Fine mapping seronegative and seropositive rheumatoid arthritis to shared and distinct HLA alleles by adjusting for the effects of heterogeneity.,American Journal of Human Genetics

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Fine mapping seronegative and seropositive rheumatoid arthritis to shared and distinct HLA alleles by adjusting for the effects of heterogeneity.
American Journal of Human Genetics ( IF 8.1 ) Pub Date : 2014-03-20 , DOI: 10.1016/j.ajhg.2014.02.013
Buhm Han ₁ , Dorothée Diogo ₂ , Steve Eyre ₃ , Henrik Kallberg ₄ , Alexandra Zhernakova ₅ , John Bowes ₃ , Leonid Padyukov ₄ , Yukinori Okada ₂ , Miguel A González-Gay ₆ , Solbritt Rantapää-Dahlqvist ₇ , Javier Martin ₈ , Tom W J Huizinga ₉ , Robert M Plenge ₁₀ , Jane Worthington ₃ , Peter K Gregersen ₁₁ , Lars Klareskog ₄ , Paul I W de Bakker ₁₂ , Soumya Raychaudhuri ₁₃

Affiliation

Division of Genetics, Brigham & Women's Hospital and Harvard Medical School, Boston, MA 02115, USA; Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA; Partners HealthCare Center for Personalized Genetic Medicine, Boston, MA 02115, USA.
Division of Genetics, Brigham & Women's Hospital and Harvard Medical School, Boston, MA 02115, USA; Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA; Partners HealthCare Center for Personalized Genetic Medicine, Boston, MA 02115, USA; Division of Rheumatology, Immunology, and Allergy, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, 02115, USA.
Arthritis Research UK Epidemiology Unit, Musculoskeletal Research Group, University of Manchester, Manchester Academic Health Sciences Centre, Manchester M13 9PT, UK; NIHR Manchester Musculoskeletal Biomedical Research Unit, Central Manchester University Hospitals NHS Foundation Trust, Manchester Academic Health Sciences Centre, Manchester M13 9PT, UK.
Rheumatology Unit, Department of Medicine, Karolinska Institutet and Karolinska University Hospital Solna, 171 76 Stockholm, Sweden.
Department of Rheumatology, Leiden University Medical Centre, 2300 RC Leiden, the Netherlands; Department of Genetics, University Medical Center Groningen and University of Groningen, 9700 RB Groningen, the Netherlands.
Rheumatology Division, Hospital Universitario Marqués de Valdecilla, Instituto de Formación e Investigación Marqués de Valdecilla, 39008 Santander, Spain.
Department of Public Health and Clinical Medicine and Department of Rheumatology, Umeå University, 901 85 Umeå, Sweden.
Instituto de Parasitologia y Biomedicina Lopez-Neyra, Consejo Superior de Investigaciones Cientificas, 18100 Armilla, Granada, Spain.
Department of Rheumatology, Leiden University Medical Centre, 2300 RC Leiden, the Netherlands.
Merck Research Laboratories, Merck & Co. Inc., Boston, MA 02115, USA.
The Feinstein Institute for Medical Research, North Shore-Long Island Jewish Health System, Manhasset, NY 11030, USA.
Division of Genetics, Brigham & Women's Hospital and Harvard Medical School, Boston, MA 02115, USA; Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA; Departments of Epidemiology and Medical Genetics, University Medical Center Utrecht, 3584 CG Utrecht, the Netherlands.
Division of Genetics, Brigham & Women's Hospital and Harvard Medical School, Boston, MA 02115, USA; Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA; Partners HealthCare Center for Personalized Genetic Medicine, Boston, MA 02115, USA; Division of Rheumatology, Immunology, and Allergy, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, 02115, USA; Arthritis Research UK Epidemiology Unit, Musculoskeletal Research Group, University of Manchester, Manchester Academic Health Sciences Centre, Manchester M13 9PT, UK.

Despite progress in defining human leukocyte antigen (HLA) alleles for anti-citrullinated-protein-autoantibody-positive (ACPA(+)) rheumatoid arthritis (RA), identifying HLA alleles for ACPA-negative (ACPA(-)) RA has been challenging because of clinical heterogeneity within clinical cohorts. We imputed 8,961 classical HLA alleles, amino acids, and SNPs from Immunochip data in a discovery set of 2,406 ACPA(-) RA case and 13,930 control individuals. We developed a statistical approach to identify and adjust for clinical heterogeneity within ACPA(-) RA and observed independent associations for serine and leucine at position 11 in HLA-DRβ1 (p = 1.4 × 10(-13), odds ratio [OR] = 1.30) and for aspartate at position 9 in HLA-B (p = 2.7 × 10(-12), OR = 1.39) within the peptide binding grooves. These amino acid positions induced associations at HLA-DRB1(∗)03 (encoding serine at 11) and HLA-B(∗)08 (encoding aspartate at 9). We validated these findings in an independent set of 427 ACPA(-) case subjects, carefully phenotyped with a highly sensitive ACPA assay, and 1,691 control subjects (HLA-DRβ1 Ser11+Leu11: p = 5.8 × 10(-4), OR = 1.28; HLA-B Asp9: p = 2.6 × 10(-3), OR = 1.34). Although both amino acid sites drove risk of ACPA(+) and ACPA(-) disease, the effects of individual residues at HLA-DRβ1 position 11 were distinct (p < 2.9 × 10(-107)). We also identified an association with ACPA(+) RA at HLA-A position 77 (p = 2.7 × 10(-8), OR = 0.85) in 7,279 ACPA(+) RA case and 15,870 control subjects. These results contribute to mounting evidence that ACPA(+) and ACPA(-) RA are genetically distinct and potentially have separate autoantigens contributing to pathogenesis. We expect that our approach might have broad applications in analyzing clinical conditions with heterogeneity at both major histocompatibility complex (MHC) and non-MHC regions.

中文翻译：

通过调整异质性的影响，将血清阴性和血清阳性类风湿关节炎精细映射到共享和不同的 HLA 等位基因。

尽管在定义抗瓜氨酸蛋白自身抗体阳性 (ACPA(+)) 类风湿性关节炎 (RA) 的人类白细胞抗原 (HLA) 等位基因方面取得了进展，但识别 ACPA 阴性 (ACPA(-)) RA 的 HLA 等位基因一直具有挑战性由于临床队列中的临床异质性。我们在 2,406 个 ACPA(-) RA 病例和 13,930 个对照个体的发现集中从免疫芯片数据中估算了 8,961 个经典 HLA 等位基因、氨基酸和 SNP。我们开发了一种统计方法来识别和调整 ACPA(-) RA 内的临床异质性，并观察到 HLA-DRβ1 中第 11 位丝氨酸和亮氨酸的独立关联 (p = 1.4 × 10(-13)，优势比 [OR] = 1.30) 和 HLA-B 中第 9 位的天冬氨酸 (p = 2.7 × 10(-12), OR = 1.39) 在肽结合槽内。这些氨基酸位置在 HLA-DRB1(*)03（在 11 处编码丝氨酸）和 HLA-B(*)08（在 9 处编码天冬氨酸）诱导关联。我们在一组独立的 427 名 ACPA(-) 病例受试者中验证了这些发现，这些受试者使用高度敏感的 ACPA 分析仔细表型，以及 1,691 名对照受试者 (HLA-DRβ1 Ser11+Leu11: p = 5.8 × 10(-4), OR = 1.28；HLA-B Asp9：p = 2.6 × 10(-3)，OR = 1.34)。尽管这两个氨基酸位点都增加了 ACPA(+) 和 ACPA(-) 疾病的风险，但 HLA-DRβ1 第 11 位的单个残基的影响是不同的 (p < 2.9 × 10(-107))。我们还在 7,279 名 ACPA(+) RA 病例和 15,870 名对照受试者中发现了与 HLA-A 位置 77 (p = 2.7 × 10(-8), OR = 0.85) 的 ACPA(+) RA 的关联。这些结果有助于越来越多的证据表明 ACPA(+) 和 ACPA(-) RA 在遗传上是不同的，并且可能具有导致发病机制的不同自身抗原。我们预计我们的方法可能在分析主要组织相容性复合体 (MHC) 和非 MHC 区域的异质性临床状况方面具有广泛的应用。

更新日期：2019-11-01

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