Genetische Mechanismen der Gewichtsregulation [Elektronische Ressource] : genomweite Ansätze und Kandidatengenstudien / von Susann Friedel

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• Publié par: friedrich-schiller-universitat_jena
• Publié le: 01 janvier 2009
• Nombre de lectures: 25
• Langue: Deutsch
• Poids de l'ouvrage: 1 Mo

Extrait

Genetische Mechanismen der
Gewichtsregulation: genomweite Ansätze und
Kandidatengenstudien





Dissertation
zur Erlangung des akademischen Grades doctor rerum naturalium
(Dr. rer. nat.)


vorgelegt dem Rat der Biologisch-Pharmazeutischen Fakultät
der Friedrich-Schiller-Universität Jena





von
Susann Friedel
Diplom-Ernährungswissenschaftlerin








geboren am 26.05.1978
in Dresden







Genetic mechanisms of body weight regulation:
Genome-wide approaches and candidate gene
studies





Dissertation
for obtaining the degree of doctor rerum naturalium
(Dr. rer. nat.)



at the
Faculty of Biology and Pharmacy, Friedrich-Schiller-University Jena





submitted by
Susann Friedel
Diploma-Trophologist







born on 26.05.1978
in Dresden































Gutachter

Prof. Dr. Michael Ristow, Jena
Prof. Dr. Johannes Hebebrand, Essen
Prof. Dr. Matthias Blüher, Leipzig


Tag der öffentlichen Verteidigung: 16. Juli 2009












































2Für G. Gläser
Indexes

List of contents

1. Introduction 1
1.1 Obesity 1
1.1.1 Definition and classification of obesity 1
1.1.2 Prevalence of obesity 2
1.1.3 Causes of obesity 3
1.1.4 Therapy 4
2. State of the art 6
2.1 Formal genetic findings 6
2.2 Candidate gene studies 8
2.2.1 Dominant forms of monogenic obesity 9
2.2.2 Recessive forms of monogenic obesity 11
2.2.3 Polygenic obesity 13
2.3 Genome-wide approaches 15
2.3.1 Genome-wide linkage analysis 15
2.3.2 Genome-wide association studies 18
2.4 Aims of the study 21
3. Publications 22
3.1 Publication I: Saar K, Geller F, Rüschendorf F, Reis A, Friedel S, 22
Schäuble N, Nürnberg P, Siegfried W, Goldschmidt HP, Schäfer H, Ziegler
A, Remschmidt H, Hinney A, Hebebrand J. Genome scan for childhood
and adolescent obesity in German families. Pediatrics.
2003;111(2):321-7.
3.2 Publication II: Hinney A, Nguyen TT, Scherag A, Friedel S, Brönner G, 30
Müller TD, Grallert H, Illig T, Wichmann HE, Rief W, Schäfer H,
Hebebrand J. Genome wide association (GWA) study for early onset
extreme obesity supports the role of fat mass and obesity associated
gene (FTO) variants. PLoS ONE. 2007 ; 2(12):e1361.
3.3 Publication III: Friedel S, Horro FF, Wermter AK, Geller F, Dempfle A, 36
Reichwald K, Smidt J, Brönner G, Konrad K, Herpertz-Dahlmann B,
Warnke A, Hemminger U, Linder M, Kiefl H, Goldschmidt HP, Siegfried W,
Remschmidt H, Hinney A, Hebebrand J. Mutation screen of the brain
derived neurotrophic factor gene (BDNF): identification of several
genetic variants and association studies in patients with obesity,
eating disorders, and attention-deficit/hyperactivity disorder. Am J
Med Genet B Neuropsychiatr Genet. 2005;132B(1):96-9.
3.4 Publication IV: Friedel S, Antwerpen B, Hoch A, Vogel C, Grassl W, Geller 41
F, Hebebrand J, Hinney A. Glucose transporter 4 gene: association
studies pertaining to alleles of two polymorphisms in extremely
obese children and adolescents and in normal and underweight
controls. Ann N Y Acad Sci.2002;967:554-7.
I Indexes

3.5 Publication V: Friedel S, Reichwald K, Scherag A, Brumm H, Wermter AK, 46
Fries HR, Koberwitz K, Wabitsch M, Meitinger T, Platzer M, Biebermann
H, Hinney A, Hebebrand J. Mutation screen and association studies in
the diacylglycerol O-acyltransferase homolog 2 gene (DGAT2), a
positional candidate gene for early onset obesity on chromosome
11q13. BMC Genet. 2007;8:17.
3.6 Publication VI: Reinehr T, Hebebrand J, Friedel S, Toschke AM, Brumm 56
H, Biebermann H, Hinney A. Lifestyle intervention in obese children
with variations in the melanocortin 4 receptor gene. Accepted for
publication in July 2008
3.7 Publication VII: Hebebrand J, Friedel S, Schäuble N, Geller F, Hinney A. 65
Perspectives: molecular genetic research in human obesity. Obes
Rev. 2003;4(3):139-46.
Summary of the studies and discussion in the context of obesity genetics 4. 74
4.1 Genome-wide approaches to identify chromosomal regions/candidate 74
genes/genetic variants involved in body weight regulation
4.1.1 Identification of chromosomal regions involved in the aetiology of early 75
onset obesity using linkage analysis in 89 families of German origin with
two or more (extremely) obese children
4.1.2 Identification of genetic variants involved in body weight regulation using a 78
genome-wide association study (GWA) for extreme, early onset obesity
4.2 Investigation of candidate genes for obesity 80
4.2.1 Analysis of the role of brain-derived neurotrophic factor precursor gene 80
(BDNF) as a candidate gene for body weight regulation and activity
(Friedel et al., 2005)
4.2.2 Involvement of two single nucleotide polymorphisms (SNPs) of the insulin- 83
responsive glucose transporter 4 gene (GLUT4) in individuals from
different weight extremes (Friedel et al., 2002)
4.2.3 Investigation of Diacylglycerol O-acyltransferase homolog 2 gene 84
(DGAT2) as a positional and functional candidate gene for early onset
obesity (Friedel et al., 2007)
4.3 Investigation of the influence of functional relevant MC4R-variants on weight loss 87
during a lifestyle intervention program (Reinehr et al., in press)
4.4 Perspectives of molecular genetic research in human obesity (Hebebrand et al., 90
2003)
5. Summary and Conclusion/Zusammenfassung und Schlussfolgerungen 94
6. References 98
7. Ehrenwörtliche Erklärung 114
8. Curriculum vitae 115
9. Wissenschaftliche Publikationen und Vorträge 116
10. Danksagung 122

I I Indexes

List of abbreviations
AAR adiposity rebound
ACTH adrenocorticotropin
ADHD attention-deficit/hyperactivity disorder
AGA Arbeitsgemeinschaft Adipositas im Kindes- und Jugendalter
AgRP/AGRP agouti-related protein
AGTL1 angiotensin receptor-like 1
AN anorexia nervosa
BDNF brain derived neurotrophic factor
BMI body mass index
BN bulimia nervosa
CDKN2A/B cyclin-dependent kinase inhibitor 2A/B
CHD coronary heart disease
cM centi Morgan
CNTF ciliary neurotrophic factor
DAG Deutsche Adipositasgesellschaft
db-/- diabetes mouse
DGAT1/2 diacylglycerol acyltransferase 1 and 2
DGI Diabetes Genetics Initiative
dHPLC denaturing high pressure liquid chromatography
DNA deoxyribonucleic acid
ECSP extreme concordant sibpair approach
ENPP1 ectonucleotide pyrophosphatase/phosphodiesterase
FTO fat mass and obesity-associated
GAD2 glutamate decarboxylase 2
GALN galanin
GHSR growth hormone secretagogue receptor
GIST genotype IBD sharing test
GLUT4 glucose transporter 4
GWAS genome wide association study
HBSC Health Behaviour in School-aged Children
IBD identical by descent
INSIG2 insulin induced gene 2
KCTD15 potassium channel tetramerisation domain
GNPDA2 glucosamine-6-phosphate deaminase 2
kg kilogram
KiGGS Kinder- und Jugendgesundheitssurvey
I II Indexes

LD linkage disequilibrium
LOD logarithm of the odds
m meter
MAF minor allele frequency
MAF v-maf musculoaponeurotic fibrosarcoma oncogene
MAPK mitogen-activated protein kinase
MC4R/MC1R melanocortin 4 receptor/ melanocortin 1 receptor
MLB LOD maximum likelihood binomial logarithm of the odd
MSH melanocyte stimulation hormone
MTCH2 mitochondrial carrier homolog 2
MZ monozygotic
NEGR1 neuronal growth regulator 1
NHANES Nutrition Examination Survey
NIDDM non insulin dependent diabetes mellitus
NPC1 Niemann-Pick disease, type C1 precursor
NT4 neurotrphin 4
NTKR2 neurotrophic tyrosine kinase, receptor, type 2
ob-/-ob/ob obese mouse
PC/PCSK prohormonconvertase
PCT percentile
POMC pro-opio