The MICA rs2596542 locus is not an island: component-aware haplotype decomposition reveals a composite MHC tag with distinct regulatory axes

Cross-population reversal of signed linkage disequilibrium (LD), or the "flip-flop" phenomenon, can arise when a tag SNP captures different extended haplotype backgrounds across populations. The MICA hepatocellular carcinoma susceptibility variant rs2596542 exemplifies this problem in the MHC, where signed LD reverses between Japanese and European populations but the relevant regulatory backgrounds are obscured by haplotypic complexity. We analyzed 7,303 biallelic SNVs surrounding rs2596542 across 26 populations using carrier-set topology classification followed by non-negative matrix factorization of carrier haplotypes. This identified two regulatory axes. Axis I, represented by components c4/c6, was population-stable and MICA-regulatory, with coherent MICA cis-eQTL enrichment and depletion for signed-LD reversal. Axis II, represented by component c5, was enriched for signed-LD reversal and showed an HLA-B{uparrow}/HLA-C{downarrow} expression signature with no MICA overlap across six GTEx tissues. In an independent Japanese HCC cohort (LIRI-JP, n = 122), Axis II-associated HLA-C downregulation remained after adjustment for clinical covariates, immune infiltration, and HLA-A expression. The previously proposed cross-population tag rs2244546 mapped to a population-stable component rather than Axis II. A parallel reanalysis of the COMT Val158Met flip-flop locus reproduced the signed-LD pattern reported by Lin et al1. and showed population-specific latent backgrounds among Val carriers. These results show that carrier-set topology combined with NMF can decompose composite marker alleles into functionally interpretable regulatory haplotype subspaces.