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The Major Histocompatibility Complex Conserved Extended Haplotype 8.1 in AIDS-Related Non-Hodgkin Lymphoma

Aissani, Brahim PhD*; Ogwaro, Kisani M MD#; Shrestha, Sadeep PhD*; Tang, Jianming PhD†††; Breen, Elizabeth C PhD; Wong, Hui-lee PhD§; Jacobson, Lisa P ScD; Rabkin, Charles S MD§; Ambinder, Richard F MD, PhD; Martinez-Maza, Otoniel PhD##**; Kaslow, Richard A MD*††#

JAIDS Journal of Acquired Immune Deficiency Syndromes: October 2009 - Volume 52 - Issue 2 - p 170-179
doi: 10.1097/QAI.0b013e3181b017d5
Basic Science

Background: Two single nucleotide polymorphisms (SNPs) in adjacent genes, lymphotoxin alpha (LTA +252G, rs909253 A>G) and tumor necrosis factor (TNF −308A, rs1800629 G>A), form the G-A haplotype repeatedly associated with increased risk of non-Hodgkin lymphoma (NHL) in individuals uninfected with HIV-1. This association has been observed alone or in combination with human leukocyte antigens HLA-B*08 or HLA-DRB1*03 in the major histocompatibility complex (MHC). Which gene variant on this highly conserved extended haplotype (CEH 8.1) in whites most likely represents a true etiologic factor remains uncertain.

Objective: We aimed to determine whether the reported association of the G-A haplotype of LTA-TNF with non-AIDS NHL also occurs with AIDS-related NHL.

Methods: SNPs in LTA and TNF and in 6 other genes nearby were typed in 140 non-Hispanic European American pairs of AIDS-NHL cases and matched controls selected from HIV-infected men in the Multicenter AIDS Cohort Study.

Results: The G-A haplotype and a 4-SNP haplotype in the neighboring gene cluster (rs537160 (A) rs1270942 (G), rs2072633 (A), and rs6467 (C)) were associated with AIDS-NHL (odds ratio = 2.7, 95% confidence interval: 1.5 to 4.8, P = 0.0009; and odds ratio = 3.2, 95% confidence interval: 1.6 to 6.6, P = 0.0008; respectively). These 2 haplotypes occur in strong linkage disequilibrium with each other on CEH 8.1.

Conclusion: The CEH 8.1-specific haplotype association of MHC class III variants with AIDS-NHL closely resembles that observed for non-AIDS NHL. Corroboration of an MHC determinant of AIDS and non-AIDS NHL alike would imply an important pathogenetic mechanism common to both.

From the Departments of *Epidemiology; #Psychiatry; and †Medicine, University of Alabama at Birmingham, Birmingham, AL; §Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD; Departments of ‖Epidemiology; and ¶Oncology, Johns Hopkins University, Baltimore, MD; and ‡Department of Psychiatry and Biobehavioral Sciences; ##Obstetrics and Gynecology; and **Microbiology, Immunology, and Molecular Genetics, UCLA, Los Angeles, CA.

Received for publication February 17, 2009; accepted May 27, 2009.

Supported by partial funding provided by R01-CA106168 (R.A.K.), R01-CA73475 (O.M.M.), P30 AI 045008 Penn Center for AIDS Research subcontract (B.A.) and P50-CA96888 (R.A.). The Multicenter AIDS Cohort Study (MACS) is funded by the National Institute of Allergy and Infectious Diseases, with additional supplemental funding from the National Cancer Institute and the National Heart, Lung, and Blood Institute. UO1-AI-35042, 5-MO1-RR-00722 (GCRC), UO1-AI-35043, UO1-AI-37984, UO1-AI-35039, UO1-AI-35040, UO1-AI-37613, and UO1-AI-35041.

Part of the data were presented at the 58th annual meeting of the American Society of Human Genetics (ASHG), November 11-15, 2008, Philadelphia, PA.

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Correspondence to: Brahim Aissani, PhD, Program in Epidemiology of Infection and Immunity, Department of Epidemiology, University of Alabama at Birmingham, 1665 University Blvd, RPHB Room 220A, Birmingham, AL 35294-0022 (e-mail:;

© 2009 Lippincott Williams & Wilkins, Inc.