Genome-wide Association Study Identifies HLA-DPB1 as a Significant Risk Factor for Severe Aplastic Anemia

被引：25

作者：

Savage, Sharon A. ^{[1
]}

Viard, Mathias ^{[2
]}

O'hUigin, Colm ^{[2
,3
]}

Zhou, Weiyin ^{[3
,4
]}

Yeager, Meredith ^{[3
,4
]}

Li, Shengchao Alfred ^{[3
,4
]}

Wang, Tao ^{[5
,6
]}

Ramsuran, Veron ^{[7
]}

Vince, Nicolas ^{[8
]}

Vogt, Aurelie ^{[3
,4
]}

Hicks, Belynda ^{[2
,4
]}

Burdett, Laurie ^{[3
,4
]}

Chung, Charles ^{[2
,4
]}

Dean, Michael ^{[1
]}

de Andrade, Kelvin C. ^{[1
]}

Freedman, Neal D. ^{[1
]}

Berndt, Sonja, I ^{[1
]}

Rothman, Nathaniel ^{[1
]}

Lan, Qing ^{[1
]}

Cerhan, James R. ^{[9
]}

Slager, Susan L. ^{[9
]}

Zhang, Yawei ^{[10
]}

Teras, Lauren R. ^{[11
]}

Haagenson, Michael ^{[6
]}

Chanock, Stephen J. ^{[1
]}

Spellman, Stephen R. ^{[5
,6
]}

Wang, Youjin ^{[1
]}

Willis, Amanda ^{[12
]}

Askar, Medhat ^{[12
]}

Lee, Stephanie J. ^{[5
,13
]}

Carrington, Mary ^{[2
,14
,15
]}

Gadalla, Shahinaz M. ^{[1
]}

机构：

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

[2] Frederick Natl Lab Canc Res, Basic Sci Program, Frederick, MD 21702 USA

[3] Leidos Biomed Res Inc, Frederick Natl Lab Canc Res, Frederick, MD 21702 USA

[4] NCI, Canc Genom Res Lab, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA

[5] Med Coll Wisconsin, Ctr Int Blood & Marrow Transplant Res, Milwaukee, WI 53226 USA

[6] Med Coll Wisconsin, Div Biostat, Milwaukee, WI 53226 USA

[7] Univ KwaZulu Natal, Sch Lab Med & Med Sci, KwaZulu Natal Res Innovat & Sequencing Platform K, Durban, South Africa

[8] Univ Nantes, Ctr Rech Transplantat & Immunol, ITUN, CHU Nantes,INSERM,UMR 1064, F-44000 Nantes, France

[9] Mayo Clin, Dept Hlth Sci Res, Rochester, MN 55902 USA

[10] Yale Med Sch, Dept Surg, Sect Surg Outcomes & Epidemiol, New Haven, CT 06520 USA

[11] Amer Canc Soc, Behav & Epidemiol Res Grp, Atlanta, GA 30303 USA

[12] Baylor Univ, Dept Pathol & Lab Med, Med Ctr, Dallas, TX 76798 USA

[13] Fred Hutchinson Canc Res Ctr, Clin Res Div, Seattle, WA 98109 USA

[14] MIT, Massachusetts Gen Hosp, Ragon Inst, 77 Massachusetts Ave, Cambridge, MA 02139 USA

[15] Harvard Univ, Cambridge, MA 02139 USA

来源：

AMERICAN JOURNAL OF HUMAN GENETICS | 2020年 / 106卷 / 02期

基金：

美国国家卫生研究院; 英国医学研究理事会;

关键词：

HLA-DP EXPRESSION; GENETIC-VARIATION; HEPATITIS-B; PDCD1; GENE; POLYMORPHISMS; VARIANTS; ALLELES; DISEASE; LOCI;

D O I：

10.1016/j.ajhg.2020.01.004

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

Severe aplastic anemia (SAA) is a rare disorder characterized by hypoplastic bone marrow and progressive pancytopenia. The etiology of acquired SAA is not understood but is likely related to abnormal immune responses and environmental exposures. We conducted a genome-wide association study of individuals with SAA genetically matched to healthy controls in discovery (359 cases, 1,396 controls) and validation sets (175 cases, 1,059 controls). Combined analyses identified linked SNPs in distinct blocks within the major histocompatibility complex on 6p21. The top SNP encodes p.Met76Val in the P4 binding pocket of the HLA class II gene HLA-DPB1 (rs1042151A>G, odds ratio [OR] 1.75, 95% confidence interval [CI] 1.50-2.03, p = 1.94 x 3 10(-13)) and was associated with HLA-DP cell surface expression in healthy individuals (p = 2.04x10(-6)). Phylogenetic analyses indicate that Val76 is not monophyletic and likely occurs in conjunction with different HLA-DP binding groove conformations. Imputation of HLA-DPB1 alleles revealed increased risk of SAA associated with Val76-encoding alleles DPB1*03:01, (OR 1.66, p = 1.52x10(-7)), DPB1*10:01 (OR 2.12, p = 0.0003), and DPB1*01:01 (OR 1.60, p = 0.0008). A second SNP near HLA-B, rs28367832G>A, reached genome-wide significance (OR 1.49, 95% CI 1.22-1.78, p = 7.27 x 10(-9)) in combined analyses; the association remained significant after excluding cases with clonal copy-neutral loss-of-heterozygosity affecting class I HLA genes (8.6% of cases and 0% of controls). SNPs in the HLA class II gene HLA-DPB1 and possibly class I (HLA-B) are associated with SAA. The replacement of Met76 to Val76 in certain HLA-DPB1 alleles might influence risk of SAA through mechanisms involving DP peptide binding specificity, expression, and/or other factors affecting DP function.

引用

页码：264 / 271

页数：8

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