GH receptor d3 polymorphism in Dutch patients with MPHD and IGHD born small or appropriate for gestational age

Objective  GH acts through the GH receptor (GHR). The GHR gene contains a genetic polymorphism caused by a deletion of exon 3 ( d3 ), with high frequency in the normal population. There is a continuing controversy whether the presence or absence of the exon 3 deletion ( d3+ vs. d3– ) affects the effect of GH in human growth.
Design, patients and measurements  For 144 patients with idiopathic isolated GH deficiency (IGHD, n  = 72) or multiple pituitary hormone deficiency (MPHD, n  = 72), amplification of the region around exon 3 of the GHR gene was performed. Clinical data and response to GH treatment were compared between GHR d3+ and d3– IGHD and MPHD patients born either small for gestational age (SGA) or appropriate for gestational age (AGA).
Results  IGHD patients born SGA had a significantly higher d3+ frequency (82%) than IGHD patients born AGA (35%, P  = 0·006). Within the group of IGHD patients born SGA, d3 – patients showed a slightly better spontaneous catch up growth before start of GH treatment than d3 + patients (1·1 ± 1·1 SD vs. 0·6 ± 1·1 SDS, P  = 0·040) There was no difference in patients first year's response to GH treatment between GHR d3 + and d3– patients.
Conclusions  In IGHD and MPHD patients, response to GH treatment was independent of GHR genotype. GHR- d3 was significantly more frequent among IGHD patients born SGA. As we are the third to report an association between birth size and GHR d3 status, it is conceivable that the GHR- d3 might affect prenatal growth in IGHD patients by a yet unknown mechanism.     

Common exon 3 polymorphism of the GH receptor (GHR) gene and effect of GH therapy on growth in Korean children with idiopathic short stature (ISS)

Objective  A human GH receptor ( GHR ) gene exon 3 polymorphism ( d3 -GHR) has been reported to be associated with responsiveness to GH therapy. We assessed the frequencies of this polymorphism in Korean control and idiopathic short stature (ISS) populations, and analysed short-term growth response to GH therapy according to GHR -exon 3 genotypes in Korean children with ISS.
Design and patients  This was a retrospective study in 158 ISS children. Auxological and endocrine parameters were measured, and the GHR -exon 3 genotype was analysed. Allelic frequencies of GHR -exon 3 genotype were compared between the ISS group and a control group. GH had been administered for 62 patients, 52 of whom remained prepubertal after the first follow-up year. Changes in height velocity (HV) and IGF-1 and IGFBP-3 concentrations following GH therapy were compared in patients with these genotypes.
Results  There was no difference in GHR -exon 3 genotype frequency between ISS and control groups of Koreans. However, the fl / fl genotype was more frequent in Koreans than in Caucasians. ISS children with d3 -GHR showed a significantly higher increment in HV ( P  = 0·002) and a marginally significant increment in IGF-1 concentration ( P  = 0·064) at the first year of GH therapy.
Conclusion  fl -GHR was more frequently detected in a Korean population than in Caucasians. The growth promotion efficacy of GH therapy differed significantly between ISS patients with and without the d3 -GHR allele. These findings indicate that the GHR -exon 3 polymorphism can affect the growth promoting efficacy of short-term GH therapy in Korean children with ISS.     

Evaluation of the association between GHR exon 3 polymorphism and polycystic ovary syndrome among Han Chinese women

Background

Polycystic ovary syndrome (PCOS) and type 2 diabetes (T2D) are two common metabolic disorders in reproductive-aged women, and both are associated with insulin resistance. Evidence has indicated that the growth hormone receptor (GHR) exon 3 polymorphism is associated with T2D and the GHRd3 allele may have the preventive effect on the disease. However, the genetic effect of this polymorphism on PCOS is unknown. The present study thus aims to evaluate the association between the GHR exon 3 polymorphism and PCOS.

Design

A total of 432 patients with PCOS and 441 healthy control subjects were included. All of them were Han Chinese women and well characterized. Genotyping experiments of GHR exon 3 polymorphism were performed with a standard protocol of PCR and gel electrophoresis.

Results

GHRd3 allele frequency in PCOS patients was significantly higher compared to the control subjects (19.1% vs. 14.3%; P = 0.007, OR = 1.416; 95% CI = 1.099–1.825). Further analyses indicated that the GHRd3 allele was associated with increased waist and hip circumstance in healthy women (P = 0.016; 0.003), and also with 1-h, 2-h and area under the curve (AUC) plasma glucose levels among PCOS patients (all P < 0.05). But, no association of GHR exon 3 polymorphism with insulin resistance in the patients was observed.

Conclusions

The present study provides the first evidence that GHR exon 3 polymorphism is associated with PCOS in Han Chinese women. The GHRd3 allele may contribute to an impact of glucose metabolism but not insulin resistance.     

A Functional Polymorphism of the NFKB1 Gene Increases the Risk for Alcoholic Liver Cirrhosis in Patients With Alcohol Dependence

Background:  The genetic basis for the predisposition to alcoholic liver cirrhosis (ALC) remains unknown. Increasing evidence supports a role for the nuclear factor (NF)-κB, the NF-κB inhibitor α (NFKBIA), and the peroxisome proliferator-activated receptor (PPAR)-γ in the pathogenesis of alcoholic liver disease, raising the possibility that common polymorphisms in genes encoding these molecules may confer susceptibility to ALC. The objective of this study was to analyze the relationship between common polymorphisms in NFKB1 , NFKBIA, and PPARG2 genes and the presence of ALC.
Methods:  A total of 258 male alcoholics (161 without liver disease and 97 with ALC) and 101 healthy controls were genotyped for the −94ins/delATTG NFKB1 , 3'-UTR+126G>A NFKBIA, and 34C>G PPARG2 polymorphisms. The association of these genetic variants with ALC was tested in alcoholic patients with alcohol abuse and alcohol dependence. A logistic regression analysis was further performed to analyze the model of inheritance.
Results:  We found an association between the presence of the deletion allele in NFKB1 polymorphism and ALC in patients with alcohol dependence. We found no association between NFKBIA and PPARG2 polymorphisms and the presence of ALC.
Conclusions:  The deletion allele of the −94ins/del NFKB1 polymorphism could be associated with a higher risk of developing ALC through an increase in inflammation, as supported by previous data.     

Association of a single nucleotide polymorphism in the secreted frizzled-related protein 4 (sFRP4) gene with bone mineral density

Background:   Wnt-β-catenin signaling pathway is involved in the regulation of bone mineral density (BMD). Secreted frizzled-related protein (sFRP) 4 that antagonize Wnt signals may modulate Wnt-β-catenin signaling pathway in the bone. Therefore, we analyzed expression of sFRP4 mRNA in primary osteoblasts and the association of a single nucleotide polymorphism (SNP) in the sFRP4 gene with BMD.
Methods:   Expression levels of sFRP4 mRNA were analyzed during the culture course of rat primary osteoblasts. Association of a SNP in the sFRP4 gene at Arg262 (CGC to CGT) with BMD was examined in 372 healthy post-menopausal Japanese women.
Results:   sFRP4 mRNA was detected and increased during the differentiation of rat primary osteoblasts. As an association study of the SNP in the sFRP4 gene, the subjects without the T allele (CC; n  = 129) had significantly higher lumbar BMD than the subjects bearing at least one T allele (TT + CT; n  = 243) (Z score; 0.054 versus −0.324; P  = 0.0188).
Conclusion:   sFRP4 mRNA was expressed and regulated in primary osteoblasts. A genetic variation at the sFRP4 gene locus is associated with BMD, suggesting an involvement of sFRP4 gene in the bone metabolism.     

The distribution of exon 3-deleted/full-length growth hormone receptor polymorphism in the Turkish population

Objective: The exon 3-deleted/full-length (d3/fl) growth hormone receptor (d3/fl-GHR) polymorphism has been associated with responsiveness to GH therapy in some children and also with adult height variation in the general population. We aimed to evaluate the distribution of d3/fl-GHR polymorphism in a Turkish population. Methods: The study included 477 (54 females/423 males) healthy adults with a mean±SD age of 31.1±9.0 years (range: 18-57). Height and body mass index (BMI) were expressed as standard deviation score (SDS) according to national standards. All adults had normal height and BMI SDSs (between -2 and +2). GHR exon 3 isoforms were studied by simple multiplex polymerase chain reaction method. Insulin-like growth factor-1 (IGF-1) and IGF-binding protein-3 (IGFBP-3) values were also measured and expressed as SDS. Results: The distribution of the GHR exon 3 genotypes in the Turkish healthy adults was 35% (n=167) for fl/fl, 39% (n=186) for fl/d3, and 26% (n=124) for d3/d3. There was no difference between genders in GHR exon 3 genotypes. Frequencies of fl allele and d3 allele were 54.5% and 45.5%, respectively. There were no differences in height SDS and BMI SDS among the three d3/fl-GHR genotype groups. There was a significant difference in IGFBP-3 SDS between fl/fl and fl/d3 groups (p=0.022). Conclusions: This study presents the results of GHR polymorphism in a Turkish population as a reference for further studies. The distribution was similiar to European populations. There were no correlations between GHR isoforms and height SDS or other clinical/biochemical characteristics of the individuals except for higher IGFBP-3 levels in the fl/d3 group as compared to the fl/fl group. Whether this finding implies an abnormality, needs further investigation. Conflict of interest:None declared.     

Association of IRF5 polymorphisms with systemic lupus erythematosus in a Japanese population: support for a crucial role of intron 1 polymorphisms

OBJECTIVE: To determine whether the IRF5 gene, which encodes interferon regulatory factor 5, is associated with systemic lupus erythematosus (SLE) in a Japanese population. METHODS: A case-control study was performed in 277 SLE patients and 201 healthy controls. Associations between the IRF5 genotype and levels of messenger RNA (mRNA) for interferon (IFN) pathway genes were examined using an mRNA expression database of HapMap samples. RESULTS: Carriers of the rs2004640T single-nucleotide polymorphism (SNP) were slightly increased among SLE patients (58.8%) as compared with controls (50.2%). When data from our Japanese population were combined with previously published data from a Korean population, the T allele frequency was found to be significantly increased in SLE patients (P = 8.3 x 10(-5)). While no association was observed for the rs10954213 SNP or the exon 6 insertion/deletion, significant associations with 3 intron 1 SNPs (-4001, rs6953165, and rs41298401) were found. The allele frequency of rs41298401G was significantly decreased in SLE patients (13.0% versus 18.7% in controls; P = 0.017), and the allele frequency of rs6953165G, which was in absolute linkage disequilibrium with -4001A, was increased in SLE patients (8.8% versus 5.2% in controls; P = 0.034). The Caucasian risk haplotype was not present; instead, a protective haplotype carrying rs2004640G, rs41298401G, the deletion in exon 6, and rs10954213A was identified. SNP rs10954213, but not intron 1 SNPs, was associated with IRF5 at the mRNA level; nevertheless, intron 1 SNPs were also associated with levels of mRNA for several IFN pathway genes, suggesting a functional role. CONCLUSION: IRF5 was found to be associated with SLE in Asian populations. Intron 1 SNPs, rather than exon 6 and 3'-untranslated region polymorphisms, appeared to play a crucial role.     

d3‐Growth hormone receptor polymorphism in acromegaly: effects on metabolic phenotype

Objective A common polymorphic variant of the growth hormone receptor (GHR) is because of genomic deletion of exon 3 and has been linked with increased responsiveness to exogenous GH. The impact of this polymorphism in acromegaly, a disease characterized by endogenous excess of GH and partial loss of IGF‐I feedback on tumoural GH secretion, is not clear. The aim of this study was to investigate possible influences of d3GHR on the GH/IGF‐I relationship and metabolic parameters in acromegaly. Design and methods Retrospective study on 76 acromegalic patients. Genotype analysis was carried out on leucocyte DNA by multiplex PCR assay. Clinical, hormonal and biochemical parameters at diagnosis were collected from patients’ medical records. Results Forty‐two patients (55·3%) were homozygotes for the allele encoding the full‐length GHR (fl/flGHR), 27 patients were heterozygotes (fl/d3) and seven homozygotes (d3/d3) for the genomic deletion of exon 3. Heterozygotes and homozygotes for the d3 allele were considered together (d3GHR) and compared with fl/flGHR patients. d3GHR and fl/flGHR patients showed no difference in GH and IGF‐I levels or in the relationship between these two parameters. Patients bearing d3GHR had a lower body mass index (BMI) than patients bearing fl/flGHR (25·8 ± 2·1 vs. 28·1 ± 4·8 kg/m², P < 0·05). Diabetes mellitus and hypertension were equally distributed, but more d3GHR patients had a normal glucose tolerance (66·7%vs. 56·3%, P < 0·05). The presence of d3GHR allele, and not BMI or age, was a significant negative predictor of insulin levels 120 min after oral glucose load (β = ?80·8, P < 0·05). Conclusions This study supports the hypothesis that the d3GHR is functionally different from the fl/fl variant mostly for the effects on body weight regulation and on glucose metabolism.     

Common polymorphisms of the growth hormone (GH) receptor do not correlate with the growth response to exogenous recombinant human GH in GH-deficient children

CONTEXT: GH acts through the GH receptor (GHR), whose polymorphisms might affect the growth response to recombinant human GH (rhGH). OBJECTIVE: The objective of this study was to investigate possible influences of GHR polymorphisms on the growth response to rhGH in GH-deficient (GHD) children. DESIGN: This was a 2-yr study (first year, spontaneous growth; second year, growth during rhGH treatment). SETTING: This study was performed at a referral center. PATIENTS: Fifty-four prepubertal GHD children (11 females; mean age, 7.8 yr; sd, 3.96) were studied. INTERVENTION: Patients were treated with rhGH (0.2 mg/kg.wk) for at least 1 yr after diagnosis. Growth velocity (GV) was measured 1 yr before treatment and during the first treatment year. GHR exons were amplified by PCR using pairs of intronic primers. The presence of single or multiple mismatches in the PCR products was revealed by denaturing high-pressure liquid chromatography. For exons in which mismatches were found by denaturing high-pressure liquid chromatography, direct sequencing was performed by automatic sequencer. MAIN OUTCOME MEASURES: Before the start of treatment, the mean height (Ht) sd score was -1.93 (sd, 0.70), and the mean GV sd score was -1.49 (sd, 1.26). RESULTS: The posttreatment (first 12 months) mean GV sd score was 3.55 (sd, 3.27). Molecular analysis revealed a high frequency of GHR polymorphisms; in particular: exon 3 deletion (Del 3) in 26 subjects (48%), polymorphism 504 A>G at codon 168 of exon 6 in 44 (82%), and polymorphism 1576 A>C at codon 526 of exon 10 in 35 (65%). In most patients, these different polymorphisms recurred in association. We found no significant differences in GV between the groups of subjects defined by the polymorphic genotypes. CONCLUSION: The most common GHR polymorphisms, alone or in association, do not appear to affect the growth response to rhGH in GHD children.     

GHR exon 3 polymorphism: association with type 2 diabetes mellitus and metabolic disorder.

Growth hormone (GH) signaling via the growth hormone receptor (GHR) forms a major part of the GH-IGF-I axis, which is crucial for controlling metabolism and anabolism. Two common variants of the GHR differ by the presence (full length or GHR(fl)) or absence of exon 3 (exon 3 deleted or GHR(d3)), the function of which is unknown. However, differential response to GH treatment has been observed with carriers of the GHR(d3) variant conferring a greater growth rate. This study investigates these GHR variants in subjects with normal glucose tolerance (NGT) and impaired glucose tolerance (IGT), including Type 2 diabetes mellitus (T2DM). DNA was extracted from blood samples from subjects with NGT (n=158), IGT (n=116) and T2DM (n=194). The T2DM subjects in set 1 (n= 39) were newly diagnosed, whilst those in set 2 (n=155) had a mean duration of 7 years. Set 1 also included NGT and IGT subjects. Genotyping by standard PCR and gel electrophoresis were carried out. A significant difference was observed between T2DM and NGT (p<0.0001) with a significantly lower frequency of GHR(d3) in T2DM (3.6% compared to 17% in NGT). Both sets of T2DM subjects with at least one GHR(d3) allele had significantly higher BMI. In the larger subset of T2DM, GHR(d3) was associated with higher CRP levels as well as age adjusted IGF-I, with a trend of higher C-peptide secretion and impaired lipid levels, indicating a phenotype with metabolic disorder when compared to the GHR(fl/fl) T2DM subjects. In conclusion, homozygosity for the GHR(d3) allele appears to be preventive of T2DM. However, when other factors cause overt T2DM, the GHR(d3) allele confers a phenotype indicative of metabolic disorder. This study supports the hypothesis that the two GHR alleles by their inclusion or exclusion of exon 3 are functionally different.     

Influence of growth hormone (GH) receptor deletion of exon 3 and full-length isoforms on GH response and final height in patients with severe GH deficiency

CONTEXT: A polymorphism of the GH receptor (GHR) gene resulting in genomic deletion of exon 3 (GHR-d3) has been associated with responsiveness to GH therapy. However, the data reported so far do vary according to the underlying condition, replacement dose, and duration of the treatment. OBJECTIVE, DESIGN: The aim of this study was to analyze the impact of the GHR genotypes in terms of the initial height velocity (HV) resulting from treatment and the impact upon adult height in patients suffering from severe isolated GH deficiency. CONTROLS, PATIENTS, SETTING: A total of 181 subjects (peak stimulated GH相似文献   

载脂蛋白H基因多态性与冠心病关系的研究

目的探讨载脂蛋白H(ApoH)外显子3、8基因多态性与冠心病(CHD)的关系。方法采用聚合酶链式反应结合限制性片段长度多态分析方法,分析了100例健康人及110例冠心病患者的ApoH外显子3、8基因型。结果CHD组外显3GG基因型的频率为81.8%,GA+AA基因型频率为11.8%,G等位基因频率为88%,A等位基因频率是12%,与对照组比较无差异,CHD组外显子8GG基因型频率为74.5%、GC基因型频率为25.5%,G等位基因频率为87%,C等位基因频率为13%,与对照组比较CHD组的GC基因型频率及C等位基因频率显著增高。结论ApoH外显子3基因多态性与CHD无相关性;8GC基因型及C等位基因与CHD有关。     

Association of the growth hormone receptor d3-variant and catch-up growth of preterm infants with birth weight of less than 1500 grams

BACKGROUND: Preterm infants with very low birth weight frequently exhibit impaired longitudinal growth during the first years of life. Recently, the d3-isoform (genomic deletion of exon 3) of the GH receptor (GHR) has been linked to an increased responsiveness to GH. OBJECTIVE: Our objective was to test whether the GHRd3 isoform is associated with postnatal catch-up growth in very low birth weight preterm infants. DESIGN AND PATIENTS: We compared the postnatal growth pattern of 77 otherwise healthy preterm infants (mean gestational age, 28.5 wk; range, 23-35 wk) with a birth weight below 1500 g (mean birth weight, 941 g) to their GHR exon 3 genotype, which was analyzed by multiplex PCR. On examination, mean age of the children was 6.0 yr (range, 4.2-8.0 yr). RESULTS: Children homozygous or heterozygous for the GHRd3 allele showed a significantly higher rate of postnatal catch-up, compared with those homozygous for the full-length allele. CONCLUSIONS: Our results define the GHR exon 3 genotype as a predictor for the postnatal growth pattern of very low birth weight preterm infants. Those who carry at least one GHRd3 allele are more likely to catch-up.     

The exon 3-deleted growth hormone receptor: molecular and functional characterization and impact on GH/IGF-I axis in physiological and pathological conditions

The GH receptor (GHR) plays a key role in the the function of the GH/IGF-I axis and is the major effector of human growth. A common polymorphic variant consisting of genomic exon 3 deletion or retention (d3-GHR and full-length GHR, respectively), described in 2000, has been linked with increased receptor activity due to enhanced signal transduction. Subsequent pharmacogenetic studies have addressed a possible role of GHR polymorphism on the response to recombinant human GH treatment first in short children and then in adults, many of them suggesting that growth response to GH may be influenced, at least in some aspects, by this polymorphism. Similar studies, performed in patients with acromegaly, assumed an influence of the d3- GHR variant in the relationship between GH and IGF-I levels. More recently, some studies have investigated the relation between GHR genotype and treatment with the GHR antagonist pegvisomant, suggesting a better clinical response to therapy related to d3-GHR genotype. This review provides a summary of the main pharmacogenetic studies performed on this current and still open topic.     

Uridine diphosphate glucuronosyl transferase 1A1 promoter polymorphism is associated with choledocholithiasis in Taiwanese patients

Background and aims:  The gene product of the uridine diphosphate glucuronosyl transferase 1A1 (UGT1A1) is crucial to bilirubin metabolism. Mutations in this gene subsequently result in disease presented with unconjugated hyperbilirubinemia. A previous study showed that a TA-repeat polymorphism in the promoter region of this gene might play a role in the metabolism of bilirubin. Whether this polymorphism might predispose choledocholithiasis is unclear.
Methods:  We recruited 32 patients who were diagnosed with pigment choledocholithiasis (common bile duct stones) by endoscopic retrograde cholangiopancreatography (ERCP) morphology and 107 population controls. The TA-repeat in the UGT1A1 promoter was genotyped.
Results:  We found that among the 32 patients, 15 (46.9%) were wild type (A[TA]₆TAA homozygous); 15 (46.9%) were a heterozygous variation (A[TA[₆TAA/A[TA]₇TAA) and 2 (6.2%) were a homozygous variation (A[TA]₇TAA). Among the controls, 81 (75.7%) were wild type, 23 (21.5%) were a heterozygous variation and 3 (2.8%) were a homozygous variation. The genotype distribution was significantly different between patients and controls.
Conclusions:  The results suggest that the UGT1A1 promoter TA-repeat polymorphism is associated with choledocholithiasis in Taiwanese patients.     

Cholecystokinin receptor A gene polymorphism in gallstone disease and gallbladder cancer

Background and Aim:  Gallbladder carcinoma (GBC) usually arises in the background of gallstone disease which may be causatively related to decreased gallbladder contractility. Cholecystokinin receptor A ( CCK-AR ) mediates signals resulting in gallbladder contraction. Deteriorating gallbladder contraction promotes gallstone formation. A common genetic polymorphism of CCK-AR may be causatively associated with the risk of gallstone and GBC. This study aimed to understand the association of CCK-AR Pst I polymorphism in gallstone disease with gallbladder cancer.
Method:  This study included 165 gallstone patients, 139 GBC patients, and 190 healthy subjects. Genotyping was done using the polymerase chain reaction–restriction fragment length polymorphism (PCR-RFLP) method.
Results:  The frequency of the A1A1 genotype of CCK-AR was significantly higher in gallstone patients than healthy individuals ( P  = 0.008 odds ratio [OR] = 2.25, and 95% confidence interval [CI]:1.2–4.1). However, there was a significant difference in the frequency of A1A1 genotype when gallstone patients were compared to GBC patients ( P  = 0.041, OR = 0.49, and 95% CI: 0.3–0.9). On stratification of GBC patients according to presence or absence of gallstones, GBC patients without stones were compared to controls and GBC patients with stones were compared to stone patients; however, no significant differences in frequencies were observed.
Conclusion:  The results suggest that the A1A1 genotype of CCK-AR is an independent genetic risk factor for gallstone disease and does not modulate the susceptibility of gallbladder cancer.     

Influence of the d3-growth hormone (GH) receptor isoform on short-term and long-term treatment response to GH replacement in GH-deficient adults

OBJECTIVE: Recombinant human GH (rhGH) replacement in adults is aimed at improving signs and symptoms of the adult GH deficiency (GHD) syndrome. In children, a common polymorphism of the GH receptor (exon-3 deletion, d3GHR) increases the response to rhGH replacement. The aim of this study was to assess the effects of this polymorphism on the response to rhGH replacement in adults. DESIGN: Prospective intervention with rhGH during 1 yr (n = 99) and in a subset during 5 yr (n = 53). PATIENTS AND METHODS: The presence of the d3GHR variant was established in GHD patients and linked to short-term and long-term effects of rhGH replacement on IGF-I, lipid metabolism, anthropometric parameters, and bone mineral density. RESULTS: Fifty-five patients had two wild-type alleles (56%), whereas 38 patients (38%) had one allele and six patients (6%) had two alleles coding the d3GHR isoform. During short-term rhGH replacement, the increase in IGF-I was higher in patients bearing at least one d3GHR allele, compared with those with two wild-type alleles (at an identical mean dose of rhGH). The decrease in total cholesterol and low-density lipoprotein cholesterol was lower in the group bearing at least one d3GHR allele, whereas the increase in high-density lipoprotein cholesterol was higher, compared with patients with the wild-type genotype. In contrast, these differential responses of GHR genotype could not be demonstrated during long-term rhGH replacement. CONCLUSION: The d3GHR genotype contributes, at least for some parameters, to the interindividual differences in efficacy of short-term, but not long-term, rhGH replacement in adults with GHD.     

GH responsiveness in a large multinational cohort of SGA children with short stature (NESTEGG) is related to the exon 3 GHR polymorphism

OBJECTIVE: The polymorphic deletion of exon 3 of the GH receptor (d3-GHR) has recently been linked to the magnitude of growth response to recombinant human GH (rhGH) therapy in short children with or without GH deficiency. We investigated this association in a large multinational cohort from the Network of European Studies of Genes in Growth (NESTEGG), comprising short children born small for gestational age (SGA). DESIGN: The study included short prepubertal SGA children treated with rhGH for 1 or 2 years. POPULATION: Two hundred and forty white Caucasian SGA children (138 male, 102 female) aged 6.6 +/- 2.3 years with a height at -3.0 +/- 0.7 SDS at start of rhGH treatment; 193 ethnically matched controls. METHODS: The GHR polymorphism (fl/fl, fl/d3 or d3/d3) was genotyped by polymerase chain reaction (PCR) multiplex assay. Growth velocity (G/V) in cm/year and changes in GV during the first and second year of rhGH treatment were evaluated. RESULTS: The change in GV was significantly greater in SGA children carrying one or two copies of the d3-GHR allele (P = 0.038 for the first year and P = 0.041 for the second year of GH treatment), but the change in height was not significantly different. Birthweight was significantly lower in SGA children with the d3/d3 genotype than in SGA children with the fl/fl genotype (P = 0.034) and in those with the fl/d3 genotype (P = 0.016). CONCLUSION: Our data, based on a large cohort, showed that the exon 3 GHR polymorphism is associated with responsiveness to rhGH treatment in SGA children with short stature.