Genetic associations for keratoconus: a systematic review and meta-analysis

Abstract

Genetic associations for keratoconus could be useful for understanding disease pathogenesis and discovering biomarkers for early detection of the disease. We conducted a systematic review and meta-analysis to summarize all reported genetic associations for the disease. We searched in the MEDLINE, Embase, Web of Science, and HuGENET databases for genetic studies of keratoconus published from 1950 to June 2016. The summary odds ratio and 95% confidence intervals of all polymorphisms were estimated using the random-effect model. Among 639 reports that were retrieved, 24 fulfilled required criteria as eligible studies for meta-analysis, involving a total of 53 polymorphisms in 28 genes/loci. Results of our meta-analysis lead to the prioritization of 8 single-nucleotide polymorphisms (SNPs) in 6 genes/loci for keratoconus in Whites. Of them 5 genes/loci were originally detected in genome-wide association studies, including FOXO1 (rs2721051, P = 5.6 × 10−11), RXRA-COL5A1 (rs1536482, P = 2.5 × 10−9), FNDC3B (rs4894535, P = 1.4 × 10−8), IMMP2L (rs757219, P = 6.1 × 10−7; rs214884, P = 2.3 × 10−5), and BANP-ZNF469 (rs9938149, P = 1.3 × 10−5). The gene COL4A4 (rs2229813, P = 1.3 × 10−12; rs2228557, P = 4.5 × 10−7) was identified in previous candidate gene studies. We also found SNPs in 10 genes/loci that had a summary P value < 0.05. Sensitivity analysis indicated that the results were robust. Replication studies and understanding the roles of these genes in keratoconus are warranted.

Analysis of multiple genetic loci reveals MPDZ-NF1B rs1324183 as a putative genetic marker for keratoconus

“…Therefore, investigations of genetic associations in different cohorts are warranted. In this study, SNPs rs4894535 ( FNDC3B ), rs9938149 ( BANP-ZNF469 ), rs7044529 ( COL5A1 ), rs214884 ( IMMP2L ), rs1328089 ( 13q33.3 ), rs10519694 ( LOX ) and rs8111998 ( 19 p12) showed consistent trends of effect with that in our previous meta-analysis,22 although the p values did not reach statistical significance. Therefore, further studies are needed to affirm the association of these SNPs in keratoconus.…”

“…In contrast, there was no significant association identified for the other 12 SNPs, although 7 of them, namely rs4894535 ( FNDC3B , p=0.89; OR=1.03, 95% CI 0.69 to 1.53), rs9938149 ( BANP-ZNF469 , p=0.84; OR=0.92, 95% CI 0.42 to 2.02), rs7044529 ( COL5A1 , p=0.15; OR=1.46, 95% CI 0.87 to 2.46), rs214884 ( IMMP2L , p=0.23; OR=1.62, 95% CI 0.74 to 3.55), rs1328089 ( 13q33.3 , p=0.66; OR=1.12, 95% CI 0.67 to 1.88), rs10519694 ( LOX , p=0.76; OR=0.9, 95% CI 0.45 to 1.8) and rs8111998 ( 19 p12, p=0.54; OR=1.21, 95% CI 0.66 to 2.2), showed consistent directions of effect with those reported in the previous meta-analysis (table 1). 22 …”

“…Sixteen SNPs in 14 genes were reported to be associated with keratoconus,22 including rs1536482 ( RXRA-COL5A1 ), rs4894535 ( FNDC3B ), rs9938149 ( BANP-ZNF469 ), rs1324183 ( MPDZ-NF1B ), rs7044529 ( COL5A1 ), rs757219 and rs214884 ( IMMP2L ), rs4839200 ( KCND3 ), rs6430585 ( UBXD2 ), rs1328089 and rs1328083 ( 13q33.3 ), rs10519694 ( LOX ), rs3735520 ( HGF ), rs8111998 ( 19 p12), rs2721051 ( FOXO1 ) and rs4954218 ( RAB3GAP1 ). Genomic DNA was extracted from peripheral blood using the QIAamp Blood Kit (Qiagen, Hilden, Germany) according to the manufacturer’s protocol.…”

“…Recently, we conducted a systematic review and meta-analysis of the genetic associations of keratoconus and evaluated potential trans-ethnic heterogeneities 22. We identified 24 eligible studies, involving a total of 53 polymorphisms in 28 genes/loci.…”

“…We identified 24 eligible studies, involving a total of 53 polymorphisms in 28 genes/loci. Among them, 16 single-nucleotide polymorphisms (SNPs) in 14 genes/loci were associated with keratoconus, with 5 SNPs, rs2721051, rs1536482, rs4894535, rs2229813 and rs2228557 being putative genetic markers for keratoconus in Caucasians 22. Notably the associations of some SNPs were only marginally significant.…”