Genetic association of rs564398 polymorphism of the ANRIL long non-coding RNA gene and risk of type 2 diabetes: A meta-analysis

Antisense non-coding RNA at the INK4 locus (ANRIL) is a long non-coding transcript localized within, and antisense to, the genes encoding the cyclin-dependent kinase inhibitor-2A/B (CDKN2A/B) on chromosome 9p21. Recent evidence implicates the CDKN2A/B locus as a causal candidate for developing type 2 diabetes mellitus (T2D). However, aggregate published information to date regarding the specifics of the statistical association between T2D and the genetic variants in the ANRIL region of the CDKN2A/B locus remains equivocal and ambiguous. To clarify this discrepancy, we performed a meta-analysis based on the genotype prevalence and allele frequency of the rs564398 polymorphism (T > C) in ANRIL gene in multiple ethnic populations. The main goal of this work was to conduct a systematic review with a meta-analysis of published data between 2007 and 2018 to determine whether the rs564398 polymorphism of ANRIL gene plays a potential role in predisposition to T2D, also to evaluate the strength, accuracy, and features of this association. We have systematically reviewed studies from databases published between 1990 and 2021. A total of 202 articles were collected, of which only 13 studies from 9 articles (including 13,510 cases and 18,231 controls) met the inclusion criteria and were selected for the statistical meta-analysis. In the present meta-analysis, we have investigated the potential associations between the selected SNP rs564398 and the predisposition to develop T2D, by conducting replicated analysis of already analyzed studies looked for this association, and expand our results by adding new articles published after 2012 and have not been reviewed in a previous meta-analysis, to form our own conclusion about the nature of this association. In contrast to other studies of the locus, we emphasized the differences of risk alleles and genotype influence among different ethnic groups. Ourmeta-analysis indicated that rs564398 [(OR 1.01, 95% CI [0.92, 1.12], P = 0.79) in the dominant model/ [(OR 1.03, 95% CI [0.91, 1.17], P = 0.64) in the recessive model/[(OR 1.00, 95% CI [0.91, 1.09], P = 0.93) in the additive (TC Vs. TT) model]/[(OR 1.00, 95% CI [0.92, 1.08], P = 0.96) in the additive (TC Vs. CC) model]/[(OR 1.02, 95% CI [0.94, 1.11], P = 0.61) in the allelic (C Vs. T) model] is not associated with the development of T2D overall. However, results also revealed slight association in some populations of the included studies. Although our results indicated a lack of association, more extensive studies with larger sample sizes and mixed ethnic groups are necessary to provide a more reliable estimation to confirm the association between rs564398 and T2D. Defining a putative molecular mechanism of rs564398 influence in the pathophysiology of T2D appears warranted.