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

Strawbridge, Rona J.; Kärvestedt, Lars; Li, Chunde; Efendić, Suad; Östenson, Claes‐Göran; Gu, Harvest F.; Brismar, Kerstin

doi:10.1016/j.ghir.2007.04.005

Cited by 33 publications

(41 citation statements)

References 24 publications

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“…Conversely, a recent study performed in acromegalic patients reported a higher proportion of patients with normal glucose tolerance (NGT) in the group of subjects bearing at least one d3GHR allele (29). This last data, along with the finding that the GHRd3 allele has a low frequency in the diabetic population, suggest a positive effect of this isoform on glucose metabolism (30). The divergent influence of the d3GHR polymorphism on glucose metabolism observed in GHD or excess underlines the notion that acromegaly and adult GHD are not simply two conditions characterized by different entities of GH secretion.…”

Section: Discussionmentioning

confidence: 92%

Influence of the d3GH receptor polymorphism on the metabolic and biochemical phenotype of GH-deficient adults at baseline and during short- and long-term recombinant human GH replacement therapy

Giavoli

Ferrante

Profka

et al. 2010

European Journal of Endocrinology

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Objective: A common polymorphic variant of GH receptor (exon 3 deletion, d3GHR) has been linked with increased response to recombinant human GH (rhGH) in some patients with or without GH deficiency (GHD). The aim of the study was to investigate the impact of the GHR genotype on the phenotype of GHD adults and on the metabolic effect of rhGH therapy. Design: Prospective study of GHD patients evaluated before and during short-(1 year, nZ100) and long-term (5 years, nZ50) rhGH therapy. Methods: Effects of rhGH on IGF1 levels, body composition (body fat percentage, BF%), body mass index, lipid profile, and glucose homeostasis (fasting insulin and glucose, insulin sensitivity indexes) were evaluated according to the presence or the absence of the d3GHR variant. Results: The different genotype did not influence basal phenotype of GHD. Short-term rhGH determined normalization of IGF1 levels, decrease in BF%, and worsening of insulin sensitivity, independently from the presence of the d3GHR allele. A significant increase in high-density lipoprotein cholesterol occurred in the d3GHR group. Normalization of IGF1 levels and decrease in BF% were maintained after 5 years. Insulin sensitivity restored to basal values, though in d3GHR patients fasting glucose remained significantly higher than at baseline. After both 1 and 5 years, percentage of subjects with impaired glucose tolerance, similar in the two groups at baseline, decreased in fl/fl while doubled in d3GHR patients. In this last group, a long-term significant reduction in total and low-density lipoprotein cholesterol was also observed. Conclusion: The functional difference of d3GHR may influence some metabolic effects of rhGH on GHD adults.

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Section: Discussionmentioning

confidence: 92%

Influence of the d3GH receptor polymorphism on the metabolic and biochemical phenotype of GH-deficient adults at baseline and during short- and long-term recombinant human GH replacement therapy

Giavoli

Ferrante

Profka

et al. 2010

European Journal of Endocrinology

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“…These two GHR isoforms present a widespread distribution in humans; since the first report, a total of 1,063 Caucasian controls have been genotyped, with the frequency of each allele being 66 and 34% for GHR fl and GHR d3, respectively [12,13,14,15,16,17]. The distribution of each genotype in the different studies was similar and reaches Hardy–Weinberg equilibrium: 43% for fl/fl, 45% for fl/d3 and 12% for d3/d3, with the exception of one study that found a lower frequency of controls homozygous for the GHR fl allele [13].…”

Section: Frequency Of Ghr Exon 3 Isoforms In the General Populationmentioning

confidence: 99%

“…Patients homozygous for the GHR d3 allele had a lower BMI SDS than those homozygous for the GHR fl allele, suggesting that this polymorphism also modulates GH metabolic actions. However, the evaluation of patients with type 2 diabetes mellitus did not show an influence of GHR exon 3 genotype on metabolic parameters, and patients harbouring the GHR d3 allele had a higher BMI than those with the G HR fl allele [16]. In both studies, a type 1 error caused by multiple testing cannot be ruled out.…”

Section: Ghr Exon 3 Isoforms and Hgh Treatment In Patients With Tsmentioning

confidence: 99%

Growth Hormone Receptor Exon 3 Isoforms and Their Implication in Growth Disorders and Treatment

Jorge¹,

Arnhold²

2009

Horm Res Paediatr

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Human recombinant growth hormone (hGH) has been used to treat short stature in several different conditions, but considerable inter-individual variation in short- and long-term growth response exists. Pharmacogenomics can provide important insights into hGH therapy. The GH receptor (GHR) is the first key molecule mediating GH action. In the past 3 years, a common GHR polymorphism reflecting the presence (GHRfl) or absence (GHRd3) of exon 3 has been under intensive investigation regarding its influence on the response to hGH therapy. Studies that evaluated response to GH treatment determined by these two GHR isoforms in children with GH deficiency, girls with Turner syndrome, children born small for gestational age and patients with acromegaly showed that patients carrying the GHRd3 allele demonstrated a greater GH sensitivity than patients homozygous for the GHRfl allele. Other studies presented contradictory data, however, which may be caused by confounding factors such as small sample sizes and differences in experimental design. This GHR exon 3 genotype is the first identified genetic factor found to modulate the individual response to GH therapy. This article reviews the historical aspects and pharmacogenetic studies published to date in relation to this GHR polymorphism. The analyses of present and future validation studies may define the use of this and other polymorphisms in clinical practice, moving from pharmacogenetics to routine application and allowing individualization of hGH doses to optimize final outcome.

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“…In a report on the response of short-term recombinant GH therapy in GH deficient adults, it has been shown that patients carrying at least one GHRd3 allele exhibited a significant increase in HDL-c levels as compared to those lacking a copy of the deletion (van der Klaauw et al 2008), implicating the critical role of growth hormone in regulating lipoprotein metabolism. Further, the GHRd3 allele has been found to show a protective effect against development of type 2 diabetes in adult life (Strawbridge et al 2007). A marginal association was shown between GHRd3 and hypertension in limited number female stroke patients (Horan et al 2006).…”

Section: Discussionmentioning

confidence: 97%

Polymorphisms in the pituitary growth hormone gene and its receptor associated with coronary artery disease in a predisposed cohort from India

Maitra

Shanker

Dash

et al. 2010

J Genet

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We investigated the promoter polymorphisms of the pituitary growth hormone gene (GH1) and exon 3 deletion polymorphism (GHRd3) in its receptor gene (GHR) in 299 angiographically proven patients with coronary artery disease (CAD) and 231 asymptomatic controls enrolled in the ongoing Indian Atherosclerosis Research Study. Real time PCR based analysis of the GHR variant showed significant association of the GHRd3 deletion allele with CAD (OR 0.48, 95% CI: 0.30-0.76, P = 0.0014) and a dominant model of inheritance (Akaike information criterion = 482). The deletion allele showed significant association with high plasma HDL-c levels (P = 0.001). Sequencing of the proximal promoter region of GH1 revealed 12 novel polymorphisms and a TAGA haplotype constituted by the functional SNPs rs2005171, rs11568828, rs2005172 and rs6171, that showed significant association with CAD alone (adjusted OR of 3.31 (95% CI = 1.33-8.29, P = 0.011) and in CAD patients with diabetes (P = 0.019). Mean standardized height was associated with three of the four haplotype-tagging SNPs in the cohort (P ≤ 0.03). Eleven of the 12 polymorphic promoter SNPs contributed to 14.7% of variation in height in females in the whole dataset (P = 0.029). CAD patients with history of stroke exhibited marginally significantly lower mean height as compared to rest of the cohort (P < 0.006). In conclusion, genetic polymorphisms in the GHR gene and its ligand, GH1, may modulate the risk of CAD in the Asian Indian population.

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

Cited by 33 publications

References 24 publications

Influence of the d3GH receptor polymorphism on the metabolic and biochemical phenotype of GH-deficient adults at baseline and during short- and long-term recombinant human GH replacement therapy

Influence of the d3GH receptor polymorphism on the metabolic and biochemical phenotype of GH-deficient adults at baseline and during short- and long-term recombinant human GH replacement therapy

Growth Hormone Receptor Exon 3 Isoforms and Their Implication in Growth Disorders and Treatment

Polymorphisms in the pituitary growth hormone gene and its receptor associated with coronary artery disease in a predisposed cohort from India

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