Genome-wide association studies have indicated that human leukocyte antigen (HLA)-DP and HLA-DQ play roles in persistent hepatitis B virus (HBV) infection in Asia. To understand the evolution of HBV-related single nucleotide polymorphisms (SNPs) and to correlate these SNPs with chronic HBV infection among different populations, we conducted a global perspective study on hepatitis-related SNPs. We selected 12 HBV-related SNPs on the HLA locus and two HBV and three hepatitis C virus immune-related SNPs for analysis. Five nasopharyngeal carcinoma-related SNPs served as controls. All SNP data worldwide from 26 populations were downloaded from 1,000 genomes. We found a dramatic difference in the allele frequency in most of the HBV- and HLA-related SNPs in East Asia compared to the other continents. A sharp change in allele frequency in 8 of 12 SNPs was found between Bengali populations in Bangladesh and Chinese Dai populations in Xishuangbanna, China ( 0.001); these areas represent the junction of South and East Asia. For the immune-related SNPs, significant changes were found after leaving Africa. Most of these genes shifted from higher expression genotypes in Africa to lower expression genotypes in either Europe or South Asia ( 0.001). During this two-stage adaptation, immunity adjusted toward a weak immune response, which could have been a survival strategy during human migration to East Asia. The prevalence of chronic HBV infection in Africa is as high as in Asia; however, the HBV-related SNP genotypes are not present in Africa, and so the genetic mechanism of chronic HBV infection in Africa needs further exploration. Two stages of genetic changes toward a weak immune response occurred when humans migrated out of Africa. These changes could be a survival strategy for avoiding cytokine storms and surviving in new environments. ( 2017;1:1005-1013).