HLA Class I and II Diversity Contributes to the Etiologic Heterogeneity of Non-Hodgkin Lymphoma Subtypes.
HLA Class I and II Diversity Contributes to the Etiologic Heterogeneity of Non-Hodgkin Lymphoma Subtypes.
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DOI：
10.1158/0008-5472.can-17-2900
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发表时间：
2018-07-15
期刊：
影响因子：
11.2
通讯作者：
Skibola CF
中科院分区：
文献类型：
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作者：
Wang SS;Carrington M;Berndt SI;Slager SL;Bracci PM;Voutsinas J;Cerhan JR;Smedby KE;Hjalgrim H;Vijai J;Morton LM;Vermeulen R;Paltiel O;Vajdic CM;Linet MS;Nieters A;de Sanjose S;Cozen W;Brown EE;Turner J;Spinelli JJ;Zheng T;Birmann BM;Flowers CR;Becker N;Holly EA;Kane E;Weisenburger D;Maynadie M;Cocco P;Albanes D;Weinstein SJ;Teras LR;Diver WR;Lax SJ;Travis RC;Kaaks R;Riboli E;Benavente Y;Brennan P;McKay J;Delfau-Larue MH;Link BK;Magnani C;Ennas MG;Latte G;Feldman AL;Doo NW;Giles GG;Southey MC;Milne RL;Offit K;Musinsky J;Arslan AA;Purdue MP;Adami HO;Melbye M;Glimelius B;Conde L;Camp NJ;Glenn M;Curtin K;Clavel J;Monnereau A;Cox DG;Ghesquières H;Salles G;Bofetta P;Foretova L;Staines A;Davis S;Severson RK;Lan Q;Brooks-Wilson A;Smith MT;Roman E;Kricker A;Zhang Y;Kraft P;Chanock SJ;Rothman N;Hartge P;Skibola CF
人类白细胞抗原（HLA）区域内越来越多的基因座与非霍奇金淋巴瘤（NHL）病因有关。在这里，我们测试一个互补的假设“杂合子优势”的作用，HLA和NHL，HLA多样性是有益的，纯合子HLA基因座与疾病风险增加。使用SNP 2 HLA从全基因组关联研究（GWAS）中估算I类和II类基因座的HLA等位基因：3，617例弥漫性大B细胞淋巴瘤（DLBCL），2，686例滤泡性淋巴瘤（FL），2，878例慢性淋巴细胞白血病/小淋巴细胞淋巴瘤（CLL/SLL），741例边缘区淋巴瘤（MZL）和8，753例欧洲血统对照。在HLA-B和-C Ⅰ类基因座（OR DLBCL=1.31，95%CI =1.06-1.60; OR MZL=1.45，95%CI =1.12-1.89）和HLA-DRB 1 Ⅱ类基因座（OR DLBCL=2.10，95%CI =1.24-3.55; OR MZL= 2.10，95%CI =0.99-4.45）纯合时，DLBCL和MZL风险均升高。随着纯合HLA II类基因座数量的总体增加，观察到FL风险增加（p趋势<0.0001，FDR=0.0005）。这些结果支持HLA接合性在NHL病因学中的作用，并表明不同的免疫途径可能是不同NHL亚型病因学的基础。
A growing number of loci within the human leukocyte antigen (HLA) region have been implicated in non-Hodgkin lymphoma (NHL) etiology. Here, we test a complementary hypothesis of “heterozygote advantage” regarding the role of HLA and NHL, whereby HLA diversity is beneficial and homozygous HLA loci are associated with increased disease risk. HLA alleles at class I and II loci were imputed from genome-wide association studies (GWAS) using SNP2HLA for: 3,617 diffuse large B-cell lymphomas (DLBCL), 2,686 follicular lymphomas (FL), 2,878 chronic lymphocytic leukemia/small lymphocytic lymphomas (CLL/SLL), 741 marginal zone lymphomas (MZL), and 8,753 controls of European descent. Both DLBCL and MZL risk were elevated with homozygosity at class I HLA-B and -C loci (OR DLBCL=1.31, 95% CI=1.06–1.60; OR MZL=1.45, 95% CI=1.12–1.89) and class II HLA-DRB1 locus (OR DLBCL=2.10, 95% CI=1.24–3.55; OR MZL= 2.10, 95% CI=0.99–4.45). Increased FL risk was observed with the overall increase in number of homozygous HLA class II loci (p-trend<0.0001, FDR=0.0005). These results support a role for HLA zygosity in NHL etiology and suggests that distinct immune pathways may underly the etiology of the different NHL subtypes.