Background/Aims: Children born preterm are more likely than full-term infants to develop eating difficulties that can affect their growth. Although this behavior is certainly influenced by their fetal and postnatal history, a large individual variability exists that results from a complex interaction between genetic and environmental factors. We performed an original pilot study to identify common genetic variants associated with eating difficulties at 2 years of age in the POLYNUCA cohort of preterm infants. Methods: Eating behavior was assessed using a parental questionnaire in a cohort of 234 very preterm infants (including 38 pairs of twins). Eighty-two common single nucleotide polymorphisms (SNPs) were selected in a total of 40 candidate genes involved in the regulation of energy homeostasis and food intake. Results: Eating behavior was strongly correlated in monozygotic (r = 0.92, p = 0.001) but not dizygotic twins (r = 0.27, p = 0.14), suggesting a strong heritability of this trait. One SNP (rs11671975) in the insulin receptor (INSR) gene was significantly associated with eating behavior. This effect was maintained after adjustment for birth weight Z score and maternal education level, two factors that are associated with eating difficulties at 2 years of age. Conclusion: The INSR gene is potentially associated with eating difficulties in preterm infants.

1.
Cerro N, Zeunert S, Simmer KN, Daniels LA: Eating behaviour of children 1.5-3.5 years born preterm: parents' perceptions. J Paediatr Child Health 2002;38:72-78.
2.
Rommel N, De Meyer AM, Feenstra L, Veereman-Wauters G: The complexity of feeding problems in 700 infants and young children presenting to a tertiary care institution. J Pediatr Gastroenterol Nutr 2003;37:75-84.
3.
Samara M, Johnson S, Lamberts K, Marlow N, Wolke D: Eating problems at age 6 years in a whole population sample of extremely preterm children. Dev Med Child Neurol 2010;52:e16-e22.
4.
Casey PH, Whiteside-Mansell L, Barrett K, Bradley RH, Gargus R: Impact of prenatal and/or postnatal growth problems in low birth weight preterm infants on school-age outcomes: an 8-year longitudinal evaluation. Pediatrics 2006;118:1078-1086.
5.
Casey PH: Growth of low birth weight preterm children. Semin Perinatol 2008;32:20-27.
6.
Lapillonne A, Griffin IJ: Feeding preterm infants today for later metabolic and cardiovascular outcomes. J Pediatr 2013;162:S7-S16.
7.
Migraine A, Nicklaus S, Parnet P, Lange C, Monnery-Patris S, Des Robert C, Darmaun D, Flamant C, Amarger V, Roze JC: Effect of preterm birth and birth weight on eating behavior at 2 y of age. Am J Clin Nutr 2013;97:1270-1277.
8.
Bouret SG, Draper SJ, Simerly RB: Trophic action of leptin on hypothalamic neurons that regulate feeding. Science 2004;304:108-110.
9.
Coupe B, Delamaire E, Hoebler C, Grit I, Even P, Fromentin G, Darmaun D, Parnet P: Hypothalamus integrity and appetite regulation in low birth weight rats reared artificially on a high-protein milk formula. J Nutr Biochem 2011;22:956-963.
10.
Coupe B, Grit I, Darmaun D, Parnet P: The timing of ‘catch-up growth' affects metabolism and appetite regulation in male rats born with intrauterine growth restriction. Am J Physiol Regul Integr Comp Physiol 2009;297:R813-R824.
11.
Vieau D, Sebaai N, Leonhardt M, Dutriez-Casteloot I, Molendi-Coste O, Laborie C, Breton C, Deloof S, Lesage J: HPA axis programming by maternal undernutrition in the male rat offspring. Psychoneuroendocrinology 2007;32(suppl 1):S16-S20.
12.
Bouret SG, Simerly RB: Development of leptin-sensitive circuits. J Neuroendocrinol 2007;19:575-582.
13.
Cho CE, Sanchez-Hernandez D, Reza-Lopez SA, Huot PS, Kim YI, Anderson GH: High folate gestational and post-weaning diets alter hypothalamic feeding pathways by DNA methylation in Wistar rat offspring. Epigenetics 2013;8:710-719.
14.
Coupe B, Amarger V, Grit I, Benani A, Parnet P: Nutritional programming affects hypothalamic organization and early response to leptin. Endocrinology 2010;151:702-713.
15.
Crespi EJ, Unkefer MK: Development of food intake controls: neuroendocrine and environmental regulation of food intake during early life. Horm Behav 2014;66:74-85.
16.
Scaglioni S, Arrizza C, Vecchi F, Tedeschi S: Determinants of children's eating behavior. Am J Clin Nutr 2011;94:2006S-2011S.
17.
Blissett J: Relationships between parenting style, feeding style and feeding practices and fruit and vegetable consumption in early childhood. Appetite 2011;57:826-831.
18.
Fisk CM, Crozier SR, Inskip HM, Godfrey KM, Cooper C, Robinson SM: Influences on the quality of young children's diets: the importance of maternal food choices. Br J Nutr 2011;105:287-296.
19.
Jones LR, Steer CD, Rogers IS, Emmett PM: Influences on child fruit and vegetable intake: sociodemographic, parental and child factors in a longitudinal cohort study. Public Health Nutr 2010;13:1122-1130.
20.
Cecil J, Dalton M, Finlayson G, Blundell J, Hetherington M, Palmer C: Obesity and eating behaviour in children and adolescents: contribution of common gene polymorphisms. Int Rev Psychiatry 2012;24:200-210.
21.
Rankinen T, Bouchard C: Genetics of food intake and eating behavior phenotypes in humans. Annu Rev Nutr 2006;26:413-434.
22.
Wardle J, Cooke L: Genetic and environmental determinants of children's food preferences. Br J Nutr 2008;99(suppl 1):S15-S21.
23.
Carnell S, Haworth CM, Plomin R, Wardle J: Genetic influence on appetite in children. Int J Obes (Lond) 2008;32:1468-1473.
24.
de Castro JM: When identical twins differ: an analysis of intrapair differences in the spontaneous eating behavior and attitudes of free-living monozygotic twins. Physiol Behav 2004;82:733-739.
25.
Fildes A, van Jaarsveld CH, Llewellyn CH, Fisher A, Cooke L, Wardle J: Nature and nurture in children's food preferences. Am J Clin Nutr 2014;99:911-917.
26.
Llewellyn CH, van Jaarsveld CH, Boniface D, Carnell S, Wardle J: Eating rate is a heritable phenotype related to weight in children. Am J Clin Nutr 2008;88:1560-1566.
27.
Llewellyn CH, van Jaarsveld CH, Johnson L, Carnell S, Wardle J: Nature and nurture in infant appetite: analysis of the Gemini twin birth cohort. Am J Clin Nutr 2010;91:1172-1179.
28.
Cooke LJ, Haworth CM, Wardle J: Genetic and environmental influences on children's food neophobia. Am J Clin Nutr 2007;86:428-433.
29.
Carnell S, Kim Y, Pryor K: Fat brains, greedy genes, and parent power: a biobehavioural risk model of child and adult obesity. Int Rev Psychiatry 2012;24:189-199.
30.
Bodeau-Livinec F, Zeitlin J, Blondel B, Arnaud C, Fresson J, Burguet A, Subtil D, Marret S, Roze JC, Marchand-Martin L, et al: Do very preterm twins and singletons differ in their neurodevelopment at 5 years of age? Arch Dis Child Fetal Neonatal Ed 2013;98:F480-F487.
31.
Rigal N, Chabanet C, Issanchou S, Monnery-Patris S: Links between maternal feeding practices and children's eating difficulties. Validation of French tools. Appetite 2012;58:629-637.
32.
Dina C, Meyre D, Gallina S, Durand E, Korner A, Jacobson P, Carlsson LM, Kiess W, Vatin V, Lecoeur C, et al: Variation in FTO contributes to childhood obesity and severe adult obesity. Nat Genet 2007;39:724-726.
33.
Willer CJ, Speliotes EK, Loos RJ, Li S, Lindgren CM, Heid IM, Berndt SI, Elliott AL, Jackson AU, Lamina C, et al: Six new loci associated with body mass index highlight a neuronal influence on body weight regulation. Nat Genet 2009;41:25-34.
34.
Bauer F, Elbers CC, Adan RA, Loos RJ, Onland-Moret NC, Grobbee DE, van Vliet-Ostaptchouk JV, Wijmenga C, van der Schouw YT: Obesity genes identified in genome-wide association studies are associated with adiposity measures and potentially with nutrient-specific food preference. Am J Clin Nutr 2009;90:951-959.
35.
Cornelis MC, Rimm EB, Curhan GC, Kraft P, Hunter DJ, Hu FB, van Dam RM: Obesity susceptibility loci and uncontrolled eating, emotional eating and cognitive restraint behaviors in men and women. Obesity (Silver Spring) 2014;22:E135-E141.
36.
Cecil JE, Tavendale R, Watt P, Hetherington MM, Palmer CN: An obesity-associated FTO gene variant and increased energy intake in children. N Engl J Med 2008;359:2558-2566.
37.
Wardle J, Llewellyn C, Sanderson S, Plomin R: The FTO gene and measured food intake in children. Int J Obes (Lond) 2009;33:42-45.
38.
Cecil JE, Watt P, Palmer CN, Hetherington M: Energy balance and food intake: the role of PPARgamma gene polymorphisms. Physiol Behav 2006;88:227-233.
39.
Cole SA, Butte NF, Voruganti VS, Cai G, Haack K, Kent JW Jr, Blangero J, Comuzzie AG, McPherson JD, Gibbs RA: Evidence that multiple genetic variants of MC4R play a functional role in the regulation of energy expenditure and appetite in Hispanic children. Am J Clin Nutr 2010;91:191-199.
40.
den Hoed M, Ekelund U, Brage S, Grontved A, Zhao JH, Sharp SJ, Ong KK, Wareham NJ, Loos RJ: Genetic susceptibility to obesity and related traits in childhood and adolescence: influence of loci identified by genome-wide association studies. Diabetes 2010;59:2980-2988.
41.
Agurs-Collins T, Fuemmeler BF: Dopamine polymorphisms and depressive symptoms predict foods intake. Results from a nationally representative sample. Appetite 2011;57:339-348.
42.
van Strien T, Snoek HM, van der Zwaluw CS, Engels RC: Parental control and the dopamine D2 receptor gene (DRD2) interaction on emotional eating in adolescence. Appetite 2010;54:255-261.
43.
Howe TH, Sheu CF, Wang TN, Hsu YW: Parenting stress in families with very low birth weight preterm infants in early infancy. Res Dev Disabil 2014;35:1748-1756.
44.
Pierrehumbert B, Nicole A, Muller-Nix C, Forcada-Guex M, Ansermet F: Parental post-traumatic reactions after premature birth: implications for sleeping and eating problems in the infant. Arch Dis Child Fetal Neonatal Ed 2003;88:F400-F404.
45.
Burklow KA, McGrath AM, Valerius KS, Rudolph C: Relationship between feeding difficulties, medical complexity, and gestational age. Nutr Clin Pract 2002;17:373-378.
46.
Dodrill P, McMahon S, Ward E, Weir K, Donovan T, Riddle B: Long-term oral sensitivity and feeding skills of low-risk pre-term infants. Early Hum Dev 2004;76:23-37.
47.
McGowan MK, Andrews KM, Fenner D, Grossman SP: Chronic intrahypothalamic insulin infusion in the rat: behavioral specificity. Physiol Behav 1993;54:1031-1034.
48.
White MF: Insulin signaling in health and disease. Science 2003;302:1710-1711.
49.
Woods SC, D'Alessio DA: Central control of body weight and appetite. J Clin Endocrinol Metab 2008;93:S37-S50.
50.
Woods SC, Decke E, Vasselli JR: Metabolic hormones and regulation of body weight. Psychol Rev 1974;81:26-43.
51.
Benoit SC, Air EL, Coolen LM, Strauss R, Jackman A, Clegg DJ, Seeley RJ, Woods SC: The catabolic action of insulin in the brain is mediated by melanocortins. J Neurosci 2002;22:9048-9052.
52.
Mebel DM, Wong JC, Dong YJ, Borgland SL: Insulin in the ventral tegmental area reduces hedonic feeding and suppresses dopamine concentration via increased reuptake. Eur J Neurosci 2012;36:2336-2346.
53.
Meye FJ, Adan RA: Feelings about food: the ventral tegmental area in food reward and emotional eating. Trends Pharmacol Sci 2014;35:31-40.
54.
Labouebe G, Liu S, Dias C, Zou H, Wong JC, Karunakaran S, Clee SM, Phillips AG, Boutrel B, Borgland SL: Insulin induces long-term depression of ventral tegmental area dopamine neurons via endocannabinoids. Nat Neurosci 2013;16:300-308.
55.
Taniguchi CM, Finger EC, Krieg AJ, Wu C, Diep AN, Lagory EL, Wei K, McGinnis LM, Yuan J, Kuo CJ, et al: Cross-talk between hypoxia and insulin signaling through Phd3 regulates hepatic glucose and lipid metabolism and ameliorates diabetes. Nat Med 2013;19:1325-1330.
56.
Burrows T, Warren JM, Baur LA, Collins CE: Impact of a child obesity intervention on dietary intake and behaviors. Int J Obes (Lond) 2008;32:1481-1488.
57.
Carnell S, Wardle J: Measuring behavioural susceptibility to obesity: validation of the child eating behaviour questionnaire. Appetite 2007;48:104-113.
58.
de Lauzon-Guillain B, Jones L, Oliveira A, Moschonis G, Betoko A, Lopes C, Moreira P, Manios Y, Papadopoulos NG, Emmett P, et al: The influence of early feeding practices on fruit and vegetable intake among preschool children in 4 European birth cohorts. Am J Clin Nutr 2013;98:804-812.
59.
Llewellyn CH, Trzaskowski M, van Jaarsveld CH, Plomin R, Wardle J: Satiety mechanisms in genetic risk of obesity. JAMA Pediatr 2014;168:338-144.
60.
Obregon AM, Amador P, Valladares M, Weisstaub G, Burrows R, Santos JL: Melanocortin-3 receptor gene variants: association with childhood obesity and eating behavior in Chilean families. Nutrition 2010;26:760-765.
61.
Rolls BJ, Engell D, Birch LL: Serving portion size influences 5-year-old but not 3-year-old children's food intakes. J Am Diet Assoc 2000;100:232-234.
62.
Cashdan E: A sensitive period for learning about food. Hum Nat 1994;5:279-291.
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