GENETICS OF OBESITY

Year 2023, Volume: 30 Issue: 4, 754 - 762, 30.12.2023

Melda Şahin , Uğur Şahin , Mustafa Calapoğlu

https://doi.org/10.17343/sdutfd.1319203

Abstract

Obesity is associated with many chronic diseases
that involve genetic and environmental factors
and are governed by their complex interactions.
Genetics is estimated to play an important role in
the predisposition to obesity and may contribute up
to 70% risk for the disease. Genetic studies have
confirmed that genes are contributory factors for
obesity. Anomalies in genes are directly responsible
for obesity-related disorders such as Bardet-Biedl
and Prader-Willi syndromes. Genetic epidemiological
approaches, particularly genome-wide association
studies, have identified numerous genes which play
important roles in human obesity. In the future, further
investigation of obesity genetics may help to develop
useful diagnostic and predictive tests for obesity
treatment. In this review, information supported by
the current literature about the genetics of obesity has
been conveyed.

Keywords

Obesity, Genetics, Gene, Heritability

OBEZİTENİN GENETİĞİ

Abstract

Obezite, genetik, çevresel faktörler ve bunların karmaşık
etkileşimleri tarafından yönetilen birçok kronik
hastalık ile ilişkilidir. Genetiğin obeziteye yatkınlıkta
önemli rol oynadığı ve hastalık riskine %70'e kadar
katkıda bulunabileceği tahmin edilmektedir. Yapılan
genetik çalışmalar, genlerin obeziteye katkıda bulunduğunu
doğrulamıştır. Genlerdeki anomaliler, Bardet-
Biedl ve Prader-Willi sendromları gibi obezite ile
ilişkili bozukluklardan doğrudan sorumludur. Genetik
epidemiyolojik yaklaşımlar, özellikle genom çapında
ilişkilendirme çalışmaları, insan obezitesinde önemli
rol oynayan çok sayıda geni tanımlamıştır. Gelecekte,
obezite genetiğinin daha fazla araştırılması,
obezite tedavisi için yararlı teşhis testleri geliştirmeye
yardımcı olabilir. Bu derleme ile obezite genetiği hakkında
güncel literatür ile desteklenmiş bilgiler aktarılmıştır.

Keywords

Obezite, Genetik, Gen, Kalıtım

References

• 1. Bautista RJH, Mahmoud AM, Königsberg M, Guerrero NELD. Obesity: Pathophysiology, monosodium glutamate-induced model and anti-obesity medicinal plants. Biomedicine & Pharmacotherapy 2019;111:503-516.
• 2. Jaacks LM, Vandevijvere S, Pan A, McGowan CJ, Wallace C, Imamura F, Ezzati M. The obesity transition: stages of the global epidemic. The lancet Diabetes & endocrinology 2019; 7(3);231-240.
• 3. Sarma S, Sockalingam S, Dash S. Obesity as a multisystem disease: Trends in obesity rates and obesity‐related complications. Diabetes, Obesity and Metabolism 2021;23:3-16.
• 4. Goodarzi MO. Genetics of obesity: what genetic association studies have taught us about the biology of obesity and its complications. The lancet Diabetes & Endocrinology 2018;6(3): 223-236.
• 5. Loos RJ, Yeo GS. The genetics of obesity: from discovery to biology. Nature Reviews Genetics 2022;23(2):120-133.
• 6. Golden A, Kessler C. Obesity and genetics. Journal of the American Association of Nurse Practitioners 2020;32(7):493-496.
• 7. Duis J, Butler MG. Syndromic and Nonsyndromic Obesity: Underlying Genetic Causes in Humans. Advanced Biology 2022;6(10):2101154.
• 8. Hurt RT, Frazier TH, McClave SA, Kaplan LM. Obesity epidemic: overview, pathophysiology, and the intensive care unit conundrum. Journal of Parenteral and Enteral Nutrition 2011;35:4S-13S.
• 9. Mahmoud R, Kimonis V, Butler MG. Genetics of obesity in humans: A clinical review. International Journal of Molecular Sciences 2022;23(19):11005.
• 10. Singh RK, Kumar P, Mahalingam K. Molecular genetics of human obesity: A comprehensive review. Comptes Rendus Biologies 2017;340(2);87-108.
• 11. Huvenne H, Dubern B, Clément K, Poitou C. Rare genetic forms of obesity: clinical approach and current treatments in 2016. Obesity Facts 2016;9(3):158-173.
• 12. Thaker VV. Genetic and epigenetic causes of obesity. Adolescent Medicine: State of the Art Reviews 2017;28(2):379.
• 13. Rohde K, Keller M, la Cour Poulsen L, Blüher M, Kovacs P, Böttcher Y. Genetics and Epigenetics in Obesity. Metabolism 2019:92;37-50.
• 14. Khera AV, Chaffin M, Wade KH, Zahid S, Brancale J, Xia R, et al. Polygenic prediction of weight and obesity trajectories from birth to adulthood. Cell 2019;177(3):587-596.e9.
• 15. Tallon JM, Narciso J, Barros A, Pereira A, Costa AM, Silva AJ. Obesity: nutrition and genetics—a short narrative review. Health 2018;10(12):1779-1788.
• 16. Speakman JR, Loos RJF, O’Rahilly S, Hirschhorn JN, Allison DB. GWAS for BMI: a treasure trove of fundamental insights into the genetic basis of obesity. International Journal of Obesity 2018; 42(8):1524-1531.
• 17. Verras GI, Tchabashvili L, Chlorogiannis DD, Mulita F, Argentou MI. Updated clinical evidence on the role of adipokines and breast cancer: a review. Cancers 2023;15(5):1572.
• 18. Gereau GB, Garrison SKD, McElligott ZA. Neurotensin and energy balance. Journal of Neurochemistry 166(2):189-200. doi: 10.1111/jnc.15868.
• 19. Vohra MS, Benchoula K, Serpell CJ, Hwa WE. AgRP/NPY and POMC neurons in the arcuate nucleus and their potential role in treatment of obesity. European Journal of Pharmacology 2022;915: 174611.
• 20. Fairbrother U, Kidd E, Malagamuwa T, Walley A. Genetics of severe obesity. Current Diabetes Reports 2018;18(10):1-9.
• 21. Vatier C, Gautier JF, Vigouroux C. Therapeutic use of recombinant methionyl human leptin. Biochimie 2012; 94(10): 2116- 2125.
• 22. Farooqi IS. Genetic and hereditary aspects of childhood obesity. Best Practice & Research Clinical Endocrinology & Metabolism 2005;19(3):359-374.
• 23. Shakya M, White A, Verchere CB, Low MJ, Lindberg I. Mice lacking PC1/3 expression in POMC-expressing cells do not develop obesity. Endocrinology 2021;162(6):bqab055.
• 24. Hilado MA, Randhawa RS. A novel mutation in the proopiomelanocortin (POMC) gene of a Hispanic child: metformin treatment shows a beneficial impact on the body mass index. Journal of Pediatric Endocrinology and Metabolism 2018;31(7):815-819.
• 25. Baxter J, Armijo PR, Flores L, Krause C, Samreen S, Tanner T. Updates on monogenic obesity in a multifactorial disease. Obesity Surgery 2019;29:4077-4083.
• 26. Kühnen P, Krude H, Biebermann H. Melanocortin-4 receptor signalling: importance for weight regulation and obesity treatment. Trends in Molecular Medicine 2019;25(2):136-148.
• 27. Krashes MJ, Lowell BB, Garfield AS. Melanocortin-4 receptor– regulated energy homeostasis. Nature Neuroscience 2016;19(2):206-219.
• 28. Chiurazzi M, Cozzolino M, Orsini RC, Di Maro M, Di Minno MND, Colantuoni A. Impact of genetic variations and epigenetic mechanisms on the risk of obesity. International Journal of Molecular Sciences 2020;21(23):9035.
• 29. Hainer V, Hainerová IA, Kunešová M, Braunerová RT, Zamrazilova H, Bendlová B. Melanocortin pathways: suppressed and stimulated melanocortin-4 receptor (MC4R). Physiological Research 2020;69(2):S245.
• 30. Xi B, Takeuchi F, Chandak GR, Kato N, Pan HW, AGEN-T2D Consortium, Mi J. Common polymorphism near the MC4R gene is associated with type 2 diabetes: data from a meta-analysis of 123,373 individuals. Diabetologia 2012;55:2660-2666.
• 31. Mǎrginean CO, Mǎrginean C, Meliţ LE. New insights regarding genetic aspects of childhood obesity: a minireview. Frontiers in Pediatrics 2018;6:271.
• 32. Speakman JR, Rance KA, Johnstone AM. Polymorphisms of the FTO Gene Are Associated with Variation in Energy Intake, but Not Energy Expenditure. Obesity 2008;16:1961-1965.
• 33. Kaur Y, De Souza RJ, Gibson WT, Meyre D. A systematic review of genetic syndromes with obesity. Obesity Reviews 2017;18(6):603-634.
• 34. Bellad, A, Bandari AK, Pandey A, Girimaji SC, Muthusamy B. A novel missense variant in PHF6 gene causing Börjeson-Forssman- Lehman syndrome. Journal of Molecular Neuroscience 2020;70: 1403-1409.
• 35. Hidestrand P, Vasconez H, Cottrill C. Carpenter syndrome. Journal of Craniofacial Surgery 2009;20(1):254-256.
• 36. Gupta D, Goyal S. Cornelia de-Lange syndrome. Journal of the Indian Society of Pedodontics & Preventive Dentistry 2005;23(1).
• 37. Raible SE, Mehta D, Bettale C, Fiordaliso S, Kaur M, Medne L, Izumi K. Clinical and molecular spectrum of CHOPS syndrome. American Journal of Medical Genetics Part A 2019;179(7):1126- 1138.
• 38. Abidi FE, Cardoso C, Lossi AM, Lowry, RB, Depetris D, Mattei MG, ve ark. Mutation in the 5’ alternatively spliced region of the XNP/ATR-X gene causes Chudley-Lowry syndrome. European Journal of Human Genetics 2005;13:176–183.
• 39. Rogers RC. Coffin–Lowry Syndrome. Cassidy and Allanson's Management of Genetic Syndromes 2021;171-184.
• 40. Willemsen MH, Vulto-van Silfhout AT, Nillesen WM, Wissink- Lindhout WM, van Bokhoven H, Philip N, Kleefstra T. Update on Kleefstra syndrome. Molecular Syndromology, 2011;2(3-5):202-212.
• 41. Milani D, Manzoni FMP, Pezzani L, Ajmone P, Gervasini C, Menni F, Esposito S. Rubinstein-Taybi syndrome: clinical features, genetic basis, diagnosis, and management. Italian Journal of Pediatrics 2015; 41(1):1-9.
• 42. Kagami M, Nagasaki K, Kosaki R, Horikawa R, Naiki Y, Saitoh S, Ogata T. Temple syndrome: comprehensive molecular and clinical findings in 32 Japanese patients. Genetics in Medicine 2017;19(12):1356-1366.
• 43. Delvallée C, Nicaise S, Antin M, Leuvrey AS, Nourisson E, Leitch CC, Muller J. A BBS1 SVA F retrotransposon insertion is a frequent cause of Bardet‐Biedl syndrome. Clinical Genetics 2021;99(2):318-324.
• 44. Marchese E, Ruoppolo M, Perna A, Capasso G, Zacchia M. Exploring key challenges of understanding the pathogenesis of kidney disease in Bardet–Biedl syndrome. Kidney International Reports 2020;5(9):1403-1415.
• 45. Florea L, Caba L, Gorduza EV. Bardet–Biedl syndrome—Multiple kaleidoscope images: insight into mechanisms of genotype– phenotype correlations. Genes 2021;12(9):1353.
• 46. Hu S, Huang B, Loi K, Chen X, Ding Q, Luo L, Yang W. Patients with Prader-Willi Syndrome (PWS) Underwent Bariatric Surgery Benefit more from High-Intensity Home Care. Obesity Surgery 2022;32(5):1631-1640.
• 47. Bittel DC, Butler MG. Prader–Willi syndrome: clinical genetics, cytogenetics and molecular biology. Expert Reviews in Molecular Medicine 2005;7(14):1-20.
• 48. Butler MG. Single gene and syndromic causes of obesity: Illustrative examples. Progress in Molecular Biology and Translational Science 2016;140:1-45.
• 49. Gardner RM, Sutherland GR, Shaffer LG. Chromosome Abnormalities and Genetic Counseling. 4th ed. Oxford University Press: 2012.
• 50. Kang S. Adipose tissue malfunction drives metabolic dysfunction in Alström syndrome. Diabetes 2021;70(2):323-325.
• 51. Li G, Vega R, Nelms K, Gekakis N, Goodnow C, McNamara P, Glynne R. A role for Alström syndrome protein, alms1, in kidney ciliogenesis and cellular quiescence. PLoS Genetics 2007;3(1): e8.
• 52. Usher LV, DaWalt LS, Hong J, Greenberg JS, Mailick MR. Trajectories of change in the behavioral and health phenotype of adolescents and adults with fragile X syndrome and intellectual disability: Longitudinal trends over a decade. Journal of Autism and Developmental Disorders 2020; 50(8):2779-2792.
• 53. Choo TH, Xu Q, Budimirovic D, Lozano R, Esler AN, Frye RE, Velinov M. Height and BMI in fragile X syndrome: A longitudinal assessment. Obesity 2022;30(3):743-750.
• 54. Kidd SA, Lachiewicz A, Barbouth D, Blitz RK, Delahunty C, McBrien D, Berry-Kravis E. Fragile X syndrome: a review of associated medical problems. Pediatrics 2014;134(5):995-1005.
• 55. Flores-Aguilar L, Iulita MF, Kovecses O, Torres MD, Levi SM, Zhang Y, Cuello AC. Evolution of neuroinflammation across the lifespan of individuals with Down syndrome. Brain 2020; 143(12):3653-3671.
• 56. Asim A, Kumar A, Muthuswamy S, Jain S, Agarwal S. Down syndrome: an insight of the disease. Journal of Biomedical Science 2015;22(1):1-9.
• 57. Nordstrøm M, Retterstøl K, Hope S, Kolset SO. Nutritional challenges in children and adolescents with Down syndrome. The Lancet Child & Adolescent Health 2020;4(6):455-464.
• 58. Fructuoso M, Rachdi L, Philippe E, Denis RG, Magnan C, Le Stunff H, Dierssen M. Increased levels of inflammatory plasma markers and obesity risk in a mouse model of Down syndrome. Free Radical Biology and Medicine 2018;114:122-130.
• 59. McMullan P, Maye P, Yang Q, Rowe DW, Germain‐Lee EL. Parental origin of Gsα inactivation differentially affects bone remodeling in a mouse model of Albright hereditary osteodystrophy. JBMR Plus 2022;6(1):e10570.
• 60. Butler MG. Imprinting disorders in humans: a review. Current Opinion in Pediatrics 2020; 32(6):719.
• 61. Tam V, Turcotte M, Meyre D. Established and emerging strategies to crack the genetic code of obesity. Obesity Reviews 2019;20(2):212-240.
• 62. Han JC. Rare syndromes and common variants of the brain-derived neurotrophic factor gene in human obesity. Progress in Molecular Biology and Translational Science 2016;140:75-95.
• 63. Pandit M, Behl T, Sachdeva M, Arora S. Role of brain derived neurotropic factor in obesity. Obesity Medicine 2020;17:100189.
• 64. Geets E, Meuwissen ME, Van Hul W. Clinical, molecular genetics and therapeutic aspects of syndromic obesity. Clinical Genetics 2019;95(1):23-40.
• 65. Rodrigues JM, Fernandes HD, Caruthers C, Braddock SR, Knutsen AP. Cohen syndrome: review of the literature. Cureus 2018;10(9).
• 66. Uyhazi KE, Binenbaum G, Carducci N, Zackai EH, Aleman, TS. Early photoreceptor outer segment loss and retinoschisis in Cohen syndrome. Ophthalmic Genetics 2018;39(3):399-404.
• 67. Limoge F, Faivre L, Gautier T, Petit JM, Gautier E, Masson D, Duplomb L. Insulin response dysregulation explains abnormal fat storage and increased risk of diabetes mellitus type 2 in Cohen Syndrome. Human Molecular Genetics 2015;24(23):6603-6613.
• 68. Stryjecki C, Alyass A, Meyre D. Ethnic and population differences in the genetic predisposition to human obesity. Obesity Reviews 2018;19(1):62-80.
• 69. Smith AC, Gropman AL. Smith–Magenis Syndrome. Cassidy and Allanson's Management of Genetic Syndromes 2021;863- 893.
• 70. Gandhi A, Wilson T, Foster R, Sisley S, Elsea S. Relationships between food-related behaviors, hyperphagia, obesity, and medication use in Smith-Magenis syndrome. Genetics in Medicine 2022;24(3):S79.
• 71. Chen K, Wang H, Lai Y. Kallmann Syndrome Due to Heterozygous Mutation in SOX10 Coexisting With Waardenburg Syndrome Type II: Case Report and Review of Literature. Frontiers in Endocrinology 2021;11:592831.
• 72. Stamou MI, Georgopoulos NA. Kallmann syndrome: phenotype and genotype of hypogonadotropic hypogonadism. Metabolism 2018;86:124-134.
• 73. Amato LGL, Montenegro LR, Lerario AM, Jorge AAL, Guerra Junior G, Schnoll C, Silveira LFG. New genetic findings in a large cohort of congenital hypogonadotropic hypogonadism. European Journal of Endocrinology 2019;181(2):103-119.