Genes · 9 authors, 6 centres
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This case-control study in a Saudi population found that the T allele of rs61876744 in the PNPLA2 gene was associated with a protective effect against keratoconus (OR=0.64, p=0.020), though it did not survive multiple testing correction. The protective effect was modestly significant in the dominant genetic model (OR=0.53, p=0.013). These findings suggest a potential genetic marker for keratoconus risk in Middle Eastern Arabs, warranting larger replication studies.
**Background:** Keratoconus (KC) is a degenerative corneal disorder with genetic and environmental risk factors. A recent genome-wide association study identified two novel loci associated with KC in European populations: rs61876744 in the PNPLA2 gene and rs138380 near CSNK1E. Additionally, polymorphisms in the APOE gene (rs429358 and rs7412) have been implicated in oxidative stress pathways relevant to KC. The genetic etiology of KC in Middle Eastern Arabs, particularly Saudi populations, remains unclear. This study aimed to evaluate the association of these four polymorphisms with KC in a Saudi cohort.
**Methods:** A retrospective case-control genetic association study was conducted at King Saud University, Riyadh. The study included 98 KC patients (mean age 25.8±7.3 years, 55 males, 43 females) and 167 healthy controls (mean age 60.1±8.1 years, 88 males, 79 females). KC diagnosis was based on specific clinical criteria including posterior corneal elevation ≥+20 μm, inferior-superior dioptric asymmetry >1.2 D, and steepest keratometry >47 D. DNA was extracted from blood samples. Genotyping of rs61876744 and rs138380 was performed using TaqMan assays, while rs429358 and rs7412 were genotyped via Sanger sequencing. Statistical analyses included Hardy-Weinberg equilibrium testing, chi-square/Fisher's exact tests, Cochran-Armitage trend test, and binary logistic regression. Bonferroni correction set significance at p<0.015 (0.05/4).
**Key Results:** The T allele frequency of rs61876744 was lower in KC cases (0.33) than controls (0.43), showing a protective effect (OR=0.64, 95% CI=0.44-0.93, p=0.020), but this did not survive multiple testing correction. In the dominant genetic model, rs61876744 showed a modestly significant protective effect (OR=0.53, 95% CI=0.32-0.88, p=0.013). No significant allelic or genotype associations were found for rs138380, rs429358, or rs7412. Analysis of APOE genotypes revealed that ε2-carriers (ε2/ε2 and ε2/ε3) had a >5-fold increased risk of KC, but this was not statistically significant (p=0.055). Logistic regression showed no significant independent effect of age, sex, or any polymorphism on KC outcome. The study had adequate power (0.96-0.97) to detect an OR of 2.0 for rs138380 and rs61876744, but was underpowered for rs7412 (power=0.37).
**Clinical Implications:** This study provides preliminary evidence that the rs61876744 polymorphism in PNPLA2 may be associated with KC in the Saudi population, with the T allele conferring a protective effect. The findings align with previous GWAS results in European populations, suggesting a potential role for PNPLA2 in KC pathogenesis, possibly through regulation of the antisense RNA transcript AP006621. The lack of association for rs138380, rs429358, and rs7412 suggests these variants may not be major risk factors in this population. However, the trend toward increased risk in ε2-carriers warrants further investigation. The study's limitations include a relatively small sample size, significant age differences between cases and controls, and lack of functional validation. Larger, multi-center studies with age- and gender-matched controls are needed to confirm these findings and explore gene-environment interactions.