02928nas a2200517   4500000000100000008004100001260001200042100001400054700002200068700001400090700001400104700001500118700001200133700002000145700001200165700001400177700001500191700001700206700001400223700001200237700001400249700001700263700001300280700001200293700001300305700001800318700001600336700001400352700001500366700001400381700001300395700001800408700002200426700001800448700001200466700001500478700001100493700001400504700001300518245014900531856009900680300001300779490000700792520159700799022001402396       2021                            d  c08/20211 aBezerra O1 aAlvarado-Arnez LE1 aMabunda N1 aSalomé G1 ade Sousa A1 aKehdy F1 aSales-Marques C1 aManta F1 aAndrade R1 aFerreira L1 aLeal-Calvo T1 aCardoso C1 aNunes K1 aGouveia M1 aMbulaiteve S1 aYeboah E1 aHsing A1 aLatini A1 aLeturiondo AL1 aRodrigues F1 aNoronha A1 aFerreira C1 aTalhari C1 aRêgo JL1 aCastellucci L1 aTarazona-Santos E1 ade Carvalho E1 aMeyer D1 aPinheiro R1 aJani I1 aPacheco A1 aMoraes M00aPutative pathogen-selected polymorphisms in the PKLR gene are associated with mycobacterial susceptibility in Brazilian and African populations.  uhttps://journals.plos.org/plosntds/article/file?id=10.1371/journal.pntd.0009434&type=printable  ae00094340 v153 a<p>Pyruvate kinase (PK), encoded by the PKLR gene, is a key player in glycolysis controlling the integrity of erythrocytes. Due to Plasmodium selection, mutations for PK deficiency, which leads to hemolytic anemia, are associated with resistance to malaria in sub-Saharan Africa and with susceptibility to intracellular pathogens in experimental models. In this case-control study, we enrolled 4,555 individuals and investigated whether PKLR single nucleotide polymorphisms (SNPs) putatively selected for malaria resistance are associated with susceptibility to leprosy across Brazil (Manaus-North; Salvador-Northeast; Rondonópolis-Midwest and Rio de Janeiro-Southeast) and with tuberculosis in Mozambique. Haplotype T/G/G (rs1052176/rs4971072/rs11264359) was associated with leprosy susceptibility in Rio de Janeiro (OR = 2.46, p = 0.00001) and Salvador (OR = 1.57, p = 0.04), and with tuberculosis in Mozambique (OR = 1.52, p = 0.07). This haplotype downregulates PKLR expression in nerve and skin, accordingly to GTEx, and might subtly modulate ferritin and haptoglobin levels in serum. Furthermore, we observed genetic signatures of positive selection in the HCN3 gene (xpEHH>2 -recent selection) in Europe but not in Africa, involving 6 SNPs which are PKLR/HCN3 eQTLs. However, this evidence was not corroborated by the other tests (FST, Tajima's D and iHS). Altogether, we provide evidence that a common PKLR locus in Africans contribute to mycobacterial susceptibility in African descent populations and also highlight, for first, PKLR as a susceptibility gene for leprosy and TB.</p>  a1935-2735