Association of polymorphisms in the intron of TCF4 gene to late-onset Fuchs endothelial corneal dystrophy: An Indian cohort study

Abstract

Purpose:Fuchs endothelial corneal dystrophy (FECD) is a progressive degenerative disease of the corneal endothelium. It is genetically heterogeneous and follows either an autosomal dominant or sporadic pattern of inheritance. Here, we have explored the association of four previously reported intronic single nucleotide polymorphisms and intronic CTG repeat expansions in TCF4 gene to FECD in an Indian cohort.Methods:The cohort consisting of 52 sporadic late-onset cases, 5 early-onset cases, and 148 controls was taken for the study. rs2286812 and rs613872 were genotyped by allele specific polymerase chain reaction (ASPCR) and PCR-based restriction digestion, respectively; rs17595731 and rs9954153 were genotyped by Taqman assay using real-time PCR. The quantitative assessment of the CTG repeat region was performed by PCR/Sanger DNA sequencing. The repeats were assessed qualitatively by short tandem repeat and triplet repeat primed PCR assays. The statistical analysis was performed using two-tailed Fisher's exact probability test.Results:SNPsrs613872 (G/T) for the ‘G’ allele (P value: 4.57 × 10−5) and rs17595731 (C/T) for the ‘C’ allele (P value: 1.87 × 10−5), respectively, showed a significant association to sporadic late-onset FECD. CTG repeat expansions were found to be associated with FECD with a P value = 2.4 × 10−3.Conclusion:rs613872, rs17595731, and CTG repeat expansions in intronic region of TCF4 are associated with increased risk of sporadic late-onset FECD in the Indian cohort studied.

Ophthalmic genetics practice and research in India: Vision in 2020

“…A comparison of the role of ZEB1 across multiple ethnicities shows that the contribution of this gene in our Indian population is concurrent with other reports (Rao et al, 2018). In another study it was found that the single nucleotide polymorphisms (SNPs) of TCF4 gene, rs613872 and rs1759573 were associated with a higher risk of sporadic late-onset FECD in Indian patients (Rao, Tharigopala, Rachapalli, Rajagopal, & Soumittra, 2017).…”

TCF4-mediated Fuchs endothelial corneal dystrophy: Insights into a common trinucleotide repeat-associated disease

“…Another important aspect of disease variation is the recognized fact that women more commonly express FECD and in general have more severe clinical presentation. This trend is consistent across diverse populations and holds true for groups with and without CTG18.1 repeat expansion ( Kuot et al, 2017 ; Nakano et al, 2015 ; Nanda et al, 2014 ; Okumura et al, 2019c ; Rao et al, 2017 ; Skorodumova et al, 2018 ; Soliman et al, 2015 ; Vasanth et al, 2015 ; Wieben et al, 2012 ; Zarouchlioti et al, 2018 ). While our current understanding of FECD lends essentially no insight into this observation, several possible explanations exist.…”

“…Interestingly, the correlation between CTG18.1 expansion and FECD is also striking, although typically lower, in other non-Caucasian ethnic groups investigated to date. This includes African Americans (35%) ( Eghrari et al, 2017a ), Indians (17% and 34%) ( Nanda et al, 2014 ; Rao et al, 2017 ), Japanese (26%) ( Nakano et al, 2015 ), Singaporean Chinese (44%) ( Xing et al, 2014 ), and Thai (39%) ( Okumura et al, 2019c ). Notably, CTG18.1 genotyping studies have consistently identified a bimodal distribution of repeat lengths, with the vast majority of patients typically harbouring repeat sizes of <30 or >50 ( Zarouchlioti et al, 2018 ).…”

“…Despite the overwhelming evidence for CTG18.1 expansion being a strong risk factor for FECD, we have limited insight regarding the incomplete penetrance and variable expression of the disease. It has been established in different ethnicities that CTG18.1 expansion is present at low levels in control populations ( Table 2 ) and small cohorts of aged individuals in absence of disease ( Del-Favero et al, 2002 ; Foja et al, 2017 ; Kuot et al, 2017 ; Luther et al, 2016 ; Mootha et al, 2014 ; Nakano et al, 2015 ; Nanda et al, 2014 ; Okumura et al, 2019c ; Rao et al, 2017 ; Skorodumova et al, 2018 ; Vasanth et al, 2015 ; Wieben et al, 2012 ; Xing et al, 2014 ; Zarouchlioti et al, 2018 ). While some proportion of these control patients may develop FECD later in life, it is clear that some individuals with a CTG18.1 repeat expansion do not.…”

Lower Fractions of TCF4 Transcripts Spanning over the CTG18.1 Trinucleotide Repeat in Human Corneal Endothelium

“…However later, a much stronger association was found to an expansion of cytosine-thymine-guanine (CTG) n repeat, known as CTG18.1 [ 5 ], in intron 3 of the TCF4 gene [ 6 ]. Currently, association of the TCF4 repeat expansion ( n > 50) and FECD has been reported in several populations [ 7 , 8 , 9 , 10 , 11 ]. In other studies, association of FECD and (CTG) n repeat length over 40 has also been shown [ 12 , 13 , 14 , 15 ].…”