A functional growth hormone receptor polymorphism, exon 3 deleted GHR, is associated with osteoarthritis in females: the results of a meta-analysis

Program: Abstracts - Orals, Featured Poster Presentations, and Posters
Session: SAT 109-133-GHRH, GH & IGF Biology & Signaling
Bench to Bedside
Saturday, June 15, 2013: 1:45 PM-3:45 PM
Expo Halls ABC (Moscone Center)

Poster Board SAT-123
Kim M.J.A. Claessen*1, Margreet Kloppenburg2, Herman Kroon3, Jessica Bijsterbosch3, Alberto M. Pereira4, Johannes A. Romijn5, Tahar van der Straaten3, Rob Nelissen3, Albert Hofman6, André G Uitterlinden7, Bouke Duijnisveld3, Nico Lakenberg3, Marian Beekman8, Joyce van Meurs9, Eline Slagboom8, Ingrid Meulenbelt3 and Nienke R. Biermasz10
1Leiden University Medical Center, Netherlands, 2Leiden University Medical Center, 3Leiden University Medical Center, Leiden, The Netherlands, 4Leiden University Medical Center, The Netherlands, 5Academic Medical Center, Amsterdam, Netherlands, 6Erasmus Medical Center, Rotterdam, 7Erasmus MC University Medical Center, Rotterdam, Netherlands, 8Leiden University Medical Center, Leiden, Netherlands, 9Erasmus MC, Rotterdam, The Netherlands, 10Leiden University Medical Center, The Netherlands, Netherlands

Genetic influences contribute considerably to the development of osteoarthritis (OA). Genetic studies have identified several genetic variants associated with primary OA, providing strong clue for the involvement of endochondral ossification in OA onset. Endochondral ossification is the main process in longitudinal skeletal growth, and is tightly regulated by a network of hormones, growth factors and extracellular matrix components. A main player in this process is Growth Hormone (GH), exerting its effects predominantly through Insulin-like Growth Factor-1 (IGF-1). This qualifies genetic variations within GH/IGF-1 genes as obvious candidates for association studies in primary OA.

Recently, presence of a common GH receptor (GHR) polymorphism, exon 3 deletion (d3-GHR), associated with increased GH sensitivity, was demonstrated to have functional consequences in patients with GH deficiency (GHD) and acromegaly, especially in heterozygotes. We aimed to assess the association between the d3-GHR polymorphism and radiographic OA in primary OA.



In the discovery study, the GARP (Genetics, ARthrosis and Progression) Study, we compared frequency of GHRfl-d3 genotype between patients with radiographic OA and controls. Radiographic OA in the knee, hip and hand was assessed by Kellgren-Lawrence. GARP patients were genotyped for 7 single nucleotide polymorphisms (SNPs) encompassing the d3-GHR gene, using 1 SNP (pairwise r2=1) as proxy for d3-GHR in cases and controls. Binary logistic regression models were performed, stratified by sex.

For replication, an additional OA cohort and patients with acromegalic arthropathy were genotyped. Meta-analysis was performed (only in females) combining these studies, using fixed- and random-effects models. For meta-analysis 299 hip OA cases, 255 knee OA cases, 293 hand OA cases and 1359 controls were available.



In female, not male, GARP patients with primary OA, GHRfl-d3 genotype was associated with OA (OR=1.5(1.1-2.1), p=0.017). This was supported by two replication studies. Meta-analysis showed evidence for association between GHRfl-d3 genotype and OA (OR=1.3(1.1-1.7), p=0.007), with strongest association in hip and hand OA.



In females with OA, the GHRfl-d3 genotype was associated with OA, indicating a role for the GH/IGF-1 axis in the pathophysiology of primary OA. This study provides new evidence for the functionality of the d3-GHR polymorphism in clinical conditions, next to the evidence in GHD and acromegaly patients.

Nothing to Disclose: KMJAC, MK, HK, JB, AMP, JAR, TV, RN, AH, AGU, BD, NL, MB, JV, ES, IM, NRB

*Please take note of The Endocrine Society's News Embargo Policy at http://www.endo-society.org/endo2013/media.cfm