Download Genetic Considerations - Pennington Biomedical Research Center

Obesity and Genes
Recent Developments
Pennington Biomedical
Research Center
Overview
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Genetic basis for obesity
The obesity epidemic
The discovery of the obesity genes
Monogenic obesity
Associations with obesity
Animal models of obesity
Conclusions
2008
--The
Human Obesity Gene Map
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Obesity
Influenced in the following ways:
 Type of food consumed
 Environmental factors
 Individual response to food and
physical activity
2008
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The Obesity epidemic
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Due to permissive genes and
the environment.
2008reviews (2007) 8 (Suppl. 1)
Obesity
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The Obesity epidemic
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Obesity is very heritable.
It is an interplay between:
Food intake, and
 Physical activity
How your body uses/acquires food and expends energy
determines our weight.
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2008
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The Discovery of the Obesity genes
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2008
Once genes are identified that are linked to
obesity, treatment can begin.
Some may have defective genes and providing the
missing protein will be effective in treating obesity.
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The Discovery of the Obesity genes
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2008
Certain molecules may control energy balance that
will be targeted for treatment.
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The Discovery of the Obesity genes
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2008
Some individuals may benefit from specific diets
and/or exercise regimes, drugs or surgery to
prevent obesity.
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Obesity due to genetic disorders
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2008
Helped to de-stigmatize human obesity
Seen as a biomedical disorder and not simply a moral
frailty.
Has led to dramatically successful therapy in a few
individuals.
One gene mutation, the melanocortin 4 receptor, may
be responsible for tens of thousands of cases of
obesity.
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Monogenic obesity
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2008
Monogenic = genetic defect in one gene
This type of genetic mutation can result in severe
forms of obesity that run in families.
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Monogenic obesity
As of now, obesity due to genetic changes is due to:
 Defect is in the satiety centers in the brain.
 Affects appetite control centers in the brain.
Obesity is not due to ‘slow metabolism’.
2008
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Monogenic obesity
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2008
A very small chemical change in the DNA has been
found to be associated with obesity-related
variables.
Subtle variants in genes can result in severe early
onset obesity, and are likely to contribute to
susceptibility to obesity in the general population.
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Monogenic obesity
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2008
A single chromosome may be linked with obesity in
several populations (10p12).
Another chromosomal region may be associated
with obesity and diabetes (6q16.3–q24.2).
A gene for an enzyme is associated with childhood
obesity and also with insulin resistance (ENPP1).
A modification in a gene increases the odds ratio
for obesity by 1.2–1.3 (Insig2).
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‘Polygenic’ contribution to obesity
Polygenic contribution to obesity could be:
 Relatively common genetic changes ‘common
variant– common disease’ model, or the
 Rare genetic changes in the ‘multiple rare
variants–common disease’ model. This may be
true in certain populations.
2008
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Mendelian Disorders or monogenic
mutations
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Mendelian disorders - single mutant genes.
There are four main patterns of inheritance:
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autosomal dominant,
autosomal recessive,
X-linked dominant, or
X-linked recessive.
~6,000 known single gene disorders
Frequency: < 1 in 200 births.
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Obese phenotype
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2008
The visible properties of an organism that are
produced by the interaction of the genotype and
the environment – such as obesity.
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Mendelian Disorders
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Phenotype
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homozygotes
heterozygotes
Carriers
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Mendelian Disorders
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Cushing’s Syndrome, two loci CNC1 and CNC2, mutations in
PRKAR1A or MEN1 genes
Cortisone Reductase Deficiency, mutations in HSD11B1 and the
H6PD gene
Isolated Growth Hormone Deficiency
X-Linked Syndromic Mental Retardation 16, MECP2 gene
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Bardet-Biedl Syndrome, (14q32.1) genes BBS8, BBS3 and
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BBS5
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Abright Hereditary Osteodystrophy-Like Syndrome
--The Human Obesity Gene Map
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Monogenic Mutations
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2008
Mutations associated with obesity are:
 Cohen syndrome
 Leptin deficiency
 Leptin receptor deficiency
 Prohormone convertase -1 deficiency
 Propopiomelanocortin deficiency
--The Human Obesity Gene Map
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Monogenic Mutations
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2008
Mutations associated with obesity cont.:
 Melanocortin 4 receptor mutation
 Melanin concentrating hormone receptor 1
(GPR24)
 ADRB2 gene
 ADRB3 gene
 Corticotrophin-releasing hormone receptors 1
and 2 (CRHR1-2
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Non Mendelian Complex Traits
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2008
Associations exist between candidate genes
and obesity- related phenotypes.
More than 400 studies covering 113 candidate
genes have reported significant associations.
--The Human Obesity Gene Map
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Associations found in humans
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Body weight, BMI, Overweight, and Obesity – 43 genes
Body composition – 13 genes, Fat distribution – 12 genes, and
Energy expenditure – 4 genes
Changes in Body weight and Body composition – 7 genes
Negative Associations with Obesity-Related Phenotypes
--The Human Obesity Gene Map
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Other Obesity-Related Phenotypes
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2008
Metabolic syndrome: waist circumference,
dietary intakes, and resting energy
expenditure.
Metabolic syndrome: BMI, waist-to-hip ratio,
and sub scapular skinfolds.
--The Human Obesity Gene Map
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Multivariate Genome-Wide Scans
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There are linkages involving BMI and blood pressure:
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systolic blood pressure,
diastolic blood pressure, and
ASP levels.
--The Human Obesity Gene Map
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Currently
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2008
135 different candidate genes linked with obesity-related phenotypes.
Obesity related associations are shown in 18 different genes in at least
five studies.
--The Human Obesity Gene Map
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Obesity in the mouse model
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2008
Mouse model is used to research the
effect of genetic changes on metabolism
In the rodent DNA, 166 genes have
been identified that, when mutated or
expressed as transgenes in the mouse,
result in phenotypes that affect body
weight and adiposity.
--The Human Obesity Gene Map
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Obesity in the mouse model
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2008
Obesity in rodents may be due to hepatic lipase activity
Some obesity is due to influences on food intake.
--The Human Obesity Gene Map
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Obesity in the mouse model
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2008
Genetic influences may lead to late-onset (Fob3a) or
early-onset (Fob3b) obesity in laboratory animals.
Gene mutations may influence insulin and lipids or
otherwise influence body weight.
Leptin level or receptors may be influenced leading to
obesity.
--The Human Obesity Gene Map
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In Conclusion…
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Obesity is related to food intake and energy balance.
Obesity is also related to subtle genetic changes that can profoundly
change the body’s response.
It is becoming clear that some genes appear to be more important than
others based on the numbers of replication from independent studies.
--The Human Obesity Gene Map
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In Conclusion
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About 20-30% of genetic associations are real and do have modest
effects on the risk of common diseases.
The goal still remains to identify the right combination of genes and
mutations that are associated with this increased risk for overweight
and obesity, and determine how environmental factors interact with
these genes and mutations to determine the risk.
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Division of Education
Pennington Biomedical Research Center
Heli J. Roy, PhD, RD
Outreach Coordinator
Phillip Brantley, PhD
Director, Division of Education
Claude Bouchard, PhD
Director, Pennington Biomedical Research Center
References
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http://obesitygene.pbrc.edu/
http://www.endotext.org/obesity/obesity8/obesityframe8.htm
http://diabetes.niddk.nih.gov/dm/pubs/pima/pathfind/pathfind.htm
http://www.niddk.nih.gov/health/endo/pubs/cushings/cushings.htm
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