Replication study of previous keratoconus genome-wide association study findings in East Asian populations

Abstract

Purpose: Previous genome-wide association study (GWAS) of keratoconus in a US-based Caucasian population reported 15 potentially associated single nucleotide polymorphisms (SNPs) from 13 distinct loci. A replication study of the GWAS findings in an Australian Caucasian population showed significant association (p<0.05) in SNPs in KCND3, RAB3GAP1, UBXD2, IMMP2L, and 13q33.3 loci. In this study, we sought to replicate the GWAS findings in East Asian populations.

Methods: Six hundred and thirty-nine Japanese samples (179 keratoconus cases and 460 controls) and 419 Korean samples (190 keratoconus cases and 229 controls) were recruited. We genotyped 15 SNPs reported in the previous GWAS using TaqMan assay. Association analysis was performed in SNP & Variation Suite 8.2.1. A meta-analysis combining the Japanese and Korean populations was performed using the Mantel-Haenszel method.

Results: The significant association was observed for rs6792542 in 3q26.2 in the meta-analysis (meta-p=0.00095: p=0.0025 in JPN, p=0.096 in KOR), and the C allele of rs6792542 had an increased risk of keratoconus (meta-OR=1.39: OR=1.49 in JPN, OR=1.27 in KOR). rs3749350 in LRRN1 and rs214884 in IMMP2L showed borderline statistical significance in the meta-analysis (meta-p=0.059: p=0.086 in JPN, p=0.32 in KOR and meta-p=0.069: p=0.15 in JPN, p=0.21 in KOR, respectively), and the T allele of rs3749350 and the G allele of rs214884 had an increased risk of keratoconus (meta-OR=1.20: OR=1.24 in JPN, OR=1.15 in KOR and meta-OR=1.35: OR=1.34 in JPN, OR=1.37 in KOR, respectively). Of these three SNPs, only rs214884 in IMMP2L have shown a significant association in previous replication study using the Australian Caucasian population. The strongest associated SNP, rs4954218 in RAB3GAP1, in Caucasians was monomorphic in the Japanese and Korean populations.

Conclusions: We were able to replicate the association of 3q26.2 rs6792542 with keratoconus in East Asian populations. In addition, we observed marginal associations of LRRN1 rs3749350 and IMMP2L rs214884 in East Asian populations. Further genetic studies with larger sample sizes are needed to elucidate the possible contributions of these three loci to the development of keratoconus.