Introduction

Body mass index (BMI)

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Obesity is a medical condition defined as
an accumulation of excess body fat that lead to many health problems and
reduced life expectancy. Obesity usually associates with hypertension,
diabetes, cardio vascular diseases (CVDs) and dyslipidemia 1. Obesity is commonly measured by the
Body mass index (BMI), which is calculated as the weight in kilograms divided
by the square of the height in meters. Normal BMI is considered between
18.5 to 24.9. However, Overweight, obesity and extreme obesity are classified
as 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 or
greater 2.

Development and building of cities has
occurred rapidly which has changed the old lifestyle of traveling, to sedentary
lifestyle, which contributed to increased obesity 3. The prevalence and
incidence of obesity are increasing rapidly to epidemic proportions in
industrial areas as well as worldwide. It has increased three folds between
1975 and 2016 and more than 1.9 billion adults were overweight in 2016 4.

The cause of obesity

Obesity results from energy imbalance
between energy intake and energy usage at which both environmental and genetic
factors play a role in its onset. Environmental risk factors include physical
inactivity, consumption of fast foods, sugary food and inadequate sleep. In
addition, genetic factors contribute to the onset of obesity. Obesity could be
due to monogenic; mutation in a single gene, or polygenic; mutations in more
than one gene. Although those genes do not directly cause obesity, they
contribute to its onset and development in parallel with other genetic
alterations 5.

Many studies that have provided data
about obesity risk factors were focused on western countries more than any
other areas. The western studies’ conclusions do not necessarily apply to other
population due to variety of genetic and environmental factors. Recent progress
via genome-wide association studies (GWAS) has identified many additional
genetic factors that appear to inflate the risk of disorders in some
individuals 6. Studying different
populations with different background such as Qatari population which has a
small population size and high consanguinity will clearly provide better
understanding of obesity risk factors world widely. Consanguinity has reached
54% in Qatar, and obesity prevalence is more than 70%. The high incidence and
prevalence of obesity has been due to lifestyle changes after discovering oil
in gulf area and increased wealth 7.

Recent GWAS studies have showed
relationship between genes and obesity, but it is not well known if those genetic
markers influence similar risks in people of different descent 3. Distribution of
diseases related to alleles between different population is uneven specially
for recessive disorder such as monogenic obesity of mutation in Leptin Receptor
8. The risk of a genetic marker identified
by GWAS might vary according to the population being studied cause populations
with different ancestry have variability of allelic frequency 9.

Genetics of obesity

Heritability of obesity

Research in the field of genetics in the past two decades has shown
that genetics play a role in obesity and early evidence came from twin studies. Twin studies aimed to
determine the genetic component of obesity through producing heritability
estimates for obesity and obesity related traits 10. Twin studies are valuable because they
allow for the comparison of the obesity concordance between monozygotic and
dizygotic twins, where both twin pairs also share to some extent similar
environment. Additional evidence of genetic contribution to obesity also came
from adoption studies 11{Grant, 2014, the genetic of obesity}. Genetic studies of twins showed that
identical twins have 70 to 90% of similarity of fat mass, while fraternal twins
have 35 to 45% indicating that genetic does contribute to obesity 12.

On genetic basis,

Obesity can be classified into three major types. These are the
Syndromic obesity, polygenic obesity and monogenic form of obesity. The brain,
specifically the hypothalamus regulates food intake by responding to signals
from adipose tissues, the digestive tract and the pancreas. Hormones including insulin,
leptin and ghrelin and others are released as signals to the brain to maintain
energy homeostasis 13

These effectors and receptors are encoded by several genes,
therefore, mutations or genetic variations in key genes involved in appetite
regulation may alter the satiety signaling and energy hemostasis, and may
contribute to obesity predisposition 14

Thrifty gene hypothesis

The thrifty gene hypothesis is a hypothesis that has been
stated to give a reason for the elevated incidence of obesity, diabetes, and
metabolic syndromes in modern life. Genetic variants that cause the buildup of
fat for conservancy of nutrition until times of need are controlled by positive
selection, and therefore it became more common in the past population 15. Consequently, in today’s times of
high caloric intake, earlier valuable alleles have become less beneficial. One
of the facts that weaken this hypothesis is that in times of famine, death was
primarily caused by infections, not losing of fat, and that obese people might
be at more risk of predation 16. In addition, examining the
hypothesis by testing obesity, diabetes, and metabolic syndrome alleles is
possible. Studies have examined for the features of risk alleles either from
ancestors or derived, minor or major alleles and statistic prevalence in
certain populations 17. The thrifty hypothesis has been
disapproved due to little support by genetic studies. It was disapproved, but
it is still in use, and is still adapted by scientists researching in eating
disorders 18.

Polygenic obesity

Polygenic obesity is the common form of obesity. It involves
the contribution of several gene variants to the susceptibility of obesity in
interaction with environmental factors, where each variant exert a small effect
on obesity 19. The genes that are involved in
polygenic obesity have various functions and pathways; examples are energy
metabolism and homeostasis, neural function, cell adhesion, regulation of ion
channels and eating behavior 20. FTO
gene is the first gene identified and associated with polygenic form of
obesity, since its discovery in a Genome wide association study (GWAS), variants
in the FTO gene has been found to be the most significant and
reproducible association with obesity 21.

Variations at other genes involved in the monogenic form of
obesity, 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 of
obesity and highlight the impotence of the leptin- melanocortin 4 receptor
pathway in energy hemostasis 20.

Syndromic obesity

Syndromic obesity is the clinical phenotype associated with
obesity. There are more than 25 Syndromic forms of obesity that have been
identified 22. The genetic bases for some of the
obesity syndrome have been studied to provide better understanding of the disease
pathogenesis and mutations 23

Prader Willi syndrome

The most common Syndromic form of obesity is Prader willi
syndrome (PWS). This syndrome has several etiologies but it always happens as a
result of expression loss of paternal gene on the imprinted chromosomal region
15q 24. There are around 75% cases of PWS
that are due to paternal deletion of chromosome 15q, 22% are due to maternal
uniparental disomy, 2% are due to imprinting errors that are caused by
microdeletion of the imprinting center at the small nuclear ribonucleoprotein
polypeptide N (SNRPN) and (SNURF) gene locus, lastly less than 1% are caused by
paternal translocation 22. Regardless of the mutation type,
all patients with PWS share similar clinical features. Poor feeding and low
muscle tone are characteristic of PWS in neonate, and during childhood it is
characterized by overeating, which can evolve into extreme hyperphagia leading
to 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 syndrome

Bardet- biedl syndrome (BBS) is a rare
form of syndromic obesity. It is a genetically heterogeneous disorder that is
mapped in at least 16 loci 25. BBS is an autosomal recessive disorder
so mutations in more than one locus are required for the expression of this
syndrome 5. Obesity, mental retardation, dysmorphic
extremities, retinal dystrophy, hypogondism and structural abnormalities of the
kidney are characteristic of BWS 25. The phenotypes of BBS are always subtle
and not always present, the features sometimes slowly evolve throughout the
first years of life as a result most BBS patients are diagnosed in late
childhood and early adulthood 22.

 

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