title: Association of common genetic variants in the MAP4K4 locus with prediabetic traits in humans.
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.
authors.affiliation: Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Centre Munich at the University of Tübingen, Tübingen, Germany.
authors.forename: Tina
authors.initials: T
authors.lastname: Sartorius
authors.forename: Harald
authors.initials: H
authors.lastname: Staiger
authors.forename: Caroline
authors.initials: C
authors.lastname: Ketterer
authors.forename: Martin
authors.initials: M
authors.lastname: Heni
authors.forename: Fausto
authors.initials: F
authors.lastname: Machicao
authors.forename: Adilson
authors.initials: A
authors.lastname: Guilherme
authors.forename: Harald
authors.initials: H
authors.lastname: Grallert
authors.forename: Matthias B
authors.initials: MB
authors.lastname: Schulze
authors.forename: Heiner
authors.initials: H
authors.lastname: Boeing
authors.forename: Norbert
authors.initials: N
authors.lastname: Stefan
authors.forename: Andreas
authors.initials: A
authors.lastname: Fritsche
authors.forename: Michael P
authors.initials: MP
authors.lastname: Czech
authors.forename: Hans-Ulrich
authors.initials: HU
authors.lastname: Häring
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D015992:Body Mass Index; D016207:Cytokines / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D005260:Female; D015870:Gene Expression; D056426:Genetic Loci; D018149:Glucose Intolerance / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D006801:Humans; D007328:Insulin / Q000378:metabolism; D007333:Insulin Resistance; D050417:Insulin-Secreting Cells / Q000201:enzymology* / Q000473:pathology; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics* / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D011236:Prediabetic State / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D011446:Prospective Studies; D017346:Protein Serine-Threonine Kinases / Q000235:genetics* / Q000378:metabolism; D012307:Risk Factors; D015398:Signal Transduction
chemical_list: D016207:Cytokines; D007328:Insulin; D047908:Intracellular Signaling Peptides and Proteins; C117090:MAP4K4 protein, human; D017346:Protein Serine-Threonine Kinases