Whether advantageous or disadvantageous phenotypes associated with low activity COMT haplotypes are ultimately expressed, is probably determined by additional genetic and non-genetic factors.Although the significant functional impact of common APS and HPS haplotypes is independent of minor SNPs situated in the coding region of the gene, it is possible that effects of APS and HPS haplotypes are modified by epistatic interactions occurring at nearby COMT gene loci not investigated here. The gene discussed is COMT; the disease is autoimmune polyendocrinopathy.