Genome‐wide association and interaction analysis for proliferative retinopathy in adults with type 2 diabetes born during famine: The <scp>DOLCE</scp> study in Ukraine

Abstract Purpose Proliferative diabetic retinopathy (PDR) is one of the leading causes of blindness in working‐age adults. We have previously shown that the risk of PDR is significantly elevated in individuals with intrauterine exposure to famine. However, the genetic mechanisms mediating this association remain unknown. The aim of the current study was to investigate the molecular underpinnings of famine‐related PDR by performing genome‐wide association (GWAS) and interaction studies (GWIS). Methods We analysed n = 2925 patients with type 2 diabetes from the DOLCE cohort of Northern Ukraine, of whom n = 1364 were born during historical famine periods (1929–1949, including the Holodomor and World War II). PDR cases were defined as individuals with either diagnosed proliferative retinopathy, laser‐treated diabetic retinopathy (DR) or blindness in either eye. GWAS and GWIS were performed using linear mixed model (LMM) adjusted for established risk factors and genetic relationship matrix. Results GWAS identified rs3795299 in IL22RA1 as the top signal ( p LMM = 1.05 × 10 −6 ), which was also the strongest gene in the gene‐based analysis ( p = 3.19 × 10 −5 ), with suggestive enrichment of response to ketones (GO) and base excision repair (KEGG) pathways. In the GWIS, the strongest signal was rs1506783 in PAPPA2 ( p LMM = 1.29 × 10 −7 ). A second biologically credible candidate was rs2230805 in ABCA1 ( p LMM = 4.44 × 10 −6 ), reaching borderline genome‐wide significance in gene‐based analysis ( p = 4.31 × 10 −6 ). Interaction analyses showed suggestive enrichment for nucleosomal DNA binding (GO), tryptophan metabolism and glycerolipid metabolism (KEGG) pathways. Furthermore, at nominal significance, we validated variants in previously reported diabetic retinopathy‐associated genes, including TCF7L2 , SLC2A1 , SLC2A11 and VDR in the GWAS, as well as 13 variants in genes including VEGF , VEGFR1 , ANGPT1 , PLXDC2 , SELP and PON2 in the GWIS. Conclusion Our findings suggest that famine‐related PDR susceptibility involves distinct developmental programming mechanisms, including altered insulin‐growth signalling ( PAPPA2 ) and lipid metabolism ( ABCA1 ), whereas immune‐related pathways ( IL22RA1 ) may contribute to the conventional glycaemia‐driven route to PDR through VEGF‐mediated angiogenesis. These genes represent potential therapeutic targets and emphasize the importance of the perinatal environment in lifelong vascular health and disease.