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.

OBJECTIVE: Upstream transcription factor 1 (USF1) regulates genes of glucose and lipid metabolism. Polymorphisms in the USF1 gene showed association with familial combined hyperlipidemia and lipid parameters. The aim of our study was to examine the associations between USF1 polymorphisms and lipid parameters as well as incident type 2 diabetes mellitus (T2DM) in German Caucasians. DESIGN: We genotyped eight polymorphisms in the USF1 gene in 2067 middle-aged (35-74 years) individuals including 498 incident T2DM cases and 1569 non-cases of the population-based case-cohort study from the MONICA/KORA Augsburg project. METHODS: Six polymorphisms and their haplotypes were analyzed using multivariable linear regression and Cox proportional hazards models. RESULTS: Polymorphism rs3737787 was inversely associated with incident T2DM in women with decreased risk for female heterozygotes compared with women homozygous for the major allele (Hazard ratio=0.57; 95% confidence intervals: 0.38-0.87; P=0.008). After correction for multiple testing, significance remained. Polymorphisms rs3813609 and rs1556259 were significantly associated with reduction in low-density lipoprotein (LDL) cholesterol (p(NOM)=0.001; p(NOM)=0.00002) in women. Analyses also indicated associations of haplotypes with LDL cholesterol in women, but the association lost statistical significance after correction for multiple testing. Total serum cholesterol (TC) and high-density lipoprotein (HDL) cholesterol were weakly associated (P<0.05) with USF1 polymorphisms in women. No significant associations were found in men. CONCLUSIONS: In this large population-based study, statistically significant associations of USF1 polymorphisms with incident T2DM and LDL cholesterol were found in women, but not in men. Genetic variants in the USF1 gene showed weak or no associations with TC and HDL cholesterol.

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.

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 non-obese 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.

Systemic low-grade inflammation and risk of coronary heart disease: results from the MONICA/KORA Augsburg cohort studies.

Atherosclerosis is characterised by a non-specific local inflammatory process accompanied by a systemic response. A number of prospective studies in initially healthy subjects and in patients with manifest atherosclerosis have now convincingly demonstrated a strong and independent association between even slightly elevated concentrations of various systemic markers of inflammation (plasma viscosity, C-reactive protein [CRP], and other acute phase reactants) and a number of cardiovascular endpoints. Presently, CRP, the classical acute phase protein, seems to be the marker of choice for the clinical situation. Initial evidence suggests that measurement of CRP adds to global risk assessment based on the Framingham risk score. The recent AHA/CDC consensus report recommends the measurement of CRP in asymptomatic subjects at intermediate risk for future coronary events (10-year risk of 10-20 %) and in selected patients after an acute coronary syndrome. Whether CRP shall alter treatment strategies in subjects without clinically manifest atherosclerosis is presently being tested in a large randomised clinical trial. In addition, recent research has suggested that CRP may not only be a risk marker, but may be directly involved in the pathogenesis of atherothrombosis. However, there are other emerging biomarkers. Lipoprotein-associated phospholipase A (2) (Lp-PLA (2)), an enzyme produced by monocytes/macrophages, T-cells and mast cells was found to generate proinflammatory and proatherogenic molecules from oxidised LDL. We tested the association of these new biomarkers with traditional risk factors and their ability to predict incident coronary events, using the MONICA/KORA database.

[Moderate alcohol consumption and plasma concentration of sensitive markers of inflammation. Comment on an atheroprotective relationship]. / Moderater Alkoholkonsum und Plasmakonzentration sensitiver Entzündungsmarker. Hinweise auf einen atheroprotektiven Zusammenhang.

BACKGROUND AND OBJECTIVE: Changes in lipoproteins and hemostasis only incompletely explain the reduced cardiovascular mortality associated with light to moderate alcohol consumption. Since increasing evidence suggests that atherosclerosis can be considered to be a chronic inflammatory process, we sought to assess the association between daily alcohol consumption and levels of sensitive markers of inflammation. STUDY PARTICIPANTS AND METHODS: 478 voluntary blood donors (358 men, 120 women) aged 40 to 68 years were categorized into four groups according to their self-reported amount of daily alcohol consumption: 0 g/day, >0 - 20 g/day, >20 - 40 g/day, and > 40 g/day. Means of various sensitive markers of inflammation (C-reactive protein (CRP), serum amyloid A (SAA), interleukin-6 (IL-6), intercellular adhesion molecule-1, plasma viscosity und albumin) were calculated and compared by bivariate and multivariate analyses. RESULTS: More than 80 % of the study participants reported to consume alcohol, mainly beer. We found statistically significantly decreased levels of SAA, CRP, and plasma viscosity in subjects with light-to-moderate alcohol intake (>0 - 20 g/day and > 20 - 40 g/day, respectively), and a trend for increased levels of albumin in these subjects compared to non-drinkers. After multivariable adjustment for potential confounders (age, gender, body mass index, cigarette smoking, years of school education, and physical activity) a significant U-shaped association (p = 0.02) between levels of SAA and the amount of daily alcohol intake remained: there were 0.75 mg/l and 0.70 mg/l lower mean levels, respectively, of SAA in subjects with light-to-moderate alcohol intake compared to those of non-drinkers. Subjects with an alcohol intake of > 40 grams per day showed a statistically significant increase in levels of interleukin-6 (0.50 pg/ml) compared to non-drinkers. CONCLUSION: Potential anti-inflammatory properties of moderate alcohol consumption might represent an additional mechanism to explain its atheroprotective effect.