Studie naar de rol van structurele en DNA sequentie variaties in kandidaatgenen voor obesitas

Datum: 27 november 2017

Locatie: UZA, Auditorium Kinsbergen - Wilrijkstraat 10 - 2650 Edegem

Tijdstip: 16 - 18 uur

Promovendus: Evi Aerts

Promotor: Wim Van Hul, Luc Van Gaal

Korte beschrijving: Doctoraatsverdediging Evi Aerts - Departement Biomedische Wetenschappen



Abstract

The heritability of obesity is generally estimated between 40-70%, indicating that genetic factors play an important role in the aetiology of obesity. So far, only a limited number of monogenic causes of obesity is known, many of which are associated with the leptin-melanocortin pathway. Despite the importance of this pathway, mutations in the genes involved in this pathway account for not more than 5% of all childhood severe obesity cases. For complex obesity, all current risk alleles together capture less than 3% of BMI variation, leaving a substantial proportion of the heritability unexplained. The remaining heritability must be found in other sources of genetic variation. Copy number variation accounts for a major proportion of human genetic variation and it is predicted to play an important role in the genetic susceptibility of common complex diseases. Since 2009, genome-wide CNV analyses have associated numerous CNV regions with early-onset extreme obesity. Further investigation of the genes in these regions might offer novel insights into the genetic architecture of obesity. The aim of this PhD research was to clarify the role of 6 selected candidate genes in the pathogenesis of obesity by mutation and CNV screening.

In the first part of this thesis, we focused on SH2B1 and the distal SH2B1-encompassing chr.16p11.2 CNV region. Based on the equal frequency of SH2B1 variants that we found among obese and lean individuals, it seems unlikely that genetic variation in this gene contributes majorly to the development of non-syndromic obesity.

In the second part, we investigated the role of NPY and its receptors (NPY2R and NPY4R) in the pathogenesis of obesity. In contrast to the study of NPY and NPY2R, the results of our NPY4R analysis indicate that NPY4R is a very important risk factor for obesity. For this gene we were able to demonstrate that the presence of structural and single-base variation within NPY4R at least partially explains the obese phenotype of 3.7% and 0.6% of our patient population, respectively.

In the third part of this thesis, we were able to confirm the link between obesity and genetic variation in FGF21 and UCP1, two key regulators of brown and beige adipogenesis.

In conclusion, we identified new and possibly pathogenic mutations and we implicated NPY4R as a new important risk factor for obesity. These results help in understanding the involvement of these genes in the pathogenesis of obesity.



Url: https://www.uantwerpen.be/nl/faculteiten/faculteit-fbd/onderzoek/doctoraatsverdedigen/