Telomere Maintenance Genes are associated with Type 2 Diabetes Susceptibility in Northwest Indian Population Group

Abstract

Telomere length attrition has been implicated in various complex disorders including Type 2 Diabetes (T2D). However, very few candidate gene association studies have been carried out worldwide targeting telomere maintenance genes. in the present study, variants in various critical telomere maintenance pathway genes for T2D susceptibility in Northwest Indian population were explored. With case-control candidate gene association study design, twelve variants from seven telomere maintenance genes were evaluated. Amongst these five variants, rs9419958 (OBFC1), rs4783704 (TERF2), rs16847897 (TERC/ LRRC31), rs10936599 (TERC/MYNN), and rs74019828 (CSNK2A2) showed significant association with T2D (at p-value ≤ 0.003, threshold set after Bonferroni correction) in the studied population. In silico analyses of these variants indicated interesting functional roles that warrant experimental validations. Findings showed that variants in telomere maintenance genes are associated with pathogenesis of T2D in Northwest Indian population. We anticipate further, such candidate gene association studies in other Indian populations and worldwide would contribute in understanding the missing heritability of T2D.

Terc Gene Cluster Variants Predict Liver Telomere Length in Mice

“…This is the first study to our knowledge demonstrating the association between this genomic region and telomere length in mice. In humans, SNPs within this cluster are the genomic predictors most consistently associated with telomere length and related disease, despite limited knowledge on the mechanism underlying this association [9][10][11][12][13][14][15][16][17]. Elaboration of this association in an animal model may thus permit critical mechanistic research, in addition to promoting understanding of between-species telomere dynamics.…”

“…Telomere length is highly heritable in human populations as a result of sequence variation in genomic networks regulating telomere length [7,8]. Variants in a gene cluster upstream-adjacent to TERC on human chromosome 3, which includes genes APRM, LRRC31, LRRC34 and MYNN, have been found to associate with telomere length [9][10][11][12][13][14], as well as related diseases, such as cancer and diabetes [9,11,[15][16][17], in several human populations by multiple independent analyses.…”

“…Only the TERC polymorphism rs2293607 has been associated with telomere length in human genomic analyses and this SNP is strongly correlated with MYNN variants [11]. Due to the close proximity between the TERC gene cluster and TERC (~0.05 Mb) in humans, it has been speculated that genes in this cluster may regulate TERC expression [13], or that they are in linkage disequilibrium with a true causal variant within or nearer to TERC [11]. In the mouse genome, the Terc gene and Terc gene cluster are also both located on chromosome 3; however, the Terc gene cluster is located distantly downstream of Terc (~60 Mb) in mice.…”

MassARRAY-based single nucleotide polymorphism analysis in breast cancer of north Indian population

“…iPLEX extension reaction was performed using pool single base extension primers. Desalting of the amplified products was performed using SpectroCLEAN resin following the protocol [ 14 , 15 ]. RS100 nanodispenser was used to transfer the cleaned extension products from 384 muti-titration PCR plate to 384 SpectroCHIP and the chip was placed in Agena MassARRAY compact mass spectrometer.…”

Telomere length in peripheral blood lymphocytes related to genetic variation in telomerase, prognosis and clinicopathological features in breast cancer patients

“…The rs16847897 is located upstream to hTERC gene in the intronic sequence of Leucine-rich repeat-containing 31 (LRRC31) gene. Based on in silico analysis, it has been documented that rs16847897 C allele downregulates the expression of the LRRC34 across multiple tissue types (40). LRRC34 is predicted to act as a ribonuclease inhibitor, possibly helping to preserve the non-coding RNA template of the telomerase holoenzyme (41).…”