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.
OBJECTIVE
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 non-obese women (98 cases, 626 non-cases; p for BMI interaction 0.0002).


CONCLUSIONS
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.
Herder
C
C
Institute for Clinical Diabetes Research, German Diabetes Centre, Leibniz Centre at Heinrich Heine University, Dusseldorf, Germany.
Klopp
N
N
Baumert
J
J
Müller
M
M
Khuseyinova
N
N
Meisinger
C
C
Martin
S
S
Illig
T
T
Koenig
W
W
Thorand
B
B
D015331:Cohort Studies; D003924:Diabetes Mellitus, Type 2 / Q000097:blood* / Q000453:epidemiology / Q000235:genetics*; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D005838:Genotype; D005858:Germany / Q000453:epidemiology; D006801:Humans; D008263:Macrophage Migration-Inhibitory Factors / Q000097:blood* / Q000235:genetics*; D008297:Male; D020641:Polymorphism, Single Nucleotide; D012307:Risk Factors
D008263:Macrophage Migration-Inhibitory Factors
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