GWAS of follicular lymphoma reveals allelic heterogeneity at 6p21.32 and suggests shared genetic susceptibility with diffuse large B-cell lymphoma.
GWAS of follicular lymphoma reveals allelic heterogeneity at 6p21.32 and suggests shared genetic susceptibility with diffuse large B-cell lymphoma.
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DOI：
10.1371/journal.pgen.1001378
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发表时间：
2011-04
期刊：
影响因子：
4.5
通讯作者：
Liu J
中科院分区：
文献类型：
--
作者：
Smedby KE;Foo JN;Skibola CF;Darabi H;Conde L;Hjalgrim H;Kumar V;Chang ET;Rothman N;Cerhan JR;Brooks-Wilson AR;Rehnberg E;Irwan ID;Ryder LP;Brown PN;Bracci PM;Agana L;Riby J;Cozen W;Davis S;Hartge P;Morton LM;Severson RK;Wang SS;Slager SL;Fredericksen ZS;Novak AJ;Kay NE;Habermann TM;Armstrong B;Kricker A;Milliken S;Purdue MP;Vajdic CM;Boyle P;Lan Q;Zahm SH;Zhang Y;Zheng T;Leach S;Spinelli JJ;Smith MT;Chanock SJ;Padyukov L;Alfredsson L;Klareskog L;Glimelius B;Melbye M;Liu ET;Adami HO;Humphreys K;Liu J
非霍奇金淋巴瘤（NHL）代表了一组不同的血液恶性肿瘤，其中滤泡性淋巴瘤（FL）是一种流行的亚型。先前的全基因组关联研究已经建立了一个标记，rs 10484561在6p21.32上的人类白细胞抗原（HLA）II类区域与FL风险增加相关。在这里，在一项三阶段全基因组关联研究中，从379例FL病例和791例对照的全基因组扫描开始，然后在1，049例病例和5，790例对照中进行验证，我们在6p21.32上确定了第二个独立的FL相关基因座rs 2647012（OR组合= 0.64，P组合= 2×10−21），位于rs 10484561（对照中r2<0.1）的962 bp处。 在相互调整后，两个SNP的关联仍然具有全基因组显著性（rs 2647012：OR调整= 0.70，P调整= 4×10−12; rs 10484561：OR调整= 1.64，P调整= 5×10−15）。 单倍型和聚结分析表明，rs 2647012出现在一个进化上不同的单倍型从rs 10484561和标签一个新的等位基因与FL风险的相反（保护）的影响。此外，在对4,449例其他NHL亚型病例中前6位FL相关SNP的随访分析中，rs 10484561与弥漫性大B细胞淋巴瘤的风险相关（OR组合= 1.36，P组合= 1.4×10−7）。 我们的研究结果揭示了影响FL易感性的HLA II类区域内等位基因异质性的存在，并表明弥漫性大B细胞淋巴瘤可能具有共同的遗传病因。这些研究结果表明，HLA II类区域在NHL中起着复杂而重要的作用。早期的研究已经在6p21.32的HLA II类区域建立了标记rs 10484561，与滤泡性淋巴瘤（FL）风险增加相关。在对1，428例FL病例和6，581例对照进行的三阶段全基因组关联研究中，我们在6p21.32上确定了第二个独立的FL相关标记rs 2647012，距离rs 10484561 962 bp。在相互调整后，两个SNPs的关联仍然在全基因组范围内显着。单倍型和聚结分析表明，rs 2647012出现在一个进化上不同的血统，从rs 10484561和标签一个新的等位基因与FL风险的相反，保护作用。此外，在对4,449例其他NHL亚型病例中前6位FL相关SNP的分析中，rs 10484561与弥漫性大B细胞淋巴瘤的风险相关。我们的研究结果揭示了FL风险中6p21.32等位基因异质性的存在，并表明与常见的弥漫性大B细胞淋巴瘤亚型有共同的遗传病因。
Non-Hodgkin lymphoma (NHL) represents a diverse group of hematological malignancies, of which follicular lymphoma (FL) is a prevalent subtype. A previous genome-wide association study has established a marker, rs10484561 in the human leukocyte antigen (HLA) class II region on 6p21.32 associated with increased FL risk. Here, in a three-stage genome-wide association study, starting with a genome-wide scan of 379 FL cases and 791 controls followed by validation in 1,049 cases and 5,790 controls, we identified a second independent FL–associated locus on 6p21.32, rs2647012 (ORcombined = 0.64, Pcombined = 2×10−21) located 962 bp away from rs10484561 (r2<0.1 in controls). After mutual adjustment, the associations at the two SNPs remained genome-wide significant (rs2647012:ORadjusted = 0.70, Padjusted = 4×10−12; rs10484561:ORadjusted = 1.64, Padjusted = 5×10−15). Haplotype and coalescence analyses indicated that rs2647012 arose on an evolutionarily distinct haplotype from that of rs10484561 and tags a novel allele with an opposite (protective) effect on FL risk. Moreover, in a follow-up analysis of the top 6 FL–associated SNPs in 4,449 cases of other NHL subtypes, rs10484561 was associated with risk of diffuse large B-cell lymphoma (ORcombined = 1.36, Pcombined = 1.4×10−7). Our results reveal the presence of allelic heterogeneity within the HLA class II region influencing FL susceptibility and indicate a possible shared genetic etiology with diffuse large B-cell lymphoma. These findings suggest that the HLA class II region plays a complex yet important role in NHL. Earlier studies have established a marker rs10484561, in the HLA class II region on 6p21.32, associated with increased follicular lymphoma (FL) risk. Here, in a three-stage genome-wide association study of 1,428 FL cases and 6,581 controls, we identified a second independent FL–associated marker on 6p21.32, rs2647012, located 962 bp away from rs10484561. The associations at two SNPs remained genome-wide significant after mutual adjustment. Haplotype and coalescence analyses indicated that rs2647012 arose on an evolutionarily distinct lineage from that of rs10484561 and tags a novel allele with an opposite, protective effect on FL risk. Moreover, in an analysis of the top 6 FL–associated SNPs in 4,449 cases of other NHL subtypes, rs10484561 was associated with risk of diffuse large B-cell lymphoma. Our results reveal the presence of allelic heterogeneity at 6p21.32 in FL risk and suggest a shared genetic etiology with the common diffuse large B-cell lymphoma subtype.
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