Hereditary Predisposition Raises Keratoconus Risk

Young woman having her eyes examined by an eye handsome
Optometry concept – young woman having her eyes examined by an eye handsome elderly doctor. Topography of the cornea.
A combination of parental consanguinity, positive family history, and eye rubbing are risks for corneal disease.

A family history of keratoconus (KC) is generally known to be a risk factor to develop the disorder, although this etiology includes both the influence of genes and environment. Unique data has been uncovered that reinforces genetic predisposition — parental consanguinity up to the second cousin — in a study published in Clinical Ophthalmology.

The study included 166 participants grouped in 83 sex- and age-matched pairs. Compared with control individuals, case patients with parental consanguinity had a nearly 3-times greater risk of developing keratoconus. The association between parent-cousin genetic relationships and KC diagnosis appeared regardless of other significant aspects of risk. This data may give clinicians added rationale for advising families affected by the disorder to watch for childhood eye-rubbing, another widely-accepted risk for KC, according to investigators.

The analysis shows that family history raised the risk by 25 times. Also, childhood eye-rubbing prior to diagnosis created a four-times greater risk. Upon multivariable analysis of the matched pairs, eye-rubbing (P =.002), positive family history (P =.006), and parental consanguinity (P =.02) were the most significant factors. None of the participants reported systemic diseases previously linked to KC such as Marfan, Ehlers-Danlos, or Down syndromes, or Leber congenital amaurosis.

All participants underwent a complete eye examination including visual acuity assessment, slit-lamp evaluation of the anterior segment, and fundoscopic examination. They also completed a questionnaire covering additional risks. In univariate analysis of the pairs, a number of variables did not indicate greater chance to develop KC; including obesity (P =.284), exposure to sunlight ≥4 hours per day (P =.311), low socio-economic status (P =.342), ocular trauma (P =.343),  prior contact lens wear (P =.724), and exposure to smoking (P =1.00). 

Three participants with KC were siblings, a sister and 2 brothers, and only 1 brother had recurrently rubbed his eyes, affirming multi-factor disease origin, the research noted. Also, it added that the inconsequential data for sunlight exposure may be due to the opposing impacts of damage by ultraviolet light (UV) with UV-prompted natural cross-linking “of corneal collagen, assumed to be protective” for KC. Further, light exposure may have been under a threshold to show impact.

Individuals in the control group had no clinical or tomographic signs of KC and displayed normal anterior and posterior segments. Previous research has demonstrated association between consanguinity and KC up to the first cousin.

The study was limited by the absence of a subgroup comparison for participants with first- and second-cousin parental relationships. Its strength was that it added data toward the origins of KC. “It is relevant to genetic influence that we found a strong association between parental consanguinity and the diagnosis of KC independent from all other significant risk factors, with 72% of cases but only 40% of controls reporting a positive history for parental consanguinity,” the researchers report.


Almusawi LA, Hamied FM. Risk factors for development of keratoconus: a matched pair case-control study. Clin Ophthalmol. 2021;15:3473-3479. doi:10.2147/OPTH.S248724.