The usual approach to discovering protective variants has been to focus on those thought to be at risk but without disease. This approach has been frequently applied to infectious disease, where exposure risk is known. Possibly most notable, a specific variant in CCR5, the gene encoding for an HIV co-receptor for binding and entry into CD4+ T cells called the CC-chemokine receptor 5, confers resistance to HIV infection. The 32 base pair deletion, CCRdelta32, results in a nonfunctioning CCR5 and confers immunity to HIV to those homozygous for the mutation (Dean, Carrington, Winkler, & Huttley, 1996; Liu et al., 1996). Importantly, identifying these variants relied on the study of highly exposed controls. Utilizing a novel study design, focusing on HIV-seropositive subjects with and without tuberculosis from high TB exposure regions, Sobota and colleagues (Sobota et al., 2016) successfully identified a TB-resistance variant in a histone mark on Chromosome 5 near IL12B. Other work using exposed controls has identified, or is aiming to identify, resistance variants for other infectious diseases, including influenza (Hsu & Spindler, 2012), malaria (Shelton et al., 2015), Kuru (Mead et al., 2009) and other prion diseases (Asante et al., 2015).
