GWAS of Follicular Lymphoma Reveals Allelic Heterogeneity at 6p21.32 and Suggests Shared Genetic Susceptibility with Diffuse Large B-cell Lymphoma

被引：80

作者：

Smedby, Karin E. ^{[1
]}

Foo, Jia Nee ^{[2
]}

Skibola, Christine F. ^{[3
]}

Darabi, Hatef ^{[4
]}

Conde, Lucia ^{[3
]}

Hjalgrim, Henrik ^{[5
]}

Kumar, Vikrant ^{[2
]}

Chang, Ellen T. ^{[6
,7
]}

Rothman, Nathaniel ^{[8
]}

Cerhan, James R. ^{[9
]}

Brooks-Wilson, Angela R. ^{[10
,11
]}

Rehnberg, Emil ^{[4
]}

Irwan, Ishak D. ^{[2
]}

Ryder, Lars P. ^{[12
]}

Brown, Peter N. ^{[13
]}

Bracci, Paige M. ^{[14
]}

Agana, Luz ^{[3
]}

Riby, Jacques ^{[3
]}

Cozen, Wendy ^{[15
]}

Davis, Scott ^{[16
,17
]}

Hartge, Patricia ^{[8
]}

Morton, Lindsay M. ^{[8
]}

Severson, Richard K. ^{[18
,19
]}

Wang, Sophia S. ^{[8
,20
,21
]}

Slager, Susan L. ^{[9
]}

Fredericksen, Zachary S. ^{[9
]}

Novak, Anne J. ^{[9
]}

Kay, Neil E. ^{[9
]}

Habermann, Thomas M. ^{[9
]}

Armstrong, Bruce ^{[22
]}

Kricker, Anne ^{[22
]}

Milliken, Sam ^{[23
]}

Purdue, Mark P. ^{[8
]}

Vajdic, Claire M. ^{[24
]}

Boyle, Peter ^{[25
]}

Lan, Qing ^{[8
]}

Zahm, Shelia H. ^{[8
]}

Zhang, Yawei ^{[26
]}

Zheng, Tongzhang ^{[26
]}

Leach, Stephen ^{[27
]}

Spinelli, John J. ^{[10
,28
]}

Smith, Martyn T. ^{[3
]}

Chanock, Stephen J. ^{[8
]}

Padyukov, Leonid ^{[29
,30
]}

Alfredsson, Lars ^{[31
]}

Klareskog, Lars ^{[29
,30
]}

Glimelius, Bengt ^{[32
,33
]}

Melbye, Mads ^{[5
]}

Liu, Edison T. ^{[2
]}

Adami, Hans-Olov ^{[4
,34
]}

机构：

[1] Karolinska Inst, Dept Med, Clin Epidemiol Unit, Stockholm, Sweden

[2] ASTAR, Genome Inst Singapore, Singapore, Singapore

[3] Univ Calif Berkeley, Sch Publ Hlth, Div Environm Hlth Sci, Berkeley, CA 94720 USA

[4] Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden

[5] Statens Serum Inst, Dept Epidemiol Res, DK-2300 Copenhagen, Denmark

[6] Canc Prevent Inst Calif, Fremont, CA USA

[7] Stanford Univ, Div Epidemiol, Dept Hlth Res & Policy, Sch Med, Stanford, CA 94305 USA

[8] NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA

[9] Mayo Clin, Coll Med, Rochester, MN USA

[10] British Columbia Canc Agcy, British Columbia Canc Res Ctr, Vancouver, BC V5Z 4E6, Canada

[11] Simon Fraser Univ, Dept Biomed Physiol & Kinesiol, Burnaby, BC V5A 1S6, Canada

[12] Univ Copenhagen Hosp, Dept Clin Immunol, DK-2100 Copenhagen, Denmark

[13] Univ Copenhagen Hosp, Dept Haematol, DK-2100 Copenhagen, Denmark

[14] Univ Calif San Francisco, Dept Epidemiol & Biostat, San Francisco, CA 94143 USA

[15] Univ So Calif, Keck Sch Med, Dept Prevent Med, Los Angeles, CA 90033 USA

[16] Fred Hutchinson Canc Res Ctr, Seattle, WA 98104 USA

[17] Univ Washington, Seattle, WA 98195 USA

[18] Wayne State Univ, Dept Family Med & Publ Hlth Sci, Detroit, MI USA

[19] Karmanos Canc Inst, Detroit, MI USA

[20] Beckman Res Inst, Div Etiol, Duarte, CA USA

[21] City Hope Natl Med Ctr, Duarte, CA USA

[22] Univ Sydney, Sydney Sch Publ Hlth, Sydney, NSW 2006, Australia

[23] St Vincents Hosp, Dept Haematol, Sydney, NSW 2010, Australia

[24] Univ New S Wales, Canc Res Ctr, Prince Wales Clin Sch, Sydney, NSW, Australia

[25] Int Prevent Res Inst, Lyon, France

[26] Yale Univ, Sch Publ Hlth, New Haven, CT USA

[27] British Columbia Canc Agcy, Canadas Michael Smith Genome Sci Ctr, Vancouver, BC V5Z 4E6, Canada

[28] Univ British Columbia, Sch Populat & Publ Hlth, Vancouver, BC V5Z 1M9, Canada

[29] Karolinska Inst, Rheumatol Unit, Dept Med, Stockholm, Sweden

[30] Karolinska Univ Hosp Solna, Stockholm, Sweden

[31] Karolinska Inst, Inst Environm Med, S-10401 Stockholm, Sweden

[32] Karolinska Inst, Dept Pathol & Oncol, S-10401 Stockholm, Sweden

[33] Uppsala Univ, Dept Radiol Oncol & Radiat Sci, Uppsala, Sweden

[34] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA

来源：

PLOS GENETICS | 2011年 / 7卷 / 04期

基金：

美国国家卫生研究院; 英国医学研究理事会; 加拿大健康研究院; 瑞典研究理事会;

关键词：

NON-HODGKIN-LYMPHOMA; GENOME-WIDE ASSOCIATION; NECROSIS-FACTOR TNF; RHEUMATOID-ARTHRITIS; INTERLYMPH-CONSORTIUM; STATISTICAL-METHOD; RISK LOCUS; CANCER; HAPLOTYPE; HLA;

D O I：

10.1371/journal.pgen.1001378

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

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 (OR(combined) = 0.64, P(combined)= 2x10(-21)) located 962 bp away from rs10484561 (r(2)< 0.1 in controls). After mutual adjustment, the associations at the two SNPs remained genome-wide significant (rs2647012: OR(adjusted) = 0.70, P(adjusted)= 4x10(-12); rs10484561: OR(adjusted) = 1.64, P(adjusted)= 5x10(-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 (OR(combined) = 1.36, P(combined) = 1.4x10(-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.

引用

页数：11

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