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Journal of Clinical Endocrinology & Metabolism , doi:10.1210/jc.2007-0176
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The Journal of Clinical Endocrinology & Metabolism Vol. 92, No. 7 2758-2763
Copyright © 2007 by The Endocrine Society

The Presence of the d3-Growth Hormone Receptor Polymorphism Is Negatively Associated with Fetal Growth but Positively Associated with Postnatal Growth in Healthy Subjects

Rikke Beck Jensen, Signe Vielwerth, Torben Larsen, Gorm Greisen, Henrik Leffers and Anders Juul

University Departments of Growth and Reproduction (R.B.J., H.L., A.J.), and Neonatology (S.V., G.G.), Rigshospitalet, DK-2100 Copenhagen, Denmark; and Department of Gynaecology and Obstetrics (T.L.), Holbaek Sygehus, Sygehus Vestsjaelland DK-4300, Denmark

Address all correspondence and requests for reprints to: Rikke Beck Jensen, M.D., University Department of Growth and Reproduction, Rigshospitalet, Section 5064, Blegdamsvej 9, DK-2100 Copenhagen Ø, Denmark. E-mail: rikke.beck{at}rh.hosp.dk.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
Context: A common polymorphism in the GH receptor (GHR) gene has been linked to increased growth response in GH-treated patients. No former study has focused on the association to prenatal growth.

Objective: The aim of the study was to evaluate the association between the d3-GHR isoforms and spontaneous pre- and postnatal growth.

Design: A prospective study was conducted on third-trimester fetal growth velocity (FGV), birth weight, birth length, and postnatal growth.

Setting: The study was conducted at Copenhagen University Hospital.

Participants: A total of 115 healthy adolescents were divided into those born small for gestational age (SGA) and appropriate for gestational age with or without intrauterine growth restriction.

Main Outcome Measures: FGV was measured by serial ultrasonography, birth weight, birth length, and adolescent height. Isoforms of the d3-GHR gene (fl/fl, d3/fl, and d3/d3) were determined.

Results: The prevalence of the d3-GHR isoforms was 50% but differed among the groups (P = 0.006), with a high prevalence (88%) in the group born SGA with verified intrauterine growth restriction. The d3-GRH allele were associated with decreased third-trimester FGV (P = 0.05) in SGA subjects. In the entire cohort, carriers of the d3-GHR allele had a significantly increased height (–0.10 vs. 0.34 SD score; P = 0.017) and change in height from birth to adolescence compared with carriers of the full-length GHR allele (0.57 vs. –0.02 SD score; P = 0.005).

Conclusions: This study showed an increased spontaneous postnatal growth velocity in the carriers of the d3-GHR allele. Interestingly, we found the opposite effect on prenatal growth in the SGA group, with a decreased FGV in carriers of the d3-GHR allele.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
ADEQUATE TRANSPLACENTAL substrate transport to the fetus is a prerequisite for normal growth, and a suboptimal environment in utero like third-trimester placental dysfunction often results in intrauterine growth restriction (IUGR). However, a limited period of IUGR may not necessarily result in smallness at birth [small for gestational age (SGA)]; despite limited substrate supply at some point during gestation, the infant may still be born appropriate for gestational age (AGA). Decreased fetal growth velocity (FGV) throughout gestation often results in smallness at birth, exemplified by small mothers giving birth to healthy but small newborns; this is thought to be genetically determined. Thus, SGA and IUGR are not necessarily synonymous entities.

The genetic and endocrine regulation of the transplacental fluxes of glucose and amino acids to the fetus is poorly understood. Associations between common genetic polymorphisms and IUGR have been proposed. The polymorphism insulin gene (INS) variable number of tandem repeats in the insulin gene seems to be related to the size at birth (1, 2), and this polymorphism is also associated with insulin resistance later in life (3), hereby linking fetal growth with adult onset of disease. Other genetic polymorphisms have been related to IUGR, such as polymorphisms in the gene encoding the CYP17 enzyme (4).

Fetal growth is generally considered independent of fetal GH levels, whereas fetal IGF-I levels are associated with fetal size (5, 6, 7, 8, 9). Genetic variations in the promotor region of the gene encoding IGF-I have been associated with low birth weight (BW) (10, 11), although controversy exists (12). Recently, genetic polymorphisms in the GH receptor (GHR) gene have been related to the postnatal growth response to exogenous GH in children born SGA (13, 14, 15), but to our knowledge, no studies have evaluated the influence of GHR genetic polymorphisms on fetal growth in humans.

The aim of this study was to investigate the association between a common genetic polymorphism in the gene encoding the GHR (fl/fl, d3/fl, and d3/d3) and spontaneous pre- and postnatal growth in a cohort of healthy young men and women.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
Participants

A total of 123 healthy young Caucasian subjects (52 males) participated in a follow-up study of a larger randomized controlled trial on fetal growth (16). The original study was performed in 1985–1987 on their mothers, from whom data were collected on third-trimester FGV and BW for gestational age. In the former study, pregnant women who had one or more risks factors (reported in detail earlier) for giving birth to a small child were recruited (16, 17). Calculations of third-trimester FGV were based on serial ultrasound measurements (three to nine measurements with a mean of four) from wk 28 until birth. A linear regression analysis was performed to calculate the changes in estimated fetal weight SD score (SDS) per 28 d, with a SE of 0.22 SDS/28 d. From these calculations, it was evaluated whether the fetus was growth restricted (IUGR) during the third trimester using the 10th percentile (equivalent to –0.39 SDS/28 d) of normal third-trimester FGV as the cutoff (18). Furthermore, the cohort was divided into infants born AGA or SGA using the 10th percentile for BW (equivalent to –1.28 SDS) as the cutoff value based on the previously published reference data (18). In the follow-up study performed in 2003–2005, it was possible to trace 547 young men and women born as singletons at term and with sufficient ultrasound data to estimate FGV. A sample of 271 was invited, including all the children who were born SGA and/or IUGR, and a random selection of one third of those born AGA. A total of 123 (52 males) agreed to participate (participation rate 45%). There were no significant differences in either BW (–0.63 vs. –0.61 SDS) or FGV in third trimester (–0.17 vs. –0.19 SDS/28 d) between the participants and nonparticipants, respectively. A DNA sample was obtained from 115 participants in whom sufficient data on prenatal growth were available; 69 participants were born AGA (25 with verified IUGR), and 46 were born SGA (17 with verified IUGR).

Study design

The participants (n = 115) arrived fasting between 0800 and 0900 h, where blood samples were drawn. Height (cm) was measured to the nearest 0.1 cm using a calibrated wall-mounted stadiometer (Force Institute, Brøndby, Denmark), and weight (kg) was measured on a digital weight scale, with a precision of 0.01 kg (Lindeltronic 8000; Copenhagen, Denmark). SDSs for height and weight were calculated based on a Danish national reference material (19). Pubertal stages were determined by Tanner’s classification (20), and testicular size was estimated using Prader’s orchidometer (21). Maternal and paternal height (SDS) was calculated using the national reference material (19), and target height (SDS) was calculated: maternal height (SDS) + paternal height (SDS)/2. Sufficient data for target height calculation were available in 95 subjects.

Hormone assays

Serum IGF-I was determined by RIA, as previously described (22). Briefly, serum was extracted by acid-ethanol and cryoprecipitated to remove interfering IGF binding proteins (IGFBPs) (23). Interassay and intraassay coefficients of variation were 9% and 6%, respectively. IGFBP-3 was determined by a RIA previously described (24). Reagents for the assay were obtained from Mediagnost GmbH (Tübingen, Germany). Sensitivity was 0.29 ng/ml (3 SD above zero standard). Interassay and intraassay coefficients of variation were 10.7% and 7.6%, respectively (25).

Genotyping

Genomic DNA was extracted from blood lymphocytes. The frequency of GHR transcript variants with retention (fl-GHR) or exclusion (d3-GHR) of exon 3 was tested by the multiplex PCR assay described by Pantel et al. (26). This was performed with primers G1, G2, and G3 (GenBank accession no. AF155912) as follows: initial step of denaturation of 3 min at 95 C, followed by 25 cycles consisting of 30 sec at 95 C, 1 min at 64 C, 1 min at 72 C, followed by an extension period at 72 C for 5 min. Amplification of DNA fragments was analyzed by electrophoresis on a 1% agarose gel stained with ethidium bromide. A 935-bp band represented the full-length (fl) allele (fl-GHR), and a 532-bp fragment represented the d3 allele (d3-GHR). To avoid possible problems caused by the multiplex PCR (27, 28), all samples were also analyzed by PCR using only the G1 and G3 primers, however, giving identical results in all cases. The distribution of the GHR genotypes did not deviate significantly from Hardy-Weinberg equilibrium.

Statistical analysis

Results were expressed as mean and SD or as median and interquartile range (IQR). Differences between the three groups with different genotypes were tested by ANOVA, and the significant results were further analyzed by the Student’s t test. Most anthropometric variables were presented as SDSs to evaluate males and females together. All variables were analyzed for normal distribution, and those with a skewed distribution were log transformed, or data were presented as median and IQR, and tested using the Mann-Whitney U test.

Ethical aspects

The study was performed according to the Helsinki II declaration, and approved by the local Ethical Committee (KF 01-229/02 and KF 01-065/03) and The Danish Data Protection Agency. Written informed consent was obtained from all participants and also from the parents/guardians of the participants under 18 yr of age.


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
The entire cohort consisted of 115 adolescents (51 males) who were all singletons born at term (37 wk > GA < 42 wk), with a mean BW deviation corrected for gestational age of –0.68 (SD 1.17) and a mean birth length (BL) SDS of –0.22 (SD 0.95). Mean third-trimester FGV assessed by serial ultrasonography was –0.18 {Delta}SDS/28 d (SD 0.39). At the follow-up study, mean age was 17.5 yr (SD 0.7), mean height SDS was 0.10 (SD 1.0), and height SDS corrected for target height was 0.13 SDS (SD 0.9). Age at follow-up and pubertal development (pubic hair, testicular volume in boys, and breast stages in girls) did not differ between subjects with the different GHR isoforms.

Of the 115 participants, 57 (50%) were homozygous for the fl allele (fl/fl), 47 (41%) were heterozygous (d3/fl), and 10 (9%) were homozygous for the d3 allele (d3/d3), hence the prevalence of the d3/fl and d3/d3 GHR isoforms (heterozygous or homozygous) was 50% in the entire cohort. The prevalence was increased in the group defined as SGA with IUGR (88%) (Fig. 1Go), and this difference was significant in an overall comparison of the four groups ({chi}2; P = 0.006).


Figure 1
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  		FIG. 1. Presence of GHR isoforms in 115 adolescents born SGA or AGA with or without IUGR. The bars represent the number of carriers of the different d3/fl-GHR Isoforms. The black bars represent the fl allele (fl/fl), the dark gray bars represent the heterozygous d3-deleted allele (d3/fl), and the light gray bars represent the homozygous d3-deleted allele (d3/d3). The cohort is divided into those born SGA and AGA with and without IUGR.

 
The clinical characteristics of the subjects according to their GHR isoforms are given in Table 1Go. There was a trend toward lower BL (ANOVA; P = 0.07) among carriers of the d3-GHR compared with the fl/fl group. Third-trimester FGV did not differ among the three groups in the entire cohort (ANOVA; P = 0.50). There were no differences in either paternal, maternal, or target height among the three groups, respectively. At follow-up, there was no significant difference between height (SDS), but when this was corrected for target height (HSDScorr), there was a significant difference between the GHR isoforms (ANOVA; P = 0.017); both the carriers of the d3/fl and d3/d3 GHR alleles were significantly taller than carriers of the fl/fl allele (P = 0.04 and P = 0.01, respectively) (Table 1Go). Carriers of at least one d3-allele had a lower weight SDS compared with the fl/fl group (median 0.29 vs. 0.89), but this did not reach statistical significance (P = 0.08). The change in height (SDS) from birth to adolescence corrected for target height ({Delta}HSDScorr) was significantly increased among the carriers of at least one d3 allele compared with the fl/fl group (mean 0.57, SD 1.05 vs. mean –0.02, SD 0.92; P = 0.005). There was a significant difference when comparing the three different isoforms (ANOVA; P = 0.01), with a significantly higher {Delta}HSDScorr in subjects carrying the d3/fl (P = 0.02) and d3/d3 (P = 0.02) isoforms compared with subjects carrying the fl/fl isoform (Fig. 2Go). To depict the time of catch-up growth, we looked at the change in weight and length during the first year of life, which was available in a part of the cohort (n = 69). There was a significantly higher change in weight from birth to 1 yr in the carriers of at least one d3 allele compared with the fl/fl group (mean –0.002 vs. –0.55; P = 0.035), and regarding length, the same tendency was found but did not reach statistical significance (mean –0.26 vs. –0.59; P = 0.13). In a multiple regression analysis with HSDScorr as dependent variable and the GHR isoforms, BW (SDS) and FGV as independent variables, we found a significant positive association with the GHR isoforms [B = 0.49, 95% confidence interval (CI) 0.21–0.76; P = 0.001) and BW SDS (B = 0.31, 95% CI 0.17–0.45; P < 0.0001), but no significant association to FGV (B = 0.19, 95% CI –0.18–0.30; P = 0.37).


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  		TABLE 1. Clinical and anthropometric measurements at birth and in adolescence according to GHR genotype

 

Figure 2
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  		FIG. 2. FGV in third trimester (expressed as {Delta}SDS/28 d) according to GHR genotypes. The black diamonds represent the fl allele (fl/fl) (n = 18), the dark gray diamonds represent the heterozygous d3-deleted allele (d3/fl) (n = 21), and the light gray diamonds represent the homozygous d3-deleted allele (d3/d3) (n = 7).

 
When analyzing the SGA group alone, there were no significant differences of BW or BL between groups with the GHR isoforms. However, we found a significant difference in FGV among the three groups (ANOVA; P = 0.05), with a lower FGV in both carriers of the d3/fl (mean –0.33, SD 0.36; P = 0.05) and the d3/d3 (mean –0.42, SD 0.30; P = 0.03) genotypes, respectively, when compared with the fl/fl group (mean –0.10, SD 0.31) (Fig. 3Go). In the SGA group, there was a trend toward a higher HSDScorr in the groups with at least one d3 allele; this did not reach significance (P = 0.08).


Figure 3
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  		FIG. 3. Change in height SDS from birth to near-final height corrected for target height. Black diamonds represent fl/fl (n = 46), dark gray diamonds represent d3/fl (n = 44), and light gray diamonds represent d3/d3 (n = 5).

 

   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
In this prospective cohort study on long-term effects of fetal growth in healthy subjects, we found that carriers of the d3-GHR allele who were born SGA had significantly decreased third-trimester FGV compared with carriers of the fl-GHR allele, and that the d3-GHR allele was more prevalent in the SGA/IUGR group. In contrast, significantly increased postnatal growth as well as adolescent height was found among carriers of the d3-GHR alleles in the entire cohort. The increase in spontaneous postnatal growth among carriers of the d3 allele is in accordance with previous studies on growth response in GH-treated children. Interestingly, the presence of the d3-GHR allele had the opposite effect on prenatal growth in the SGA group, with a decreased FGV in the heterozygous and homozygous d3-GHR groups. To our knowledge, this is the first study to examine the associations between d3-GHR genotypes and prenatal growth, as well as spontaneous postnatal growth.

Prenatal growth

Hormonal regulation of normal fetal growth is not fully understood, but fetal insulin is one of the major signals of nutrient availability promoting fetal growth via anabolic effects on the metabolism and via stimulation of IGF-I secretion. Traditionally, hormone regulation has been thought to be independent of fetal GH levels, but some reports seem to challenge this. First, several reports have uniformly reported decreased BLs of newborns with GH deficiency (GHD) corresponding to –1.1 SDS (n = 44) (29), –1.3 to –1.7 SDS (n = 14) (30), –0.57 SDS (n = 11) (31), and –0.83 SDS (n = 52) (32), respectively. Second, decreased BLs corresponding to –1.0 SDS in 82 newborns with GHR dysfunction were reported (33). Moreover, GHRs (GHR mRNA expression) have been demonstrated in fetal tissues as early as the first trimester of fetal life (34), which could theoretically be activated after GH binding. Together, these findings suggest that fetal GH may play an important direct role in regulation of fetal growth (30, 32).

Furthermore, GH may play an indirect role in regulation of fetal growth. The pregnancy-specific GH variant (termed placental GH) is primarily expressed in the syncytiotrophoblasts of the placenta and is secreted into the maternal circulation. Placental GH secretion gradually replaces maternal pituitary GH during pregnancy and is positively associated with fetal growth (35). It is suggested that placental GH operates indirectly via changes in maternal IGF-I and/or maternal metabolism regulating substrate supply to the fetus. GHRs are present in abundance in placenta, and placental GHs have similar binding affinity toward these receptors compared with that of pituitary GHs (36). Placental GH may theoretically stimulate GHRs on the surface of the syncytiotrophoblast by autocrine or paracrine actions, thereby affecting placental growth, placental IGF-I production, or substrate transfer to the fetus. The different isoforms of the GHR gene are also present in placenta, and binding studies have demonstrated that placental GH and pituitary GH have similar affinities toward the heterozygous (d3/fl) and homozygous (d3/d3) d3-GHR isoforms compared with the fl-GHR isoform (fl/fl) (37). Importantly, pituitary GH binding to the d3-GH-R may result in increased intracellular signaling compared with binding to the fl-GHR at equimolar concentrations, despite similar binding characteristics (15). It remains unknown whether or not differences in the intracellular signaling events after GHR activation could result in different biological actions of placental GH, depending on the presence of specific GHR isoforms at the cell surface.

Prevalence of the d3-GHR isoform

The prevalence of the d3-GHR isoform (heterozygous or homozygous) in the present study was 50%, with a distribution of 41% (d3/fl) and 9% (d3/d3) between heterozygous and homozygous individuals, respectively. The prevalence of homozygous d3/d3 carriers is comparable to the prevalence found in other studies (11–15%) (13, 27, 38, 39). Interestingly, when our present cohort was divided into four groups according to third-trimester FGV and BW, there was a strikingly high prevalence of the d3-GHR isoforms (88%) in the group born SGA with verified IUGR. Thus, our study indicates that the polymorphism in the gene encoding the GHR is associated with fetal growth, suggesting that GH is involved in regulation of fetal growth in contrast to the general belief. One of the limitations of this study is the small sample size, which was due to the antenatal selection of the offspring of the mothers participating in a former cohort study. The relatively low participation rate (45%) of a limited cohort reduced the sample size. However, other studies investigating the relationship between the GHR genotypes and postnatal growth have similar sample sizes, thus larger epidemiological studies are needed to confirm the findings.

Postnatal growth

The majority of SGA children show catch-up growth during the first 2 yr of life. It is not entirely understood why the remaining 5–10% do not catch up and, thereby, reach a final height below the normal range (40, 41, 42). Linear growth in childhood is regulated by the GH-IGF-I axis, and alterations of this axis will influence the growth rate. Most SGA children have a moderately decreased GH secretion (43). It remains to be seen if GH binding properties or changes in the GH signaling pathways are altered in SGA children.

Recent clinical studies have demonstrated an association between the presence of a d3-GHR allele and an increased growth response to GH treatment in SGA children, as well as in other groups of GH-treated patients (GHD, Turner syndrome, and idiopathic short stature) (13, 15, 44), although controversy exists (45, 46). Recently, Dos Santos et al. (15) found that among SGA children, carriers of the d3-GHR isoforms (d3/fl and d3/d3) had an increased growth response after GH treatment, compared with carriers of the fl-GHR isoform, in accordance with the findings of Binder et al. (13). By contrast, Carrascosa et al. (14) did not find such associations. These varying results may reflect the use of different GH doses in the three studies because a high GH dose could potentially mask the difference between the d3/fl-GHR genotypes. In addition to the findings among GH-treated SGA individuals, the majority of studies found positive associations between the d3-GHR isoform and an increased growth response to GH treatment in patients with Turner syndrome (13), idiopathic short stature (15), and GHD (44), although it was not found in all studies (45, 46).

In our present study, we found that subjects carrying the d3-GHR isoforms had an increased postnatal growth as well as an increased near-final height. Importantly, the majority of the SGA subjects in our study had spontaneous catch-up growth and a near-final height within the normal limits. In line with this, Audi et al. (27) found that the fl-GHR genotype was more common in the group of short SGA children without spontaneous catch-up growth compared with healthy subjects. In contrast, population-based studies of healthy subjects found no association between the d3-GHR genotype and final adult height (27, 39) or bone mineral density (39).

Recent preliminary reports revealed contrasting results. One study suggested that d3-GHR carriers had lower IGF-I and were more insulin resistant (assessed by homeostasis model of assessment) compared with carriers of the fl-GHR allele (47). Conversely, type 2 diabetics who were homozygous for the d3-GHR allele had higher IGF-I levels (48). We found no differences in IGF-I serum levels between GHR genotypes.

In conclusion, we found that carriers of the d3-GHR allele who were born SGA had significantly decreased third-trimester FGV, and that the d3-GHR alleles were significantly more prevalent in the SGA/IUGR group compared with subjects with normal BW. In contrast, a significantly increased adolescent height and a significantly increased change in height from birth to adolescence were found among carriers of the d3-GHR alleles. Thus, variations in the gene encoding the GHR seem oppositely associated with fetal and postnatal growth, respectively.


   Footnotes
 
Disclosure Statement: R.B.J., S.V., and G.G. received financial support for the project from Novo Nordisk A/S. T.L., H.L., and A.J. have nothing to declare.

First Published Online April 10, 2007

Abbreviations: AGA, Appropriate for gestational age; BL, birth length; BW, birth weight; CI, confidence interval; FGV, fetal growth velocity; fl, full-length; GHD, GH deficiency; GHR, GH receptor; HSDScorr, height SDS corrected for target height; IGFBP, IGF binding protein; IQR, interquartile range; IUGR, intrauterine growth restriction; SDS, SD score; SGA, small for gestational age.

Received January 24, 2007.

Accepted April 2, 2007.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

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