Rare Variants in the RPGRIP1 Gene Are Associated With Age–Related Maculopathy (ARM)

Abstract

Abstract: : Purpose: Homozygous or compound heterozygous rare variants in the retinitis pigmentosa GTPase regulator interacting protein (RPRGIP1) gene cause Leber congenital amaurosis (LCA). We have previously demonstrated that heterozygous RPGRIP1 defects (as in the parents of LCA patients) cause functional deficit in photoreceptors. Moreover, RPGRIP1 is located in the 14q11.2 region, which overlaps with a previously mapped ARM locus. Hence, we tested the hypothesis that heterozygous rare RPGRIP1 alleles increase susceptibility to ARM. Methods: Cohorts of ARM patients and matched controls were ascertained at three independent centers in the U.S., Germany and The Netherlands. At all centers, subjects were diagnosed according to the same modified International Classification System. Genetic variation in the RPGRIP1 gene was analyzed by a combination of DHPLC, PCR–RFLP and direct sequencing in 940 study subjects, including 490 ARM cases and 450 matched controls. Statistical analysis was performed by Fisher exact and Pearson Χ² tests. Results: Screening of all exons and adjacent intronic sequences of RPGRIP1 revealed 36 sequence variants. Of these, 22 were in the coding region, including 11 rare (<1%) and 4 common (>10%) amino acid–changing variants. The combined data from all 3 centers suggested statistically significant differences in the frequency of rare variants between ARM–affected individuals and age–matched controls, (0.02 vs 0.008; p=0.015). When analyzed separately, the data from the U.S. center (370 subjects) was statistically significant (0.035 vs 0.008; p=0.008), while the data from German (350 subjects; 0.006 vs 0.008; p=0.5) and Dutch (225 subjects; 0.015 vs 0.005; p=0.25) centers were not. Allele frequencies of the 4 common missense variants were showing a trend to be higher in ARM patients in 2/3 centers; however, the difference did not reach statistical significance. Conclusions: The combined data from 3 centers suggest that rare variants in RPGRIP1 predispose individuals to ARM. However, similar to several other genes in previous studies, (limited) data from independent centers are not in complete agreement, if analyzed separately.

Keywords: age-related macular degeneration • candidate gene analysis • genetics