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  • 1
    Online Resource
    Online Resource
    Polymorphisms in MEN1 and DRD2 genes are associated with the occurrence and characteristics of pituitary adenomas
    Oxford University Press (OUP) ; 2016
    In:  European Journal of Endocrinology Vol. 175, No. 2 ( 2016-08), p. 145-153
    Details
    In: European Journal of Endocrinology, Oxford University Press (OUP), Vol. 175, No. 2 ( 2016-08), p. 145-153
    Abstract: Although pituitary adenomas (PAs) affect a significant proportion of the population, only a fraction have the potential to become clinically relevant during an individual’s lifetime, causing hormonal imbalance or complications due to mass effect. The overwhelming majority of cases are sporadic and without a clear familial history, and the genotype–phenotype correlation in PA patients is poorly understood. Our aim was to investigate the involvement of genes known for their role in familial cases on drug response and tumor suppression in the development and pathology of PAs in a patient group from Latvia. Design The study included 143 cases and 354 controls, we investigated the role of single-nucleotide polymorphisms (SNPs) in seven genes ( SSTR2 , SSTR5 , DRD2 , MEN1 , AIP , GNAS , and PRKAR1A ) associated with pituitary tumor occurrence, phenotype, and clinical symptoms. Methods Genotyping of 96 tag and nonsynonymous SNPs was performed in the genomic regions of interest. Results We discovered a significant association (OR=17.8, CI 0.95=2.18–145.5, P =0.0002) between a rare MEN1 mutation (rs2959656) and clinically active adenoma in our patients. Additionally, rs7131056 at DRD2 was associated with a higher occurrence of extrasellar growth in patients with prolactinoma and somatotropinoma (OR=2.79, CI 0.95=1.58–4.95, P =0.0004). Conclusions rs2959656, a nonsynonymous variant in MEN1 , is associated with the development of clinically active PA. Furthermore, rs7131056 in DRD2 contributes to either faster growth of the adenoma or reduced symptomatic presentation, allowing PAs to become larger before detection.
    Type of Medium: Online Resource
    ISSN: 0804-4643 , 1479-683X
    URL: Article
    DOI: 10.1530/EJE-15-0879
    RVK:
    WA 15000
    Language: Unknown
    Publisher: Oxford University Press (OUP)
    Publication Date: 2016
    detail.hit.zdb_id: 1485160-X
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  • 2
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    Online Resource
    Single nucleotide polymorphisms in the intergenic region between metformin transporter OCT2 and OCT3 coding genes are associated with short-term response to metformin monotherapy in type 2 diabetes mellitus patients
    Oxford University Press (OUP) ; 2016
    In:  European Journal of Endocrinology Vol. 175, No. 6 ( 2016-12), p. 531-540
    Details
    In: European Journal of Endocrinology, Oxford University Press (OUP), Vol. 175, No. 6 ( 2016-12), p. 531-540
    Abstract: High variability in clinical response to metformin is often observed in type 2 diabetes (T2D) patients, and it highlights the need for identification of genetic components affecting the efficiency of metformin therapy. Aim of this observational study is to evaluate the role of tagSNPs (tagging single nucleotide polymorphisms) from genomic regions coding for six metformin transporter genes with respect to the short-term efficiency. Design 102 tagSNPs in 6 genes coding for metformin transporters were genotyped in the group of 102 T2D patients treated with metformin for 3 months. Methods Most significant hits were analyzed in the group of 131 T2D patients from Slovakia. Pharmacokinetic study in 25 healthy nondiabetic volunteers was conducted to investigate the effects of identified polymorphisms. Results In the discovery group of 102 patients, minor alleles of rs3119309, rs7757336 and rs2481030 were significantly nominally associated with metformin inefficiency ( P  = 1.9 × 10 −6 to 8.1 × 10 −6 ). Effects of rs2481030 and rs7757336 did not replicate in the group of 131 T2DM patients from Slovakia alone, whereas rs7757336 was significantly associated with a reduced metformin response in combined group. In pharmacokinetic study, group of individuals harboring risk alleles of rs7757336 and rs2481030 displayed significantly reduced AUC ∞ of metformin in plasma. Conclusions For the first time, we have identified an association between the lack of metformin response and SNPs rs3119309 and rs7757336 located in the 5′ flanking region of the genes coding for Organic cation transporter 2 and rs2481030 located in the 5′ flanking region of Organic cation transporter 3 that was supported by the results of a pharmacokinetic study on 25 healthy volunteers.
    Type of Medium: Online Resource
    ISSN: 0804-4643 , 1479-683X
    URL: Article
    DOI: 10.1530/EJE-16-0347
    RVK:
    WA 15000
    Language: Unknown
    Publisher: Oxford University Press (OUP)
    Publication Date: 2016
    detail.hit.zdb_id: 1485160-X
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  • 3
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    Online Resource
    Identification of somatostatin receptor type 5 gene polymorphisms associated with acromegaly
    Oxford University Press (OUP) ; 2011
    In:  European Journal of Endocrinology Vol. 165, No. 4 ( 2011-10), p. 517-525
    Details
    In: European Journal of Endocrinology, Oxford University Press (OUP), Vol. 165, No. 4 ( 2011-10), p. 517-525
    Abstract: 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.
    Type of Medium: Online Resource
    ISSN: 0804-4643 , 1479-683X
    URL: Article
    DOI: 10.1530/EJE-11-0416
    RVK:
    WA 15000
    Language: Unknown
    Publisher: Oxford University Press (OUP)
    Publication Date: 2011
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  • 4
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    Online Resource
    Similar cardiovascular outcomes in patients with diabetes and established or high risk for coronary vascular disease treated with dulaglutide with and without baseline metformin
    Oxford University Press (OUP) ; 2021
    In:  European Heart Journal Vol. 42, No. 26 ( 2021-07-08), p. 2565-2573
    Details
    In: European Heart Journal, Oxford University Press (OUP), Vol. 42, No. 26 ( 2021-07-08), p. 2565-2573
    Abstract: Recent European Guidelines for Diabetes, Prediabetes and Cardiovascular Diseases introduced a shift in managing patients with type 2 diabetes at high risk for or established cardiovascular (CV) disease by recommending GLP-1 receptor agonists and SGLT-2 inhibitors as initial glucose-lowering therapy. This is questioned since outcome trials of these drug classes had metformin as background therapy. In this post hoc analysis, the effect of dulaglutide on CV events was investigated according to the baseline metformin therapy by means of a subgroup analysis of the Researching Cardiovascular Events with a Weekly Incretin in Diabetes (REWIND) trial. Research design and methods  Patients in REWIND (n = 9901; women: 46.3%; mean age: 66.2 years) had type 2 diabetes and either a previous CV event (31%) or high CV risk (69%). They were randomized (1:1) to sc. dulaglutide (1.5 mg/weekly) or placebo in addition to standard of care. The primary outcome was the first of a composite of nonfatal myocardial infarction, nonfatal stroke, and death from cardiovascular or unknown causes. Key secondary outcomes included a microvascular composite endpoint, all-cause death, and heart failure. The effect of dulaglutide in patients with and without baseline metformin was evaluated by a Cox regression hazard model with baseline metformin, dulaglutide assignment, and their interaction as independent variables. Adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated by a Cox regression model with adjustments for factors differing at baseline between people with vs. without metformin, identified using the backward selection. Results  Compared to patients with metformin at baseline (n = 8037; 81%), those without metformin (n = 1864; 19%) were older and slightly less obese and had higher proportions of women, prior CV events, heart failure, and renal disease. The primary outcome occurred in 976 (12%) participants with baseline metformin and in 281 (15%) without. There was no significant difference in the effect of dulaglutide on the primary outcome in patients with vs. without metformin at baseline [HR 0.92 (CI 0.81–1.05) vs. 0.78 (CI 0.61–0.99); interaction P = 0.18]. Findings for key secondary outcomes were similar in patients with and without baseline metformin. Conclusion  This analysis suggests that the cardioprotective effect of dulaglutide is unaffected by the baseline use of metformin therapy.
    Type of Medium: Online Resource
    ISSN: 0195-668X , 1522-9645
    URL: Article
    DOI: 10.1093/eurheartj/ehaa777
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2021
    detail.hit.zdb_id: 2001908-7
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