Phenotype = The observable physical or biochemical characteristics of an organism, as determined by both genetic makeup and environmental influences.
The recent increase in the prevalence of obesity in the US and other countries is driven by changes in the type of food consumed, environmental factors such as decreased activity due to increased use of cars even for short trips, and decreased activity during recreational time (more video games, TV, and other entertainment that is sedentary).
The obesity epidemic begun in the late 70’s and continues through today, although there are some signs that it is leveling off. Because there has been such a rapid rise in obesity in the last 30-40 years, there is misconception that it is NOT due to genetic factors since our genes have not had a chance to change in such a short time.
In fact, obesity is very heritable. Many studies of families, adoptees, twins, and most powerfully, adopted twins have all confirmed that inherited factors may be responsible for 45–75% of the variation in individual fatness level. These heritable factors are involved with energy intake, energy expenditure and the division of nutrients between fat and lean tissue.
The discovery of obesity genes can lead to health benefits. These will come in at least three ways. First, some genetic obesity syndromes are very severe, occur at a young age and are associated with other developmental and clinical manifestations. Some conditions can be treated. For example, replacing leptin in congenital leptin deficiency, will lead to the development of effective therapy for these uncommon disorders.
Second, genetic studies can help reveal ways in which certain molecules control energy balance, metabolism of various chemicals such as insulin, glucose, hormones, and enzymes involved in digestion and metabolism, and may direct researchers to find targets for pharmacological intervention in more common forms of obesity.
Third, it is possible that, by recognizing genetic reasons that predispose individuals to obesity, there may be some subgroups that might benefit from specific diets and/or exercise regimes, drugs, or surgery.
Importantly, the discovery of these genetic disorders has helped destigmatize human obesity and allowed it to be seen as a biomedical disorder and not simply a moral frailty. In one case, discovery of the causative genetic defect has led to dramatically successful therapy in a few individuals. Finally, mutations in one gene, the melanocortin 4 receptor, may be responsible for tens of thousands of cases of obesity. Knowledge of the specific molecular mechanisms in this and other genetic disorders should lead to better mechanism-directed pharmacotherapy in the future.
Monogenic or Mendelian mutation is when there is mutation in one gene. There are many different types of single mutations that can occur that result in many commonly know diseases such as phenolketoneurea, cystic fibrosis and hemophilia. Many mutations also result in excess weight or obesity. Mutations in the melanocortin 4 receptor represent by far the commonest form of monogenic obesity. Thus far, up to 5% of all severe obese children have such a mutation. Children with MC4 mutations show striking acceleration of linear growth and markedly increased bone mass at an early age. The continuing dissection of heterogeneity of severe obesity should aid genetic counseling, prognostication and development of specific therapies. This type of obesity only represent a small fraction of those with obesity (albeit a group with disproportionate physical and psychosocial morbidity and health costs), the implications of these discoveries have been profound.
The genetic defects found to date all impair satiety, affecting the function of appetite control centers in the brain rather than being due to a ‘slow metabolism’. This indicates that we must think of human food intake not as an entirely voluntarily controllable phenomenon but one driven by powerful biological signals from relatively primitive brain areas. When these basic signaling mechanisms are severely disrupted, it is very difficult to overcome the drive to eat.
Recently, single nucleotide polymorphisms (SNPs) in proopiomelanocortin, a precursor peptide used to synthesize many important molecules in the body such as melanin (skin pigmentation), adrenocorticotrophin, a hormone necessary for steroid hormone synthesesis and more. There are eight potential cleavage sites within the polypeptide precursor and, depending on tissue type and the available convertases, processing may yield as many as ten biologically active peptides involved in diverse cellular functions. The encoded protein is synthesized mainly in corticotroph cells of the anterior pituitary. In other tissues, including the hypothalamus, placenta, and epithelium, all cleavage sites may be used, giving rise to peptides with roles in pain and energy homeostasis, melanocyte stimulation, and immune modulation. Mutations in this gene have been associated with early onset obesity, adrenal insufficiency, and red hair pigmentation. Thus, as is the case with common forms of type 2 diabetes, it does appear that subtle variants in genes, which when mutated result in severe early onset obesity, are likely to contribute to susceptibility to obesity in the general population. For a comprehensive list of all linkage studies performed, see Human Obesity Gene Map (http://obesitygene.pbrc.edu/).
A region on chromosome 10p12 that showed significant linkage with obesity in several populations. Examining candidate genes within the region, gene GAD2, the gene encoding glutamic acid decarboxylase 65, an enzyme involved in gamma aminobutyric acid (GABA) synthesis was found to be significantly linked to obesity. A region on chromosome 6q16.3–q24.2 has been associated with significant Logarithm of Odds (LOD) scores in relation to obesity and diabetes phenotypes. An SNP in ENPP1, a gene in this region which encodes an ecto-phosphatase, was found to associate with childhood obesity and also with insulin resistance. Further studies in other populations will be required to establish the reproducibility of these observations. The pace of discovery will change with the advent of genome–wide association studies. Very recently, using such an approach, a SNP close to the Insig2 gene has been identified which, when present in homozygous form, increases the odds ratio for obesity by 1.2–1.3.
Given the undoubted environmental influences on obesity in the general population, the multiple molecular mechanisms that could influence adiposity and the unknown genetic architecture of obesity susceptibly, it is unsurprising that progress in the identification of genes influencing susceptibility to common forms of obesity has been slower. It is not yet clear whether the genetic architecture of common obesity will conform more to the ‘common variant– common disease’ model, in which some relatively common polymorphisms have modest but widespread effects on risk, or the ‘multiple rare variants–common disease’ model, where multiple different rare alleles underlie genetic susceptibility. Polymorphisms in multiple candidate genes, selected by virtue of their known biological function and/or their role in the causation of monogenic obesity syndromes in humans or animal models, have been examined in population and case–control studies to determine whether they influence the risk of adiposity. The Trp64Arg variant in the Beta-3 adrenergic receptor gene has been the subject of more than 60 independent studies and four meta-analyses and, while evidence seems to point to some effect, especially in Asian subjects, this effect does not seem to generalize to other populations. The Val103Ile variant in the MC4R receptor, present in only 2–3% of the general population, has been studied in large KORA study and found to reduce the risk of obesity This conclusion has been supported by a recent meta-analysis.
Mendelian: Of, relating to, or designating Gregor Mendel or his theories of genetics. Mendelian disorders are those that are caused by single mutant genes. There are four main patterns of inheritance: autosomal dominant autosomal recessive X-linked dominant X-linked recessive. In AUTOSOMAL DOMINANT INHERITANCE, the abnormality or abnormalities usually appear in every generation. Each affected child of an affected parent has a 50% chance of inheriting the disease. In AUTOSOMAL RECESSIVE INHERITANCE, the parents of an affected individual may not express the disease. On average, the chance of an affected child's brothers or sisters having the disease are 1 in 4. Males and females are equally likely to be affected. For a child to have symptoms of an autosomal recessive disorder, the child must receive the defective gene from BOTH parents. Because most recessive disorders are rare, a child is at increased risk of a recessive disease if the parents are related. Related individuals are more likely to have inherited the same rare gene from a common ancestor. In X-LINKED RECESSIVE INHERITANCE, the incidence of the disease is much higher in males than females. Since the abnormal gene is carried on the X chromosome, males do not transmit it to their sons -- they do transmit it to their daughters. The presence of one normal X chromosome masks the effects of the X chromosome with the abnormal gene. So, almost all of the daughters of an affected man appear normal, but they are all carriers of the abnormal gene. The sons of these daughters then have a 50% chance of receiving the defective gene. In X-LINKED DOMINANT INHERITANCE, the presence of the defective gene appears in females even if there is also a normal X chromosome present. Since males pass the Y chromosome to their sons, affected males will not have affected sons, but all of their daughters will be affected. Sons or daughters of affected females will have a 50% chance of getting the disease. Single gene defects are rare, with a frequency of less than 1 in 200 births, but since there are about 6,000 known single gene disorders, their combined impact is significant.
Phenotype = the physical characteristics that are determined by our genes, such as green eyes, black hair, short fingers, muscular body, etc.
The observed effect of a gene (the appearance of a disorder) is called the phenotype. A phenotype expressed in the same way (in both homozygotes and heterozygotes) is dominant. A phenotype expressed only in homozygotes (those that have two of the same gene variant on both strands of DNA) is recessive. Heterozygotes for a recessive gene are called carriers. Carriers usually don't show the disease, but the gene can frequently be identified by sensitive laboratory tests.
These are some common genetic conditions, or Mendelian conditions with one gene defect. In Abright Hereditary Osteodystrophy-Like Syndrome, severe impairment in lipid accumulation.
These mutations are all associated with overweight and obesity. For example, leptin deficiency can result in significant obesity that is resolved with leptin injections.
Additional conditions related to obesity.
Many complex traits are thought to be inherited since they often run in families. However, these complex traits do not show typical mendelian pedigree patterns. These nonmendelian diseases may depend on several susceptibility loci, with a variable contribution from environmental factors. Discovering the major susceptibility locus may be the key to advances in understanding the pathophysiology of a disease. Genetic association studies assess correlations between marker alleles and trait differences on a population scale.
Many common diseases ranging from cancer to Alzheimer’s disease are polygenic in nature, with more than one gene contributing to disease susceptibility in the population. Association studies considering only one or a small fraction of genetic variants may well fail to demonstrate differences in allele frequency, which in itself have a role in the development of central obesity.
Excess body fat, obesity, is one of the most common disorders today. The location of the body fat is a major determinant of the degree of excess morbidity and mortality due to obesity. At least two components of body fat are associated with obesity-related adverse health outcomes. These are the amount of subcutaneous truncal or abdominal fat, and the amount of visceral fat located in the abdominal cavity. Each of these components of body fat is associated with varying degrees of metabolic abnormalities and independently predicts adverse health outcomes. The pathogenesis of central obesity is complex. Identification of an effect of a polymorphism will be the first, simple step on a more challenging path toward elucidation of the biological pathways involved, and crucially, the gene–gene and gene–environment interactions. Other genome scans reporting linkages with obesity-related phenotypes include two genome scans for traits related to the metabolic syndrome and genome scans on waist circumference, dietary intakes, and resting energy expenditure. Tang et al. conducted a genome-wide linkage analysis of a metabolic syndrome factor using 13 traits related to the metabolic syndrome which included three obesity-related phenotypes: BMI, waist-to-hip ratio, and sub scapular skinfolds. They identified a QLT for the metabolic syndrome factor on a particular chromosome. Since the genetic heritability of the central obesity phenotype is less than 50%, most of the variation in phenotype is not genetic in any simple sense. For this reason it would seem imperative to put more effort in controlling for potential environmental confounders in the study design.
There is an association between body mass index and blood pressure: both with systolic and diastolic measures there are associations with obesity.
Based on the evidence reviewed there are now 135 different candidate genes that have been associated and/or linked with obesity-related phenotypes. The majority of the candidate genes associated with obesity have been identified in association studies. Researchers have a total of 18 different genes that have shown associations with obesity-related phenotypes in at least five studies.
Transgenesis = The transfer of cloned genetic material from one species or breed to another.
Allele= One member of a pair or series of genes that occupy a specific position on a specific chromosome.
The mosue model has been very useful in assessing dietary influences on obesity. There are many mouse models also used for assessing changes in insulin and glucose metabolism. Most of the research on leptin has been done on mouse models.
Genetic influences on obesity development
Publication # 7 Obesity and GenesRecent Developments Pennington Biomedical Research Center
Overview Genetic basis for obesity The obesity epidemic The discovery of the obesity genes Monogenic obesity Associations with obesity Animal models of obesity Conclusions2009 2 --The Human Obesity Gene Map
ObesityInfluenced in the following ways: Type of food consumed Environmental factors Individual response to food and physical activity2009 3
The Obesity epidemic Due to permissive genes and the environment.2009 Obesity reviews (2007) 8 (Suppl. 1) 4
The Obesity epidemic 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.2009 5
The Discovery of the Obesity genes 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.2009 6
The Discovery of the Obesity genes Certain molecules may control energy balance that will be targeted for treatment.2009 7
The Discovery of the Obesity genes Some individuals may benefit from specific diets and/or exercise regimes, drugs, or surgery to prevent obesity.2009 8
Obesity due to genetic disorders 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.2009 9
Monogenic obesity Monogenic = genetic defect in one gene This type of genetic mutation can result in severe forms of obesity that run in families.2009 10
Monogenic obesityAs 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’.2009 11
Monogenic obesity 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.2009 12
Monogenic obesity 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).2009 13
‘Polygenic’ contribution to obesityPolygenic 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.2009 14
Mendelian Disorders or monogenic mutations Mendelian disorders - single mutant genes. There are four main patterns of inheritance: autosomal dominant autosomal recessive X-linked dominant X-linked recessive. ~6,000 known single gene disorders Frequency: < 1 in 200 births.2009 15
Obese phenotype The visible properties of an organism that are produced by the interaction of the genotype and the environment – such as obesity.2009 16
Non Mendelian Complex Traits Associations exist between candidate genes and obesity- related phenotypes. More than 400 studies covering 113 candidate genes have reported significant associations.2009 21 --The Human Obesity Gene Map
Associations found in humans 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 Phenotypes2009 22 --The Human Obesity Gene Map
Other Obesity-Related Phenotypes Metabolic syndrome: waist circumference, dietary intakes, and resting energy expenditure. Metabolic syndrome: BMI, waist-to-hip ratio, and sub scapular skinfolds.2009 23 --The Human Obesity Gene Map
Multivariate Genome-Wide Scans There are linkages involving BMI and blood pressure: systolic blood pressure diastolic blood pressure ASP levels.2009 24 --The Human Obesity Gene Map
Currently 135 different candidate genes linked with obesity-related phenotypes. Obesity related associations are shown in 18 different genes in at least five studies.2009 25 --The Human Obesity Gene Map
Obesity in the mouse model 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.2009 --The Human Obesity Gene Map 26
Obesity in the mouse model Obesity in rodents may be due to hepatic lipase activity Some obesity is due to influences on food intake.2009 27 --The Human Obesity Gene Map
Obesity in the mouse model 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.2009 28 --The Human Obesity Gene Map
In Conclusion… 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.2009 29 --The Human Obesity Gene Map
In Conclusion 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.2009 30
Division of Education Pennington Biomedical Research CenterHeli J. Roy, PhD, MBA, RDOutreach CoordinatorPhillip Brantley, PhDDirector, Division of EducationSteven Heymsfield, MDDirector, Pennington Biomedical Research CenterBeth Kalicki, BS Edited: October 2009
About Our CompanyThe Pennington Biomedical Research Center is a world-renowned nutrition research center.Mission:To promote healthier lives through research and education in nutrition and preventive medicine.The Pennington Center has several research areas, including:Clinical Obesity ResearchExperimental ObesityFunctional FoodsHealth and Performance EnhancementNutrition and Chronic DiseasesNutrition and the BrainDementia, Alzheimer’s and healthy agingDiet, exercise, weight loss and weight loss maintenanceThe research fostered in these areas can have a profound impact on healthy living and on the prevention of common chronic diseases,such as heart disease, cancer, diabetes, hypertension and osteoporosis.The Division of Education provides education and information to the scientific community and the public about research findings,training programs and research areas, and coordinates educational events for the public on various health issues.We invite people of all ages and backgrounds to participate in the exciting research studies being conducted at the Pennington Centerin Baton Rouge, Louisiana. If you would like to take part, visit the clinical trials web page at www.pbrc.edu or call (225) 763-3000.2009 32