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OBEKON Consortium

OBEKON Consortium. Investigation of the genomic background of obesity using single nucleotide polymorphism analysis in candidate genes. Csaba Szalai, Á gnes F. Semsei, Ildik ó Ungv á ri, Petra Kiszel, P é ter Antal, Andr á s Falus. Genetics of obesity. The majority is multifactorial

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OBEKON Consortium

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  1. OBEKON Consortium Investigation of the genomic background of obesity using single nucleotide polymorphism analysis in candidate genes Csaba Szalai, Ágnes F. Semsei, Ildikó Ungvári, Petra Kiszel, Péter Antal, András Falus CECON II. Budapest

  2. Genetics of obesity • The majority is multifactorial • Concordance in monozygotic twins: 0.7-0.9 • In dizygotic twins: 0.35-0.45 • λs = 3.5 • Heritability rate of fat mass and fat distribution: 40-70% • Food preference, activity etc. • Most associatedgenes expressed in CNS

  3. Aim of the study • What SNPs can contribute to the susceptibility to obesityin the Hungarian population? • Candidate gene association study.

  4. Patients 1337 Hungarian adults(873 women and 464 men) • 838 obese (BMI>30) • 500 controls (BMI<25)

  5. Selection of 55 candidate genes for obesity Some examples of the selected candidate genes

  6. Selection of 120 SNPs in the candidate genes

  7. Genotyping method • Multiplex PCR, single base extension • Beckman GenomeLab SNPstream Genotyping System Extend Detect Anneal

  8. Gedeon Richter Ltd.-Semmelweis University SNP Core facility (http://www.dgci.sote.hu/en ) Beckman GenomeLab SNPstream Genotyping SystemThroughput 4,608 to 800,000 genotypes in 24 hours (12 plex) 18,432 to 3,200,000 genotypes in 24 hours (48 plex)Multiplex level 12 –48 plex PCR and Primer extension

  9. Statistical analysis • Two steps: • Standard statistical methods: logistic regression, chi square • Bayesian Multilevel Analysis

  10. ResultsGenes and SNPs associated with obesity in the whole population (9 SNPs in 6 genes)

  11. Different results in men and women • Only in women: ALOX5, ALOX5AP, ZFP90, ACE, UCP3 • Only in men: HSD11B • In both: FTO

  12. Heritability is gender specific • Girls whose mothers are classified as clinically obese are significantly more likely obese in childhood, with a similar relationship existing between obese fathers and their sons. • Trend does not exist between mothers and their sons and fathers and their daughters

  13. FTO = fat mass and obesity associatedOR = 3.0 (2.1-4.2) P<5x10-10!OR = 0.33 (0.23-0.47) • All obesity GWA identified FTO • Exact function is not known • Expressed in CNS (esp.: hippocampus, cerebellum and hypothalamus) • FTO mutant mice: • reduced fat mass • increased energy expenditure • unchanged physical activity.

  14. ALOX5 OR=1.5 (1.1-1.9); OR = 0.43 (0.,25-0.74) • Synthesis of leukotrienes from arachidonic acid. • Alox5 −/− mice had significantly increased fat mass, plasma leptin levels and fasting glucose levels, but lower fasting insulin levels

  15. IGF2OR = 1.5 (1.1-2.2) • This gene encodes a member of the insulin family of polypeptide growth factors that is involved in development and growth. • It is an imprinted gene and is expressed only from the paternally inherited allele. • It is a candidate gene for eating disorders

  16. Zfp90OR = 1.72 (1.03-2.88) • These preliminary data suggest that Zfp90 may have an uncharacterized role in the regulation of obesity traits. • Mice with extra copies of ZFP90 had higher overall fat levels than wild-type controls. • ZFP90 could be antagonized to treat obesity

  17. Next 50 clinical parameters , 120 SNPs and expression data • Bayesian Multilevel Analysis (BMLA) • BMLA enables the analysis of relevance at different abstraction levels: model-based pairwise relevance, relevance of variable sets, and interaction models of relevant variables.

  18. Summary • Genetic polymorphisms play an important role in the susceptibility of obesity in the Hungarian population. • There are considerable differences between men and women in the genetic background. • Those genes and pathways associated with obesity are potential targets for tailoring therapy for a healthier body weight.

  19. Thank you for your attention!

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