Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Article
  • Published:

Association between small for gestational age and paternally inherited 5′ insulin haplotypes

International Journal of Obesity volume 32, pages 372–380 (2008)Cite this article

Abstract

Objective:

To test the association between small for gestational age and polymorphisms in the insulin gene in newborns and their mothers, as well as the effect of the parental transmission of haplotypes.

Subjects:

Pairs of healthy African-American full-term newborns (N=207) and mothers were recruited from Memphis TN and Jackson MS with birth weights ranging from 2210 to 4735 g.

Methods:

Six single nucleotide polymorphisms (SNPs) located in the insulin (INS) and insulin-like growth factor 2 (IGF2) genes were genotyped in mothers and newborns. Haplotypes composed of three SNPs in the 5′ region of the INS–IGF2 locus were computationally inferred. Odds ratios for risk of small for gestational age (SGA) birth were calculated for individual SNPs and inferred haplotypes in the newborns and in the mothers using logistic regression. For 162 mother – newborn pairs the parental transmission of the haplotypes could be inferred, and the risks for SGA birth were calculated for the three common haplotypes in this sample.

Results:

Three INS SNPs exhibited significant association with risk for SGA birth. The SNP alleles associated with increased risk for SGA were opposite in the maternal and newborn genomes, implying opposing influences on the rate of fetal growth. Consistent with these results, haplotypes composed of complementary nucleotide sequences (CAC at rs3842738, rs689 and rs3842748, respectively, in the newborn versus GTG in the mother) were significantly associated with risk for SGA birth. In analyses of haplotypes according to parental transmission, the same trend in risk for SGA was observed for both maternally and paternally transmitted haplotypes, although a significant difference in risk was observed only for paternally transmitted haplotypes.

Conclusion:

Polymorphisms near the 5′ end of the INS–IGF2 locus are significantly associated with risk for SGA birth with a major effect due to the paternally transmitted haplotype, which is preferentially expressed due to imprinting.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1

Similar content being viewed by others

References

  1. Mathews TJ, MacDorman MF . Infant mortality statistics from the 2003 period linked birth/infant death data set. Natl Vital Stat Rep 2006; 54: 1–29.

    CAS  PubMed  Google Scholar 

  2. McIntire DD, Bloom SL, Casey BM, Leveno KJ . Birth weight in relation to morbidity and mortality among newborn infants. N Engl J Med 1999; 340: 1234–1238.

    Article  CAS  PubMed  Google Scholar 

  3. Hay Jr WW, Catz CS, Grave GD, Yaffe SJ . Workshop summary: fetal growth: its regulation and disorders. Pediatrics 1997; 99: 585–591.

    Article  PubMed  Google Scholar 

  4. O'Keeffe MJ, O'Callaghan M, Williams GM, Najman JM, Bor W . Learning, cognitive, and attentional problems in adolescents born small for gestational age. Pediatrics 2003; 112: 301–307.

    Article  PubMed  Google Scholar 

  5. Jelliffe-Pawlowski LL, Hansen RL . Neurodevelopmental outcome at 8 months and 4 years among infants born full-term small-for-gestational-age. J Perinatol 2004; 24: 505–514.

    Article  PubMed  Google Scholar 

  6. Lundgren M, Cnattingius S, Jonsson B, Tuvemo T . Intellectual performance in young adult males born small for gestational age. Growth Horm IGF Res 2004; 14 (Suppl A): 7–8.

    Article  Google Scholar 

  7. Bernstein I, Gabbe SG . Intrauterine growth retardation. In: Gabbe SG, Niebyl JR, Simpson JL, Annas GJ (eds). Obstetrics: Normal and Problem Pregnancies, 3rd edn. Churchill Livingstone: New York, 1989, pp 863–886.

    Google Scholar 

  8. Innes KE, Byers TE, Marshall JA, Baron A, Orleans M, Hamman RF . Association of a woman's own birth weight with her subsequent risk for pregnancy-induced hypertension. Am J Epidemiol 2003; 158: 861–870.

    Article  PubMed  Google Scholar 

  9. Innes KE, Byers TE, Marshall JA, Baron A, Orleans M, Hamman RF . Association of a woman's own birth weight with subsequent risk for gestational diabetes. JAMA 2002; 287: 2534–2541.

    Article  PubMed  Google Scholar 

  10. Frontini MG, Srinivasan SR, Xu J, Berenson GS . Low birth weight and longitudinal trends of cardiovascular risk factor variables from childhood to adolescence: the Bogalusa heart study. BMC Pediatr 2004; 4: 22.

    Article  PubMed  PubMed Central  Google Scholar 

  11. Rich-Edwards JW, Colditz GA, Stampfer MJ, Willett WC, Gillman MW, Hennekens CH et al. Birthweight and the risk for type 2 diabetes mellitus in adult women. Ann Intern Med 1999; 130: 278–284.

    Article  CAS  PubMed  Google Scholar 

  12. Lithell HO, McKeigue PM, Berglund L, Mohsen R, Lithell UB, Leon DA . Relation of size at birth to non-insulin dependent diabetes and insulin concentrations in men aged 50–60 years. BMJ 1996; 312: 406–410.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Lawlor DA, Ronalds G, Clark H, Smith GD, Leon DA . Birth weight is inversely associated with incident coronary heart disease and stroke among individuals born in the 1950s: findings from the Aberdeen Children of the 1950 s Prospective Cohort Study. Circulation 2005; 112: 1414–1418.

    Article  PubMed  Google Scholar 

  14. Huxley R, Neil A, Collins R . Unravelling the fetal origins hypothesis: is there really an inverse association between birthweight and subsequent blood pressure? Lancet 2002; 360: 659–665.

    Article  PubMed  Google Scholar 

  15. Huxley R, Owen CG, Whincup PH, Cook DG, Colman S, Collins R . Birth weight and subsequent cholesterol levels: exploration of the ‘fetal origins’ hypothesis. JAMA 2004; 292: 2755–2764.

    Article  CAS  PubMed  Google Scholar 

  16. Barker DJ . Mother, Babies, and Health in Later Life. Churchill Livingstone: London, 1998.

    Google Scholar 

  17. Smith GD, Sterne J, Tynelius P, Lawlor DA, Rasmussen F . Birth weight of offspring and subsequent cardiovascular mortality of the parents. Epidemiology 2005; 16: 563–569.

    Article  PubMed  Google Scholar 

  18. Andersen AM, Osler M . Birth dimensions, parental mortality, and mortality in early adult age: a cohort study of Danish men born in 1953. Int J Epidemiol 2004; 33: 92–99.

    Article  PubMed  Google Scholar 

  19. Jaquet D, Swaminathan S, Alexander GR, Abajian C . Significant paternal contribution to the risk of small for gestational age. BJOG 2005; 112: 153–159.

    Article  PubMed  Google Scholar 

  20. Clausson B, Lichtenstein P, Cnattingius S . Genetic influence on birthweight and gestational length determined by studies in offspring of twins. BJOG 2000; 107: 375–381.

    Article  CAS  PubMed  Google Scholar 

  21. Svensson AC, Pawitan Y, Cnattingius S, Reilly M, Lichtenstein P . Familial aggregation of small-for-gestational-age births: the importance of fetal genetic effects. Am J Obstet Gynecol 2006; 194: 475–479.

    Article  PubMed  Google Scholar 

  22. Magnus P, Bakketeig LS, Hoffman H . Birth weight of relatives by maternal tendency to repeat small-for-gestational-age (SGA) births in successive pregnancies. Acta Obstet Gynecol Scand Suppl 1997; 165: 35–38.

    CAS  PubMed  Google Scholar 

  23. Klebanoff MA, Meirik O, Berendes HW . Second-generation consequences of small-for-dates birth. Pediatrics 1989; 84: 343–347.

    CAS  PubMed  Google Scholar 

  24. Wang X, Zuckerman B, Coffman GA, Corwin MJ . Familial aggregation of low birth weight among whites and blacks in the United States. N Engl J Med 1995; 333: 1744–1749.

    Article  CAS  PubMed  Google Scholar 

  25. Strauss RS, Dietz WH . Growth and development of term children born with low birth weight: effects of genetic and environmental factors. J Pediatr 1998; 133: 67–72.

    Article  CAS  PubMed  Google Scholar 

  26. Selling KE, Carstensen J, Finnstrom O, Sydsjo G . Intergenerational effects of preterm birth and reduced intrauterine growth: a population-based study of Swedish mother-offspring pairs. BJOG 2006; 113: 430–440.

    Article  CAS  PubMed  Google Scholar 

  27. La Batide-Alanore A, Tregouet DA, Jaquet D, Bouyer J, Tiret L . Familial aggregation of fetal growth restriction in a French cohort of 7822 term births between 1971 and 1985. Am J Epidemiol 2002; 156: 180–187.

    Article  PubMed  Google Scholar 

  28. Moore GE, Abu-Amero SN, Bell G, Wakeling EL, Kingsnorth A, Stanier P et al. Evidence that insulin is imprinted in the human yolk sac. Diabetes 2001; 50: 199–203.

    Article  CAS  PubMed  Google Scholar 

  29. Giannoukakis N, Deal C, Paquette J, Goodyer CG, Polychronakos C . Parental genomic imprinting of the human IGF2 gene. Nat Genet 1993; 4: 98–101.

    Article  CAS  PubMed  Google Scholar 

  30. Vafiadis P, Bennett ST, Colle E, Grabs R, Goodyer CG, Polychronakos C . Imprinted and genotype-specific expression of genes at the IDDM2 locus in pancreas and leucocytes. J Autoimmun 1996; 9: 397–403.

    Article  CAS  PubMed  Google Scholar 

  31. Paquette J, Giannoukakis N, Polychronakos C, Vafiadis P, Deal C . The INS 5′ variable number of tandem repeats is associated with IGF2 expression in humans. J Biol Chem 1998; 273: 14158–14164.

    Article  CAS  PubMed  Google Scholar 

  32. Le Stunff C, Fallin D, Schork NJ, Bougneres P . The insulin gene VNTR is associated with fasting insulin levels and development of juvenile obesity. Nat Genet 2000; 26: 444–446.

    Article  CAS  PubMed  Google Scholar 

  33. Bennett ST, Wilson AJ, Cucca F, Nerup J, Pociot F, McKinney PA et al. IDDM2-VNTR-encoded susceptibility to type 1 diabetes: dominant protection and parental transmission of alleles of the insulin gene-linked minisatellite locus. J Autoimmun 1996; 9: 415–421.

    Article  CAS  PubMed  Google Scholar 

  34. Le Stunff C, Fallin D, Bougneres P . Paternal transmission of the very common class I INS VNTR alleles predisposes to childhood obesity. Nat Genet 2001; 29: 96–99.

    Article  CAS  PubMed  Google Scholar 

  35. Huxtable SJ, Saker PJ, Haddad L, Walker M, Frayling TM, Levy JC et al. Analysis of parent-offspring trios provides evidence for linkage and association between the insulin gene and type 2 diabetes mediated exclusively through paternally transmitted class III variable number tandem repeat alleles. Diabetes 2000; 49: 126–130.

    Article  CAS  PubMed  Google Scholar 

  36. Meigs JB, Dupuis J, Herbert AG, Liu C, Wilson PW, Cupples LA . The insulin gene variable number tandem repeat and risk of type 2 diabetes in a population-based sample of families and unrelated men and women. J Clin Endocrinol Metab 2005; 90: 1137–1143.

    Article  CAS  PubMed  Google Scholar 

  37. Hansen SK, Gjesing AP, Rasmussen SK, Glumer C, Urhammer SA, Andersen G et al. Large-scale studies of the HphI insulin gene variable-number-of-tandem-repeats polymorphism in relation to Type 2 diabetes mellitus and insulin release. Diabetologia 2004; 47: 1079–1087.

    Article  CAS  PubMed  Google Scholar 

  38. Lindsay RS, Hanson RL, Wiedrich C, Knowler WC, Bennett PH, Baier LJ . The insulin gene variable number tandem repeat class I/III polymorphism is in linkage disequilibrium with birth weight but not Type 2 diabetes in the Pima population. Diabetes 2003; 52: 187–193.

    Article  CAS  PubMed  Google Scholar 

  39. Stead JD, Hurles ME, Jeffreys AJ . Global haplotype diversity in the human insulin gene region. Genome Res 2003; 13: 2101–2111.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Verhaeghe J, Van Bree R, Van Herck E, Laureys J, Bouillon R, Van Assche FA . C-peptide, insulin-like growth factors I and II, and insulin-like growth factor binding protein-1 in umbilical cord serum: correlations with birth weight. Am J Obstet Gynecol 1993; 169: 89–97.

    Article  CAS  PubMed  Google Scholar 

  41. Wolf HJ, Ebenbichler CF, Huter O, Bodner J, Lechleitner M, Foger B et al. Fetal leptin and insulin levels only correlate in large-for-gestational age infants. Eur J Endocrinol 2000; 142: 623–629.

    Article  CAS  PubMed  Google Scholar 

  42. Christou H, Connors JM, Ziotopoulou M, Hatzidakis V, Papathanassoglou E, Ringer SA et al. Cord blood leptin and insulin-like growth factor levels are independent predictors of fetal growth. J Clin Endocrinol Metab 2001; 86: 935–938.

    Article  CAS  PubMed  Google Scholar 

  43. Giudice LC, de Zegher F, Gargosky SE, Dsupin BA, de las Fuentes L, Crystal RA et al. Insulin-like growth factors and their binding proteins in the term and preterm human fetus and neonate with normal and extremes of intrauterine growth. J Clin Endocrinol Metab 1995; 80: 1548–1555.

    CAS  PubMed  Google Scholar 

  44. Dunger DB, Ong KK, Huxtable SJ, Sherriff A, Woods KA, Ahmed ML et al. Association of the INS VNTR with size at birth. ALSPAC Study Team. Avon Longitudinal Study of Pregnancy and Childhood. Nat Genet 1998; 19: 98–100.

    Article  CAS  PubMed  Google Scholar 

  45. Ong KK, Petry CJ, Barratt BJ, Ring S, Cordell HJ, Wingate DL et al. Maternal-fetal interactions and birth order influence insulin variable number of tandem repeats allele class associations with head size at birth and childhood weight gain. Diabetes 2004; 53: 1128–1133.

    Article  CAS  PubMed  Google Scholar 

  46. Bennett AJ, Sovio U, Ruokonen A, Martikainen H, Pouta A, Taponen S et al. Variation at the insulin gene VNTR (variable number tandem repeat) polymorphism and early growth: studies in a large Finnish birth cohort. Diabetes 2004; 53: 2126–2131.

    Article  CAS  PubMed  Google Scholar 

  47. Vu-Hong TA, Durand E, Deghmoun S, Boutin P, Meyre D, Chevenne D et al. The INS VNTR locus does not associate with smallness for gestational age (SGA) but interacts with SGA to increase insulin resistance in young adults. J Clin Endocrinol Metab 2006; 91: 2437–2440.

    Article  CAS  PubMed  Google Scholar 

  48. Mitchell SM, Hattersley AT, Knight B, Turner T, Metcalf BS, Voss LD et al. Lack of support for a role of the insulin gene variable number of tandem repeats minisatellite (INS-VNTR) locus in fetal growth or type 2 diabetes-related intermediate traits in United Kingdom populations. J Clin Endocrinol Metab 2004; 89: 310–317.

    Article  CAS  PubMed  Google Scholar 

  49. Bennett ST, Todd JA . Human type 1 diabetes and the insulin gene: principles of mapping polygenes. Annu Rev Genet 1996; 30: 343–370.

    Article  CAS  PubMed  Google Scholar 

  50. Ong KK, Phillips DI, Fall C, Poulton J, Bennett ST, Golding J et al. The insulin gene VNTR, type 2 diabetes and birth weight. Nat Genet 1999; 21: 262–263.

    Article  CAS  PubMed  Google Scholar 

  51. International HapMap consortium. A haplotype map of the human genome. Nature 2005; 437: 1299–1320.

    Article  Google Scholar 

  52. Lewontin RC . The interaction of selection and linkage. I. General considerations; heterotic models. Genetics 1964; 49: 49–67.

    CAS  PubMed  PubMed Central  Google Scholar 

  53. Clayton D . SNPHAP: a program for estimating frequencies of large haplotypes of SNPs. Version 1.0, 2002, http://www-gene.cimr.cam.ac.uk/clayton/software/.

  54. Cunningham FG, Leveno KJ, Bloom SL, Hauth JC, Gilstrap III L, Wenstrom KD . Williams Obstetrics 22nd edn. McGraw-Hill: New York, 2005, 1441pp.

    Google Scholar 

  55. Waterworth DM, Bennett ST, Gharani N, McCarthy MI, Hague S, Batty S et al. Linkage and association of insulin gene VNTR regulatory polymorphism with polycystic ovary syndrome. Lancet 1997; 349: 986–990.

    Article  CAS  PubMed  Google Scholar 

  56. Hattersley AT, Beards F, Ballantyne E, Appleton M, Harvey R, Ellard S . Mutations in the glucokinase gene of the fetus result in reduced birth weight. Nat Genet 1998; 19: 268–270.

    Article  CAS  PubMed  Google Scholar 

  57. Lohmueller KE, Pearce CL, Pike M, Lander ES, Hirschhorn JN . Meta-analysis of genetic association studies supports a contribution of common variants to susceptibility to common disease. Nat Genet 2003; 33: 177–182.

    Article  CAS  PubMed  Google Scholar 

  58. Le Fur S, Auffray C, Letourneur F, Cruaud C, Le Stunff C, Bougneres P . Heterogeneity of class I INS VNTR allele association with insulin secretion in obese children. Physiol Genomics 2006; 25: 480–484.

    Article  PubMed  Google Scholar 

  59. Kralovicova J, Gaunt TR, Rodriguez S, Wood PJ, Day IN, Vorechovsky I . Variants in the human insulin gene that affect pre-mRNA splicing: is -23HphI a functional single nucleotide polymorphism at IDDM2? Diabetes 2006; 55: 260–264.

    Article  CAS  PubMed  Google Scholar 

  60. Kistner EO, Infante-Rivard C, Weinberg CR . A method for using incomplete triads to test maternally mediated genetic effects and parent-of-origin effects in relation to a quantitative trait. Am J Epidemiol 2006; 163: 255–261.

    Article  PubMed  Google Scholar 

Download references

Acknowledgements

We are grateful to an anonymous reviewer and to Dr Ian Macdonald for extremely helpful comments on earlier versions of the manuscript. We also thank Dr Clarice Weinberg for pointing out several caveats in the interpretation of our results. This work was supported in part by grants from the Children's Foundation Research Center of Memphis at Le Bonheur Children's Medical Center, the Accredo Foundation, and the Center of Genomics and Bioinformatics at the University of Tennessee Health Science Center. Additional funds were provided by the University of Tennessee Health Science Center General Clinical Research Center (Grant number M01-RR00211). We acknowledge the assistance of Laura Bufkin, RN, Dr Kimberly Fisher, Sandy Grimes, RN and Taurus Rogers with subject recruitment and the technical expertise of Jeanette Peeples.

Author information

Author notes

  1. C K Klauser

    Present address: 6Current address: Department of Obstetrics and Gynecology, New York University, 560 First Avenue, Suite 7N, New York, NY 10016, USA,

Authors and Affiliations

  1. Department of Pediatrics, University of Tennessee Health Science Center, Memphis, TN, USA

    R M Adkins

  2. Center of Genomics and Bioinformatics, University of Tennessee Health Science Center, Memphis, TN, USA

    R M Adkins & J Krushkal

  3. Department of Preventive Medicine, University of Tennessee Health Science Center, Memphis, TN, USA

    J Krushkal & G Somes

  4. Department of Obstetrics and Gynecology, University of Mississippi Medical Center, Jackson, MS, USA

    C K Klauser & J C Morrison

  5. Department of Obstetrics and Gynecology, Naval Medical Center Portsmouth, Portsmouth, VA, USA

    E F Magann

Authors
  1. R M Adkins
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. J Krushkal
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. C K Klauser
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. E F Magann
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. J C Morrison
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. G Somes
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to R M Adkins.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Adkins, R., Krushkal, J., Klauser, C. et al. Association between small for gestational age and paternally inherited 5′ insulin haplotypes. Int J Obes 32, 372–380 (2008). https://doi.org/10.1038/sj.ijo.0803700

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.ijo.0803700

Keywords

This article is cited by

Search

Advanced search

Quick links