Genetische Faktoren bei Adipositas

Zusammenfassung

Molekular-genetische Studien konnten bislang nur einen kleinen Anteil der interindividuellen Variabilität des Körpergewichts erklären, obwohl die Erblichkeit hoch ist. Bei den sehr wenigen bislang bekannten monogenen Formen der Adipositas führt der Ausfall eines einzelnen Genproduktes meist zu einer extremen Adipositas. Der größere Teil der Streubreite des Körpergewichts wird mutmaßlich durch das Zusammenspiel vieler einzelner Genvarianten erklärt, wobei jeder einzelnen Variante nur ein geringer Effekt zugeschrieben werden kann (polygene Adipositas). Mittels einer großen Meta-Analyse mit etwa 250 000 Personen europäischer Herkunft wurde eine Vielzahl von genetischen Varianten (so genannten Einzelnukleotidaustauschen) identifiziert, die für die Adipositas relevant sind. Die Effektstärken dieser Varianten auf das Körpergewicht sind zumeist klein, so dass sie insgesamt nur circa 1–2 % der Varianz des Body-Mass-Indexes (BMI) erklären. Neuere Studien beschäftigen sich mit den Wechselwirkungen von genetischen Faktoren und Umweltfaktoren (z.B. Lebensstil) und zeigen, dass einer genetischen Prädisposition z.B. mittels körperlicher Aktivität entgegengewirkt werden kann.

Es gibt momentan keine Konsensuserklärung, weshalb die identifizierten genetischen Faktoren die Erblichkeit bei komplexen Erkrankungen nicht vollständig erklären können. Auch die biologischen und vor allem klinischen Konsequenzen der identifizierten genetischen Varianten sind bislang unklar. Es bleibt weiterhin aktueller Forschungsgegenstand, die Funktionalität einzelner genetischer Bereiche zu untersuchen. Mutmaßlich werden in den nächsten Jahren einige funktionelle Varianten aufgeklärt, wodurch letztendlich ihr vermuteter therapeutischer Nutzen deutlicher warden kann.

Summary

Although the heritability of obesity is high, molecular-genetic studies explain up to now only a small part of the inter-individual variability of body weight. Monogenic obesity is very infrequent; loss of one single gene product leads to extreme obesity. The main part of the variability of body weight seems to be explained by interaction of many gene variants, whereas the effect of each single variant is small (polygenic obesity).

In a large meta-analysis of about 250,000 individuals with European descent more than 30 genetic variants (alleles at so called single nucleotide polymorphisms) were shown to be associated with obesity. The effects of these variants on body weight are small and explain in total only about 1–2% of the variance of the body mass index (BMI).

Recent studies have investigated the interaction of genetic and environmental factors (e.g. lifestyle). They have shown that a genetic predisposition can for instance be attenuated by physical activity. Up to now there is no consensus explanation, why identified genetic variants do not fully explain the heritability of complex diseases. Furthermore, the biological and clinical consequences of these genetic variants are largely unknown. It is a current research challenge, to investigate the function of such genetic variants and regions in order to evaluate the therapeutic relevance of the genetic findings.

Schlüsselwörter

Genetik - Epigenetik - Gen-Umwelt-Interaktion - polygen - monogen - Adipositas

Keywords

Genetics - epigenetics - gene-environment interaction - polygenetic - monogenetic - obesity

• Literatur

• 1 Andreasen CH, Stender-Petersen KL, Mogensen MS. et al. Low physical activity accentuates the effect of the FTO rs9939609 polymorphism on body fat accumulation. Diabetes 2008; 57: 95-101.
• 2 Barker DJ, Osmond C. Infant mortality, childhood nutrition, and ischaemic heart disease in England and Wales. Lancet 1986; 01: 1077-1081.
• 3 Berulava T, Horsthemke B. The obesity-associated SNPs in intron 1 of the FTO gene affect primary transcript levels. Eur J Hum Genet 2010; 18: 1054-1056.
• 4 Bloss CS, Schork NJ, Topol EJ. Effect of direct-toconsumer genomewide profiling to assess disease risk. N Engl J Med 2011; 364: 524-534.
• 5 Blüher S, Sergeyev E, Moser A. et al. Syndromale Adipositas. Adipositas 2011; 05: 195-200.
• 6 Bollati V, Baccarelli A. Environmental epigenetics. Heredity (Edinb) 2010; 105: 105-112.
• 7 Buiting K. Prader-Willi syndrome and Angelman syndrome. Am J Med Genet C Semin Med Genet 2010; 154C: 365-376.
• 8 Delahanty LM, Pan Q, Jablonski KA. et al. Genetic predictors of weight loss and weight regain after intensive lifestyle modification, metformin treatment, or standard care in the Diabetes Prevention Program. Diabetes Care 2012; 35: 363-366.
• 9 Dempfle A, Hinney A, Heinzel-Gutenbrunner M. et al. Large quantitative effect of melanocortin-4 receptor gene mutations on body mass index. J Med Genet 2004; 41: 795-800.
• 10 Djiane J, Attig L. Role of leptin during perinatal metabolic programming and obesity. J Physiol Pharmacol 2008; 59 (Suppl. 01) 55-63.
• 11 Farooqi IS, Jebb SA, Langmack G. et al. Effects of recombinant leptin therapy in a child with congenital leptin deficiency. N Engl J Med 1999; 341: 879-884.
• 12 Fischer J, Koch L, Emmerling C. et al. Inactivation of the Fto gene protects from obesity. Nature 2009; 458: 894-898.
• 13 Fraga MF, Ballestar E, Paz MF. et al. Epigenetic differences arise during the lifetime of monozygotic twins. Proc Natl Acad Sci U S A 2005; 102: 10604-10609.
• 14 Frayling TM, Timpson NJ, Weedon MN. et al. A common variant in the FTO gene is associated with body mass index and predisposes to childhood and adult obesity. Science 2007; 316: 889-894.
• 15 Gerken T, Girard CA, Tung YC. et al. The obesity associated FTO gene encodes a 2-oxoglutarate-dependent nucleic acid demethylase. Science 2007; 318: 1469-1472.
• 16 Geller F, Reichwald K, Dempfle A. et al. Melanocortin-4 receptor gene variant I103 is negatively associated with obesity. Am J Hum Genet 2004; 74: 572-581.
• 17 Gieger C, Geistlinger L, Altmaier E. et al. Genetics meets metabolomics: a genome-wide association study of metabolite profiles in human serum. PLoS Genet 2008; 04: e1000282.
• 18 Grau K, Hansen T, Holst C. et al. Macronutrientspecific effect of FTO rs9939609 in response to a 10-week randomized hypo-energetic diet among obese Europeans. Int J Obes 2009; 33: 1227-1234.
• 19 Hinney A, Bettecken T, Tarnow P. et al. Prevalence, spectrum, and functional characterization of melanocortin-4 receptor gene mutations in a representative population-based sample and obese adults from Germany. J Clin Endocrinol Metab 2006; 91: 1761-1769.
• 20 Hinney A, Nguyen TT, Scherag A. et al. Genome wide association (GWA) study for early onset extreme obesity supports the role of fat mass and obesity associated gene (FTO) variants. PLoS One 2007; 02: e1361.
• 21 Hinney A, Vogel CI, Hebebrand J. From monogenic to polygenic obesity: recent advances. Eur Child Adolesc Psychiatry 2010; 19: 297-310.
• 22 Holzapfel C, Grallert H, Huth C. et al. Genes and lifestyle factors in obesity: results from 12 462 subjects from MONICA/KORA. Int J Obes 2010; 34: 1538-1545.
• 23 Jacquemont S, Reymond A, Zufferey F. et al. Mirror extreme BMI phenotypes associated with gene dosage at the chromosome 16p11.2 locus. Nature 2011; 478: 97-102.
• 24 Jarick I, Vogel CI, Scherag S. et al. Novel common copy number variation for early onset extreme obesity on chromosome 11q11 identified by a genome-wide analysis. Hum Mol Genet 2011; 20: 840-852.
• 25 Kaminsky ZA, Tang T, Wang SC. et al. DNA methylation profiles in monozygotic and dizygotic twins. Nat Genet 2009; 41: 240-245.
• 26 Kilpeläinen TO, Qi L, Brage S. et al. Physical activity attenuates the influence of FTO variants on obesity risk: a meta-analysis of 218,166 adults and 19,268 children. PLoS Med 2011; 08: e1001116.
• 27 Kuehnen P, Mischke M, Wiegand S. et al. An Alu element-associated hypermethylation variant of the POMC gene is associated with childhood obesity. PLoS Genet 2012; 08: e1002543.
• 28 Loos RJ. Genetic determinants of common obesity and their value in prediction. Best Pract Res Clin Endocrinol Metab 2012; 26: 211-226.
• 29 Manolio TA, Collins FS, Cox NJ. et al. Finding the missing heritability of complex diseases. Nature 2009; 461: 747-753.
• 30 Plagemann A, Harder T, Brunn M. et al. Hypothalamic proopiomelanocortin promoter methylation becomes altered by early overfeeding: an epigenetic model of obesity and the metabolic syndrome. J Physiol 2009; 587: 4963-4976.
• 31 Qi Q, Chu AY, Kang JH. et al. Sugar-sweetened beverages and genetic risk of obesity. N Engl J Med 2012; 367: 1387-1396.
• 32 Rief W, Conradt M, Dierk JM. et al. Is information on genetic determinants of obesity helpful or harmful for obese people? – A randomized clinical trial. J Gen Intern Med 2007; 22: 1553-1559.
• 33 Slomko H, Heo HJ, Einstein FH. Minireview: Epigenetics of obesity and diabetes in humans. Endocrinology 2012; 153: 1025-1030.
• 34 Sonestedt E, Roos C, Gullberg B, Ericson U, Wirfalt E, Orho-Melander M. Fat and carbohydrate intake modify the association between genetic variation in the FTO genotype and obesity. Am J Clin Nutr 2009; 90: 1418-1425.
• 35 Speliotes EK, Willer CJ, Berndt SI. et al. Association analyses of 249,796 individuals reveal eighteen new loci associated with body mass index. Nat Genet 2010; 42: 937-948.
• 36 Stunkard AJ, Sorensen TI, Hanis C. et al. An adoption study of human obesity. N Engl J Med 1986; 314: 193-198.
• 37 Stunkard AJ, Foch TT, Hrubec Z. A twin study of human obesity. JAMA 1986; 256: 51-54.
• 38 Stutzmann F, Vatin V, Cauchi S. et al. Non-synonymous polymorphisms in melanocortin-4 receptor protect against obesity: the two facets of a Janus obesity gene. Hum Mol Genet 2007; 16: 1837-1844.
• 39 Wain LV, Armour JA, Tobin MD. Genomic copy number variation, human health, and disease. Lancet 2009; 374: 340-350.
• 40 Walters RG, Jacquemont S, Valsesia A. et al. A new highly penetrant form of obesity due to deletions on chromosome 16p11.2. Nature 2010; 463: 671-675.
• 41 Zhang W, Dolan ME. Impact of the 1000 genomes project on the next wave of pharmacogenomic discovery. Pharmacogenomics 2010; 11: 249-256.