Sex Likely Not a Disease-Modifying Factor Among Women, Men With Stargardt Disease

A reported association between sex and mild ABCA4 alleles among patients with Stargardt disease did not hold up upon reevaluation.

A recently reported association between sex and mild ABCA4 alleles among patients with Stargardt disease did not hold up upon reevaluation in a new study.

Researchers at Columbia University performed a study, published in JAMA Ophthalmology, analyzing 655 patients with autosomal recessive Stargardt disease (STGD1) in an effort to determine whether a prior study’s finding that the disease occurred more often among females with mild ABCA4 was reproducible. Their analysis did not support sex as a potential disease-modifying variable.

STGD1 is the most common form of inherited retinal degeneration caused by mutations in the ABCA4 locus. The disease typically causes vision loss during childhood or adolescence. For most, vision loss progresses slowly over time to 20/200 or worse; complete blindness is rare.

The disease has exceptional clinical heterogeneity, but all cases are explained by variation in the allele, the authors said. Results from a study by Runhart et al published in JAMA Ophthalmology last year found that in 25% of patients with STDG1 who carried a combination of a mild and a severe allele, sex may play a modifying role in the disease. However, no other such association is known to exist for any other hereditary eye disease, the authors said.

Differences by sex tend to result from many factors. Three major population-based studies found increased risk among females for age-related macular degeneration (AMD), yet more recent large-scale studies found no such association; the American Academy of Ophthalmology and the World Health Organization do not consider females at greater risk. These issues motivated the authors to try to independently replicate the earlier study.

A total of 644 patients with genetically confirmed cases of STGD1 were included in the new analysis. The proportion of women was slightly higher in the entire cohort and in most allele categories, but none of the differences were found to be statistically significant.

The proportion of women carrying the c.5603A>T, p.(Asn1868Ile) allele was 7% (95% CI, −9% to 23%) higher than in the subgroup not carrying any mild alleles (P = .32). The proportion of women carrying the c. 5882G>A p.(Gly1961Glu) allele was 2% (95% CI, −12% to 15%) higher than in the subgroup not carrying any mild alleles (2-tailed Fisher exact test, P = .77). The difference was 3% (95% CI, −8% to 14%; P = .48) between the total mild allele and no mild allele categories.

Selection bias may be behind the reason that studies sometimes find a genetic predilection toward women, the authors said. Women tend to seek health care in a way that may lead to overestimation of disease prevalence. The authors said Runhart et al acknowledged the phenomenon but disregarded its potential effect.

In addition, health-seeking behavior was different among the groups. Patients with early-onset STGD1 with severe alleles had such profound vision loss that they had no choice but to seek medical attention, whereas those with milder symptoms had such a choice, especially those whose symptoms did not manifest until late adulthood. Furthermore, the only complex traits with reported sex imbalance are AMD and central serous chorioretinopathy, where hormonal imbalance is a proven cause.


Lee W, Zernant J, Nagasaki T, Allikmets R. Reevaluating the association of sex with ABCA4 alleles in patients with Stargardt disease. JAMA Ophthalmol. Published online April 1, 2021. doi:10.1001/jamaophthalmol.2021.0460

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