09.04.2009 Doctoral dissertation: Association of tenomodulin gene with obesity and inflammation

Obesity is associated with chronic low-grade inflammation and dysregulations in the endocrinological functions of peripheral tissues, including adipose tissue. It predisposes the individual to chronic diseases, including cardiovascular diseases and type 2 diabetes (T2D), but also to other conditions affecting the quality of life, such as age-related macular degeneration (AMD). Many of the obesity-related conditions exhibit abnormal angiogenesis as a part of the pathophysiology.

Previous studies have demonstrated that long-term weight reduction can change the gene expression profile of adipose tissue in overweight individuals with impaired fasting glucose or impaired glucose tolerance (IGT). In the GENOBIN study, which was performed in the Department of Nutrition and Food and Health Research Centre of University of Kuopio, one of the most downregulated genes was tenomodulin (TNMD). TNMD is located in the X-chromosome and has been shown to inhibit angiogenesis. In her PhD thesis, Anna-Maija Tolppanen investigated the role of TNMD as a susceptibility gene for obesity- and inflammation-related traits.

The association of single nucleotide polymorphisms (SNPs) with obesity and indicators of glucose and lipid metabolism were investigated in 507 overweight individuals with IGT who participated in the Finnish Diabetes Prevention Study (DPS), and in a cross-sectional population-based cohort of middle-aged men (the METSIM study, n=5298). In addition, the association with proinflammatory markers was studied in DPS and the association with AMD in a separate sample of 475 non-diabetic individuals.

Three markers were associated with conversion from IGT to T2D in DPS, but not with the prevalence of T2D in METSIM. The same genotypes that had elevated risk for developing T2D were associated with elevated serum concentrations of inflammation markers in DPS and with higher serum cholesterol concentrations in the obese men of both study populations. In women, the sequence variation of TNMD was associated with serum concentrations of proinflammatory factors, central obesity and prevalence of AMD. The associations with inflammatory mediators were modified by central obesity and the status of glucose metabolism.

In conclusion, these results suggest that the genetic variation of TNMD might be related to the risk for components of metabolic syndrome, a constellation of dyslipidaemia, central obesity, insulin resistance and chronic low-grade inflammation, especially in the high-risk individuals.

The public examination will take place on Saturday the 18th of April at 12 noon in the lecture hall ML 3 of University of Kuopio with PhD Ruth Loos (Medical Research Council, Cambridge, UK) as opponent and Professor Matti Uusitupa (University of Kuopio) as custos.

Suomenkielinen väitöstiedote:
http://www.uku.fi/vaitokset/2009/ISBN978-951-27-1166-6amtolppanen.htm