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 CECON II. Budapest

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.

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.

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.

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

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

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

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.

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

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

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)

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

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

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

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

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

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

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

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

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

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

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

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