Genetic Profiles in the Obese Population Ana Carolina Proenca da Fonseca, Patricia Torres Bozza, and Pedro Hernan Cabello Contents Introduction 10s Monogenic Obesity 108 Homeostti Pathways Involved inthe Regulation of Appeste and Satity 108 Non-syndromie Form of Obesity 109 Leptin Gene Aberrations M0 ‘The Meanocortin Pathway 16 Syndromie Form of Obesity, us Polygenic or Common Obesity. 19 Relevant Candidates 120 ‘Ongoing Studies and Future Perspectives 120 References ma ‘Abstract Based on the genetic etiology, obesity could be divided into two main categories: polygenic and monogenic (syndromic and |A.C.P. da Fonseca (3) [Laboratory of Inmiunopharnacology, Oswaldo Cruz Insitute, Oswaldo Cruz Foundation, Rio de Janeiro, Brazil Human Genetics Laboratory, Oswaldo Cruz Institute, ‘Oswaldo Cruz Foundation, Rio de Janeiro, Brazil ‘email: ana proenca@ioe loeruz br PT. Bossa Laboratory of Inmunopharmacology, Oswaldo Cruz Insite, Oswaldo Cruz Foundation, Rio de Janeiro, Brazil, P.H.Cebetlo Human Genetics Laboratory, Oswaldo Cruz Institute, ‘Oswaldo Cruz Foundation, Rio de Janeiro, Brazil, ‘Human Genetics Laboratory, Grande Rio University, Rio 4e Janeito, Brazil (© Springer Nature Switzerland AG 2020 nnon-syndromic) forms, The polygenic form of obesity is caused by a combination of envi- ronmental factors and several genetic variants, ‘with minor effects, The monogenic forms are ccaused by mutations in single genes with ‘major effects. We focus on the recent advances and future perspectives in the field of genetic obesity, to provide a comprehensive review covering the underlying mechanisms involved in the development of obesity, Keywords Obesity « Genetic of obesity - Leptin ‘melanocortin pathway Mutation » BMI - Severe early-onset obesity 107 4. Faintuch and S. Paintuch (eds), Obesity and Diabetes, htps:ifdo.or/10.10019978-3-030-83370-0.§108 A.G.P. da Fonseca etal Introduction Obesity can cause adverse health effects due to its association with several diseases, such as type 2 diabetes (T2D), hypertension, metabolic syn- drome, cardiovascular diseases, and some cancers (Garvey et al. 2016, WHO 2019). These comorbidities associated with obesity contribute to reducing lifespan, and are responsible for three million deaths per year (Finucane et al. 2011; De Lorenzo et al. 2016), Globally, 650 million adults and 124 million children and adolescents (aged 5-19 years) were ‘obese in 2016. Currently, the global prevalence is 13% and will reach 20% by 2025, ifthe post-2000 tends continue (Garvey et al. 2016; WHO 2019) One of the major contributors to population weight gain is energy imbalance, caused by the ingestion of high-calorie foods that exceeds ‘energy expenditure, However, not all. subjects with obesogenic lifestyle develop this disorder, suggesting a strong genetic component (Pigeyre and Meyre 2018). The percentage of obesity that ‘can be attributed to genetics ranges from 40 to 70%, according to previous studies using mono- zygotic and dizygotic twins (Wardle etal. 2008). The etiology of obesity is extremely complex, being influenced by multiple interactions among. environmental, hormonal, lifestyle, metabolic, nutritional, and genetic factors (De Lorenzo ct al. 2016). Common forms of obesity are multi- factorial and polygenic, caused by an interaction of environmental factors with multiple genetic variants with minor effects, However, rare mono- genie forms were identified in humans and mice, Which are caused by mutations with major effects in a single gene (Fig. 8.1) (da Fonseca et al. 2017). Several genes have been associated with ‘human obesity, in which they could be related to either polygenic, monogenic, or both forms (Locke et al. 2015; Saced et al. 2015; Hasnain 2016; Tung et al. 2017). Monogenic Obesity ‘Monogenie forms of obesity are caused by a loss- offunction mutation in a single gene (Albuquerque et al, 2015). ‘These single-gene disorders result from variants of disturbing genes that encode receptors or ligands involved in appetite and satiety regulation as well as metabolism (da Fonseca et al. 2017). They can be divided into two different groups: syndromic obesity is usually associated with cognitive delay, dysmorphic characterises and, organ-specific developmental abnormalities; whereas mono- genic non-syndromic obesity is associated with intense hyperphagia, early-onset severe obesity and in some cases neuroendocrine dysfunctions. These forms can have a Mendelian autosomal (dominant and recessive) or X-linked inheritance (Pigeyze and Meyre 2018). Although monogenic forms of obesity are rare in humans, the identifi- cation of affected individuals allows for personalized clinical management, genetic counseling and, in some cases, specific pharma- ological therapy. Homeostatic Pathways Involved in the Regulation of Appetite and Satiety Inthe carly 1900s, clinical and experimental stud~ ies have postulated the involvement of the hypo- thalamus in the regulation of satiety, appetite, and body weight. Firstly, mice and cals were submit- ted to chemical and electrical experiments that damaged their hypothalamus, which result in an increase or loss of bodyweight depending on the size and region of the lesion (Hetherington and Ranson 1940; Anand and Brobeck 1951). In ‘humans, patients with brain tumors in the hypo: thalamic area can become obese (Daousi et al 2005). Later, the existence of a specific system in the hypothalamus that can rogulatc energy homeostasis called leptin-melanocortin pathway ‘was discovered (Fig, 8.2) (Cone 2005; Morton et al. 2006; Larder et al. 2014),8 Genetic Profiles in the Obese Population Fig. 8.1. Poiygenic obesity ‘cus due toa combination ‘of muliple genetic variants with common, low and raze frequency that have to low up fo intermedinte effect However, monogenic “obesity is cased by rate or ‘ery rare mutations with high effects Effect size Very rare The brain controls energy balance through ‘obtaining information about the energy stock by peripheral hormones, and then it is used to regu Tate the neuronal circuit into the hypothalamus (Cone 2005; Larder et al. 2014). During fasting and low energy stock, the stomach secretes ghrelin that binds to its receptor in the orexigenie neurons, stimulating the expression of neuropep- tide ¥ (NPY) and agouti-elated protein (AgRP) Orexigenic neurons project from the arcuate nucleus (ARC) to the paraventricular nucleus (PVN) of hypothalamus, stimulating food intake and suppressing energy expenditure (Cone 2005: Veter etal. 2010; Sutton et al. 2016). However, leptinis secreted by white adipose tissue when the ‘body accumulates adiposity and/or energy replacement oceurs, It crosses the blood-brain boarier and binds to leptin receptor (LEPR), localized in the ARC. Leptin acts suppressing NPY and AgRP ‘expression as well as inducing the proopiomela- nocontin (POMC), cocaine, and amphetamine- related transcript production in anorexigenic neurons (Vetter et al. 2010; Albuquerque et a 2015; da Fonseca etal. 2017), POMC is cleaved and processed by prohormone convertase 1/3 (PCI, encoded by proprotein convertase subtil isinkexin type 1 [PCSKT] gene), which produces Line Non-sydromic Variant frequency Rare common e-melanocyte-stimulating hormone _(a-MSH) (Freemark 2018). These products bind to the melanocortin-4 receptor (MC4R) in the PVN, resulting in a decreased energy intake and an increased basal energy expenditure (Vetter et al 2010; Larder et al. 2014; da Fonseca et al. 2017; Freemark 2018). Interestingly, genetic variants involved in leptin-melanocortin pathway have been associated with the development of severe early-onset obesity (Wabitsch et al. 2014; Saeed et al. 2015; da Fonseca et a. 2019b). Non-syndromic Form of Obesity Over the past two decades, a large number of different genetic variants in the ligands or receptors, which disrupt the signaling of the leptin-melanocortin pathway were identitied, resulting in hyperphagia, severe obesity in early childhood and in some cases, endocrine and immune disorders (Asai et al. 2013; Tung et al, 2017). All these mutations were found in thirteen genes, including LEP, LEPR, POMC, PCSKI, and MAR (Table 8.1). The non-syndromic form of obesity can affect up to 2-5% of the severely obese subjects and is transmitted under Mende- lian autosomal recessive or dominant categoryno A.C. da Fonseca etl Fig. 8.2 Schematic presentation of hypothalamic leptin ‘melanacontin pathovay. Leptin is secreted by adipore ese ‘and binds to is receptor located in two ses of neurons in the arcuate nuclei of hypothalamus, Leptin activates the anorexigenic pathway and inhibits orexgenic system, resulting in decreased food intake and increased basal energy expenditure. In contrast, ghrelin is produced by Stomach and activates the oreigenie neurons, inteasing (da Fonseca et al, 2017; Freemark 2018; Saeed et al, 2018). Leptin Gene Aberrations ‘Congenital leptin deticiency (OMIM#614962) is fa very rare autosomal recessive disorder caused by homozygous mutation in LEP gene on chro- mosome 7431.3, In 1997, Montague and collaborators described for the first time a ‘human leptin deficiency caused by a frameshift homozygous mutation (€.398delG; —_p. Gly133_{8*14). ‘This variant was identified in two severely obese children who are cousins, within a highly consanguineous family of Pakistani origin. The same mutation was reported. B the caloric intake and suppressing the energy expended. LLEPR, receptor of leptin: GHSR, growth hormone secre- tagogue receptor; NPY. neuropeptide Y; AGRP, agouti- related protein; NPYIR, neuropeptide Y receptor YI5 POMC, proopiomelanocortin; CART, cocaine and amphetamine related transcrip; MCAR, melanocortin-+ receptor in another two children of Pakistani origin but unrelated to the earlier found patients (Faroogi et al. 2002; Gibson et al, 2004). Eleven other pathogenic mutations have since been reported, ‘These genetic variants were identified in patients from consanguineous families in Colombi Pakistan, German, Turkey, India, and Egypt and from a non-consanguincous family in Austria, With the exception of two mutations (p. AsnlO3Lys and p.ArglOSTrp), all. pathogenic LEP variants found are population specitic and hhave not been identified in other ethnic groups. (Saved et al. 2015; Hasnain 2016). To date, less than 50 subjects have been described to be homozygous for loss-of-function mutations in LEP gene. 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However, Wabitsch and collaborators. (2014, 2015) described three probands carrying different homozygous LEP mutations (p.Aspl00Tyr and p-AsplO3Lys) with hyperleptinemia, In these ‘cases, the mutant leptin is produced and secreted but is not functional, Leptin Receptor Disorders Leptin receptor deficiency (OMIM#614963) is another autosomal recessive disorder, caused by hhomozygous/compound heterozygous mutations in LEPR gene on chromosome 1p31. Clement and collaborators (1998) reported the first cases of LEPR deficiency in three siblings with eatly- ‘onset morbid obesity froma consanguineous fam ily of Kabilian origin (north of Algeria). ARer that, several LEPR pathogenic mutations have ‘been reported in probands from European, Egyp- tian, Pakistani, and Turkish origin (Gill et al 2014; Saved et al. 2014, 2015; Huvenne et al 2015). Gill et al. @2014) have performed. whole. fexome sequencing in five individuals with extreme obesity of four consanguincous families (four probands and one affected sibling). They identified two novel LEPR frameshift mutations (PHis160Leus"9 and p.CysI86Alafs*27), resulting in a truncated receptor that lacks the domain requited for leptin signal transduction, Interestingly, large deletion ‘observed in six unrelated subjects with early- ‘onset_morbid obesity from Reunion Island (Indian Ocean, France), suggesting a founder cffect. Dus to the high frequency of this large deletion, a quantitative real-time PCR was devel- ‘oped to detect heterozygous carters in this popu- lation (Huvenne et al. 2015), fone novel was Clinical Profile Since LEPR deficiency also disrupts leptin signal- ing, clinical hallmarks of affected patients are similar to those with homozygous LEP mutations. ‘These patients had typical features including severe early-onset obesity, hyperphagia, hypogonadotropic hypogonadism, impaired immune system, and neuroendocrine/metabolic dysfunction (Le Beyec et al. 2013; Gill et al 2014), Selected LEP-deficient probands could be pharmacologically treated with recombinant lep- tin (metreleptin/Myalept), leading to reduction in food intake, fat mass, and metabolic and endo- crine abnormalities (Wabitsch et al, 2014; Roth et al. 2018), However, the drug is not approved for this indication, just for lipodystrophy. LEPR deficiency patients usually have ele- vated circulation leptin concentrations, reflecting the loss of sensitivity of the receptor. There is no evidence that metreleptin could be useful; how: ever, Setmelanotide is currently undergoing advanced clinical trials for such indication, reportedly meeting all defined endpoints. (Globenewswire.com 2019), The Melanocortin Pathway Proopiomelanocortin Gene Similarly to LEP and LEPR, rare pathogenic ‘mutations described in POMC and PCSK/ were associated with severe early-onset obesity, trans mitted under Mendelian autosomal recessive. POMC gene is located on chromosome 2p23.3 and encodes a complex pro-peptide which is processed post-transcriptionally to produce sev- eral bioactive peptides (adrenocorticotropin, [ACTH], Brendorphin, and aj, y- MSH). ‘These peptides bind to melanocortin receptors and act on energy balance, skin pigmentation, adrenal steroidogenesis, and thermoregulation, Alpha: and beta-MSH activate MC3R and MC4R as well as antagonize the action of AgRP, involved in the control of satiety and appetite (Cawley et al, 2016). Homozygous or hheterozygous pathogenic mutations have been reported in 17 probands from Netherland, Slove- nian, German, Switzerland, Indian, Turkish, Iraqi, and Hispanic origins (Anisimova et al. 2016; (Ozsu and Bahm 2017; Cetinkaya et al, 2018), “The first cases of severe obesity due to POMC deticiency (OMIM#609734) were observed in two unrelated children from Germany. The first proband carried compound heterozygote variants8 Genetic Profiles in the Obese Population Ww (c433delC and €.313G>T), which disrupt the corrected synthesis of ACTH and a-MSH, and the second proband was homozygous for a muta- tion in the splice site c.-11C>A) that climinates POMC translation, Both children presented severe carly-onset obesity, adrenal insuflicienc) and red hair pigmentation. Later, the same group described three new cases with similar clinical phenotype (Krude et al. 2003), The hypopigmentation is due to inadequate activation ‘of MCIR by POMC peptides in the skin. How- ‘ever, Faroogi et al. (2006) identified a novel POMC homozygous frameshift mutation (€:206deIC) in a 2-year-old male proband with severe obesity, hypocortisolism, and brown hair with dark red roots, This result suggests that patients with severe early-onset obesity and adre- nal insufliciency should be evaluated to POMC ‘mutations even in the absence of red hair pigmen- tation (Mendiratta et al, 2011). Despite POMC deficiency being a rare disorder, several studies have reported that the defective allele in the het- ‘erozygous state may contribute to the obesity susceptibility (Faroogi et al. 2001; Challis etal 2002; Lee et al. 2006; Samuels et al. 2013). Proprotein Convertase Gene Congenital proprotein convertase (PCI/3) defi- ciency (OMIM#500955) is caused by loss-of- function mutations in the proprotein convertase subtilisin Kexin type I (PCSK1) gene located on 15. (Frank et al. 2013; Martin etal, 2013; Hiirter et al. 2016). PCI isa member ‘of the serine endoproteases family, which is ‘expressed in endocrine and neuronal cells. In the hypothalamus, PC1/3 is involved in the POMC processing, which results in the production of c-MSH (Smith and Funder 1988; Tao 2005; Vetter et al. 2010). Homozygous and compound heterozygous mutations in the PCSKT gene were described in several patients with hyperphagia, severe malabsorptive diarthea, central diabetes insipidus, growth hormone deficiency, primary hypogonadism, and other abnormalities (Frank et al. 2013; Martin et al 2013; Wilschanski et al. 2014; Harter et al 2016). The functional consequences of PCSKI chromosome 5 endocrines ‘mutations may have an important role in the severity and variety of the clinical phenotype (Martin et al. 2013). Interestingly, Philippe et al. 2015) reported a novel nonsense heterozygous mutation in PCSKI that was co-segregate with obesity in a French family, following a dominant mode of inheritance. Therefore, rare pathogenic mutations in PCSKT may be associated with an autosomal dominant or recessive form of Mende- lian obesity (Martin et al. 2013; Philippe et al. 2015), Melanocortin Receptor Genes Melanocortin 4 receptor (MC4R) deficiency (OMIM#618406) is the most common cause of non-syndromic monogenic obesity. This disorder is caused by heterozygous, heterozygous com- pound, and homozygous deleterious variants in MCAR gene, located on chromosome 18q21.32 (Doulla et al. 2014; da Fonseca et al. 2017; Drabkin et al, 2018). Several rare pathogenic variants were identified in the MC4R gene, which could lead to partial or complete loss of receptor function (Collet et al. 2017), MC4R variations are inherited in an autosomal codomi- nant model, with a high degree of expressivity and penetrance in heterozygous carriers (Faroogi ct al. 2003; Faroogi 2015). Previous studies have reported that patients with heterozygous ‘mutations have a less severe phenotype compared to homozygous carriers (Faroogi et al. 2003; Drabkin et al. 2018). MCAR is expressed in the PVN and is the receptor for «MSH, regulating appetite and satiety. Consistent with this role, loss-of-function MC4R variants are associated ‘with hyperphagia and severe early-onset obesity. Moreover, some patients can also exhibit severe hyperinsulinemia and increased linear growth (Faroogi ct al. 2003; Melchior etal. 2012; Doulla et al. 2014; da Fonseca et al. 2019). Recently, our group described for the first time Brazilian case with MCAR start lost mutation (p. Met”), This variant was identified in a 29-years- ‘old female patient with childhood-onset obesity, moderate binge-eating disorder, and high caloric intake (4900 calories per day) (da Fonseca et al 2019b). Since pharmacological agents are beingne A.G.P. da Fonseca etal developed to weat patients with MC4R defi- ciency, it is extremely important to assess the sequence of this gene in severe early-onset abe sity individuals in order to identify pathogenic variations that would benefit from this treatment (Chen et al. 2015; Collet et al. 2017), Setmelanotide has entered two phase III clini- cal trials in 2017, including pro-opiomelanocortin (POMC) deficiency obesity, besides leptin recep- tor (LEPR) deficiency obesity, with encouraging results (Globenewswire.com 2019). Other Genes Besides MC4R protein, BDNF haploinsuf ficiency has also been associated with severe early-onset obesity. This protein is a member of the nerve growth factor family, involved in the proliferation, survival, and differentiation of neurons (Tapia-Arancibia etal. 2004). previous study has also indicated that BDNF acts on leptin- melanocortin pathway and may be a downstream target of MCAR signaling (Xu etal. 2003), Gray etal. (2006) reported a child harboring a de novo chromosomal inversion (46, XX, inv (11) (p13p15.3), which disrupts one copy of BDNF gene located on chromosome 11p13. ‘Additionally, deletion of entire BDNF gene in a mother and a child were associated with severe ‘obesity and developmental delay (Harcourt etal 2018). However, data regarding point pathogenic mutations inthe BDNF are scarce in the literature Recently, Serra-Juhé etal. (2019) have analyzed 463, severe early-onset obese patients and 480 controls from the Spanish population, They identified three rare variants in four patients and none in normal-weight individuals. Two of these mutations were predicted to be pathogenic (p. ec123Val_and p.Cysl4IGly) by in silico analyses. These probands presented obesity and mil to severe hyperphagia. Two ofthese patients also exhibited liver steatosis and insulin resis- tance with dyslipidemia. None of them showed ‘congenital and behavioral issues. ‘Syndromic Form of Obesity ‘Syndromic forms of obesity are used to describe ‘obese subjects with particular phenotypes, such as mental retardation, dysmorphic features, and organ-specific developmental abnormalities. At least four rare syndromes are associated with severe hyperphagia and obesity, caused by chro- ‘mosomal abnormalities and genetic variations in genes that are involved in appetite and satiety control, suggesting an origin at the level of the central nervous system (Bell et al. 2005). Syndromic obesity includes Prader Willi (OMIMA176270), Bardet-Bicdl (OMIM#209900), Alstom (OMIM#203800), and Cohen (OMIM#216550) syndromes (Albuquerque et al. 2015). The genetic basis of these syndromes is extremely heterogeneous, and ‘may be inherited in either an autosomal dominant for a recessive fashion, Prader Willi Syndrome Prader Willi syndrome (PWS) is the most com ‘mon form (1 in 10,000-15,000 live births), alfect- ing an estimated 350,000—100,000 individuals in the world (Irizarry and Hagg 2018). PWS is an autosomal dominant disorder characterized by peculiar facial features, infantile hypotonia, hypo- thalamic hypogonadism, short stature, mild men- tal retardation, and behavioral problems and hyperphagia resulting in severe obesity. Most of the cases are caused by a patemally inherited deletion at the chromosomal region 1Sql1-q13 (70%) and less frequently by maternal uniparen- tal disomy 15 (-20-80%). Additionally, rare cases (-5%) are affected by imprinting defects and chromosome 15 translocations or rearrangements (Bell et al. 2005; Butler 2011; Ivizarry and Flagg 2018). “The responsible gene(s) for PWS development as well as hyperphagia and obesity phenotype in these patients is still unknown, though several candidate genes have been reported. Interestingly, patients with PWS exhibit high plasma levels of ghrelin at any age, suggesting an interaction among increased appetite, obesity, and leptin- melanocortin pathway (Feigerlové et al, 2008),8 Genetic Profiles in the Obese Population no However, ghrelin-reducing agents do not dimin- ish hyperphagia or body mass in subjects with PWS (De Waele et al. 2008). Recently, Burnett and colleagues performed an clegant study showing that neuroendocrine PWS-associated phenotypes may be a result of reduced expression ‘of prohormone convertase 1, which impacts on the processing of proinsulin, pro-GH releasing hormone and proghelin (Bumett et al. 2017) Further studies are necessary to clarify the role ‘of PCI in PWS cases. Bardet-Biedl Syndrome Bardet-Bied! syndrome (BBS) is a rare disorder (1 in 125,000-160,000 in Europe) characterized. by early-onset obesity, progressive rod-cone dys- trophy, polydactyly, learning disabilities, pro- ‘gressive renal dysfunction, hypogonadism, and genital abnormalities (Irizarry and Hagq 2018). It has a typically a autosomal recessive inheri tance, but some families may have a tiallelic mode of transmission (i., interaction of two or more loci) (Beales et al, 2003; Khan et al. 2016). BBS is a genetically heterogencous disorder ‘caused by mutations in atleast 19 foci (also called BBS genes), all of which have a key role in ciliary development or intralagellar transport (Fan etal 2004; Khan etal. 2016; Irizarry and Hagg 2018). Previous functional studies in single-cell ‘organisms have shown that certain BBS genes are specific to ciliated cells, which are important for mammalian development, contributing to correctly position the organs in the body. Dys function in these ciliated cells may explain the alterations in pigmentary epithelial and structural abnormalities; however, the exact mechanisms leading to the obesity phenotype ate still unknown (Irizarry and Hagg 2018). Experimental studies have shown that BBS mice are leptin resistant with decreased expression of POMC, suggesting that BBS genes may have an impor- tant role in maintaining leptin sensitivity in POMC neurons localized into the hypothalamus. ‘These results might suggest that BBS genes can impact on the anorexigenic pathway leading to hyperphagia and obesity (Rahmouni et al. 2008). Alstrom and Cohen Syndrome Alstrom syndrome (AS) is an extremely rare auto- somial recessive disorder caused by mutations in the ALMS1 gene on chromosome 2p13. As cases. exhibit progressive cone-rod dystrophy leading to juvenile blindness, sensorineural hearing loss, ‘and early-onset obesity (Maffei et al. 2017). Screening for ALMS/ gene in these affected patients showed a strong clustering of pathogenic ‘mutations in exons 8, 10, and 16. Moreover, the majority of disease-causing mutations were non- sense or frameshift, which result in premature protein truncation (Irizarry and Hagq 2018). Sim- ilar to BBS, AS is caused by mutations disrupting, neuronal cilia function, which may impact on appetite and satiety responses (Davenport et al 2007), Finally, Cohen syndrome is also an autosomal recessive disease caused by mutations in COHI gene (also called VPS/3B) located at chromo- some 8q22 (Albuquerque et al. 2015). This gene encodes a transmembrane protein that has an important role in the development and function of eye, hematological system, and central nervous system, The mechanism by which abnormalities in this protein lead to the Cohen syndrome phe- notype is still unknown; however, the affected patients show mental retardation, obesity, hypo- tonia and craniofacial, ocular, and limb abnormalities. Pathogenic mutations in COHI are rare around the world, but it is overrepre: sented in some populations, such as Finnish, Jap ancse, Caucasian, and Jewish (Rodrigues ot al. 2018), Polygenic or Common Obesity ‘The common form of obesity is multifactorial and polygenic, caused by an association between environmental factors and multiple genetic variants that have a slight effect on body weigh Several approaches have been used to find genetic variants associated with obesity or obesity-related traits, particularly genome-wide association study (GWAS). This approach evaluates a huge number cof polymorphisms across the genome in a large120 A.G.P. da Fonseca etal sample and through statistical analysis, it allows. identifying the loci associated with shifts of BMI ‘or other anthropometric measurements (for exam: ple, the waist-hip ratio [WHR]) (Albuquerque ct al, 2015; da Fonseca et al. 2017). To date, GWAS discovered more than 100 obesity- associated loci, in which genetic variants explain only a small portion of heritability in obesity (Speliotes et al. 2010; Locke et al. 2015; Wu et al. 2018). Recently, Wu etal. (2018) performed GWAS for BMI and WHR using 242 monozygotic and 140 dizygotic twin pairs. A total of 291 loci were nominally associated with BMI-WHR, playing an important role in different pathways, such as homeostasis, olfactory transduction, and platelet production. Despite the robust studies and the vast number of obesity-associated loci, most of the genetic variability in BMI unexplained, Relevant Candidates ‘Among the loci ientitied by GWAS, FTO gene hhas been consistently associated with obesity in different populations (Frayling ct al. 2007 Albuquerque et al. 2013; da Fonseca et al 2019a). FTO is a nueleie acid demethylase that hhas an important role in energy homeostasis, suggesting that this enzyme influences obesity at the epigenetic level (Gerken eta. 2007). Interest- ingly, polymorphisms in the intron 1 of FTO may have an effect on appetitelsatiety, food choices, ‘expended energy, and body weight (McCaffery et al 2012; Qi et al. 2014; Magno et al. 2018; Rivas et al. 2018). Additionally, several common genetic variants of BDNF gene were associated with obesity or obesity-related traits (Beckers cf al, 2008; Thorleifsson et al. 2009; Spetiotes tal, 2010), A polymomphism (184074134) near BDNF gene was associated with the reduction of BMI and waist circumference in the Norther Han Chinese ancestry (Han et al, 2013). This polymorphism was also associated with obesity in the Japanese population; however, this result ‘was not observed in a Brazilian population (Hotta et al, 2009; da Fonseca et al. 2019). The discrepancy of the results may be explained by differences in the genetic background of the populations. Besides FTO and BDNF, GWAS have also identified other obesity-associated loci that are expressed or known to actin the central nervous system, involved in regulation of food intake and energy expenditure, Several of these genes have been previously associated with severe eatly- onset obesity (MC4R, POMC, SH2BI, and BBS4), suggesting an overlap of the genetic back- ‘ground between monogenic and polygenic form of obesity (Speliotes et al. 2010; Locke et al. 2015), Ongoing Studies and Future Perspectives ‘The use of genetic knowledge to prediet subjects, thigh risk of developing obesity, especially in an fobesogenic environment, may be useful in preventing this disease (Srivastava et al. 2016), Currently, patients with suspicion of monogenic obesity (syndromie and non-syndromic) can be screened based on diagnostic hypothesis using chromosomal microarray analysis, candidate ‘gene sequencing, whole genome/exome sequenc- ing, conventional cytogenetic, and/or fluores cence in situ hybridization. Theses analyses can contribute to identifying the causal variants allowing molecular diagnosis, clinical manage ‘ment, genetic counseling, and in some cases, spe- cific treatment (Pigeyre et al. 2016). Obesity teatment based on genotype (personalized medicine) is being pursued in patients with congenital leptin deficiency, and especially leptin receptor deficiency. caused by pathogenic mutations in LEPR gene. ‘The MC4R agonist (Setmelanotide) has been shown to decrease food intake and body weight in patients POMC deficiency as well. This agonist binds to MCAR in these patients, replacing the ‘missing aMSH activity in the leptin-melanocortin system (Khnen et al. 2016; Collet et al. 2017). Kunen et al. (2016) have treated two POMC deficient suibjects using subcutaneous injection of setmelanotide, Both patients showed a18 Genetic Profiles in the Obese Population 121 substantial reduction in hunger and weight loss (patient 1: 51.0 kg after 42 weeks; patient 2: 20.5 kg after 12 weeks), improving their quality ‘of life. In addition, sctmelanotide can also reduce body weight in MC4R deficient patients (on average 0.6 kg/week). It is speculated that setmelanotide may be effective in treating other ‘genetic obesity disorders, including PCSKI defi- ciency and Prader-Willi syndrome (Kihnen etal 2016), References Albuquerque D, Nobrega C, Manco L (2013) Association ‘of FTO polymorphisms with obesity and obesity- related outcomes in Portuguese children. 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