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Obesity: genetic update by CGH analysis and its potential clinical implications

OBEKON Consortium. Obesity: genetic update by CGH analysis and its potential clinical implications. Viola Tamási and András Falus Semmelweis University, Faculty of Medicine, Department of Genetics, Cell- and Immunobiology, H-1445 Budapest, POB. 370., Hungary. O B E K O N Consortium.

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Obesity: genetic update by CGH analysis and its potential clinical implications

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  1. OBEKON Consortium Obesity: genetic update by CGH analysis and its potential clinical implications Viola Tamási and András Falus Semmelweis University, Faculty of Medicine, Department of Genetics, Cell- and Immunobiology, H-1445 Budapest, POB. 370., Hungary CECON II. Budapest

  2. O B E K O N Consortium Obesity rate in the USA National Institute of Diabetes & Digestive & Kidney Diseases (NIDDK),WebMD.com, Center for Disease Control.

  3. O B E K O N Consortium Obesity rate in the USA National Institute of Diabetes & Digestive & Kidney Diseases (NIDDK),WebMD.com, Center for Disease Control.

  4. O B E K O N Consortium Obesity rate in the USA National Institute of Diabetes & Digestive & Kidney Diseases (NIDDK),WebMD.com, Center for Disease Control.

  5. O B E K O N Consortium Obesity rate in the USA National Institute of Diabetes & Digestive & Kidney Diseases (NIDDK),WebMD.com, Center for Disease Control.

  6. O B E K O N Consortium Obesity rate in the USA National Institute of Diabetes & Digestive & Kidney Diseases (NIDDK),WebMD.com, Center for Disease Control.

  7. O B E K O N Consortium Obesity rate in the USA National Institute of Diabetes & Digestive & Kidney Diseases (NIDDK),WebMD.com, Center for Disease Control.

  8. O B E K O N Consortium Obesity rate in the USA National Institute of Diabetes & Digestive & Kidney Diseases (NIDDK),WebMD.com, Center for Disease Control.

  9. O B E K O N Consortium Obesity rate in the USA National Institute of Diabetes & Digestive & Kidney Diseases (NIDDK),WebMD.com, Center for Disease Control.

  10. O B E K O N Consortium Obesity rate in the USA National Institute of Diabetes & Digestive & Kidney Diseases (NIDDK),WebMD.com, Center for Disease Control.

  11. O B E K O N Consortium Obesity is a risk factor for many diseases Epigenetic factors, enviroment • Osteoartritis • Cardiovascular disease • Gastrointestinal disease • Metabolic syndrome • Cancer • Psychiatric disease Obesity Genetic factors Not all people are affected equally by our unhealthy lifestyles; some are protected from the deleterious obesogenic enviroment whereas others carry genevariants rendering them particulary sense of it.

  12. O B E K O N Consortium So What Is the Evidence that Genes AreInvolved at All? • Twin studies • Measures of adiposity in geneticly related subjects (in family): skinfold thickness, waist circumference, and total and regional fat distribution Around 70% of the individual variation in adiposity between people is apparently due to genetic factors.

  13. O B E K O N Consortium Etology of genetic obesity • Non-syndromic obesity: Monogenic obesity (one gene is mutated) Polygenic obesity (more genes are mutated) • Syndromic obesity

  14. O B E K O N Consortium Monogenic obesity -the leptin-melanocortin pathway Monogenic dominant MC4-R Monogenic recessive Leptin Leptin-R POMC PC-1

  15. O B E K O N Consortium Monogenic obesity - genetic addiction to food TaqIA mutations Decreased D2DR People need to eat more food to get the same sense of reward

  16. O B E K O N Consortium Genetic Obesity Syndromes Prader-Willi: Visual problems (PWS, 15q del) Bardet Biedl: Poor muscle tone, low levels of sex hormones, hunger,(BBS, 15) Ablstrom: Hearing loss, blindness (ALMS1 mut.) Cohen: Developmental delay, intellectual disability, microcephaly (BFLS, PHD finger protein 6 splicing mut.) Carpenter: Craniofacial malformations, syndactyly (8q22, COH1 mut.) defect in the primary cilium: defect in communication The role this disruption in communication plays in these obesity syndromes is not fully understood, but the association is noted.

  17. O B E K O N Consortium CGH- a method to investigate chromosomal abnormalities

  18. O B E K O N Consortium Genome scans in obese families from several ethnic groups have identified common regions linked to obesity Regions of the genome linked to obesity-related phenotypes in six different populationsfrom Mutch DM, Clément K. Unraveling the genetics of human obesity. PLosGenet 2006;2(12):e188

  19. O B E K O N Consortium CGH studies within the OBEKON project • Samples: Obese subjects (BMI>30, 5 male and 5 female) who are obese from early childhood, and whose obesity could be inherited from parents were included in this study. • Methods: Tissue digestion, labeling, hybridization, and data analysis of genomic DNA were performed according to the Agilent Technologies protocol version 2.0 for 105 K arrays. For data analysis, DNA Analytics software (version 4.0.85) was used. The starting and ending points of the aberrations were confirmed by the ADM-2 algorithm with 6.0 threshold (p<0.05). • Control DNA: Promega Female/Male control (Cat. # G1521, G1471)

  20. O B E K O N Consortium Number and size of the common aberrant regions 40 02 October 2009 CECON II. Budapest 20

  21. O B E K O N Consortium Number and size of the common aberrant regions 33 5 2 40 02 October 2009 CECON II. Budapest 21

  22. O B E K O N Consortium Number and size of the common aberrant regions 33 28 5 2 40 02 October 2009 CECON II. Budapest 22

  23. O B E K O N Consortium Number and size of the common aberrant regions 33 28 5 2 40 15 7 6 02 October 2009 CECON II. Budapest 23

  24. O B E K O N Consortium Number and size of the common aberrant regions 33 14 28 5 2 40 15 7 6 8 4 2 02 October 2009 CECON II. Budapest 24

  25. O B E K O N Consortium Number and size of the common aberrant regions 33 14 28 5 2 40 15 7 6 8 4 2 02 October 2009 CECON II. Budapest 25

  26. O B E K O N Consortium Chromosomal position of common aberrations found in all of the obese subjects Gain Loss 26 02 October 2009 CECON II. Budapest

  27. Genes found on the commonly aberrated regions O B E K O N Consortium Chromosome 11 CCDC15:Coiled-coil domain containing 15 SLC37A2:Solute carrier family 37 (glycerol-3-phosphate transporter), member 2 Chromosome 20 MYBL2V:myb myeloblastosis viral oncogene homolog (avian)-like 2 GTSF1L: Gametocyte specific factor 1-like TOX2: TOX high mobility group box family member 2 Chromosome 3 TTLL3: tubulin tyrosine ligase-like family, member 3 Chromosome 4 AFAP1: actin filament associated protein 1 Chromosome 5 MCC: mutated in colorectal cancers Chromosome 6 LYRM4: LYR motif containing 4 FARS2: Phenylalanyl-tRNA synthetase 2, mitochondrial 02 October 2009 CECON II. Budapest 27

  28. Genes found on the commonly aberrated regions O B E K O N Consortium Chromosome 11 CCDC15:Coiled-coil domain containing 15 SLC37A2:Solute carrier family 37 (glycerol-3-phosphate transporter), member 2 Chromosome 20 MYBL2V:myb myeloblastosis viral oncogene homolog (avian)-like 2 GTSF1L: Gametocyte specific factor 1-like TOX2: TOX high mobility group box family member 2 Chromosome 3 TTLL3: tubulin tyrosine ligase-like family, member 3 Chromosome 4 AFAP1: actin filament associated protein 1 Chromosome 5 MCC: mutated in colorectal cancers Chromosome 6 LYRM4: LYR motif containing 4 FARS2: Phenylalanyl-tRNA synthetase 2, mitochondrial 02 October 2009 CECON II. Budapest 28

  29. SPX; Sugar-phosphate-Channel exchanger Family O B E K O N Consortium Localized in ER membrane Function: involved in sugar metabolism Genetic abnormalities and diseases: SPX1: highly polymorphic, triplicated in Down syndrome SPX2, SPX3: no related genetic deseases SPX4: Mutations related to Glycogen Storage Diseases (GPD) SPX2: highly expressed in macrophages present in obese WAT 02 October 2009 CECON II. Budapest 29

  30. Conclusions O B E K O N Consortium • A total of 82 potential aberration regions were found with array CGH analysis, which are present in at least 80% of the subjects. • From that 14 aberrations are present in all obese subjects. • On these regions 10 genes could be related to obesity (CCDC15, SLC37A2, MYBL2V, GTSF1L, TOX2, TTLL3, AFAP1,MCC, LYRM4, FARS2). • Based on present knowladge, SPX2 (SLC37A2), a member of sugar-phosphate - channel exchanger family could be important in obesity. 02 October 2009 CECON II. Budapest 30

  31. References: • Redon R, Ishikawa S, Fitch KR, Feuk L, Perry GH, Andrews TD, Fiegler H, Shapero MH, Carson AR, Chen W, Cho EK, Dallaire S, Freeman JL, González JR, Gratacòs M, Huang J, Kalaitzopoulos D, Komura D, Macdonald JR, Marshall CR, Mei R, Montgomery L, Nishimura K, Okamura K, Shen F, Somerville MJ, Tchinda J, Valsesia A, Woodwark C, Yang F, Zhang J, Zerjal T, Zhang J, Armengol L, Conrad DF, Estivill X, Tyler-Smith C, Carter NP, Aburatani H, Lee C, Jones KW, Scherer SW, Hurles ME. Global variation in copy number in the human genome Nature 444, 444-454 (23 November 2006). • S. Ichihara, Y. Yamada. Genetic factors for human obesity.Cell. Mol. Life Sci. 65 (2008) 1086 – 1098. • Goldstone A, Beales P. Genetic Obesity Syndromes. Front Horm Res. Basel, Karger, 2008, vol 36, pp 37-60. • Kim JY, Tillison K, Zhou S, Wu Y, Smas CM. The major facilitator superfamily member Slc37a2 is a novel macrophage- specific gene selectively expressed in obese white adipose tissue. Am J Physiol Endocrinol Metab. 2007 Jul;293(1):E110-20. • Bartoloni L, Antonarakis SE. The human sugar-phosphate/phosphate exchanger family SLC37. Pflugers Arch. 2004 Feb;447(5):780-3. Epub 2003 Jun 17.

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