Population genetics of 
‐rs6683977, LINKAGE DISEQUILIBRIUM WITH OTHER ALL RELAPSE AND FUNCTIONAL REGULATORY VARIANTS Functional genomic studies were unable to identify if rs6683977 directly affects PDE4B expression, but other three SNPs in intron 7 were functionally validated as “positive regulatory elements” (PRE) : rs494735, rs502958 and, in particular, rs12142375, which has an allele‐specific regulatory effect (Figure ). In Native Americans from Peru, rs6683977.G is in strong linkage disequilibrium (LD) with the PRE rs12142375.G ( r 2 = 1, both at very high frequencies; Figure ), but not with the other two PRE SNPs. In these Peruvian populations PDE4B ‐rs6683977 is also in strong LD ( r 2 = 1) with other variants in intron 7, including rs546784 and rs641262 (Figure ), associated with ALL relapse in the St. Jude multi‐ethnic cohort. Notably, we show that the sum of frequencies of PDE4B haplotypes including the ALL relapse risk alleles rs546784.T, rs6683977.G, rs641262.T, and the functional allele rs12142375.G is higher in Native Americans from Mexico (0.92) and Peru (0.82–0.95) than in other 1000GP populations, particularly in Europeans (0.43; Table ). Our study has the limitation of being a population genetics study on healthy individuals. Association and functional studies of PDE4B ‐rs6683977.G with relapse in patients with ALL from Latin American countries are a pending task. Clinical studies on the use of PDE4B ‐rs6683977.G haplotypes information to prescribe an extra‐phase of ALL chemotherapy would be the gold standard. In conclusion, the ALL relapse associated allele PDE4B ‐rs6683977.G is highly prevalent in Native American (Figure ), as well as in African and East Asian populations, but only in Native Americans both individual and local‐chromosome ancestries are associated with ALL relapse in the multi‐ethnic St. Jude cohort. This result posits the hypothesis, to be tested, that effect sizes of PDE4B ‐rs6683977.G on ALL relapse may vary with ancestry, as has been recently observed for susceptibility SNPs for ALL in the ERG gene in Hispanics. PDE4B ‐rs6683977.G is in LD with other SNPs also associated with ALL relapse (Table ) and with functional variants in intron 7 (Figure , Table ) both in Native American and also East Asians. The intronic region encompassing PDE4B ‐rs6683977 has been functionally validated as a spatially active chromatin segment, harboring active enhancers, even if this validation has been performed in cell lines with European ancestry background and not in cell lines derived from Native American individuals, a pending task. Functional databases  reveal that the region around PDE4B ‐rs6683977, including other ALL relapse markers, has several DNase I hypersensitive binding sites, transcription factor ChIP‐seq clusters and histone marks of active enhancers (H3K4me1, H3K4me3, and H3K27ac) in a European ancestry lymphoblastoid cell line (Figure ). Accordingly, the importance of PDE4B for the ALL treatment outcome is likely related to the association of its overexpression with glucocorticoids resistance. , , , Our findings are consistent with the role of admixture mapping hits found by Yang et al., expand their results by revealing the very high prevalence of PDE4B ‐rs6683977.G and associated haplotypes in neglected Native American populations, and provide further support to the therapeutic decision of an extra phase of chemotherapy in populations with predominant Native American ancestry. Our study exemplifies how knowledge generated in US‐Hispanics is relevant for their even more vulnerable and neglected Native American ancestors along the American continent. 

The authors declared no competing interests for this work. 

R.G.M., E.T.‐S., and F.R.‐S. wrote the manuscript. E.T.‐S. and F.R.‐S. designed the research. R.G.M., J.M.S.D., W.C.S.M., and F.R.‐S. performed the research. R.G.M., J.M.S.D., M.L.S., W.C.S.M., Z.B., and F.R.‐S. analyzed the data. A.C.P., M.S.‐M., C.G.‐H., C.Z., T.P.L., A.L., R.H.G., J.G.M., V.B., H.G., and T.D.O.'C. contributed new reagents/analytical tools. 

Supplementary Table S1 Click here for additional data file. Supplementary Table S2 Click here for additional data file. Supplementary Table S3 Click here for additional data file. Supplementary Figure S1 Click here for additional data file. Data S1 Click here for additional data file. 

