Molecular Studies on Congenital Hypothyroidism in Indian Population

Abstract

The core objective of our effort is to estimate the TSH and T4 levels for newborn screening and identification of nucleotide variations (novel and known variants). We also aimed at establishing cut-off value of TSH depending on the birth weight of newborns, meta-analysis, and elucidating the functional relevance of these SNPs using in silco approaches. Finally, application of multifactor dimensionality reduction analysis and machine learning tools were applied in the differential diagnosis of Congenital Hypothyroidism (CH). The thesis is divided into three objectives. newlineThe first objective of the current work dealt with the high iprevalence of iCH iamong Indian inewborns that iprompted us to iestablish ipopulation-specific reference ranges of Thyroid Stimulating Hormone (TSH) and to iexplore the icontribution of the icommon single nucleotide variants (SNV) in Thyroid Stimulating Hormone Receptor (TSHR), Thyroid Peroxidase (TPO), Thyroglobulin (TG) and Dual Oxidase 2 (DUOX2) genes towards CH. A total of 1144 newborns were screened for CH. SNV profiling (n=22) spanning 3 genes, i.e. TSHR, TPO and TG were carried out in confirming CH cases (n=45). In screen negative cases (n=700), 10 TSHR SNPs were explored to establish association with CH. No mutation found in DUOX2. In newborns with optimal birth weight, the cut-off was 10mU/L. Two rare SNPs i.e. g.IVS14-19 GgtC in TPO and c.1262 CgtT in TG were observed in CH cases. In DUOX2 gene, no SNP was identified in the two 12 and 16 exons. newlineThe second objective of the current study is to explore the association of TSHR rs1991517 genetic variant with CH through a case-control study followed by a meta-analysis. 7 previous published studies and our current study were included in this meta-analysis. The allele contrast model showed that the presence of G- allele increased CH risk by 45% and 41% in fixed effect and random effect models, respectively.