KLK10 polymorphisms from the same 19 Anti-GAD-Ab SPS and 20 immune controls were analysed using LDpair, LDmatrix, LDhap, and 1000-Genomes Project (EUR). Variants were annotated with Ensembl and gnomAD, and their significance was explored using GWAS Catalog, FORGEdb/RegulomeDB, GTEx, and large proteogenomic studies.

Variant-phased analysis identified two dominant KLK10 haplotypes with strong linkage disequilibrium: the Variant-haplotype in 95% of SPS patients and the Ancestral-haplotype in 90% of controls. A splice-region polymorphism perfectly distinguished the two haplotypes and was associated with transcript isoforms having different 5′-Untranslated Regions (5'UTRs) and untranslated first exons, which affect mRNA stability and tissue-specific expression. The Variant-haplotype, but not the Ancestral-haplotype, was found to correlate with promoter/5′UTR sub-blocks containing SNPs linked to reduced mRNA expression and KLK10 protein levels (GTEx, proteogenomics), suggesting KLK10 haplotype-specific regulatory effects. Two non-SPS family members with diabetes and very high Anti-GAD-Ab titers were homozygous for the Ancestral-haplotype; in contrast, the family member with SPS had inherited the Variant-haplotype from her healthy mother. From 1000-Genomes project, the Ancestral-haplotype is rare (<2%) in African-ancestry populations; in contrast, the Variant-haplotype is relatively common, probably explaining the high frequency of SPS among African Americans.