Representation of Women Among Individuals With Mild Variants in ABCA4-Associated Retinopathy: A Meta-Analysis

Abstract

Importance: Previous studies indicated that female sex might be a modifier in Stargardt disease, which is an ABCA4-associated retinopathy.

Objective: To investigate whether women are overrepresented among individuals with ABCA4-associated retinopathy who are carrying at least 1 mild allele or carrying nonmild alleles.

Data sources: Literature data, data from 2 European centers, and a new study. Data from a Radboudumc database and from the Rotterdam Eye Hospital were used for exploratory hypothesis testing.

Study selection: Studies investigating the sex ratio in individuals with ABCA4-AR and data from centers that collected ABCA4 variant and sex data. The literature search was performed on February 1, 2023; data from the centers were from before 2023.

Data extraction and synthesis: Random-effects meta-analyses were conducted to test whether the proportions of women among individuals with ABCA4-associated retinopathy with mild and nonmild variants differed from 0.5, including subgroup analyses for mild alleles. Sensitivity analyses were performed excluding data with possibly incomplete variant identification. χ2 Tests were conducted to compare the proportions of women in adult-onset autosomal non-ABCA4-associated retinopathy and adult-onset ABCA4-associated retinopathy and to investigate if women with suspected ABCA4-associated retinopathy are more likely to obtain a genetic diagnosis. Data analyses were performed from March to October 2023.

Main outcomes and measures: Proportion of women per ABCA4-associated retinopathy group. The exploratory testing included sex ratio comparisons for individuals with ABCA4-associated retinopathy vs those with other autosomal retinopathies and for individuals with ABCA4-associated retinopathy who underwent genetic testing vs those who did not.

Results: Women were significantly overrepresented in the mild variant group (proportion, 0.59; 95% CI, 0.56-0.62; P < .001) but not in the nonmild variant group (proportion, 0.50; 95% CI, 0.46-0.54; P = .89). Sensitivity analyses confirmed these results. Subgroup analyses on mild variants showed differences in the proportions of women. Furthermore, in the Radboudumc database, the proportion of adult women among individuals with ABCA4-associated retinopathy (652/1154 = 0.56) was 0.10 (95% CI, 0.05-0.15) higher than among individuals with other retinopathies (280/602 = 0.47).

Conclusions and relevance: This meta-analysis supports the likelihood that sex is a modifier in developing ABCA4-associated retinopathy for individuals with a mild ABCA4 allele. This finding may be relevant for prognosis predictions and recurrence risks for individuals with ABCA4-associated retinopathy. Future studies should further investigate whether the overrepresentation of women is caused by differences in the disease mechanism, by differences in health care-seeking behavior, or by health care discrimination between women and men with ABCA4-AR.

Figure 1.. Genotype-Phenotype Model

A, Model showing the association between the ABCA4 genotype and the retinal phenotype,^, including a possible modifier effect and the distinction between mild variants with complete penetrance and those with reduced penetrance. B, Suggested association between variant severity and remaining ABCA4 function. Variant severity is depicted based on literature and the female:male proportion in this meta-analysis.

Figure 2.. Forest Plot of Proportions of Women Among Individuals With Mild Variants With Reduced Penetrance

Box sizes are proportionate to the number of individuals per study. Data from Khan et al were derived from 2 studies^, that were taken up separately in this meta-analysis. Data from Lille University Hospital were divided based on the technique used to identify genetic variants. The dashed line indicates the total proportion of women; diamond, combined estimate of the proportion of women with the 95% confidence interval; black bar, prediction interval of the estimated combined proportion; dotted line, proportion of 0.5, with which the data were compared.

Figure 3.. Forest Plot of Proportions of Women Among Individuals With Nonmild Variants

Box sizes are proportionate with the number of individuals per study. Data from Khan et al were derived from 2 studies^, that were taken up separately in this meta-analysis. Data from Lille University Hospital were divided based on the technique used to identify genetic variants. The dashed line indicates the total proportion of women; diamond, combined estimate of the proportion of women with the 95% confidence interval; black bar, prediction interval of the estimated combined proportion; dotted line, proportion of 0.5, with which the data were compared.

Figure 4.. Summarized Forest Plot of Proportions of Women Among Individuals With Specific Mild Variants With Reduced Penetrance in the Main Analysis

The diamonds indicate the combined estimate of the proportion of women with the 95% confidence interval per variant. The dark blue box indicates the data for c.769-784C>T, which were reported in Runhart et al and Khan et al. The dotted line indicates the proportion of 0.5, with which the data were compared.