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Integrative Biology

Longitudinal weight differences, gene expression and blood biomarkers in BMI-discordant identical twins

International Journal of Obesity volume 39, pages 899–909 (2015)Cite this article

Subjects

Abstract

Background:

Body mass index (BMI) discordant monozygotic (MZ) twins allow an examination of the causes and consequences of adiposity in a genetically controlled design. Few studies have examined longitudinal BMI discordance in MZ pairs.

Objectives:

The aim of this work was to study the development over time of BMI discordance in adolescent and adult MZ twin pairs and to examine lifestyle, metabolic, inflammatory and gene expression differences associated with concurrent and long-term BMI discordance in MZ pairs.

Subjects/methods:

BMI data from 2775 MZ twin pairs, collected in eight longitudinal surveys and a biobank project between 1991 and 2011, were analyzed to characterize longitudinal discordance. Lifestyle characteristics were compared within discordant pairs (ΔBMI⩾3 kg m−2) and biomarkers (lipids, glucose, insulin, C-reactive protein, fibrinogen, interleukin (IL)-6, tumor necrosis factor-α and soluble IL-6 receptor and liver enzymes aspartate aminotransferase, alanine aminotransferase and gamma glutamyl transferase) and gene expression were compared in peripheral blood from discordant pairs who participated in the Netherlands Twin Register biobank project.

Results:

The prevalence of discordance ranged from 3.2% in 1991 (mean age=17, s.d.=2.4) to 17.4% (N=202 pairs) in 2009 (mean age=35, s.d.=15) and was 16.5% (N=174) among pairs participating in the biobank project (mean age=35, s.d.=12). Of the 699 MZ pairs with BMI data from 3 to 5 time points, 17 pairs (2.4%) were long-term discordant (at all available time points; mean follow-up range=6.4 years). Concurrently discordant pairs showed significant differences in self-ratings of which twin eats most (P=2.3 × 10−13) but not in leisure time exercise activity (P=0.28) and smoking (P>0.05). Ten out of the 14 biomarkers showed significantly more unfavorable levels in the heavier of twin of the discordant pairs (P-values <0.001); most of these biomarker differences were largest in longitudinally discordant pairs. No significant gene expression differences were identified, although high ranking genes were enriched for Gene Ontology terms highlighting metabolic gene regulation and inflammation pathways.

Conclusions:

BMI discordance is uncommon in adolescent identical pairs but increases with higher pair-mean of BMI at older ages, although long-term BMI discordance is rare. In discordant pairs, the heavier twin had a more unfavorable blood biomarker profile than the genetically matched leaner twin, in support of causal effects of obesity.

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References

  1. van Dongen J, Slagboom PE, Draisma HH, Martin NG, Boomsma DI . The continuing value of twin studies in the omics era. Nat Rev Genet 2012; 13: 640–653.

    Article  CAS  Google Scholar 

  2. Zwijnenburg PJG, Meijers Heijboer H, Boomsma DI . Identical but not the same: the value of discordant monozygotic twins in genetic research. Am J Med Genet B Neuropsychiatr Genet 2010; 153: 1134–1149.

    Google Scholar 

  3. Halfvarson J, Jess T, Magnuson A, Montgomery SM, Orholm M, Tysk C et al. Environmental factors in inflammatory bowel disease: a co-twin control study of a Swedish-Danish twin population. Inflamm Bowel Dis 2006; 12: 925–933.

    Article  Google Scholar 

  4. Lehn H, Derks EM, Hudziak JJ, Heutink P, van Beijsterveldt TC, Boomsma DI . Attention problems and attention-deficit/hyperactivity disorder in discordant and concordant monozygotic twins: evidence of environmental mediators. J Am Acad Child Adolesc Psychiatry 2007; 46: 83–91.

    Article  Google Scholar 

  5. Vadlamudi L, Dibbens LM, Lawrence KM, Iona X, McMahon JM, Murrell W et al. Timing of de novo mutagenesis—a twin study of sodium-channel mutations. N Engl J Med 2010; 363: 1335–1340.

    Article  CAS  Google Scholar 

  6. Wong CC, Caspi A, Williams B, Houts R, Craig IW, Mill J . A longitudinal twin study of skewed X chromosome-inactivation. PLoS One 2011; 6: e17873.

    Article  CAS  Google Scholar 

  7. Weksberg R, Shuman C, Caluseriu O, Smith AC, Fei YL, Nishikawa J et al. Discordant KCNQ1OT1 imprinting in sets of monozygotic twins discordant for Beckwith-Wiedemann syndrome. Hum Mol Genet 2002; 11: 1317–1325.

    Article  CAS  Google Scholar 

  8. Schousboe K, Willemsen G, Kyvik KO, Mortensen J, Boomsma DI, Cornes BK et al. Sex differences in heritability of BMI: a comparative study of results from twin studies in eight countries. Twin Res 2003; 6: 409–421.

    Article  Google Scholar 

  9. Mook-Kanamori DO, van Beijsterveldt CE, Steegers EA, Aulchenko YS, Raat H, Hofman A et al. Heritability estimates of body size in fetal life and early childhood. PLoS One 2012; 7: e39901.

    Article  CAS  Google Scholar 

  10. Elks CE, den HM, Zhao JH, Sharp SJ, Wareham NJ, Loos RJ et al. Variability in the heritability of body mass index: a systematic review and meta-regression. Front Endocrinol (Lausanne) 2012; 3: 29.

    Article  Google Scholar 

  11. Hardy R, Wills AK, Wong A, Elks CE, Wareham NJ, Loos RJ et al. Life course variations in the associations between FTO and MC4R gene variants and body size. Hum Mol Genet 2010; 19: 545–552.

    Article  CAS  Google Scholar 

  12. Ye K, Beekman M, Lameijer EW, Zhang Y, Moed MH, van den Akker EB et al. Aging as accelerated accumulation of somatic variants: whole-genome sequencing of centenarian and middle-aged monozygotic twin pairs. Twin Res Hum Genet 2013; 16: 1026–1032.

    Article  Google Scholar 

  13. Naukkarinen J, Rissanen A, Kaprio J, Pietilainen KH . Causes and consequences of obesity: the contribution of recent twin studies. Int J Obes (Lond) 2012; 36: 1017–1024.

    Article  CAS  Google Scholar 

  14. Graner M, Seppala-Lindroos A, Rissanen A, Hakkarainen A, Lundbom N, Kaprio J et al. Epicardial fat, cardiac dimensions, and low-grade inflammation in young adult monozygotic twins discordant for obesity. Am J Cardiol 2012; 109: 1295–1302.

    Article  Google Scholar 

  15. Hakala P, Rissanen A, Koskenvuo M, Kaprio J, Ronnemaa T . Environmental factors in the development of obesity in identical twins. Int J Obes Relat Metab Disord 1999; 23: 746–753.

    Article  CAS  Google Scholar 

  16. Kannisto K, Pietilainen KH, Ehrenborg E, Rissanen A, Kaprio J, Hamsten A et al. Overexpression of 11beta-hydroxysteroid dehydrogenase-1 in adipose tissue is associated with acquired obesity and features of insulin resistance: studies in young adult monozygotic twins. J Clin Endocrinol Metab 2004; 89: 4414–4421.

    Article  CAS  Google Scholar 

  17. Kaye SM, Pietilainen KH, Kotronen A, Joutsi-Korhonen L, Kaprio J, Yki-Jarvinen H et al. Obesity-related derangements of coagulation and fibrinolysis: a study of obesity-discordant monozygotic twin pairs. Obesity (Silver Spring) 2012; 20: 88–94.

    Article  CAS  Google Scholar 

  18. Mustelin L, Pietilainen KH, Rissanen A, Sovijarvi AR, Piirila P, Naukkarinen J et al. Acquired obesity and poor physical fitness impair expression of genes of mitochondrial oxidative phosphorylation in monozygotic twins discordant for obesity. Am J Physiol Endocrinol Metab 2008; 295: E148–E154.

    Article  CAS  Google Scholar 

  19. Pietilainen KH, Rissanen A, Kaprio J, Makimattila S, Hakkinen AM, Westerbacka J et al. Acquired obesity is associated with increased liver fat, intra-abdominal fat, and insulin resistance in young adult monozygotic twins. Am J Physiol Endocrinol Metab 2005; 288: E768–E774.

    Article  Google Scholar 

  20. Pietilainen KH, Kannisto K, Korsheninnikova E, Rissanen A, Kaprio J, Ehrenborg E et al. Acquired obesity increases CD68 and tumor necrosis factor-alpha and decreases adiponectin gene expression in adipose tissue: a study in monozygotic twins. J Clin Endocrinol Metab 2006; 91: 2776–2781.

    Article  CAS  Google Scholar 

  21. Pietilainen KH, Bergholm R, Rissanen A, Kaprio J, Hakkinen AM, Sattar N et al. Effects of acquired obesity on endothelial function in monozygotic twins. Obesity (Silver Spring) 2006; 14: 826–837.

    Article  Google Scholar 

  22. Pietilainen KH, Sysi-Aho M, Rissanen A, Seppanen-Laakso T, Yki-Jarvinen H, Kaprio J et al. Acquired obesity is associated with changes in the serum lipidomic profile independent of genetic effects—a monozygotic twin study. PLoS One 2007; 2: e218.

    Article  Google Scholar 

  23. Pietilainen KH, Naukkarinen J, Rissanen A, Saharinen J, Ellonen P, Keranen H et al. Global transcript profiles of fat in monozygotic twins discordant for BMI: pathways behind acquired obesity. PLoS Med 2008; 5: e51.

    Article  Google Scholar 

  24. Pietiläinen KH, Rissanen A, Laamanen M, Lindholm AK, Markkula H, Yki-Jarvinen H et al. Growth patterns in young adult monozygotic twin pairs discordant and concordant for obesity. Twin Res 2004; 7: 421–429.

    Article  Google Scholar 

  25. Rissanen A, Hakala P, Lissner L, Mattlar CE, Koskenvuo M, Ronnemaa T . Acquired preference especially for dietary fat and obesity: a study of weight-discordant monozygotic twin pairs. Int J Obes Relat Metab Disord 2002; 26: 973–977.

    Article  CAS  Google Scholar 

  26. Mitchell KS, Mazzeo SE, Aggen SH, Maes HH, Kendler KS, Neale MC et al. Characteristics of monozygotic male and female twins discordant for overweight: a descriptive study. Eat Behav 2008; 9: 366–369.

    Article  Google Scholar 

  27. Souren NY, Tierling S, Fryns JP, Derom C, Walter J, Zeegers MP . DNA methylation variability at growth-related imprints does not contribute to overweight in monozygotic twins discordant for BMI. Obesity (Silver Spring) 2011; 19: 1519–1522.

    Article  CAS  Google Scholar 

  28. Dandona P, Aljada A, Chaudhuri A, Mohanty P, Garg R . Metabolic syndrome: a comprehensive perspective based on interactions between obesity, diabetes, and inflammation. Circulation 2005; 111: 1448–1454.

    Article  Google Scholar 

  29. Dantzer R, O'Connor JC, Freund GG, Johnson RW, Kelley KW . From inflammation to sickness and depression: when the immune system subjugates the brain. Nat Rev Neurosci 2008; 9: 46–56.

    Article  CAS  Google Scholar 

  30. Festa A, D'Agostino Jr R, Tracy RP, Haffner SM . Elevated levels of acute-phase proteins and plasminogen activator inhibitor-1 predict the development of type 2 diabetes: the insulin resistance atherosclerosis study. Diabetes 2002; 51: 1131–1137.

    Article  CAS  Google Scholar 

  31. Hansson GK . Inflammation, atherosclerosis, and coronary artery disease. N Engl J Med 2005; 352: 1685–1695.

    Article  CAS  Google Scholar 

  32. Hotamisligil GS, Shargill NS, Spiegelman BM . Adipose expression of tumor necrosis factor-alpha: direct role in obesity-linked insulin resistance. Science 1993; 259: 87–91.

    Article  CAS  Google Scholar 

  33. Miller AH, Maletic V, Raison CL . Inflammation and its discontents: the role of cytokines in the pathophysiology of major depression. Biol Psychiatry 2009; 65: 732–741.

    Article  CAS  Google Scholar 

  34. Nomiyama T, Perez-Tilve D, Ogawa D, Gizard F, Zhao Y, Heywood EB et al. Osteopontin mediates obesity-induced adipose tissue macrophage infiltration and insulin resistance in mice. J Clin Invest 2007; 117: 2877–2888.

    Article  CAS  Google Scholar 

  35. Hotamisligil GS . Endoplasmic reticulum stress and the inflammatory basis of metabolic disease. Cell 2010; 140: 900–917.

    Article  CAS  Google Scholar 

  36. Ozcan U, Cao Q, Yilmaz E, Lee AH, Iwakoshi NN, Ozdelen E et al. Endoplasmic reticulum stress links obesity, insulin action, and type 2 diabetes. Science 2004; 306: 457–461.

    Article  Google Scholar 

  37. Stienstra R, Tack CJ, Kanneganti TD, Joosten LA, Netea MG . The inflammasome puts obesity in the danger zone. Cell Metab 2012; 15: 10–18.

    Article  CAS  Google Scholar 

  38. Strowig T, Henao-Mejia J, Elinav E, Flavell R . Inflammasomes in health and disease. Nature 2012; 481: 278–286.

    Article  CAS  Google Scholar 

  39. Srinivasan SR, Bao W, Wattigney WA, Berenson GS . Adolescent overweight is associated with adult overweight and related multiple cardiovascular risk factors: the Bogalusa Heart Study. Metabolism 1996; 45: 235–240.

    Article  CAS  Google Scholar 

  40. Elder SJ, Lichtenstein AH, Pittas AG, Roberts SB, Fuss PJ, Greenberg AS et al. Genetic and environmental influences on factors associated with cardiovascular disease and the metabolic syndrome. J Lipid Res 2009; 50: 1917–1926.

    Article  CAS  Google Scholar 

  41. Freathy RM, Bennett AJ, Ring SM, Shields B, Groves CJ, Timpson NJ et al. Type 2 diabetes risk alleles are associated with reduced size at birth. Diabetes 2009; 58: 1428–1433.

    Article  CAS  Google Scholar 

  42. Horikoshi M, Yaghootkar H, Mook-Kanamori DO, Sovio U, Taal HR, Hennig BJ et al. New loci associated with birth weight identify genetic links between intrauterine growth and adult height and metabolism. Nat Genet 2013; 45: 76–82.

    Article  CAS  Google Scholar 

  43. Boomsma DI, de Geus EJ, Vink JM, Stubbe JH, Distel MA, Hottenga JJ et al. Netherlands Twin Register: from twins to twin families. Twin Res Hum Genet 2006; 9: 849–857.

    Article  Google Scholar 

  44. Willemsen G, de Geus EJ, Bartels M, van Beijsterveldt CE, Brooks AI, Estourgie-van Burk GF et al. The Netherlands Twin Register biobank: a resource for genetic epidemiological studies. Twin Res Hum Genet 2010; 13: 231–245.

    Article  Google Scholar 

  45. Willemsen G, Vink JM, Abdellaoui A, den BA, van Beek JH, Draisma HH et al. The adult Netherlands twin register: twenty-five years of survey and biological data collection. Twin Res Hum Genet 2013; 16: 271–281.

    Article  Google Scholar 

  46. Jansen R, Batista S, Brooks AI, Tischfield JA, Willemsen G, van GG et al. Sex differences in the human peripheral blood transcriptome. BMC Genomics 2014; 15: 33.

    Article  Google Scholar 

  47. Wright FA, Sullivan PF, Brooks AI, Zou F, Sun W, Xia K et al. Heritability and genomics of gene expression in peripheral blood. Nat Genet 2014; 46: 430–437.

    Article  CAS  Google Scholar 

  48. R Core Team R: A language and environment for statistical computing. R Foundation for Statistical Computing: Vienna, Austria. http://www.R-project.org/ 2013.

  49. Speliotes EK, Willer CJ, Berndt SI, Monda KL, Thorleifsson G, Jackson AU et al. Association analyses of 249,796 individuals reveal 18 new loci associated with body mass index. Nat Genet 2010; 42: 937–948.

    Article  CAS  Google Scholar 

  50. Eden E, Navon R, Steinfeld I, Lipson D, Yakhini Z . GOrilla: a tool for discovery and visualization of enriched GO terms in ranked gene lists. BMC Bioinformatics 2009; 10: 48.

    Article  Google Scholar 

  51. Mootha VK, Lindgren CM, Eriksson KF, Subramanian A, Sihag S, Lehar J et al. PGC-1alpha-responsive genes involved in oxidative phosphorylation are coordinately downregulated in human diabetes. Nat Genet 2003; 34: 267–273.

    Article  CAS  Google Scholar 

  52. Subramanian A, Tamayo P, Mootha VK, Mukherjee S, Ebert BL, Gillette MA et al. Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles. Proc Natl Acad Sci USA 2005; 102: 15545–15550.

    Article  CAS  Google Scholar 

  53. Pietilainen KH, Korkeila M, Bogl LH, Westerterp KR, Yki-Jarvinen H, Kaprio J et al. Inaccuracies in food and physical activity diaries of obese subjects: complementary evidence from doubly labeled water and co-twin assessments. Int J Obes (Lond) 2010; 34: 437–445.

    Article  CAS  Google Scholar 

  54. Knowler WC, Fowler SE, Hamman RF, Christophi CA, Hoffman HJ, Brenneman AT et al. 10-year follow-up of diabetes incidence and weight loss in the Diabetes Prevention Program Outcomes Study. Lancet 2009; 374: 1677–1686.

    Article  Google Scholar 

  55. Safer DJ . Diet, behavior modification, and exercise: a review of obesity treatments from a long-term perspective. South Med J 1991; 84: 1470–1474.

    Article  CAS  Google Scholar 

  56. Sims EA, Horton ES . Endocrine and metabolic adaptation to obesity and starvation. Am J Clin Nutr 1968; 21: 1455–1470.

    Article  CAS  Google Scholar 

  57. Rosen ED, Spiegelman BM . Adipocytes as regulators of energy balance and glucose homeostasis. Nature 2006; 444: 847–853.

    Article  CAS  Google Scholar 

  58. Jinks JL, Fulker DW . Comparison of the biometrical genetical, MAVA, and classical approaches to the analysis of the human behavior. Psychol Bull 1970; 73: 311–349.

    Article  CAS  Google Scholar 

  59. Hussain SS, Bloom SR . The regulation of food intake by the gut-brain axis: implications for obesity. Int J Obes (Lond) 2013; 37: 625–633.

    Article  CAS  Google Scholar 

  60. Alberti KG, Eckel RH, Grundy SM, Zimmet PZ, Cleeman JI, Donato KA et al. Harmonizing the metabolic syndrome: a joint interim statement of the International Diabetes Federation Task Force on Epidemiology and Prevention; National Heart, Lung, and Blood Institute; American Heart Association; World Heart Federation; International Atherosclerosis Society; and International Association for the Study of Obesity. Circulation 2009; 120: 1640–1645.

    Article  CAS  Google Scholar 

  61. Wang XA, Zhang R, Zhang S, Deng S, Jiang D, Zhong J et al. Interferon regulatory factor 7 deficiency prevents diet-induced obesity and insulin resistance. Am J Physiol Endocrinol Metab 2013; 305: E485–E495.

    Article  CAS  Google Scholar 

  62. Vandanmagsar B, Youm YH, Ravussin A, Galgani JE, Stadler K, Mynatt RL et al. The NLRP3 inflammasome instigates obesity-induced inflammation and insulin resistance. Nat Med 2011; 17: 179–188.

    Article  CAS  Google Scholar 

  63. Sanchez J, Priego T, Pico C, Ahrens W, De HS, Fraterman A et al. Blood cells as a source of transcriptional biomarkers of childhood obesity and its related metabolic alterations: results of the IDEFICS study. J Clin Endocrinol Metab 2012; 97: E648–E652.

    Article  CAS  Google Scholar 

  64. Telle-Hansen VH, Halvorsen B, Dalen KT, Narverud I, Wesseltoft-Rao N, Granlund L et al. Altered expression of genes involved in lipid metabolism in obese subjects with unfavourable phenotype. Genes Nutr 2013; 8: 425–434.

    Article  CAS  Google Scholar 

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Acknowledgements

This work was supported by Genetics of Mental Illness: a lifespan approach to the genetics of childhood and adult neuropsychiatric disorders and comorbid conditions (ERC-230374). We thank all the twins who participated in this study.

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Authors and Affiliations

  1. Department of Biological Psychology, VU University Amsterdam, Amsterdam, The Netherlands

    J van Dongen, G Willemsen, E J C de Geus & D I Boomsma

  2. EMGO Institute for Health and Care Research, VU University Medical Center, Amsterdam, The Netherlands

    J van Dongen, G Willemsen, B W J Penninx, E J C de Geus & D I Boomsma

  3. Department of Molecular Epidemiology, Leiden University Medical Center, Leiden, The Netherlands

    B T Heijmans & P E Slagboom

  4. Good Biomarker Sciences, Leiden, The Netherlands

    J Neuteboom & C Kluft

  5. Department of Psychiatry, VU University Medical Center, Amsterdam, The Netherlands

    R Jansen & B W J Penninx

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  1. J van Dongen
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  2. G Willemsen
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Correspondence to J van Dongen.

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van Dongen, J., Willemsen, G., Heijmans, B. et al. Longitudinal weight differences, gene expression and blood biomarkers in BMI-discordant identical twins. Int J Obes 39, 899–909 (2015). https://doi.org/10.1038/ijo.2015.24

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