploview software (http://www.broadinstitute.org/scientific-community/science/programs/medical-and-population-genetics/haploview/haploview). The 14 tagging SNPs were rs12465765 (G/A), rs6543087 (A/T), rs11674694 (C/T), rs11894820 (C/T), rs13003883 (T/A), rs17205284 (C/T), rs4851502 (G/A), rs2236936 (C/G), rs2236935 (A/G), rs17801985 (A/G), rs972372 (G/A), rs3771904 (A/T), rs11678405 (T/C), and rs1003376 (G/C).

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