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(HNF-1), HNF-4, and HNF-6 Genes and Size at Birth in a Population-Based Sample of Young Danish Subjects1
Steno Diabetes Center and Hagedorn Research Institute (S.K.R., S.A.U., T.H., K.A., A.M.M., K.B.-J., O.P.), Gentofte, Denmark; and Center of Preventive Medicine, Glostrup University Hospital (K.B.-J.), Glostrup, Denmark
Address all correspondence and requests for reprints to: Søren K. Rasmussen, M.Sc., Steno Diabetes Center/Hagedorn Research Institute, Niels Steensens Vej 2, DK-2820 Gentofte, Denmark.
Abstract
Reduced size at birth has been proposed to be a risk factor for
insulin resistance and type 2 diabetes. It is, however, not known
whether this association is explained by unfavorable intrauterine
environment or by specific susceptibility genotypes predisposing for
both reduced fetal growth and insulin resistance and type 2 diabetes.
The present study was performed to evaluate whether previously
identified amino acid polymorphisms of genes that from animal models
have been suggested to play important roles during fetal development
are associated with alterations in size at birth. The study population
comprised 380 subjects randomly recruited from a population of young
Danish Caucasian individuals, aged 18–32 yr. The original data of
birth length and weight for 331 of 380 subjects were obtained from the
midwife records. The Gly/Arg972 of insulin receptor
substrate-1 (IRS-1), the Thr/Ile130 of the hepatocyte
nuclear factor-4
(HNF-4), the Pro/Ala75 of HNF-6, and
the Ile/Leu27, Ala/Val98, and
Ser/Asn487 polymorphisms of the HNF-1 gene were examined
for association with birth weight and length and the ponderal index.
Using a generalized linear model, including gender and the genotype as
fixed variables, and applying Bonferroni correction for multiple
testing, we could not demonstrate any significant differences in these
estimates among wild-type, heterozygous, and homozygous carriers with
respect to any of the gene variants. In conclusion, common variability
in the genes encoding the IRS-1, HNF-1, HNF-4, and HNF-6 proteins
can be excluded as major factors influencing size at birth among Danish
Caucasian subjects.
REDUCED SIZE at birth has been proposed to be a risk factor for insulin resistance and type 2 diabetes (1, 2, 3, 4). Initially, this association was suggested to be due to unfavorable intrauterine environment, making low birth weight only a marker of an yet unidentified intrauterine factor associated with increased risk of type 2 diabetes later in life. This hypothesis challenged the current idea of the existence of type 2 diabetes susceptibility genotypes for the development of the disease. However, an alternative explanation might be a coincidence of specific susceptibility genotypes for both reduced fetal growth and type 2 diabetes.
Recently, it was observed that mutations in the
glucokinase gene associated with the type 2 form of maturity-onset
diabetes of the young (MODY) result in a reduced birth weight, most
likely caused by changes in fetal insulin secretion (5). Additionally,
polymorphisms of the variable number of tandem repeats locus that
influence insulin gene transcription have been shown to be related to
altered birth weight (6), suggesting that genetic factors might be
involved in intrauterine growth retardation. However, the molecular
mechanism behind abnormal fetal growth is unknown, but might occur as a
result of alterations in the insulin secretion or insulin signaling
pathways. Such alterations could be a result of variability of genes
known to be involved in the pathogenesis of type 2 diabetes, insulin
resistance, impaired insulin secretion, or growth retardation. In this
study we focused on previously identified variants in the insulin
receptor substrate 1 (IRS-1), hepatocyte nuclear factor-1
(HNF-1), HNF-4, and HNF-6 genes in relation to birth weight and
length and ponderal index.
Disruption of the IRS-1 gene causes a 50% reduction in
intrauterine growth in mice (7, 8). Furthermore, we have recently
demonstrated that a common Gly/Arg972
polymorphism of the IRS-1 gene interacts with obesity to decrease
insulin sensitivity in humans (9). A crucial role for the HNF-1 in
controlling embryonic development was suggested by analysis of HNF-1
null mice, which were smaller at birth and were born at less than half
the expected frequency compared to their wild-type littermates (10).
Mutations in HNF-1 are responsible for the type 3 form of MODY, and
three common amino acid polymorphisms were identified in this gene,
Ile/Leu27, Ala/Val98, and
Ser/Asn487 (11), of which the
Ala/Val98 variant was associated with insulin
secretory dysfunction, as estimated during an oral glucose tolerance
test (OGTT) (12, 13). Also, the MODY1 gene, HNF-4, in which a
Thr/Ile130 was identified (14), plays an
important part in early development, as mice lacking HNF-4 die early
in embryogenesis (15). HNF-6 is a related transcription factor, which
stimulates transcription of the HNF-4 gene (16). Therefore, this
gene might also be of importance during fetal life, although we do not
yet have indications from studies of knockout mice. A common
Pro/Ala75 variant was recently described in this
gene (17).
The purpose of the present study was to analyze whether these amino acid polymorphisms are associated with decreased birth weight and length or ponderal index in a population-based sample of young Danish Caucasian subjects.
Subjects and Methods
Subjects
The study population comprised 380 subjects randomly recruited from a population of young Caucasians, aged 18–32 yr (18). The original birth length and birth weight data of 331 of 380 subjects were obtained from the midwife records stored in the Danish Provincial Archives for Zealand, Lolland/Falster, and Bornholm Islands. The measurements of birth length and weight were taken to nearest 1 cm and 50 g, respectively. Ponderal index was calculated as (birth weight)/(birth length)3. Physiological and anthropometric characteristics of this population sample have been presented previously (18).
Before participation, informed consent was obtained from all subjects. The study was approved by the ethical committee of Copenhagen and was performed in accordance with the principles of the Declaration of Helsinki II.
Screening for polymorphisms in the IRS-1, HNF-1, HNF-4, and
HNF-6 genes
The assays for detection of the genetic variants have been
described in detail previously: Gly/Arg972 of
IRS-1 (9); Ile/Leu27,
Ala/Val98, and Ser/Asn487
of HNF-1 (11); Thr/Ile130 of HNF-4 (14),
and Pro/Ala75 of HNF-6 (17).
Statistics
Differences in continuous variables between groups of subjects were tested with a generalized model, including genotype and gender as fixed variables. Subgroup analyses of the Ser/Asn487 variant were conducted using the generalized model, in which the genotype was included as a dichotomous variable (homozygous carriers vs. heterozygous/wild-type carriers). Data represent means (SD). The Statistical Package of Social Science (SPSS, Inc., Chicago, IL) for Windows (version 9.0) was used for statistical analysis.
Results and Discussion
Birth weight and length and ponderal index data of the
present study population stratified in accordance with the genotype of
Gly/Arg972 of IRS-1,
Thr/Ile130 of HNF-4,
Pro/Ala75 of HNF-6, and the
Ile/Leu27, Ala/Val98, and
Ser/Asn487 of the HNF-1, respectively, are
given in Table 1
. Using a generalized
linear model in which adjustments for gender were made, no differences
in birth length, birth weight, or the ponderal index between groups of
genotypes were obtained with respect to
Gly/Arg972 of IRS-1,
Thr/Ile130 of HNF-4,
Pro/Ala75 of HNF-6, and
Ile/Leu27 or Ala/Val98 of
HNF-1 (Table 1). There was a significant difference
(P = 0.04) in ponderal index across the three genotype
groups of the Ser/Asn487 variant of HNF-1. No
differences in birth weight or length between these groups were
observed. In this respect it should be noted that the ponderal index
might be a more specific indicator of fetal malnutrition than low birth
weight (19). Subgroup analysis revealed that Asn/Asn487
HNF-1 carriers had a 5% reduction in ponderal index
(P = 0.02) compared to heterozygous and wild-type
carriers. The power of the present study to detect this difference is
actually more than 80%. However, as repeated analyses of three
continuous variables on seven gene variants have been performed, we
applied Bonferroni correction for multiple testing, which turned down
the significant difference.
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had a 20% impairment in ß-cell function as estimated during an oral
glucose tolerance test (12, 13). However, the present study failed to
show that this association is mediated through estimates of fetal
growth retardation. A tentative difference in birth weight or ponderal
index of 20% between carriers of the variant and wild-type carriers
would have been detected with a power of more than 99%, thereby
excluding the risk of false negative results. Previous studies have demonstrated a direct relationship between impaired fetal growth and insulin resistance in adult life (3, 22). Interestingly, recent analyses in the present study population showed a positive association between low birth weight, but not low ponderal index, and low values of the insulin sensitivity index (21). Previously, we also demonstrated in this study group that obese carriers of the Gly/Arg972 variant of IRS-1 gene had a 50% reduction in insulin sensitivity index compared to obese wild-type carriers. Furthermore, this variant was in 32D(IR) cell lines observed to cause a 32% decrease in thymidine incorporation into DNA, suggesting a role of the Gly/Arg972 variant on mitogenesis (23). However, the negative results of the present study suggest that these effects of the Gly/Arg972 variant are explained by postnatal events.
The fact that the present study failed to demonstrate any relationship between variability in four candidate genes for type 2 diabetes and low birth weight might have several explanations. Although there is accumulating evidence that low birth weight predisposes to the development of type 2 diabetes in adult life, it is unclear whether this association is causal, whether low birth weight per se is only a marker of an intrauterine or maternal factor associated with an increased risk of type 2 diabetes, or whether the association is explained by gene variants predisposing to both low birth weight and type 2 diabetes. There is no evidence of a major influence of any of the examined variants on type 2 diabetes susceptibility. Thus, only minor effects of these variants on size at birth would be expected, and despite the fact that this study is favored by very exact determinations of birth size, these effects might be undetectable. Furthermore, it is important to note that although the growth of a fetus obviously is influenced by its genes, the relative contributions of genes to the variation in size at birth are unknown, and several nongenetic maternal and fetal factors also contribute to the determination of size at birth (24, 25, 26, 27).
From the present study, which elucidates the effect of
amino acid polymorphisms of the IRS-1, HNF-1, HNF-4, and HNF-6 on
human fetal growth, we conclude that common variability in these genes
can be excluded as a major factor influencing size at birth among
Danish Caucasian subjects.
Acknowledgments
We thank Annemette Forman, Lene Aabo, Dorte GøthJohansen, Bente Mottlau, Susanne Kjellberg, Lis Ølholm, and Maja Lis Halkjær for dedicated and careful technical assistance and Grete Lademann for secretarial support.
Footnotes
1 The work was supported by grants from the Danish Medical Research
Council, the Danish Research Academy, the University of Copenhagen, the
Velux Foundation, the Danish Diabetes Association and EEC
(BMH4-CT-950662). 
Received January 8, 2000.
Revised March 20, 2000.
Accepted March 29, 2000.
References
knockout mouse. Mol Cel Biol. 18:3059–3068. gene in Danish
Caucasians with late-onset NIDDM. Diabetologia. 40:473–475.[CrossRef][Medline]
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responses to an oral glucose challenge. Diabetes. 46:912–916.[Abstract]
gene contributes to the
interindividual variation in serum C-peptide response during an oral
glucose tolerance test: evidence from studies of 231 glucose-tolerant
first degree relatives of type 2 diabetic probands. J Clin
Endocrinol Metab. 83:4506–4509. in Caucasians with maturity onset NIDDM. Diabetologia. 40:980–983.[CrossRef][Medline]
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