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<p>Burkitt lymphoma (BL) is a B-cell malignancy that disproportionately affects children in sub-Saharan Africa. We performed a genome-wide association study (GWAS) in a combined set of 800 childhood cases and 3865 controls in East Africa, controlling for age, sex, country, population-specific principal components, and a genetic relationship matrix. This analysis identified a BL-protective region within chromosome 21q22.12 tagged by the rs111457485-T allele (odds ratio [OR] = 0.57; <i>p</i> = 5.7 × 10<sup>−9</sup>). The results were robust in standard meta-analysis (OR = 0.57, <i>p</i> &lt; 1.6 × 10<sup>−8</sup>), sensitivity analyses (removing genomic outliers and related individuals), and after adjustment for Epstein-Barr virus (EBV) status. Genomic analyses revealed long-range (over ~700 kb) chromatin interactions between the chr21q22.12 locus and the <i>RUNX1</i>-P1 promoter region. The African-specific rs2242780-C allele (<i>r</i><sup><i>2</i></sup> = 0.69 with the rs111457485-T allele in the study controls) showed increased enhancer activity in in-vitro Luciferase reporter assays (<i>p</i> = 4.5 × 10<sup>−10</sup>), nominating it as the likely functional variant for the BL-associated loci. In addition to the association with reduced BL risk in GWAS (OR = 0.62, <i>p</i> = 2.24 × 10<sup>−8</sup>), the rs2242780-C allele was also associated with better survival in patients with abdominal-only BL in exploratory analyses (hazard ratio = 0.39, <i>p</i> = 0.038, 106 patients, 59 deaths). Our GWAS uncovered novel BL-protective loci near <i>RUNX1</i>, offering insights into the genetic etiology of BL in African children.</p>

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A genome-wide association study identifies an African-specific locus on chromosome 21q22.12 associated with Burkitt lymphoma risk and survival

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年7月11日

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  • Diptavo Dutta,
  • Mateus H. Gouveia,
  • Bryan R. Gorman,
  • Atuahene Adu-Gyamfi,
  • Chia-Han Lee,
  • Martin D. Ogwang,
  • Patrick Kerchan,
  • Steven J. Reynolds,
  • Constance N. Tenge,
  • Pamela A. Were,
  • Walter N. Wekesa,
  • Robert K. Tenge,
  • Nestory Masalu,
  • Esther L. Kawira,
  • Tobias Kinyera,
  • Isaac Otim,
  • Hadijah Nabalende,
  • Herry Dhudha,
  • Bosco Candia,
  • Janet Abaru,
  • Wusheng Yan,
  • Oscar Florez-Vargas,
  • Yi Xie,
  • Michelle Ho,
  • Leona W. Ayers,
  • Kishor Bhatia,
  • James J. Goedert,
  • Ruth M. Pfeiffer,
  • Michelle Manning,
  • Amy Hutchinson,
  • Nathan Cole,
  • Wen Luo,
  • Belynda Hicks,
  • George Chagaluka,
  • W. Thomas Johnston,
  • Nora Mutalima,
  • Eric Borgstein,
  • George N. Liomba,
  • Steven Kamiza,
  • Nyengo Mkandawire,
  • Elizabeth M. Molyneux,
  • Collins Mitambo,
  • Robert Newton,
  • Reiner Siebert,
  • Michael Dean,
  • Meredith Yeager,
  • Stephen J. Chanock,
  • Ludmila Prokunina-Olsson,
  • Sam M. Mbulaiteye

摘要

Burkitt lymphoma (BL) is a B-cell malignancy that disproportionately affects children in sub-Saharan Africa. We performed a genome-wide association study (GWAS) in a combined set of 800 childhood cases and 3865 controls in East Africa, controlling for age, sex, country, population-specific principal components, and a genetic relationship matrix. This analysis identified a BL-protective region within chromosome 21q22.12 tagged by the rs111457485-T allele (odds ratio [OR] = 0.57; p = 5.7 × 10−9). The results were robust in standard meta-analysis (OR = 0.57, p < 1.6 × 10−8), sensitivity analyses (removing genomic outliers and related individuals), and after adjustment for Epstein-Barr virus (EBV) status. Genomic analyses revealed long-range (over ~700 kb) chromatin interactions between the chr21q22.12 locus and the RUNX1-P1 promoter region. The African-specific rs2242780-C allele (r2 = 0.69 with the rs111457485-T allele in the study controls) showed increased enhancer activity in in-vitro Luciferase reporter assays (p = 4.5 × 10−10), nominating it as the likely functional variant for the BL-associated loci. In addition to the association with reduced BL risk in GWAS (OR = 0.62, p = 2.24 × 10−8), the rs2242780-C allele was also associated with better survival in patients with abdominal-only BL in exploratory analyses (hazard ratio = 0.39, p = 0.038, 106 patients, 59 deaths). Our GWAS uncovered novel BL-protective loci near RUNX1, offering insights into the genetic etiology of BL in African children.