Introduction measured by the Body mass index (BMI),

IntroductionBody mass index (BMI)Obesity is a medical condition defined asan accumulation of excess body fat that lead to many health problems andreduced life expectancy.

Obesity usually associates with hypertension,diabetes, cardio vascular diseases (CVDs) and dyslipidemia 1. Obesity is commonly measured by theBody mass index (BMI), which is calculated as the weight in kilograms dividedby the square of the height in meters. Normal BMI is considered between18.5 to 24.

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9. However, Overweight, obesity and extreme obesity are classifiedas the following: the BMI for overweight is 25.0 or greater and less than 30.0,obesity BMI is 30.0 or greater and lastly extreme obesity is BMI 40.

0 orgreater 2. Development and building of cities hasoccurred rapidly which has changed the old lifestyle of traveling, to sedentarylifestyle, which contributed to increased obesity 3. The prevalence andincidence of obesity are increasing rapidly to epidemic proportions inindustrial areas as well as worldwide.

It has increased three folds between1975 and 2016 and more than 1.9 billion adults were overweight in 2016 4. The cause of obesityObesity results from energy imbalancebetween energy intake and energy usage at which both environmental and geneticfactors play a role in its onset. Environmental risk factors include physicalinactivity, consumption of fast foods, sugary food and inadequate sleep. Inaddition, genetic factors contribute to the onset of obesity. Obesity could bedue to monogenic; mutation in a single gene, or polygenic; mutations in morethan one gene. Although those genes do not directly cause obesity, theycontribute to its onset and development in parallel with other geneticalterations 5.

Many studies that have provided dataabout obesity risk factors were focused on western countries more than anyother areas. The western studies’ conclusions do not necessarily apply to otherpopulation due to variety of genetic and environmental factors. Recent progressvia genome-wide association studies (GWAS) has identified many additionalgenetic factors that appear to inflate the risk of disorders in someindividuals 6. Studying differentpopulations with different background such as Qatari population which has asmall population size and high consanguinity will clearly provide betterunderstanding of obesity risk factors world widely.

Consanguinity has reached54% in Qatar, and obesity prevalence is more than 70%. The high incidence andprevalence of obesity has been due to lifestyle changes after discovering oilin gulf area and increased wealth 7. Recent GWAS studies have showedrelationship between genes and obesity, but it is not well known if those geneticmarkers influence similar risks in people of different descent 3. Distribution ofdiseases related to alleles between different population is uneven speciallyfor recessive disorder such as monogenic obesity of mutation in Leptin Receptor8. The risk of a genetic marker identifiedby GWAS might vary according to the population being studied cause populationswith different ancestry have variability of allelic frequency 9. Genetics of obesityHeritability of obesityResearch in the field of genetics in the past two decades has shownthat genetics play a role in obesity and early evidence came from twin studies. Twin studies aimed todetermine the genetic component of obesity through producing heritabilityestimates for obesity and obesity related traits 10. Twin studies are valuable because theyallow for the comparison of the obesity concordance between monozygotic anddizygotic twins, where both twin pairs also share to some extent similarenvironment.

Additional evidence of genetic contribution to obesity also camefrom adoption studies 11{Grant, 2014, the genetic of obesity}. Genetic studies of twins showed thatidentical twins have 70 to 90% of similarity of fat mass, while fraternal twinshave 35 to 45% indicating that genetic does contribute to obesity 12. On genetic basis, Obesity can be classified into three major types. These are theSyndromic obesity, polygenic obesity and monogenic form of obesity. The brain,specifically the hypothalamus regulates food intake by responding to signalsfrom adipose tissues, the digestive tract and the pancreas. Hormones including insulin,leptin and ghrelin and others are released as signals to the brain to maintainenergy homeostasis 13These effectors and receptors are encoded by several genes,therefore, mutations or genetic variations in key genes involved in appetiteregulation may alter the satiety signaling and energy hemostasis, and maycontribute to obesity predisposition 14Thrifty gene hypothesis The thrifty gene hypothesis is a hypothesis that has beenstated to give a reason for the elevated incidence of obesity, diabetes, andmetabolic syndromes in modern life. Genetic variants that cause the buildup offat for conservancy of nutrition until times of need are controlled by positiveselection, and therefore it became more common in the past population 15.

Consequently, in today’s times ofhigh caloric intake, earlier valuable alleles have become less beneficial. Oneof the facts that weaken this hypothesis is that in times of famine, death wasprimarily caused by infections, not losing of fat, and that obese people mightbe at more risk of predation 16. In addition, examining thehypothesis by testing obesity, diabetes, and metabolic syndrome alleles ispossible. Studies have examined for the features of risk alleles either fromancestors or derived, minor or major alleles and statistic prevalence incertain populations 17. The thrifty hypothesis has beendisapproved due to little support by genetic studies.

It was disapproved, butit is still in use, and is still adapted by scientists researching in eatingdisorders 18.Polygenic obesity Polygenic obesity is the common form of obesity. It involvesthe contribution of several gene variants to the susceptibility of obesity ininteraction with environmental factors, where each variant exert a small effecton obesity 19. The genes that are involved inpolygenic obesity have various functions and pathways; examples are energymetabolism and homeostasis, neural function, cell adhesion, regulation of ionchannels and eating behavior 20. FTOgene is the first gene identified and associated with polygenic form ofobesity, since its discovery in a Genome wide association study (GWAS), variantsin the FTO gene has been found to be the most significant andreproducible association with obesity 21.

Variations at other genes involved in the monogenic form ofobesity, such as MC4R, BDNF and LEPR have been also found to be associated with common obesity.Such overlap reflects the shared underlying mechanism between both forms ofobesity and highlight the impotence of the leptin- melanocortin 4 receptorpathway in energy hemostasis 20.Syndromic obesity Syndromic obesity is the clinical phenotype associated withobesity. There are more than 25 Syndromic forms of obesity that have beenidentified 22. The genetic bases for some of theobesity syndrome have been studied to provide better understanding of the diseasepathogenesis and mutations 23Prader Willi syndromeThe most common Syndromic form of obesity is Prader willisyndrome (PWS). This syndrome has several etiologies but it always happens as aresult of expression loss of paternal gene on the imprinted chromosomal region15q 24. There are around 75% cases of PWSthat are due to paternal deletion of chromosome 15q, 22% are due to maternaluniparental disomy, 2% are due to imprinting errors that are caused bymicrodeletion of the imprinting center at the small nuclear ribonucleoproteinpolypeptide N (SNRPN) and (SNURF) gene locus, lastly less than 1% are caused bypaternal translocation 22.

Regardless of the mutation type,all patients with PWS share similar clinical features. Poor feeding and lowmuscle tone are characteristic of PWS in neonate, and during childhood it ischaracterized by overeating, which can evolve into extreme hyperphagia leadingto obesity, mental retardation, short stature and hypogondotropic hypogonadism 5, 23.       Pic 2: Clinical features of PWS: a) 2 ½ years old girl   b) 21 year old man 23.

Bardet- biedl syndromeBardet- biedl syndrome (BBS) is a rareform of syndromic obesity. It is a genetically heterogeneous disorder that ismapped in at least 16 loci 25. BBS is an autosomal recessive disorderso mutations in more than one locus are required for the expression of thissyndrome 5. Obesity, mental retardation, dysmorphicextremities, retinal dystrophy, hypogondism and structural abnormalities of thekidney are characteristic of BWS 25.

The phenotypes of BBS are always subtleand not always present, the features sometimes slowly evolve throughout thefirst years of life as a result most BBS patients are diagnosed in latechildhood and early adulthood 22. 

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