search text   Advanced Search

This Article Abstract Full Text (PDF) P3Rs: Submit a response Alert me when this article is cited Alert me when P3Rs are posted Alert me if a correction is posted Citation Map Services E-mail this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Add to My File Cabinet Download to citation manager Citing Articles Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Landmann, E. Articles by Gortner, L. Search for Related Content PubMed PubMed Citation Articles by Landmann, E. Articles by Gortner, L. Related Collections Nutrition & Metabolism

Absence of the Wild-type Allele (192 Base Pairs) of a Polymorphism in the Promoter Region of the IGF-I Gene but Not a Polymorphism in the Insulin Gene Variable Number of Tandem Repeat Locus Is Associated With Accelerated Weight Gain in Infancy

^a Pediatric Center, Department of Pediatrics and Neonatology, Justus-Liebig-University Giessen, Giessen, Germany
^b Institute for Medical Biostatistics and Epidemiology, Philipps University, Marburg, Germany
^c Public Health Service of the City of Giessen, Giessen, Germany
^d Department of Pediatrics and Neonatology, University of Saarland, Homburg/Saar, Germany

	ABSTRACT

TOP ABSTRACT PATIENTS AND METHODS RESULTS DISCUSSION CONCLUSIONS REFERENCES

 
OBJECTIVE. Our goal was to investigate whether a polymorphism in the insulin-like growth factor I promoter gene (IGF-I, wild-type, 192 base pairs) and in the insulin gene (INS) variable number of tandem repeat locus influence birth weight and weight gain in infancy.

PATIENTS AND METHODS. We obtained genomic DNA from 768 children. Exclusion criteria were multiple births, gestational diabetes, maternal diabetes, gestational age <37 weeks, >42 weeks, or unclear, and any condition potentially influencing weight gain. SD scores were calculated and adjusted for gestational age and gender. A gain in SD scores for weight between birth and 1 year >0.67 SD scores was defined as accelerated weight gain. Genotyping was performed by fragment length analysis (IGF-I) and by fragment length analysis after using a restriction enzyme-based assay (INS variable number tandem repeat).

RESULTS. Accelerated weight gain was present in 205 of 768 children. IGF-I and INS variable number tandem repeat genotype were not associated with birth weight. The IGF-I 192-base pair allele was less frequent in children with accelerated weight gain and was shown to reduce the risk for accelerated weight gain in a logistic regression model.

CONCLUSION. The IGF-I 192-base pair allele may reduce the risk for rapid weight gain in early infancy.

Key Words: fetal growth restriction • infant • genetic predisposition • obesity • weight gain

Abbreviations: IGF-I—insulin-like growth factor I • VNTR— variable number of tandem repeats • INS—insulin gene • OR—odds ratio • PCR—polymerase chain reaction • CI—confidence interval

Associations between low birth weight and an increased risk for developing insulin resistance and related disorders in adulthood are well established in population studies.^1,2 However, recent studies have suggested that accelerated early postnatal weight gain, a pattern that can predominantly be observed in children with lower birth weight,³ and not low birth weight itself increases the risk for insulin resistance and related disease.^4–7 This observation is not restricted to children born small for gestational age: Accelerated early weight gain, often referred to as "catch-up growth," could be associated with decreased insulin sensitivity, adiposity, and higher blood pressure as early as at school age.^8–11 Therefore, the exploration of factors that influence weight gain in infancy is of high interest.

In addition to environmental factors, such as type of infant feeding, common genetic variations might influence birth weight, accelerate early postnatal weight gain, and predispose to the development of adult disease. Variations in the genes encoding for insulin and for the insulin-like growth factor I (IGF-I) are of particular interest, because insulin and IGF-I do not only play a crucial role in glucose homeostasis but also are essential growth factors in fetal and early postnatal life. An allele length variation at the variable number tandem repeat (VNTR) locus, a 14- to 15-base pair (bp) oligonucleotide minisatellite in the promoter region of the insulin gene (INS), is known to have functional effects on INS transcription.¹² INS VNTR allele lengths fall into 2 general classes: class I with an average of 570 bp and class III with an average of 2200 bp.¹² This polymorphism has been implicated in susceptibility to type 2 diabetes.^13,14 Whether the VNTR genotype influences early postnatal weight gain has not yet been studied.

In a Dutch cohort, the absence of the wild-type allele (192 bp) of a polymorphism in the promoter region of the IGF-I gene was associated with low birth weight¹⁵ and accelerated postnatal weight gain. Postnatal weight gain, however, was not defined as weight gain during infancy but as a shift in weight quartile between birth and adulthood.

The objectives of our study were to investigate whether the INS VNTR genotype and the polymorphism in the IGF-I gene are associated with (1) birth weight and (2) accelerated weight gain during the first year of life. Identification of polymorphisms influencing early weight gain may provide additional insight into the mechanisms of early weight gain and, therefore, be helpful for risk stratification.

	PATIENTS AND METHODS

TOP ABSTRACT PATIENTS AND METHODS RESULTS DISCUSSION CONCLUSIONS REFERENCES

 
Study Population
Children aged 5.5 to 7 years were recruited at the 2002–2003 obligatory health examination before school entry in the region of Giessen, Germany. Giessen lies in the federal state of Hesse and has 72 500 inhabitants, an average socioeconomic level, and an average annual migration rate. At the examination, buccal swabs for DNA extraction and the children's measurements (height and weight) were obtained. Their blood pressures were taken by an oscillometric, automated device (Welch Allyn, Skaneateles Falls, New York, NY) following the recommendations of the American Academy of Pediatrics.¹⁶

Auxologic data from birth until the age of 6 years were taken from data obtained at the obligatory well-child visits. In Germany, information about the child's perinatal history, as well as auxologic data and information about health status assessed at the well-child visits are documented in a standardized way. Specific information about current parental weight and length, maternal smoking during pregnancy, and the duration of breastfeeding were obtained by a questionnaire.

Exclusion criteria were multiple births; gestational diabetes; maternal diabetes; unclear gestational age; gestational age <37 and >42 weeks; and children with identifiable syndromes, chronic illness, endocrine disorders, or any other condition that may influence weight gain. The analysis was confined to white children of German nationality with complete data on well-child visits. The local ethics committee approved the study; informed parental consent was obtained.

Statistical Analysis
We calculated SD scores based on this population. SD scores for weight and length at birth were adjusted for gender and gestational age. SD scores for weight and length at the age of 1 and 6 years were adjusted for gender and exact age at date of examination. A gain in SD score for weight between birth and 1 year >0.67 was defined as accelerated weight gain, thus taking a commonly used definition.^8,17

Odds ratios (ORs) were calculated to assess the influence of gender, smoking during pregnancy, and breastfeeding on accelerated weight gain. Differences with respect to parental length and parental BMI between children with and without accelerated weight gain were calculated by t tests.

The Hardy-Weinberg equilibrium of the INS VNTR polymorphism genotype and of the IGF-I promoter polymorphism were tested with ² goodness-of-fit tests. A linear regression model was used to determine associations between birth weight and genotype. Mean birth weights grouped according to genotype were compared by analysis of variance. Genotype frequencies were compared by using the Cochran-Armitage trend test. Allele frequencies were compared by Pearson's ² test.

A multiple linear regression model was used to assess the impact of variables that might be associated with accelerated weight gain during the first year of life. A logistic regression model and Mann-Whitney U tests were used to assess the influence of accelerated weight gain on blood pressure and BMI at the age of 6 years. Analyses were performed using the statistical packages SAS 8.02 (SAS Institute, Inc, Cary, NC) and Stata 8.2 (Stata Corp, College Station, TX).

Polymorphism Analysis
Genomic DNA was obtained from buccal swabs using commercial kits (QIAamp DNA Mini Kit; Qiagen, Valencia, CA). To assess the INS VNTR genotype, we analyzed the samples for the –23 A/T diallelic polymorphism, which is in virtually complete (>99.5% concordance in white populations) linkage disequilibrium with the INS VNTR.¹⁸ DNA was amplified by using site-specific primers,¹² with each 25-µL reaction containing 120 ng DNA, 0.4 mL of 50 mM MgCl₂ (GIBCO BRL, Invitrogen, Karlsruhe, Germany), 1 µL (10 µM) of forward primer, 1 µL (10 µM) of reverse primer, 1 µL (10 mmol/L) of oligonucleotides (Finnzymes, Oy, Espoo, Finland), 2.5 µL of 10 x reaction buffer (GIBCO BRL, Invitrogen), and 0.2 µL of Platinum Taq DNA polymerase (GIBCO BRL, Invitrogen). The forward primer was labeled with 6-carboxy-fluorescine and the reverse primer was labeled with hexachloro-6-carboxy-fluorescine. Both primers were purchased from Carl Roth GmbH and Company (Karlsruhe, Germany). Running conditions were 93°C for 30 seconds; 54°C for 1 minute; and 72°C for 1 minute, followed by a final extension time of 10 minutes at 72°C. Genomic DNA was amplified for 34 cycles. For each reaction, 25 µL were digested in 2 U HphI (New England Biolabs, Beverly, MA) at 37°C for 16 hours, and the size of each digested product was determined by autosequencer (Genetic Analyzer 3100; Applied Biosystems, Foster City, CA) in comparison with internal standards (GeneScan 350 ROX ABI-Prism; Applied Biosystems).

Polymerase chain reaction (PCR) was performed by using oligonucleotide primers designed to amplify the polymorphic cytosine-adenine repeat 1kilobase upstream of the human IGF-I gene. The reaction was conducted in a final volume of 25 µL containing 100 ng of genomic DNA, 1 µL (10 pmol/µL) of forward primer (5'-GCTAGCCAGCTGGTGTTATT-3'), 1 µL (10 pmol/µL) of reverse primer (5'-ACCACTCTGGGAGAAGGGTA-3'), 2 µL of MgCl₂ (50 mmol/L) (Applied Biosystems), 0.6 µL of dNTP (10 mmol/L) (Finnzymes Oy, Espoo, Finland), and 0.2 µL (5 U/µL) of AmpliTaqDNA Polymerase (Applied Biosystems). PCR was performed in 96-well plates (94°C for 2 minutes; 39 cycles of 30 seconds at 94°C, 30 seconds at 57°C, and 45 seconds at 72°C; 72°C for 10 minutes; 4°C hold). All primers were purchased from Carl Roth (Carl Roth GmbH and Company). The forward primer was labeled with 6-carboxy-fluorescine. The size of the PCR products was determined by gene sequencer (Genetic Analyzer 3100; Applied Biosystems). The size of the PCR products was determined in comparison with internal standards (GS 400 HD Standard; Applied Biosystems). In addition, each different product size, as shown by different peaks, was sequenced twice by the dideoxy chain method confirming the product size.¹⁹ For sequencing, we also used the gene sequencer. The company's standard protocols were used for fragment length analyses and for sequencing.

	RESULTS

TOP ABSTRACT PATIENTS AND METHODS RESULTS DISCUSSION CONCLUSIONS REFERENCES

 
A total of 768 children were included in the study. Their mean birth weight was 3464 ± 443 g (mean ± SD). Between birth and 1 year of age, 205 infants (26.7%) gained >0.67 SD scores, indicating clinically significant accelerated weight gain. Children with accelerated weight gain between birth and 1 year of age were lighter and shorter at birth than those without accelerated weight gain. There was no difference in parental height or BMI (Table 1). Accelerated weight gain was associated with smoking in pregnancy (OR: 2.81; 95% confidence interval [CI]: 1.85–4.31) and was less frequent in breastfed children (OR: 0.66; 95% CI: 0.45–0.98 for children ever breastfed and OR: 0.61; 95% CI: 0.44–0.85 for children breastfed 3 months; Table 2).

Polymorphism in the Promoter Region of the IGF-I Gene
For the 192-bp allele, 39.7% of the children were homozygous, 43.6% were heterozygous, and 16.6% were noncarriers. The genotype distribution shows no deviation from the Hardy-Weinberg equilibrium and is similar to previously reported distributions in a white population.¹⁵ No association was seen between the IGF-I promoter polymorphism and weight or length at birth. Comparing genotype frequencies and allele frequencies, the 192-bp allele was shown to be negatively associated with accelerated weight gain between birth and 1 year of age (P = .011 for genotypes; P = .008 for alleles; Table 3). In a subsequent analysis, we investigated whether the IGF-I promoter polymorphism influences weight gain during the first year directly by comparing the mean change in SD scores over genotypes. The whole group shows nominally significant differences, and the analyses of the subgroups reveal that this is caused by the different frequencies of children with accelerated weight gain in the genotype categories (ie, there is no effect in the category of children without accelerated weight gain) (Table 4).

	DISCUSSION

TOP ABSTRACT PATIENTS AND METHODS RESULTS DISCUSSION CONCLUSIONS REFERENCES

 
In this group of children, which was exposed to an adequate or possibly even overly adequate energy supply during infancy, 26.7% showed accelerated weight gain during their first year of life. This proportion is comparable to that observed in other contemporary cohorts.^8,20 Children with accelerated weight gain were lighter and shorter at birth than other children, and their mothers had a higher prevalence of smoking during pregnancy, indicating that fetal growth in these children had been restricted.

Accelerated weight gain during infancy has been shown previously to increase the risk for developing insulin resistance, higher blood pressure, and obesity.^8,10,11,21 We also found an association in our group of children between accelerated weight gain in infancy and a higher systolic blood pressure, as well as a higher BMI at the age of 6 years. Identifying polymorphisms associated with accelerated postnatal weight gain could uncover mechanisms of early weight gain and might be considered in risk stratification.

Our data do not show an association between VNTR class and weight gain during the first year of life, nor do they substantiate the relationship between VNTR class and birth weight reported by Dunger et al.¹⁷ In a cohort of children, this group showed higher birth weights in class III homozygotes. In a study of Pima Indian children,²² a relationship in the opposite direction (ie, lower birth weights in class III homozygotes) was revealed. Our data did not verify this finding either.

Our findings conform those of the studies in a United Kingdom²³ and in a large Finnish²⁰ population, which also failed to confirm an association between VNTR genotype and birth weight. These inconsistent findings are not likely to be explained by ethnic differences in VNTR subclass composition, presence or absence of nearby modifying variants, or differences in linkage disequilibrium structure, as these are known to be broadly similar in all non-African populations.²⁴ However, differences between study subjects (eg, in environmental exposures, antenatal management, and secular trends) may have an effect on the power to detect VNTR association effects. Our results did not reveal convincing evidence that INS gene VNTR class variation influences birth weight and/or weight gain in infancy.

We did not find an association between IGF-I promoter genotype and birth weight. Thus, as in a study in 2 United Kingdom cohorts,²⁵ our data do not replicate the findings of the Dutch study.¹⁵ Our subjects and those in both United Kingdom cohorts were born in the 1990s and the 1970s, respectively, whereas the subjects enrolled in the Dutch study were born in the 1930s. Environmental factors (eg, maternal and postnatal nutrition) and secular trends are likely to explain the differences.

Our study demonstrated that the 192-bp allele is more common in children without accelerated weight gain during infancy. The multivariate analysis revealed the presence of at least one 192-bp allele to reduce the risk for accelerated weight gain substantially. This is the first study, to our knowledge, that shows that the absence of the 192-bp allele is an independent risk factor for accelerated weight gain during the first year of life in a contemporary well nourished group of children.

It is unclear by which mechanism this polymorphism may accelerate weight gain in infancy. Because this polymorphic region is located close to the transcription start site and is known to contain specific regulatory elements, it has been discussed that this allelic variation leads to changes in the promoter, thereby influencing transcription of IGF-I. Alternatively, it has been hypothesized that the polymorphism is in linkage disequilibrium with another regulatory element thereby influencing transcription of IGF-I. By influencing IGF-I plasma concentrations, the polymorphism might also affect bone growth and bone density. Homozygosity for the 192-bp allele was shown to be more common in a small group of patients with idiopathic osteoporosis.²⁷ However, our finding might also be a chance finding.

In adults, conflicting results have been reported with respect to the influence of the 192-bp allele on circulating IGF-I concentrations and on adult height.^25–27 No studies have been published examining the influence of this gene variant on the regulation of IGF-I or other hormones and growth factors during infancy. IGFs are known to be important for the delicate balance between ß-cell replication and apoptosis (reviewed in²⁸). By influencing IGF-I plasma concentrations, the polymorphism might exert effects on pancreatic ß-cell growth and development, thus possibly influencing early postnatal metabolism and weight gain.

	CONCLUSIONS

TOP ABSTRACT PATIENTS AND METHODS RESULTS DISCUSSION CONCLUSIONS REFERENCES

 
We identified the absence of the 192-bp allele as an independent risk factor for accelerated weight gain. If these results are replicated in additional independent population studies, this polymorphism may be useful in risk stratification and in studying mechanisms of weight gain in infancy.

	ACKNOWLEDGMENTS

 
We thank the children and their parents who participated in the study. We especially thank Barbara Breitbach, MD, Astrid Klinke, MD, and Barbara Pohl-Hondrich, MD, from the Giessen Public Health Service for support and cooperation.

	FOOTNOTES

 
Accepted Aug 29, 2006.

Address correspondence to Eva Landmann, MD, Pediatric Center, Department of Pediatrics and Neonatology, Feulgenstrasse 12, 35392 Giessen, Germany. E-mail: eva.landmann{at}paediat.med.uni-giessen.de

Financial Disclosure: Mr Geller now works for deCODE Genetics, Reykjavik, Iceland, and holds stock in that company. However, his work on this manuscript is related solely to his employment at Philipps University.

	REFERENCES

TOP ABSTRACT PATIENTS AND METHODS RESULTS DISCUSSION CONCLUSIONS REFERENCES

 

1. Gluckman PD, Hanson MA. Living with the past: evolution, development, and patterns of disease. Science. 2004;305 :1733 –1736[Abstract/Free Full Text]
2. McMillen IC, Robinson JS. Developmental origins of the metabolic syndrome: prediction, plasticity, and programming. Physiol Rev. 2005;85 :571 –633[Abstract/Free Full Text]
3. Karlberg J, Albertsson-Wikland K. Growth in full-term small-for-gestational-age infants: from birth to final height. Pediatr Res. 1995;38 :733 –739[ISI][Medline]
4. Singhal A, Lucas A. Early origins of cardiovascular disease: is there a unifying hypothesis? Lancet. 2004;363 :1642 –1645[CrossRef][ISI][Medline]
5. Soto N, Bazaes RA, Pena V, et al. Insulin sensitivity and secretion are related to catch-up growth in small-for-gestational-age infants at age 1 year: results from a prospective cohort. J Clin Endocrinol Metab. 2003;88 :3645 –3650[Abstract/Free Full Text]
6. Jaquet D, Deghmoun S, Chevenne D, Collin D, Czernichow P, Levy-Marchal C. Dynamic change in adiposity from fetal to postnatal life is involved in the metabolic syndrome associated with reduced fetal growth. Diabetologia. 2005;48 :849 –855[CrossRef][ISI][Medline]
7. Euser AM, Finken MJ, Keijzer-Veen MG, et al. Associations between prenatal and infancy weight gain and BMI, fat mass, and fat distribution in young adulthood: a prospective cohort study in males and females born very preterm. Am J Clin Nutr. 2005;81 :480 –487[Abstract/Free Full Text]
8. Ong KK, Ahmed ML, Emmett PM, Preece MA, Dunger DB. Association between postnatal catch-up growth and obesity in childhood: prospective cohort study. BMJ. 2000;320 :967 –971[Abstract/Free Full Text]
9. Huxley RR, Shiell AW, Law CM. The role of size at birth and postnatal catch-up growth in determining systolic blood pressure: a systematic review of the literature. J Hypertens. 2000;18 :815 –831[CrossRef][ISI][Medline]
10. Ong KK, Petry CJ, Emmett PM, et al. Insulin sensitivity and secretion in normal children related to size at birth, postnatal growth, and plasma insulin-like growth factor-I levels. Diabetologia. 2004;47 :1064 –1070[ISI][Medline]
11. Baird J, Fisher D, Lucas P, Kleijnen J, Roberts H, Law C. Being big or growing fast: systematic review of size and growth in infancy and later obesity. BMJ. 2005;331 :929[Abstract/Free Full Text]
12. Bennett ST, Lucassen AM, Gough SC, et al. Susceptibility to human type 1 diabetes at IDDM2 is determined by tandem repeat variation at the insulin gene minisatellite locus. Nat Genet. 1995;9 :284 –292[CrossRef][ISI][Medline]
13. Huxtable SJ, Saker PJ, Haddad L, 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[Abstract]
14. 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[Abstract/Free Full Text]
15. Vaessen N, Janssen JA, Heutink P, et al. Association between genetic variation in the gene for insulin-like growth factor-I and low birthweight. Lancet. 2002;359 :1036 –1037[CrossRef][ISI][Medline]
16. National High Blood Pressure Education Program, Working Group on High Blood Pressure in Children and Adolescents. The fourth report on the diagnosis, evaluation, and treatment of high blood pressure in children and adolescents. Pediatrics. 2004;114 :555 –576[Free Full Text]
17. Dunger OK, Huxtable SJ, Sherriff A, et al. Association of the INS VNTR with size at birth. Nat Gen. 1998;19 :98 –100[ISI][Medline]
18. Bennett ST, Todd JA. Human type 1 diabetes and the insulin gene: principles of mapping polygenes. Annu Rev Genet. 1996;30 :343 –370[CrossRef][ISI][Medline]
19. Sanger F, Nicklen S, Coulson AR. DNA sequencing with chain-terminating inhibitors. Proc Natl Acad Sci U S A. 1977;74 :5463 –5467[Abstract/Free Full Text]
20. Bennett AJ, Sovio U, Ruokonen A, 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[Abstract/Free Full Text]
21. Law CM, Shiell AW, Newsome CA, et al. Fetal, infant, and childhood growth and adult blood pressure: a longitudinal study from birth to 22 years of age. Circulation. 2002;105 :1088 –1092[Abstract/Free Full Text]
22. 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[Abstract/Free Full Text]
23. Mitchell SM, Hattersley AT, Knight B, 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[Abstract/Free Full Text]
24. Stead JD, Jeffreys AJ. Structural analysis of insulin minisatellite alleles reveals unusually large differences in diversity between Africans and non-Africans. Am J Hum Genet. 2002;71 :1273 –1284[CrossRef][ISI][Medline]
25. Frayling TM, Hattersley AT, McCarthy A, et al. A putative functional polymorphism in the IGF-I gene: association studies with type 2 diabetes, adult height, glucose tolerance, and fetal growth in U.K. populations. Diabetes. 2002;51 :2313 –2316[Abstract/Free Full Text]
26. Vaessen N, Heutink P, Janssen JA, et al. A polymorphism in the gene for IGF-I: functional properties and risk for type 2 diabetes and myocardial infarction. Diabetes. 2001;50 :637 –642[Abstract/Free Full Text]
27. Rosen CJ, Kurland ES, Vereault D, et al. Association between serum insulin growth factor-I (IGF-I) and a simple sequence repeat in IGF-I gene: implications for genetic studies of bone mineral density. J Clin Endocrinol Metab. 1998;83 :2286 –2290[Abstract/Free Full Text]
28. Van Haeften TW, Twickler TB. Insulin-like growth factors and pancreas beta cells. Eur J Clin Invest. 2004;34 :249 –255[CrossRef][ISI][Medline]

This Article Abstract Full Text (PDF) P3Rs: Submit a response Alert me when this article is cited Alert me when P3Rs are posted Alert me if a correction is posted Citation Map Services E-mail this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Add to My File Cabinet Download to citation manager Citing Articles Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Landmann, E. Articles by Gortner, L. Search for Related Content PubMed PubMed Citation Articles by Landmann, E. Articles by Gortner, L. Related Collections Nutrition & Metabolism

	Home | My Pediatrics | Journal Information | Current Issue | Past Issues | Subscriptions & Services | Contact Us Click here for faster international access © 2006 American Academy of Pediatrics. All rights reserved.