02097nas a2200337   4500000000100000008004100001260001300042653001100055653002400066653002000090653001100110653001200121653001400133653003200147100001300179700001800192700001400210700001600224700001900240700001300259700001200272700001500284700001800299245010200317856006200419300001200481490000600493050001400499520123200513022001401745       2001                            d  c2001 Jun10aBrazil10aGenes, MHC Class II10aGenetic Linkage10aHumans10aleprosy10aPhenotype10aTumor Necrosis Factor-alpha1 aShaw M A1 aDonaldson I J1 aCollins A1 aPeacock C S1 aLins-Lainson Z1 aShaw J J1 aRamos F1 aSilveira F1 aBlackwell J M00aAssociation and linkage of leprosy phenotypes with HLA class II and tumour necrosis factor genes.  uhttp://www.nature.com/gene/journal/v2/n4/pdf/6363754a.pdf  a196-2040 v2  aSHAW 20013 a<p>Previous analyses indicate major gene control of susceptibility to leprosy per se and the HLA class II region has been implicated in determining susceptibility and control of clinical phenotype. Segregation analysis using data from 76 Brazilian leprosy multi-case pedigrees (1166 individuals) supported a two locus model as the best fit: a recessive major gene and a recessive modifier gene(s) (single locus vs two locus model, P = 0.0007). Combined segregation and linkage analysis to the major locus, showed strong linkage to HLA class II (HLA-DQB1 P = 0.000002, HLA-DQA1 P = 0.000002, HLA-DRB1 P = 0.0000003) and tumour necrosis factor genes (TNF P = 0.00002, LTA P = 0.003). Extended transmission disequilibrium testing, using multiple affected family members, demonstrated that the common allele TNF*1 of the -308 promoter region polymorphism showed linkage and/or association with disease per se, at a high level of significance (P < 0.0001). Two locus transmission disequilibrium testing suggested susceptibility (TNF*1/LTA*2) and protective (TNF*2/LTA*2) haplotypes in the class iii region. Taken together the segregation and HLA analyses suggest the possibility of more than one susceptibility locus in the MHC.</p>  a1466-4879