Department of Neurology, University of California, San Francisco, CA, United States of America.
Université de Nantes, CHU Nantes, Inserm, Centre de Recherche en Transplantation et Immunologie, UMR 1064, ITUN, Nantes, France.
PLoS One. 2021 Aug 9;16(8):e0254945. doi: 10.1371/journal.pone.0254945. eCollection 2021.
To explore the nature of genetic-susceptibility to multiple sclerosis (MS) in African-Americans.
Recently, the number of genetic-associations with MS has exploded although the MS-associations of specific haplotypes within the major histocompatibility complex (MHC) have been known for decades. For example, the haplotypes HLA-DRB115:01~HLA-DQB106:02, and HLA-DRB103:01~ HLA-DQB102:01 have odds ratios (ORs) for an MS-association orders of magnitude stronger than many of these newly-discovered associations. Nevertheless, all these haplotypes are part of much larger conserved extended haplotypes (CEHs), which span both the Class I and Class II MHC regions. African-Americans are at greater risk of developing MS compared to a native Africans but at lesser risk compared to Europeans. It is the purpose of this manuscript to explore the relationship between MS-susceptibility and the CEH make-up of our African-American cohort.
DESIGN/METHODS: The African-American (AA) cohort consisted of 1,305 patients with MS and 1,155 controls, who self-identified as being African-American. For comparison, we used the 18,492 controls and 11,144 MS-cases from the predominantly European Wellcome Trust Case Control Consortium (WTCCC) and the 28,557 phased native Africans from the multinational "Be the Match" registry. The WTCCC and the African-Americans were phased at each of five HLA loci (HLA-A, HLA-C, HLA-B, HLA-DRB1 and HLA-DQB1) and the at 11 SNPs (10 of which were in non-coding regions) surrounding the Class II region of the DRB1 gene using previously-published probabilistic phasing algorithms.
Of the 32 most frequent CEHs, 18 (56%) occurred either more frequently or exclusively in Africans) whereas 9 (28%) occurred more frequently or exclusively in Europeans. The remaining 5 CEHs occurred in neither control group although, likely, these were African in origin. Eight of these CEHs carried the DRB115:03~DQB106:02a36 haplotype and three carried the DRB1*15:01DQB1*06:02~a1 haplotype. In African Americans, a single-copy of the European CEH (03:01_07:02_07:02_15:01_06:02_a1) was associated with considerable MS-risk (OR = 3.30; p = 0.0001)-similar to that observed in the WTCCC (OR = 3.25; p<10-168). By contrast, the MS-risk for the European CEH (02:01_07:02_07:02_15:01_06:02_a1) was less (OR = 1.49; ns)-again, similar to the WTCCC (OR = 2.2; p<10-38). Moreover, four African haplotypes were "protective" relative to a neutral reference, to three European CEHs, and also to the five other African CEHs.
The common CEHs in African Americans are divisible into those that are either African or European in origin, which are derived without modification from their source population. European CEHs, linked to MS-risk, in general, had similar impacts in African-Americans as they did in Europeans. By contrast, African CEHs had mixed MS-risks. For a few, the MS-risk exceeded that in a neutral-reference group whereas, for many others, these CEHs were "protective"-perhaps providing a partial rationale for the lower MS-risk in African-Americans compared to European-Americans.
探索非洲裔美国人多发性硬化症（MS）遗传易感性的本质。
尽管几十年来一直知道主要组织相容性复合体（MHC）内特定单倍型与 MS 的关联，但最近与 MS 相关的遗传关联数量呈爆炸式增长。例如，HLA-DRB115:01~HLA-DQB106:02 和 HLA-DRB103:01~HLA-DQB102:01 等单倍型与 MS 关联的优势比（OR）比许多新发现的关联要大几个数量级。然而，所有这些单倍型都属于更大的保守扩展单倍型（CEH），跨越了 I 类和 II 类 MHC 区域。与非洲本土人相比，非洲裔美国人患 MS 的风险更高，但与欧洲人相比，患病风险较低。本文的目的是探讨 MS 易感性与我们的非洲裔美国人队列的 CEH 组成之间的关系。
非洲裔美国人（AA）队列由 1305 名 MS 患者和 1155 名对照组成，他们自认为是非洲裔美国人。为了进行比较，我们使用了来自主要是欧洲的惠康信托基金会病例对照联盟（WTCCC）的 18492 名对照和 11144 名 MS 病例，以及来自跨国“成为匹配”登记处的 28557 名相分化的非洲人。WTCCC 和非洲裔美国人在五个 HLA 基因座（HLA-A、HLA-C、HLA-B、HLA-DRB1 和 HLA-DQB1）和 DRB1 基因周围的 11 个 SNP（其中 10 个位于非编码区）上进行了相位化，使用先前发表的概率相位化算法。
在 32 个最常见的 CEH 中，有 18 个（56%）发生在非洲人中更为频繁或排他性地发生，而 9 个（28%）发生在欧洲人中更为频繁或排他性地发生。其余 5 个 CEH 既没有出现在对照组中，尽管这些 CEH 可能是非洲起源的。其中 8 个 CEH 携带 DRB115:03~DQB106:02a36 单倍型，3 个携带 DRB1*15:01DQB1*06:02~a1 单倍型。在非洲裔美国人中，一个欧洲 CEH（03:01_07:02_07:02_15:01_06:02_a1）的单拷贝与相当大的 MS 风险相关（OR = 3.30；p = 0.0001）-与 WTCCC 观察到的相似（OR = 3.25；p<10-168）。相比之下，欧洲 CEH（02:01_07:02_07:02_15:01_06:02_a1）的 MS 风险较低（OR = 1.49；ns）-再次与 WTCCC 相似（OR = 2.2；p<10-38）。此外，与中性参考、三个欧洲 CEH 和另外五个非洲 CEH 相比，有四个非洲单倍型是“保护性”的。
非洲裔美国人的常见 CEH 可分为源自非洲或欧洲的单倍型，这些单倍型是从其源人群体中未经修饰而产生的。一般来说，与 MS 风险相关的欧洲 CEH 在非洲裔美国人中的影响与在欧洲人相似。相比之下，非洲 CEH 具有混合的 MS 风险。对于一些 CEH，MS 风险超过中性参考组，而对于许多其他 CEH，则具有“保护”作用-这也许为非洲裔美国人比欧洲裔美国人 MS 风险较低提供了部分理由。
