Endocrine Abstracts (2008) 16 P461

d3-growth hormone receptor polymorphism (d3-GHR) is associated with low BMI and better glucose metabolism in acromegaly

Maura Arosio1, Marcello Filopanti2, Laura Montefusco1, Luca Olgiati2, Cristina Lucia Ronchi2, Marco Losa3, Carmen La Porta2, Francesca Coletti1, Andrea Lania2, Paolo Beck-Peccoz2 & Anna Spada2


1Endocrine and Diabetes Unit, Department of Medical Sciences, San Giuseppe-Milanocuore Hospital, University of Milan, AFaR, Milan, Italy; 2Endocrine and Diabetes Unit, Department of Medical Sciences, University of Milan, Fondazione Ospedale Maggiore Policlinico, Mangiagalli and Regina Elena, IRCCS, Milan, Italy; 3Neurosurgery Unit, San Raffaele Hospital, Milan, Italy.


Background: The d3-growth hormone receptor (GHR) polymorphism is a common variant characterized by genomic deletion of exon 3 (d3) of the GHR gene. It could be linked to a better growth response to GH, but the findings are controversial. Due to the lack of IGF-I feedback on the tumoral GH secretion, acromegaly seems to be a good model to study functional characteristics of this polymorphism. Aim of the study was to investigate possible influences of d3-GHR on GH and IGF-I relationship and on metabolic parameters in acromegaly.

Methods: A retrospective study was conducted on 76 acromegalic patients Genotype analysis was carried out on blood leukocyte DNA by multiplex PCR assay. Clinical, hormonal and biochemical parameters were considered at diagnosis and taken from medical records of the patients.

Results: Forty-one patients (54%) were homozygotes for the full length GHR (d3−), while 35 patients (d3+) carried one (fl/d3 GHR, n=28, 36.8%) or two (d3/d3, n=7, 9.2%) copies of the d3 allele variant. No significant differences in sex, age, tumor size, GH and IGF-I levels, fasting serum glucose and insulin levels were found between patients d3− and d3+. Overall a positive correlation between log GH and IGF-I levels was found, but the relationship was similar in patients carrying or not carrying copies of the d3 allele. Body mass index (BMI) was significantly lower in d3+ than in d3-patients (25.8±2.1 vs 28.1±4.8 kg/m2, mean±S.D., P=0.011). In addition, serum glucose and insulin concentrations measured 2 h after OGTT in a subgroup of patients were also significantly lower in d3+. Finally, a linear regression analysis showed d3-GHR allele to be a significant negative predictor of HbA1c levels (B=−0.8±0.3, P=0.025).

Conclusions: This study supports the hypothesis that the d3 polymorphic variant of the GHR is functionally different from the full length variant mostly for the effects on glucose metabolism and body weight regulation.