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

31
Obesity: genetic update by CGH analysis and its potential clinical implications OBEKON OBEKON Consortium 02 October 2009 1 CECON II. Budapest Viola Tamási and András Falus Semmelweis University, Faculty of Medicine, Department of Genetics, Cell- and Immunobiology, H-1445 Budapest, POB. 370., Hungary

description

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. - PowerPoint PPT Presentation

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

Page 1: Obesity: genetic update by CGH analysis and its potential clinical implications

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

OBEKONOBEKONConsortium

02 October 2009 1CECON II. Budapest

Viola Tamási and András FalusSemmelweis University, Faculty of Medicine, Department of Genetics, Cell- and Immunobiology, H-1445

Budapest, POB. 370., Hungary

Page 2: Obesity: genetic update by CGH analysis and its potential clinical implications

Obesity rate in the USAObesity rate in the USA

National Institute of Diabetes & Digestive & Kidney Diseases (NIDDK),WebMD.com, Center for Disease Control.

O B E K O NO B E K O NConsortium

Page 3: Obesity: genetic update by CGH analysis and its potential clinical implications

National Institute of Diabetes & Digestive & Kidney Diseases (NIDDK),WebMD.com, Center for Disease Control.

Obesity rate in the USAObesity rate in the USA

O B E K O NO B E K O NConsortium

Page 4: Obesity: genetic update by CGH analysis and its potential clinical implications

National Institute of Diabetes & Digestive & Kidney Diseases (NIDDK),WebMD.com, Center for Disease Control.

Obesity rate in the USAObesity rate in the USA

O B E K O NO B E K O NConsortium

Page 5: Obesity: genetic update by CGH analysis and its potential clinical implications

National Institute of Diabetes & Digestive & Kidney Diseases (NIDDK),WebMD.com, Center for Disease Control.

Obesity rate in the USAObesity rate in the USA

O B E K O NO B E K O NConsortium

Page 6: Obesity: genetic update by CGH analysis and its potential clinical implications

National Institute of Diabetes & Digestive & Kidney Diseases (NIDDK),WebMD.com, Center for Disease Control.

Obesity rate in the USAObesity rate in the USA

O B E K O NO B E K O NConsortium

Page 7: Obesity: genetic update by CGH analysis and its potential clinical implications

National Institute of Diabetes & Digestive & Kidney Diseases (NIDDK),WebMD.com, Center for Disease Control.

Obesity rate in the USAObesity rate in the USA

O B E K O NO B E K O NConsortium

Page 8: Obesity: genetic update by CGH analysis and its potential clinical implications

National Institute of Diabetes & Digestive & Kidney Diseases (NIDDK),WebMD.com, Center for Disease Control.

Obesity rate in the USAObesity rate in the USA

O B E K O NO B E K O NConsortium

Page 9: Obesity: genetic update by CGH analysis and its potential clinical implications

National Institute of Diabetes & Digestive & Kidney Diseases (NIDDK),WebMD.com, Center for Disease Control.

Obesity rate in the USAObesity rate in the USA

O B E K O NO B E K O NConsortium

Page 10: Obesity: genetic update by CGH analysis and its potential clinical implications

National Institute of Diabetes & Digestive & Kidney Diseases (NIDDK),WebMD.com, Center for Disease Control.

Obesity rate in the USAObesity rate in the USA

O B E K O NO B E K O NConsortium

Page 11: Obesity: genetic update by CGH analysis and its potential clinical implications

Obesity is a risk factor for many diseasesObesity is a risk factor for many diseases

Osteoartritis Cardiovascular disease Gastrointestinal disease Metabolic syndrome CancerPsychiatric disease

Epigenetic factors, enviroment

Genetic factors

Obesity

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 NO B E K O NConsortium

Page 12: Obesity: genetic update by CGH analysis and its potential clinical implications

So What Is the Evidence that Genes AreSo What Is the Evidence that Genes AreInvolved at All?Involved 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 NO B E K O NConsortium

Page 13: Obesity: genetic update by CGH analysis and its potential clinical implications

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 NO B E K O NConsortium

Page 14: Obesity: genetic update by CGH analysis and its potential clinical implications

Monogenic obesity Monogenic obesity -- the leptin-melanocortin pathwaythe leptin-melanocortin pathway

Monogenic dominant

MC4-R

Monogenic recessive

Leptin

Leptin-R

POMC

PC-1

O B E K O NO B E K O NConsortium

Page 15: Obesity: genetic update by CGH analysis and its potential clinical implications

Monogenic obesity - Monogenic obesity - genetic addiction to foodgenetic addiction to food

TaqIA mutations

People need to eat more food to get the same sense of reward

Decreased D2DR

O B E K O NO B E K O NConsortium

Page 16: Obesity: genetic update by CGH analysis and its potential clinical implications

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 NO B E K O NConsortium

Page 17: Obesity: genetic update by CGH analysis and its potential clinical implications

O B E K O NO B E K O NConsortium

CGH- a method to investigate chromosomal abnormalities

Page 18: Obesity: genetic update by CGH analysis and its potential clinical implications

Genome scans in obese families from several ethnic groups have Genome scans in obese families from several ethnic groups have identified common regions linked to obesityidentified 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 NO B E K O NConsortium

Page 19: Obesity: genetic update by CGH analysis and its potential clinical implications

CGH studies within the OBEKON projectCGH 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 NO B E K O NConsortium

Page 20: Obesity: genetic update by CGH analysis and its potential clinical implications

O B E K O NO B E K O NConsortium

02 October 2009 20CECON II. Budapest

0%

20%

40%

60%

80%

100%

1

Present in 100% ofsubjects

Present in 90% ofsubjects

Present in 80% ofsubjects

40

Number and size of the common aberrant regionsNumber and size of the common aberrant regions

Page 21: Obesity: genetic update by CGH analysis and its potential clinical implications

O B E K O NO B E K O NConsortium

02 October 2009 21CECON II. Budapest

0%

20%

40%

60%

80%

100%

1

Present in 100% ofsubjects

Present in 90% ofsubjects

Present in 80% ofsubjects

05

1015

2025

3035

<1 Kb 1-100 Kb >100 Kb40

33

5 2

Number and size of the common aberrant regionsNumber and size of the common aberrant regions

Page 22: Obesity: genetic update by CGH analysis and its potential clinical implications

O B E K O NO B E K O NConsortium

02 October 2009 22CECON II. Budapest

0%

20%

40%

60%

80%

100%

1

Present in 100% ofsubjects

Present in 90% ofsubjects

Present in 80% ofsubjects

05

1015

2025

3035

<1 Kb 1-100 Kb >100 Kb

28

40

33

5 2

Number and size of the common aberrant regionsNumber and size of the common aberrant regions

Page 23: Obesity: genetic update by CGH analysis and its potential clinical implications

O B E K O NO B E K O NConsortium

02 October 2009 23CECON II. Budapest

0%

20%

40%

60%

80%

100%

1

Present in 100% ofsubjects

Present in 90% ofsubjects

Present in 80% ofsubjects

05

1015

2025

3035

<1 Kb 1-100 Kb >100 Kb

0

5

10

15

20

<1 Kb 1-100 Kb >100 Kb

28

40

33

5 2

67

15

Number and size of the common aberrant regionsNumber and size of the common aberrant regions

Page 24: Obesity: genetic update by CGH analysis and its potential clinical implications

O B E K O NO B E K O NConsortium

02 October 2009 24CECON II. Budapest

0%

20%

40%

60%

80%

100%

1

Present in 100% ofsubjects

Present in 90% ofsubjects

Present in 80% ofsubjects

05

1015

2025

3035

<1 Kb 1-100 Kb >100 Kb

0

5

10

15

20

<1 Kb 1-100 Kb >100 Kb

0

2

4

6

8

10

<1 Kb 1-100 Kb >100 Kb

14

28

40

33

5 2

67

15

8

42

Number and size of the common aberrant regionsNumber and size of the common aberrant regions

Page 25: Obesity: genetic update by CGH analysis and its potential clinical implications

O B E K O NO B E K O NConsortium

02 October 2009 25CECON II. Budapest

0%

20%

40%

60%

80%

100%

1

Present in 100% ofsubjects

Present in 90% ofsubjects

Present in 80% ofsubjects

05

1015

2025

3035

<1 Kb 1-100 Kb >100 Kb

0

5

10

15

20

<1 Kb 1-100 Kb >100 Kb

0

2

4

6

8

10

<1 Kb 1-100 Kb >100 Kb

14

28

40

33

5 2

67

15

8

42

Number and size of the common aberrant regionsNumber and size of the common aberrant regions

Page 26: Obesity: genetic update by CGH analysis and its potential clinical implications

O B E K O NO B E K O NConsortium

02 October 2009 26CECON II. Budapest

Gain

Loss

Chromosomal position of common aberrations found in all of the obese subjectsChromosomal position of common aberrations found in all of the obese subjects

Page 27: Obesity: genetic update by CGH analysis and its potential clinical implications

Genes found on the commonly aberrated regions

O B E K O NO B E K O NConsortium

02 October 2009 27CECON II. Budapest

Chromosome 11CCDC15: Coiled-coil domain containing 15 SLC37A2: Solute carrier family 37 (glycerol-3-phosphate transporter), member 2

Chromosome 20MYBL2V: myb myeloblastosis viral oncogene homolog (avian)-like 2 GTSF1L: Gametocyte specific factor 1-like TOX2: TOX high mobility group box family member 2

Chromosome 3TTLL3: tubulin tyrosine ligase-like family, member 3

Chromosome 4AFAP1: actin filament associated protein 1

Chromosome 5MCC: mutated in colorectal cancers

Chromosome 6LYRM4: LYR motif containing 4FARS2: Phenylalanyl-tRNA synthetase 2, mitochondrial

Page 28: Obesity: genetic update by CGH analysis and its potential clinical implications

Genes found on the commonly aberrated regions

O B E K O NO B E K O NConsortium

02 October 2009 28CECON II. Budapest

Chromosome 11CCDC15: Coiled-coil domain containing 15 SLC37A2: Solute carrier family 37 (glycerol-3-phosphate transporter), member 2

Chromosome 20MYBL2V: myb myeloblastosis viral oncogene homolog (avian)-like 2 GTSF1L: Gametocyte specific factor 1-like TOX2: TOX high mobility group box family member 2

Chromosome 3TTLL3: tubulin tyrosine ligase-like family, member 3

Chromosome 4AFAP1: actin filament associated protein 1

Chromosome 5MCC: mutated in colorectal cancers

Chromosome 6LYRM4: LYR motif containing 4FARS2: Phenylalanyl-tRNA synthetase 2, mitochondrial

Page 29: Obesity: genetic update by CGH analysis and its potential clinical implications

SPX; Sugar-phosphate-Channel exchanger Family

O B E K O NO B E K O NConsortium

02 October 2009 29CECON II. Budapest

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)

Function: involved in sugar metabolism

SPX2: highly expressed in macrophages present in obese WAT

Localized in ER membrane

Page 30: Obesity: genetic update by CGH analysis and its potential clinical implications

Conclusions

O B E K O NO B E K O NConsortium

02 October 2009 30CECON II. Budapest

• 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.

Page 31: Obesity: genetic update by CGH analysis and its potential clinical implications

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.