Exome Sequencing Reveals a Putative Role for HLA-C*03:02 in Control of HIV-1 in African Pediatric Populations.
Exome Sequencing Reveals a Putative Role for HLA-C*03:02 in Control of HIV-1 in African Pediatric Populations.
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DOI：
10.3389/fgene.2021.720213
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发表时间：
2021
影响因子：
3.7
通讯作者：
Hanchard NA
中科院分区：
文献类型：
--
作者：
Kyobe S;Mwesigwa S;Kisitu GP;Farirai J;Katagirya E;Mirembe AN;Ketumile L;Wayengera M;Katabazi FA;Kigozi E;Wampande EM;Retshabile G;Mlotshwa BC;Williams L;Morapedi K;Kasvosve I;Kyosiimire-Lugemwa J;Nsangi B;Tsimako-Johnstone M;Brown CW;Joloba M;Anabwani G;Bhekumusa L;Mpoloka SW;Mardon G;Matshaba M;Kekitiinwa A;Hanchard NA
人类白细胞抗原（HLA）I类分子将内源性加工的抗原呈递给T细胞，并与HIV-1疾病进展的差异有关。HLA等位基因型显示出相当大的地理和个体间差异，HIV-1疾病的进展速度也是如此，其中疾病的长期非进展（LTNP）具有潜在遗传贡献的大多数证据。然而，大多数LTNP的遗传分析都发生在欧洲血统的成年人中，限制了观察到的相关性对携带疾病负担的不同人群的潜在转移性。这对感染HIV-1的儿童来说尤其如此。在这里，使用外显子组测序（ES）来推断HLA等位基因型，我们确定与HIV-1 LTNP在两个不同的非洲儿科人群。我们对乌干达和博茨瓦纳的394名LTNP和420名快速进展者进行了病例对照关联研究，这些患者是从儿童HIV-1人群的电子病历中回顾性确定的。我们利用高深度ES进行高分辨率HLA等位基因分型，并评估HLA I类等位基因和LTNP之间的关联证据。16个HLA等位基因和单倍型有显着不同的频率在乌干达和博茨瓦纳之间，与等位基因的差异更为突出的HLA-A相比，HLA-B和C等位基因型。3种HLA等位基因型与LTNP相关，其中HLA C等位基因型与LTNP相关（HLA B等位基因57：03，aOR 3.21，Pc = 0.0259; B等位基因58：01，aOR 1.89，Pc = 0.033; C等位基因03：02，aOR 4.74，Pc = 0.033）。总之，这些等位基因传达了16.5%的非进展的估计人群归因风险（PAR）。我们还观察到HLA-B等位基因57：03-C等位基因07：01（aOR 5.40，Pc = 0.025）和HLA-B等位基因58：01-C等位基因03：02（aOR 4.88，Pc = 0.011）与PAR 9.8%的新单倍型关联，以及HLA-C等位基因03：02与B等位基因58：01（aOR 4.15，Pc = 0.005）的先前未报道的独立加性效应和杂合子优势，这似乎限制了疾病进展，尽管这些等位基因之间的LD较弱（r2 = 0.18）。这些协会仍然不分性别或国家。在非洲最大的HIV研究之一中，我们发现了典型HLA-B等位基因和一种新的HLA-C关联的保护作用的证据，这种关联似乎增加了儿科人群中现有的HIV-1控制等位基因。我们的研究结果概述了在遗传学研究中使用多种族人群的价值，并提供了一种与正在进行的疫苗研究相关的新的HIV-1关联。
Human leucocyte antigen (HLA) class I molecules present endogenously processed antigens to T-cells and have been linked to differences in HIV-1 disease progression. HLA allelotypes show considerable geographical and inter-individual variation, as does the rate of progression of HIV-1 disease, with long-term non-progression (LTNP) of disease having most evidence of an underlying genetic contribution. However, most genetic analyses of LTNP have occurred in adults of European ancestry, limiting the potential transferability of observed associations to diverse populations who carry the burden of disease. This is particularly true of HIV-1 infected children. Here, using exome sequencing (ES) to infer HLA allelotypes, we determine associations with HIV-1 LTNP in two diverse African pediatric populations. We performed a case-control association study of 394 LTNPs and 420 rapid progressors retrospectively identified from electronic medical records of pediatric HIV-1 populations in Uganda and Botswana. We utilized high-depth ES to perform high-resolution HLA allelotyping and assessed evidence of association between HLA class I alleles and LTNP. Sixteen HLA alleles and haplotypes had significantly different frequencies between Uganda and Botswana, with allelic differences being more prominent in HLA-A compared to HLA-B and C allelotypes. Three HLA allelotypes showed association with LTNP, including a novel association in HLA-C (HLA-B∗57:03, aOR 3.21, Pc = 0.0259; B∗58:01, aOR 1.89, Pc = 0.033; C∗03:02, aOR 4.74, Pc = 0.033). Together, these alleles convey an estimated population attributable risk (PAR) of non-progression of 16.5%. We also observed novel haplotype associations with HLA-B∗57:03-C∗07:01 (aOR 5.40, Pc = 0.025) and HLA-B∗58:01-C∗03:02 (aOR 4.88, Pc = 0.011) with a PAR of 9.8%, as well as a previously unreported independent additive effect and heterozygote advantage of HLA-C∗03:02 with B∗58:01 (aOR 4.15, Pc = 0.005) that appears to limit disease progression, despite weak LD (r2 = 0.18) between these alleles. These associations remained irrespective of gender or country. In one of the largest studies of HIV in Africa, we find evidence of a protective effect of canonical HLA-B alleles and a novel HLA-C association that appears to augment existing HIV-1 control alleles in pediatric populations. Our findings outline the value of using multi-ethnic populations in genetic studies and offer a novel HIV-1 association of relevance to ongoing vaccine studies.
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影响因子：
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作者：
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通讯作者：
Kootstra NA
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通讯作者：
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