Retinopathy of prematurity (ROP) remains one of the leading causes of preventable childhood blindness worldwide, and despite decades of research, its pathogenesis is still imperfectly understood. While clinicians traditionally focus on oxygen regulation and angiogenic signaling, a growing body of evidence suggests that inflammatory pathways play an equally pivotal role. New research from the University of Oklahoma now adds a surprising player to the field: genetic variants in the surfactant protein genes SFTPA1 and SFTPA2, better known for their role in pulmonary immunity.
Surfactant proteins A and D (SP-A, SP-D) are immunomodulatory collectins expressed not only in the lung, but — importantly — in multiple retinal cell types. Preclinical data have shown that SP-A influences retinal angiogenesis, localizing to vascular structures and promoting a pro-angiogenic phenotype. The study authors hypothesized that single-nucleotide polymorphisms (SNPs) in surfactant protein genes might alter susceptibility to ROP.
In a prospective case–control study of 59 infants born <32 weeks’ gestation or <1500 g, the investigators genotyped key SNPs in SFTPA1, SFTPA2 and SFTPD. Infants were followed through routine ROP screening, with analyses controlling for major clinical confounders such as gestational age (GA), bronchopulmonary dysplasia (BPD) and days on supplemental oxygen.
Overall, 39% of the infants developed ROP, and as expected, lower GA and longer oxygen exposure significantly increased risk.
The standout result was a significant association between the SFTPA2 SNP rs1965707 and increased odds of ROP, in both the full cohort and the subgroup with BPD.
Even after adjusting for GA and oxygen exposure, rs1965707 remained highly significant. Notably, the authors identified a gene–environment interaction: increasing GA was protective only in infants with the wildtype C/C genotype, but not in carriers of the risk allele. This suggests that SP-A2 may modulate how retinal vasculature responds to developmental or oxygen-related stress.
Mechanistically, rs1965707 localizes to the carbohydrate recognition domain, a region crucial for SP-A receptor binding and macrophage activation — cells known to influence physiological retinal angiogenesis. Although the nucleotide substitution does not alter the encoded amino acid, the authors propose that it may affect mRNA splicing, protein folding or receptor affinity.
A second SFTPA2 SNP, rs17886395, showed a weaker but notable association, while SFTPA1 and SFTPD variants did not demonstrate significant effects in this cohort. The widely studied protective haplotype 6A2/1A0, known in lung disease, did not confer protection against ROP.
This pilot analysis identifies the first reported genetic associations between surfactant protein polymorphisms and ROP, highlighting novel pathways that may influence endothelial function and angiogenesis independently of oxygen toxicity. If validated in larger cohorts, these findings could enable earlier risk stratification — potentially before clinical signs emerge — and open the door to targeted mechanistic studies of SP-A–mediated retinal vascular development.
Surfactant proteins A and D (SP-A, SP-D) are immunomodulatory collectins expressed not only in the lung, but — importantly — in multiple retinal cell types. Preclinical data have shown that SP-A influences retinal angiogenesis, localizing to vascular structures and promoting a pro-angiogenic phenotype. The study authors hypothesized that single-nucleotide polymorphisms (SNPs) in surfactant protein genes might alter susceptibility to ROP.
In a prospective case–control study of 59 infants born <32 weeks’ gestation or <1500 g, the investigators genotyped key SNPs in SFTPA1, SFTPA2 and SFTPD. Infants were followed through routine ROP screening, with analyses controlling for major clinical confounders such as gestational age (GA), bronchopulmonary dysplasia (BPD) and days on supplemental oxygen.
Overall, 39% of the infants developed ROP, and as expected, lower GA and longer oxygen exposure significantly increased risk.
The standout result was a significant association between the SFTPA2 SNP rs1965707 and increased odds of ROP, in both the full cohort and the subgroup with BPD.
Even after adjusting for GA and oxygen exposure, rs1965707 remained highly significant. Notably, the authors identified a gene–environment interaction: increasing GA was protective only in infants with the wildtype C/C genotype, but not in carriers of the risk allele. This suggests that SP-A2 may modulate how retinal vasculature responds to developmental or oxygen-related stress.
Mechanistically, rs1965707 localizes to the carbohydrate recognition domain, a region crucial for SP-A receptor binding and macrophage activation — cells known to influence physiological retinal angiogenesis. Although the nucleotide substitution does not alter the encoded amino acid, the authors propose that it may affect mRNA splicing, protein folding or receptor affinity.
A second SFTPA2 SNP, rs17886395, showed a weaker but notable association, while SFTPA1 and SFTPD variants did not demonstrate significant effects in this cohort. The widely studied protective haplotype 6A2/1A0, known in lung disease, did not confer protection against ROP.
This pilot analysis identifies the first reported genetic associations between surfactant protein polymorphisms and ROP, highlighting novel pathways that may influence endothelial function and angiogenesis independently of oxygen toxicity. If validated in larger cohorts, these findings could enable earlier risk stratification — potentially before clinical signs emerge — and open the door to targeted mechanistic studies of SP-A–mediated retinal vascular development.
