Despite extensive work on influenza, a number of questions still remain open about why individuals are differently susceptible to the disease and why only some strains lead to epidemics. Here we study the effect of human leukocyte antigen (HLA) genotype heterogeneity on possible cytotoxic T-lymphocyte (CTL) response to 186 influenza H1N1 genomes. To enable such analysis, we reconstruct HLA genotypes in different populations using a probabilistic method. We find that epidemic strains in general correlate with poor CTL response in populations. Our analysis shows that large populations can be classified into a small number of groups called response-types, specific to a given viral strain. Individuals of a response-type are expected to exhibit similar CTL responses. Extent of CTL responses varies significantly across different populations and increases with increase in genetic heterogeneity. Overall, our analysis presents a conceptual advance towards understanding how genetic heterogeneity influences disease susceptibility in individuals and in populations. We also obtain lists of top-ranking epitopes and proteins, ranked on the basis of conservation, antigenic cross-reactivity and population coverage, which provide ready short-lists for rational vaccine design. Our method is fairly generic and has the potential to be applied for studying other viruses.