Association of Common Genetic Variants in the MAP4K4 Locus with Prediabetic Traits in Humans

Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Centre Munich at the University of Tübingen, Tübingen, Germany
PLoS ONE (Impact Factor: 3.23). 10/2012; 7(10):e47647. DOI: 10.1371/journal.pone.0047647
Source: PubMed


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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    • "In this regard, MAP4K4 might prove a worthwhile target. Increased activity of MAP4K4 is associated with TNF-a-dependent disorders in addition to heart failure, like obesity and diabetes (Elbein et al., 2009; Isakson et al., 2009; Sartorius et al., 2012), and many consequences of TNF-a signaling , though importantly, not all, are dependent on MAP4K4 (Bouzakri et al., 2009; Guilherme et al., 2008; Tang et al., 2006; Tesz et al., 2007; Wang et al., 2013). Similarly, in the context of skeletal muscle differentiation , TNF-a is inhibitory, but silencing MAP4K4 only marginally rescued differentiation (Wang et al., 2013). "
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