Replication study of THADA rs13429458 variant with PCOS susceptibility and its related traits in Indian women

Abstract

Aim

The aetiopathogenesis of the multigenic multifactorial endocrinopathy, polycystic ovary syndrome (PCOS) has been explored using linkage, candidate gene and genome-wide association studies. Contradictory reports of replication studies attributed to phenotypic, ethnic and geographic variations are available. In this study, we investigated the association of Han Chinese GWAS polymorphism (rs13429458) in thyroid adenoma-associated gene (THADA) with PCOS susceptibility and its related traits in Indian women.

Methods

We genotyped rs13429458 of THADA by direct sequencing and investigated its association with PCOS and its related traits in controls (N = 150) and PCOS women (N = 348). All women were extensively phenotyped in terms of anthropometric, hormonal and metabolic parameters. Association of polymorphism with PCOS risk and its related traits was carried out by regression analysis.

Results

Genotypic and allele frequencies for rs13429458 were not different between controls and PCOS. Women with PCOS carrying variant allele showed significantly reduced fasting glucose levels, and decreased free and bioavailable testosterone and free androgen index.

Conclusion

To our knowledge, this is the first study to demonstrate that although this polymorphism does not alter PCOS susceptibility, it favorably impacts glucose metabolism and hyperandrogenism in Indian women with PCOS only. This study highlights that genetic predisposition markers for PCOS may differ with ethnicity and phenotypic variations.

THADA rs13429458变异与PCOS易感性及其相关性状在印度女性中的相关研究 摘要

目的：多基因多因素内分泌疾病、多囊卵巢综合征 (PCOS) 的发病机制已经通过连锁、候选基因和全基因组关联研究进行了探索。由于表型、种族和地理变异, 复制研究的报告相互矛盾。在这项研究中, 我们调查了印度女性甲状腺腺瘤相关基因 (THADA) 以及中国汉族 GWAS 多态性 (rs13429458) 与 PCOS 易感性及其相关特征的关联。

方法：我们通过直接测序对 THADA 的 rs13429458 进行基因分型, 并在对照组（N = 150）和 PCOS 女性（N = 348）中研究其与 PCOS 及其相关性状的关联。所有女性都在人体测量学、激素水平和代谢参数方面进行了广泛的表型分析。多态性与PCOS风险及其相关性状的关联通过回归分析进行评估。

结果：rs13429458的基因型和等位基因频率在对照组和 PCOS 之间没有差异。携带变异等位基因的 PCOS 女性空腹血糖水平显著降低, 游离睾酮和生物可利用睾酮以及游离雄激素指数降低。

结论：据我们所知, 这项研究首次证明虽然多态性不会改变 PCOS 易感性, 但它对仅患有 PCOS印度女性糖代谢和高雄激素血症有积极影响。该研究强调, PCOS 的遗传易感性标志物可能因种族和表型变异而异。

Keywords:

• Genetics
• GWAS
• hyperandrogenism
• PCOS
• phenotype
• THADA

Acknowledgements

The authors are thankful to staff of the multidisciplinary PCOS clinic at ICMR-NIRRH. The authors acknowledge fellowship to RD from University Grants Commission, India. The authors are deeply appreciative for all the technical support received from Ms. Nanda Joshi, Ms. Sushma Khavale and Ms. Gayatri Shinde.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Additional information

Funding

This work is supported by National Institute for Research in Reproductive Health [RA/917/05-2020] and Indian Council of Medical Research (ICMR), New Delhi, India.