PEDIATRICS Vol. 118 No. 6 December 2006, pp. 2374-2379 (doi:10.1542/10.1542/peds.2006-0146)
ARTICLE |
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
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ABSTRACT |
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 TOP ABSTRACT PATIENTS AND METHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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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.
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PATIENTS AND METHODS |
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TOPABSTRACTPATIENTS AND METHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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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.
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RESULTS |
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TOPABSTRACTPATIENTS AND METHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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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).
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INS VNTR Polymorphism
The INS VNTR genotype distribution in this study was 39.3%, 47.9%, and 12.8% for class I/I, I/III, and III/III, respectively. This is in Hardy-Weinberg equilibrium and similar to reports from other white populations.17,18 No association was seen between the INS VNTR genotype and weight or length at birth. Genotype and allele frequencies did not differ significantly between children with and without accelerated weight gain during the first year of life.
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).
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In a logistic regression model, which estimates the influence of IGF-I genotype on the dependent variable "accelerated weight gain between birth and the age of 1 year," the variables maternal smoking during pregnancy, gender, parental BMI, and breastfeeding
3 months were also included (Table 5). Carrying the 192-bp allele may reduce the risk for accelerated weight gain during the first year of life (OR: 0.76; 95% CI: 0.6–0.97). Maternal smoking during pregnancy increased the risk for accelerated weight gain (OR: 2.76; 95% CI: 1.73–4.4), and there was a tendency for breastfeeding 3 months to decrease the risk of accelerated weight gain during the first year of life (OR: 0.7; 95% CI: 0.48–1.02; Table 5).
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Birth Weight, Accelerated Weight Gain in Infancy, and BMI at 6 Years of Age
The correlation between birth weight and BMI at the age of 6 years was low (r = 0.14). BMI at the age of 6 years was higher in children showing accelerated weight gain from birth and age 1 year (16.2 ± 2.3 vs 15.4 ± 1.6 kg/m2; P < .001 [mean ± SD]). This association was confirmed in a logistic regression model (Table 6). Furthermore, we found a weak correlation between BMI and systolic blood pressure at age 6 (rs = 0.29).
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Birth Weight, Accelerated Weight Gain in Infancy, and Blood Pressure at the Age of 6 Years
There was no correlation between birth weight and systolic blood pressure at the age of 6 years (r = 0.04). Children with accelerated weight gain during the first year of life had higher systolic blood pressure values at 6 years of age compared with children without an acceleration in weight gain (107 ± 9 vs 104 ± 9 mm Hg; P < .001 [mean ± SD]). The association between accelerated weight gain during the first year of life and systolic blood pressure was confirmed in a logistic regression model (Table 6). Diastolic blood pressure values did not differ between both groups (66 ± 6.5 mm Hg for both groups).
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DISCUSSION |
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TOPABSTRACTPATIENTS AND METHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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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.
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CONCLUSIONS |
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TOPABSTRACTPATIENTS AND METHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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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.
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ACKNOWLEDGMENTS |
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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.
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FOOTNOTES |
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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.
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