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      Identification of somatostatin receptor type 5 gene polymorphisms associated with acromegaly

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          Abstract

          Objective

          The aim of this study was to characterize the genetic variance of somatostatin receptor 5 (SSTR5) and investigate the possible correlation of such variants with acromegaly risk and different disease characteristics.

          Design and methods

          The SSTR5 gene coding region and 2000 bp upstream region was sequenced in 48 patients with acromegaly and 96 control subjects. Further, three single nucleotide polymorphisms (SNPs) were analyzed in the same group of acromegaly patients and in an additional group of 475 age- and sex-matched controls.

          Results

          In total, 19 SNPs were identified in the SSTR5 gene locus by direct sequencing. Three SNPs (rs34037914, rs169068, and rs642249) were significantly associated with the presence of acromegaly using the initial controls. The allele frequencies were significantly ( P<0.01) different between the acromegaly patients and the additional large control group. rs34037914 and rs642249 remained significantly associated with acromegaly after Bonferroni correction and permutation tests (odds ratio (OR)=3.38; 95% confidence interval (CI), 1.78–6.42; P=0.00016 and OR=2.41; 95% CI, 1.41–4.13; P=0.0014 respectively). Haplotype reconstruction revealed two possible risk haplotypes determined by rs34037914 (633T) and rs642249 (1044A) alleles. Both haplotypes were found in significantly higher frequency in acromegaly patients compared with controls ( P<0.001). In addition, the 663T allele was significantly associated with a younger age of acromegaly diagnosis (unstandardized regression coefficient β=−10.4; P=0.002), increased body mass index ( β=4.1; P=0.004), higher number of adenoma resection ( P<0.001) and lack of observable tumor shrinkage after somatostatin analog treatment ( P=0.014).

          Conclusions

          Our results demonstrate a previously undetected strong association of two SSTR5 SNPs with acromegaly. The data also suggest a possible involvement of SSTR5 variants in decreased suppression of GH production and increased tumor proliferation.

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          Most cited references44

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          A note on exact tests of Hardy-Weinberg equilibrium.

          Deviations from Hardy-Weinberg equilibrium (HWE) can indicate inbreeding, population stratification, and even problems in genotyping. In samples of affected individuals, these deviations can also provide evidence for association. Tests of HWE are commonly performed using a simple chi2 goodness-of-fit test. We show that this chi2 test can have inflated type I error rates, even in relatively large samples (e.g., samples of 1,000 individuals that include approximately 100 copies of the minor allele). On the basis of previous work, we describe exact tests of HWE together with efficient computational methods for their implementation. Our methods adequately control type I error in large and small samples and are computationally efficient. They have been implemented in freely available code that will be useful for quality assessment of genotype data and for the detection of genetic association or population stratification in very large data sets.
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            Acromegaly pathogenesis and treatment.

            Dysregulated growth hormone (GH) hypersecretion is usually caused by a GH-secreting pituitary adenoma and leads to acromegaly - a disorder of disproportionate skeletal, tissue, and organ growth. High GH and IGF1 levels lead to comorbidities including arthritis, facial changes, prognathism, and glucose intolerance. If the condition is untreated, enhanced mortality due to cardiovascular, cerebrovascular, and pulmonary dysfunction is associated with a 30% decrease in life span. This Review discusses acromegaly pathogenesis and management options. The latter include surgery, radiation, and use of novel medications. Somatostatin receptor (SSTR) ligands inhibit GH release, control tumor growth, and attenuate peripheral GH action, while GH receptor antagonists block GH action and effectively lower IGF1 levels. Novel peptides, including SSTR ligands, exhibiting polyreceptor subtype affinities and chimeric dopaminergic-somatostatinergic properties are currently in clinical trials. Effective control of GH and IGF1 hypersecretion and ablation or stabilization of the pituitary tumor mass lead to improved comorbidities and lowering of mortality rates for this hormonal disorder.
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              Guidelines for acromegaly management: an update.

              The Acromegaly Consensus Group reconvened in November 2007 to update guidelines for acromegaly management. The meeting participants comprised 68 pituitary specialists, including neurosurgeons and endocrinologists with extensive experience treating patients with acromegaly. EVIDENCE/CONSENSUS PROCESS: Goals of treatment and the appropriate imaging and biochemical and clinical monitoring of patients with acromegaly were enunciated, based on the available published evidence. The group developed a consensus on the approach to managing acromegaly including appropriate roles for neurosurgery, medical therapy, and radiation therapy in the management of these patients.
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                Author and article information

                Journal
                Eur J Endocrinol
                EJE
                European Journal of Endocrinology
                BioScientifica (Bristol )
                0804-4643
                1479-683X
                October 2011
                : 165
                : 4
                : 517-525
                Affiliations
                [1 ]simpleLatvian Biomedical Research and Study Centre Ratsupites Street 1, LV-1067, RigaLatvia
                [2 ]simpleDepartment of Endocrinology simplePauls Stradins Clinical University Hospital Pilsonu Street 13, LV1002, RigaLatvia
                [3 ]simpleFaculty of Medicine simpleUniversity of Latvia Sarlotes Street 1a, LV1001, RigaLatvia
                [4 ]simpleDepartment of Endocrinology simpleRiga Eastern Clinical University Hospital Riga, Hipokrata Street, LV1038Latvia
                [5 ]simpleDepartment of Neuroscience, Functional Pharmacology simpleUppsala University, BMC PO Box 593, 751 24, UppsalaSweden
                Author notes
                (Correspondence should be addressed to J Klovins at Latvian Biomedical Research and Study Centre; Email: klovins@ 123456biomed.lu.lv )
                Article
                EJE110416
                10.1530/EJE-11-0416
                3178914
                21810856
                c2f4ee65-c922-42d2-916d-c4b92bee6430
                © 2011 European Society of Endocrinology

                This is an Open Access article distributed under the terms of the European Journal of Endocrinology's Re-use Licence which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                : 10 May 2011
                : 11 July 2011
                : 2 August 2011
                Funding
                Funded by: Latvian Council of Science
                Award ID: 10.0010.04
                Funded by: ESF
                Award ID: 1DP/1.1.1.2.0/09/APIA/VIAA/150
                Funded by: Swedish Research Council
                Categories
                Clinical Study

                Endocrinology & Diabetes
                Endocrinology & Diabetes

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