Abstract
Previous reports have implicated the tumor necrosis factor (TNF__~−~~308~__) locus to non‐Hodgkin's lymphoma (NHL) outcome. The purpose of the study was to examine other chromosome components of the HLA 8.1 ancestral haplotype (AH) and their relation to the clinical course of NHL. HLA class I, II, TNF~−~~308~__, and lymphotoxin alpha (LTA~+252~) alleles were analyzed in 154 newly diagnosed NHL patients. Three locus haplotypes were inferred from the unphased genotypes by a Bayesian implementation of the expectation maximization (EM) algorithm using the PHASE 2.1 program. TNF~−~~308A~__ was the only allele associated with fever, poor performance status, elevated β2‐microglobulin, TNF and its p75 receptor plasma levels. Although TNF~−~~308A~__ was in strong linkage disequilibrium with the remaining alleles of 8.1 AH, only HLA‐A*01 and HLA‐B*08 showed association with prognostic variables. A part of 8.1 AH (A*01‐B*08‐TNF~−~~308A~) was predictive for shorter freedom from progression and overall survival (RR = 2.47, P = 0.041; RR = 3.15; P = 0.0049), an association that was stronger than TNF~−~__~308A~ alone and independent from International Prognostic Index (RR = 1.55, P < 0.001; RR = 2.36; P < 0.0001). A*01‐B*08‐TNF~−~~308A~__ fragment of 8.1AH remained an independent predictive factor in a multivariate model. We conclude that 8.1 AH is an important contributor to NHL outcome. In contrast to A*01‐B*08‐TNF~−~____~308A~__, the remaining alleles (Cw*07, DRB1*03, LTA~+252G~) associated with the 8.1 AH seem to be its passive components. © 2007 Wiley‐Liss, Inc.