Association study of RHBDD1-COL4A4 gene polymorphisms with susceptibility to lattice degeneration of the retina in a Japanese population

Abstract

Purpose: Lattice degeneration of the retina is a vitreoretinal disorder characterized by a visible fundus lesion predisposing the patient to retinal tears and detachment. We previously reported a significant association between the RHBDD1-COL4A4 gene polymorphisms and lattice degeneration of the retina. In this study, we performed an in-depth genetic analysis of the RHBDD1-COL4A4 region to clarify the contribution of the region in the development of lattice degeneration of the retina.<br />

Methods: We performed an imputation analysis on 34 single-nucleotide polymorphisms (SNPs) data genotyped in previous study to evaluate the potential association of un-genotyped RHBDD1-COL4A4 SNPs. The genotypes of 574 Japanese patients with lattice degeneration of the retina and 608 Japanese healthy controls were imputed using MACH v1.0 (http://www.sph.umich.edu/csg/abecasis/MACH/index.html). For the reference panel, we used the 1000 Genomes Phase I datasets of East Asian population (Japanese in Tokyo (JPT), Han Chinese in Beijing (CHB) and Southern Han Chinese (CHS)). For quality control, we excluded SNPs which have a squared correlation between imputed and true genotypes < 0.3 or are not in Hardy-Weinberg equilibrium (P<0.001). In addition, we assessed the functional impact of possible candidate variant on RHBDD1 or COL4A4 mRNA expression using Blood eQTL browser (http://genenetwork.nl/bloodeqtlbrowser/).<br />

Results: A total of 768 SNPs (734 imputed and 34 genotyped SNPs) in the RHBDD1-COL4A4 region were included in the association analysis. rs7558081 genotyped in previous study was most strongly associated with lattice degeneration of the retina (P=1.4E-5, OR=1.43, 95%CI=1.22-1.69). Another 11 SNPs (9 imputed and 2 genotyped SNPs) showed significant evidence of association with the disease (P<0.01). These 12 SNPs were located in the COL4A4 region and were in strong linkage disequilibrium (D’≥0.79, r²≥0.53). rs7558081, intronic SNP, significantly affected COL4A4 mRNA expression in peripheral blood (P=9.9E-6).<br />

Conclusions: Our results suggest that the COL4A4 intronic variant, rs7558081, contributes to the development of lattice degeneration of the retina through a mechanism of altered COL4A4 gene expression. To confirm our findings, future validation studies with other ethnic populations are needed.<br />