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Background  Variants in  CDKN2B / CDKN2B-AS1  have been reported to modulate glaucoma risk in several GWAS across different populations.  CDKN2B / CDKN2A  encodes tumor suppressor proteins p16 INK4A /p15 INK4B  which influences cell proliferation/senescence in RGCs, the degeneration of which is a risk factor for glaucoma.  CDKN2B-AS1  codes a long non-coding RNA in antisense direction and is involved in influencing nearby  CDKN2A/CDKN2B  via regulatory mechanisms.    Methods  Current study investigated four SNPs (rs2157719, rs3217992, rs4977756, rs1063192) of aforementioned genes in a case–control study in a North Indian cohort. Genotyping was done with Taqman chemistry. In addition, an updated meta-analysis was performed.    Results  Two SNPs, rs3217992 and rs2157719 were found to be significantly associated with the disease. The frequency of ‘T’ allele of rs3217992 was significantly lower in cases (POAG/PACG) [ p  = 0.045; OR = 0.80(CI = 0.65–0.99) and  p  = 0.024; OR = 0.73(CI = 0.55–0.96)], respectively than in controls. Genetic model analysis revealed that TT + CT genotype confers 0.73-fold protection against POAG [ p  = 0.047; OR = 0.73(CI = 0.54–0.99)] and trend assumed additive model gives 0.53 times higher protection against PACG progression. However the association of rs3217992 with POAG and PACG did not remain significant after Bonferroni correction. For rs2157719, the ‘C’ allele was found to be less prevalent among cases (POAG/PACG) with respect to controls. Cochran Armitage trend test assuming additive model revealed 0.77 and 0.64-fold protection against POAG and PACG respectively. Bonferroni correction ( p  corr  = 0.003) was applied and the association of rs2157719 remained significant in PACG cases but not among POAG cases ( p  = 0.024). The ‘CC’ genotype also confers protection against primary glaucoma (POAG/PACG) among males and female subjects. The frequency rs1063192 and rs4977756 did not vary significantly among subjects, however the haplotype ‘CATA’ was found to be associated with increased glaucoma risk. An updated meta-analysis conducted on pooled studies on POAG cases and controls revealed significant association between rs1063192, rs2157719, rs4977756 and POAG except rs3217992.    Conclusion  The study concludes significant association between  INK4  variants and primary glaucoma in the targeted North Indian Punjabi cohort. We believe that deep-sequencing of  INK4  locus may help in identifying novel variants modifying susceptibility to glaucoma. Functional studies can further delineate the role of  CDKN2B  and  CDKN2B-AS1  in primary glaucoma for therapeutic intervention.

bmc medical genomics

Genetic association between CDKN2B/CDKN2B-AS1 gene polymorphisms with primary glaucoma in a North Indian cohort: an original study and an updated meta-analysis