Low bone mineral density and renal malformation in Mexican patients with Turner syndrome are associated with single nucleotide variants in vitamin D-metabolism genes

Abstract

Turner syndrome (TS) is a common genetic disorder. TS-phenotype includes short stature, gonadal dysgenesis, cardiac and kidney malformations, low bone mineral density (low-BMD) and thyroiditis. TS-phenotype varies from patient to patient and the cause is not clear, the genomic background may be an important contributor for this variability. Our aim was to identify the association of specific single nucleotide variants in the PTPN22, VDR, KL, and CYP27B1 genes and vitamin D-metabolism, heart malformation, renal malformation, thyroiditis, and low-BMD in 61 Mexican TS-patients. DNA samples were genotyped for SNVs: rs7975232 (VDR), rs9536282 (KL), rs4646536 (CYP27B1), and rs1599971 (PTPN22) using the KASP assay. Chi-square test under a recessive model and multifactorial dimensionality reduction method were used for analysis. We found a significant association between renal malformation and the rs9536282 (KL) variant and between rs4646536 (CYP27B1) and low-BMD, these variants may have modest effects on these characteristics but contribute to the variability of the TS phenotype. In addition, we identified gene–gene interactions between variants in genes KL, CYP27B1 and VDR related to vitamin D-metabolism and low-BMD in TS-patients. Our results support the idea that the genetic background of TS-patients contributes to the clinical variability seen in them.

Chinese abstract

特纳综合征（TS）是一种常见的遗传性疾病。TS表型包括身材矮小、性腺发育不全、心脏和肾脏畸形、低骨密度（低BMD）和甲状腺炎。TS表型因患者而异, 其原因不明, 基因组背景可能是导致这种变异的重要因素。我们的目的是在61名墨西哥TS患者中确定PTPN22、VDR、KL和CYP27B1基因中特异性单核苷酸变异与维生素D代谢、心脏畸形、肾畸形、甲状腺炎和低BMD的关系。使用KASP对单核苷酸变异（SNVs）位点: rs7975232 (VDR), rs9536282 (KL), rs4646536 (CYP27B1), 和 rs1599971(PTPN22)的DNA样本进行基因分型分析。采用隐性模型下的卡方检验和多因素降维方法进行分析。我们发现肾畸形与rs9536282（KL）变异体以及rs4646536（CYP27B1）和低BMD之间存在显著相关性, 这些变异体对这些特征可能有轻微影响, 但有助于TS表型的变异。此外, 我们还鉴定了与维生素D代谢和低BMD相关的基因KL、CYP27B1和VDR变异之间的基因-基因相互作用。我们的研究结果支持了TS患者的遗传背景有助于其临床变异性的观点。

Keywords:

• Turner syndrome
• low bone mineral density
• rs7975232 (VDR)
• rs9536282 (KL)
• rs4646536 (CYP27B1)

Ethical approval

The Ethics and Research Committees from the Instituto Nacional de Pediatría approved this study (084/2010 and 057/2015).

Disclosure statement

The authors have no conflicts of interest to declare.

Acknowledgments

We acknowledge all patients who participated in the study, the Academic Writing Team of the Coordinación de Estudios de Posgrado, UNAM for their help with this manuscript and María Antonieta Mora for fruitful discussions.

Additional information

Funding

This work is supported by the FONCYCIT 95419, CONACYT-FOSSSIS 142040, INP 084/2010 and 057/2015. CONACyT-scholarship 250639 for RBR.