Exploring Genetic Associations Between Autoimmune Diseases and Pathological Scars

BACKGROUNDAutoimmune diseases and pathological scars share inflammatory and fibroproliferative features, but observational evidence cannot establish whether their co-occurrence reflects causation or shared biology. We used bidirectional Mendelian randomization (MR) to test genetic associations between clinically defined autoimmune diseases and pathological scars.

METHODSWe analyzed 10 autoimmune diseases and 2 pathological scar phenotypes (keloids and hypertrophic scars) in both directions, comprising 40 primary IVW tests. Autoimmune-disease instruments were selected at p < 5 × 10−8 and scar instruments at p < 5 × 10−6 because few genome-wide significant scar loci were available. Independent SNPs were obtained by LD clumping (r2 < 0.001; 10 000 kb), and variants with F ≤ 10 were excluded. Multiplicative random-effects inverse-variance weighted (IVW) analysis was primary, with MR-Egger, weighted median, mode-based estimators, Cochran's Q, MR-Egger intercept, leave-one-out analysis, MR-PRESSO, and radial MR as sensitivity analyses. Benjamini–Hochberg false discovery rate (FDR) correction was applied across the 40 primary tests.

RESULTSThree associations met nominal significance based on raw p values: hypertrophic scars with celiac disease (OR = 1.099, 95% CI 1.036–1.165, p = 0.00157; 2 SNPs), rheumatoid arthritis with hypertrophic scars (OR = 1.119, 95% CI 1.026–1.220, p = 0.0107; 19 SNPs), and type 1 diabetes with keloids (OR = 1.212, 95% CI 1.048–1.401, p = 0.0090; 12 SNPs). None survived FDR correction (minimum FDR-adjusted p = 0.0628). The remaining 37 primary tests had raw p ≥ 0.05.

CONCLUSIONThe analyses identified only nominal associations that were not robust to multiple-testing correction and therefore do not provide reliable evidence of causality. The results offer an initial framework for investigating potential shared genetic signals and should be treated as hypothesis-generating pending independent validation.

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