Effect of macrophage migration inhibitory factor (MIF) gene variants and MIF serum concentrations on the risk of type 2 diabetes: results from the MONICA/KORA Augsburg Case–Cohort Study, 1984–2002

Abstract

Aims/hypothesis Macrophage migration inhibitory factor (MIF) is a central mediator of innate immunity. Our aim was to investigate the triangular association between MIF genotypes, circulating MIF concentrations and incident type 2 diabetes, and to use a Mendelian randomisation approach to assess the causal role of MIF. Methods Using a case-cohort design within the population-based MONICA/KORA Augsburg Study, based on 502 individuals with incident type 2 diabetes (293 men, 209 women) and 1,632 non-cases (859 men, 773 women), we determined MIF serum levels at baseline and genotyped four MIF single nucleotide polymorphisms (SNPs). Results The C allele of SNP rs1007888 (3.8 kb 3′ of the translation termination codon) was associated with increased circulating MIF. MIF genotype rs1007888CC was associated with an increased risk of type 2 diabetes in women [hazard ratio (95% CI) 1.74 (1.02-2.97)], but not in men [1.17 (0.75-1.81)]. Elevated MIF serum levels were associated with higher type 2 diabetes risk also only in women [HR (95% CI) 1.95 (1.15-3.29) comparing extreme quartiles after multiple adjustment], but not in men (p for interaction 0.039). The association between MIF levels and incident type 2 diabetes was significantly higher in obese women (111 cases, 147 non-cases) compared with nonobese women (98 cases, 626 non-cases; p for BMI interaction 0.0002). Conclusions/interpretation The consistent triangular relationship between genotypes, serum levels and incident type 2 diabetes in women indicates that MIF may play a causal role in the aetiology of type 2 diabetes and that elevated MIF levels confer a higher disease risk.

Genetic variants in the USF1 gene are associated with low-density lipoprotein cholesterol levels and incident type 2 diabetes mellitus in women: results from the MONICA/KORA Augsburg case–cohort study, 1984–2002

“…On this source population, we applied a case-cohort study consisting of a random sample (called subcohort; nZ1885) of the source population stratified by sex and survey, and all incident T2DM cases (nZ555) in the source population diagnosed up to December 31, 2002 as it was described more detailed previously (31,(35)(36)(37).…”

Anti-inflammatory effect of lifestyle changes in the Finnish Diabetes Prevention Study

“…Prospective studies have demonstrated that elevated circulating concentrations of several acute-phase proteins, cytokines, chemokines and soluble adhesion molecules precede the development of type 2 diabetes by many years [8][9][10][11][12][13][14]. Among these immune mediators, C-reactive protein (CRP) and IL-6 have been investigated for potential associations with incident type 2 diabetes in most prospective studies.…”

Macrophage migration inhibitory factor deficiency leads to age-dependent impairment of glucose homeostasis in mice

“…While most of these studies were performed in the setting of stress, several reports have also documented an association between MIF, obesity, and insulin resistance (IR) in a physiological environment. MIF secretion and serum concentration are increased in obese individuals or in patients with type 2 diabetes (Church et al 2005, Skurk et al 2005, Herder et al 2008, and a polymorphism in the MIF gene promoter has been linked to obesity (Sakaue et al 2006). In addition, several reports have described that an elevated level of MIF is associated with decreased b-cell function and IR (Benigni et al 2000, Church et al 2005, Sakaue et al 2006).…”