A PHLDB1 variant associated with the nonfunctional pituitary adenoma
Previous studies have revealed that PHLDB1 single-nucleotide polymorphisms (SNPs) are associated with glioma risk. Nonetheless, the association between PHLDB1 SNPs and the risk of pituitary adenoma has not been studied. The present study evaluated the association of PHLDB1 SNPs with the risk of pituitary adenomas.
We genotyped 27 PHLDB1 tagging and exon SNPs in a case–control study that included 148 patients who got a diagnosis of nonfunctional pituitary adenoma (NFPA) and 375 normal controls within the Korean population. Statistical analyses of the association between PHLDB1 SNPs and the NFPA risk were conducted using logistic regression.
We detected an association between a PHLDB1 SNP and the risk of NFPA in the Korean population. Rs67307131 in intron 2 was significantly associated with NFPA (odds ratio [OR] = 2.15, 95% confidence interval [CI] 1.44–3.20; P = 0.0002 in the dominant model). In the referent analysis, a higher OR and stronger association (lower P value) were observed among patients with the “C/T” genotype (OR = 2.39, 95% CI 1.60–3.58; P = 0.00002). In a functional analysis with a SNP annotation tool, this SNP was predicted to be a CpG site and copy number variant; these properties are associated with susceptibility to diseases.
Our findings suggest that genetic variation of PHLDB1 may be associated with the risk of NFPA. This is the first report of an association between PHLDB1 variants and NFPA. Further research is needed to confirm the impact of this SNP on NFPA susceptibility.
KeywordsPHLDB1 Nonfunctional pituitary adenoma (NFPA) Single nucleotide polymorphism (SNP)
This study was supported by Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education (2017035989).
Compliance with ethical standards
Conflict of interest
All authors declare that they have no conflict of interest.
All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.
Informed consent was obtained from all individual participants included in the study.
- 3.Gibo H, Hokama M, Kyoshima K, Kobayashi S (1993) Arteries to the pituitary. Nihon Rinsho. Jpn J Clin Med 51:2550–2554Google Scholar
- 5.Gomes L, Lemos MC, Paiva I, Ribeiro C, Carvalheiro M, Regateiro FJ (2005) CYP2D6 genetic polymorphisms are associated with susceptibility to pituitary tumors. Acta Med Port 18:339–343Google Scholar
- 7.Altas M, Bayrak OF, Ayan E, Bolukbasi F, Silav G, Coskun KK, Culha M, Sahin F, Sevli S, Elmaci I (2010) The effect of polymorphisms in the promoter region of the MMP-1 gene on the occurrence and invasiveness of hypophyseal adenoma. Acta Neurochir (Wien) 152:1611–1617. https://doi.org/10.1007/s00701-010-0671-0 discussion 1617CrossRefGoogle Scholar
- 8.Ye Z, Li Z, Wang Y, Mao Y, Shen M, Zhang Q, Li S, Zhou L, Shou X, Chen J, Song Z, Ma Z, Zhang Z, Li Y, Ye H, Huang C, Wang T, He W, Zhang Y, Xie R, Qiao N, Qiu H, Huang S, Wang M, Shen J, Wen Z, Li W, Liu K, Zhou J, Wang L, Ji J, Chen H, Cheng H, Shi Z, Zhu Y, Geng D, Yao Z, Tang W, Lu B, Pan L, Bao W, Wu J, Zheng K, Shi Y, Zhao Y (2015) Common variants at 10p12.31, 10q21.1 and 13q12.13 are associated with sporadic pituitary adenoma. Nat Genet 47:793–797. https://doi.org/10.1038/ng.3322ng.3322 CrossRefGoogle Scholar
- 9.Elston MS, McDonald KL, Clifton-Bligh RJ, Robinson BG (2009) Familial pituitary tumor syndromes. Nat Rev Endocrinol 5:453–461. https://doi.org/10.1038/nrendo.2009.126nrendo.2009.126 CrossRefGoogle Scholar
- 10.Freda PU, Chung WK, Matsuoka N, Walsh JE, Kanibir MN, Kleinman G, Wang Y, Bruce JN, Post KD (2007) Analysis of GNAS mutations in 60 growth hormone secreting pituitary tumors: correlation with clinical and pathological characteristics and surgical outcome based on highly sensitive GH and IGF-I criteria for remission. Pituitary 10:275–282. https://doi.org/10.1007/s11102-007-0058-2 CrossRefGoogle Scholar
- 11.Newey PJ, Nesbit MA, Rimmer AJ, Head RA, Gorvin CM, Attar M, Gregory L, Wass JA, Buck D, Karavitaki N, Grossman AB, McVean G, Ansorge O, Thakker RV (2013) Whole-exome sequencing studies of nonfunctioning pituitary adenomas. J Clin Endocrinol Metab 98:E796–E800. https://doi.org/10.1210/jc.2012-4028jc.2012-4028 CrossRefGoogle Scholar
- 12.Vandeva S, Jaffrain-Rea ML, Daly AF, Tichomirowa M, Zacharieva S, Beckers A (2010) The genetics of pituitary adenomas. Best Pract Res Clin Endocrinol Metab 24:461–476. https://doi.org/10.1016/j.beem.2010.03.001S1521-690X(10)00028-X CrossRefGoogle Scholar
- 13.Rutherford S, Cai G, Lopez-Alvarenga JC, Kent JW, Voruganti VS, Proffitt JM, Curran JE, Johnson MP, Dyer TD, Jowett JB, Bastarrachea RA, Atwood LD, Goring HH, Maccluer JW, Moses EK, Blangero J, Comuzzie AG, Cole SA (2007) A chromosome 11q quantitative-trait locus influences change of blood-pressure measurements over time in Mexican Americans of the San Antonio Family Heart Study. Am J Hum Genet 81:744–755. https://doi.org/10.1086/521151 CrossRefGoogle Scholar
- 16.Shete S, Hosking FJ, Robertson LB, Dobbins SE, Sanson M, Malmer B, Simon M, Marie Y, Boisselier B, Delattre JY, Hoang-Xuan K, El Hallani S, Idbaih A, Zelenika D, Andersson U, Henriksson R, Bergenheim AT, Feychting M, Lonn S, Ahlbom A, Schramm J, Linnebank M, Hemminki K, Kumar R, Hepworth SJ, Price A, Armstrong G, Liu Y, Gu X, Yu R, Lau C, Schoemaker M, Muir K, Swerdlow A, Lathrop M, Bondy M, Houlston RS (2009) Genome-wide association study identifies five susceptibility loci for glioma. Nat Genet 41:899–904. https://doi.org/10.1038/ng.407ng.407 CrossRefGoogle Scholar
- 19.Thakker RV (2010) Multiple endocrine neoplasia type 1 (MEN1). Best Pract Res Clin Endocrinol Metab 24:355–370. https://doi.org/10.1016/j.beem.2010.07.003S1521-690X(10)00070-9 CrossRefGoogle Scholar
- 20.Melmed S (2011) Pathogenesis of pituitary tumors. Nat Rev Endocrinol 7:257–266. https://doi.org/10.1038/nrendo.2011.40nrendo.2011.40 CrossRefGoogle Scholar
- 24.Katoh M (2003) Identification and characterization of human LL5A gene and mouse Ll5a gene in silico. Int J Oncol 23:1477–1483Google Scholar
- 25.Ling C, Pease M, Shi L, Punj V, Shiroishi MS, Commins D, Weisenberger DJ, Wang K, Zada G (2014) A pilot genome-scale profiling of DNA methylation in sporadic pituitary macroadenomas: association with tumor invasion and histopathological subtype. PLoS ONE 9:e96178. https://doi.org/10.1371/journal.pone.0096178PONE-D-13-46388 CrossRefGoogle Scholar
- 26.Inoue K, Lupski JR (2002) Molecular mechanisms for genomic disorders. Annu Rev Genom Hum Genet 3:199–242. https://doi.org/10.1146/annurev.genom.3.032802.120023032802.120023 CrossRefGoogle Scholar