全基因组纯合性与四种非霍奇金淋巴瘤亚型的风险

Genome-wide homozygosity and risk of four non-Hodgkin lymphoma subtypes.

作者信息

Moore Amy, Machiela Mitchell J, Machado Moara, Wang Sophia S, Kane Eleanor, Slager Susan L, Zhou Weiyin, Carrington Mary, Lan Qing, Milne Roger L, Birmann Brenda M, Adami Hans-Olov, Albanes Demetrius, Arslan Alan A, Becker Nikolaus, Benavente Yolanda, Bisanzi Simonetta, Boffetta Paolo, Bracci Paige M, Brennan Paul, Brooks-Wilson Angela R, Canzian Federico, Caporaso Neil, Clavel Jacqueline, Cocco Pierluigi, Conde Lucia, Cox David G, Cozen Wendy, Curtin Karen, De Vivo Immaculata, de Sanjose Silvia, Foretova Lenka, Gapstur Susan M, Ghesquières Hervè, Giles Graham G, Glenn Martha, Glimelius Bengt, Gao Chi, Habermann Thomas M, Hjalgrim Henrik, Jackson Rebecca D, Liebow Mark, Link Brian K, Maynadie Marc, McKay James, Melbye Mads, Miligi Lucia, Molina Thierry J, Monnereau Alain, Nieters Alexandra, North Kari E, Offit Kenneth, Patel Alpa V, Piro Sara, Ravichandran Vignesh, Riboli Elio, Salles Gilles, Severson Richard K, Skibola Christine F, Smedby Karin E, Southey Melissa C, Spinelli John J, Staines Anthony, Stewart Carolyn, Teras Lauren R, Tinker Lesley F, Travis Ruth C, Vajdic Claire M, Vermeulen Roel C H, Vijai Joseph, Weiderpass Elisabete, Weinstein Stephanie, Doo Nicole Wong, Zhang Yawei, Zheng Tongzhang, Chanock Stephen J, Rothman Nathaniel, Cerhan James R, Dean Michael, Camp Nicola J, Yeager Meredith, Berndt Sonja I

机构信息

Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD 20892, USA.

Departamento de Biologia Geral, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte 31270-901, Brazil.

出版信息

J Transl Genet Genom. 2021;5:200-217. doi: 10.20517/jtgg.2021.08. Epub 2021 Jun 17.

DOI:10.20517/jtgg.2021.08

PMID:34622145

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC8494431/

Abstract

AIM

Recessive genetic variation is thought to play a role in non-Hodgkin lymphoma (NHL) etiology. Runs of homozygosity (ROH), defined based on long, continuous segments of homozygous SNPs, can be used to estimate both measured and unmeasured recessive genetic variation. We sought to examine genome-wide homozygosity and NHL risk.

METHODS

We used data from eight genome-wide association studies of four common NHL subtypes: 3061 chronic lymphocytic leukemia (CLL), 3814 diffuse large B-cell lymphoma (DLBCL), 2784 follicular lymphoma (FL), and 808 marginal zone lymphoma (MZL) cases, as well as 9374 controls. We examined the effect of homozygous variation on risk by: (1) estimating the fraction of the autosome containing runs of homozygosity (FROH); (2) calculating an inbreeding coefficient derived from the correlation among uniting gametes (F3); and (3) examining specific autosomal regions containing ROH. For each, we calculated beta coefficients and standard errors using logistic regression and combined estimates across studies using random-effects meta-analysis.

RESULTS

We discovered positive associations between FROH and CLL (β = 21.1, SE = 4.41, = 1.6 × 10) and FL (β = 11.4, SE = 5.82, = 0.02) but not DLBCL ( = 1.0) or MZL ( = 0.91). For F3, we observed an association with CLL (β = 27.5, SE = 6.51, = 2.4 × 10). We did not find evidence of associations with specific ROH, suggesting that the associations observed with FROH and F3 for CLL and FL risk were not driven by a single region of homozygosity.

CONCLUSION

Our findings support the role of recessive genetic variation in the etiology of CLL and FL; additional research is needed to identify the specific loci associated with NHL risk.

摘要

目的

隐性基因变异被认为在非霍奇金淋巴瘤（NHL）病因中起作用。基于纯合单核苷酸多态性（SNP）的长连续片段定义的纯合性片段（ROH），可用于估计已测和未测的隐性基因变异。我们试图研究全基因组纯合性与NHL风险。

方法

我们使用了来自四项常见NHL亚型的八项全基因组关联研究的数据：3061例慢性淋巴细胞白血病（CLL）、3814例弥漫性大B细胞淋巴瘤（DLBCL）、2784例滤泡性淋巴瘤（FL）和808例边缘区淋巴瘤（MZL）病例，以及9374例对照。我们通过以下方式研究纯合变异对风险的影响：（1）估计包含纯合性片段的常染色体比例（FROH）；（2）计算源自结合配子间相关性的近交系数（F3）；（3）检查包含ROH的特定常染色体区域。对于每项，我们使用逻辑回归计算β系数和标准误，并使用随机效应荟萃分析合并各研究的估计值。

结果

我们发现FROH与CLL（β = 21.1，SE = 4.41，P = 1.6 × 10）和FL（β = 11.4，SE = 5.82，P = 0.02）之间存在正相关，但与DLBCL（P = 1.0）或MZL（P = 0.91）无关。对于F3，我们观察到与CLL存在关联（β = 27.5，SE = 6.51，P = 2.4 × 10）。我们未发现与特定ROH存在关联的证据，这表明观察到的FROH和F3与CLL和FL风险的关联并非由单个纯合区域驱动。