MRC Integrative Epidemiology Unit, University of Bristol, Oakfield Grove, Bristol, BS8 2BN, UK.
Infection Sciences, North Bristol NHS Trust, Bristol, England, UK.
Malar J. 2022 Nov 17;21(1):342. doi: 10.1186/s12936-022-04352-x.
Inducible expression of heme oxygenase-1 (encoded by the gene HMOX1) may determine protection from heme released during malaria infections. A variable length, short tandem GT(n) repeat (STR) in HMOX1 that may influence gene expression has been associated with outcomes of human malaria in some studies. In this study, an analysis of the association between variation at the STR in HMOX1 on severe malaria and severe malaria subtypes is presented in a large, prospectively collected dataset (MalariaGEN).
The HMOX1 STR was imputed using a recently developed reference haplotype panel designed for STRs. The STR was classified by total length and split into three alleles based on an observed trimodal distribution of repeat lengths. Logistic regression was used to assess the association between this repeat on cases of severe malaria and severe malaria subtypes (cerebral malaria and severe malarial anaemia). Individual analyses were performed for each MalariaGEN collection site and combined for meta-analysis. One site (Kenya), had detailed clinical metadata, allowing the assessment of the effect of the STR on clinical variables (e.g. parasite count, platelet count) and regression analyses were performed to investigate whether the STR interacted with any clinical variables.
Data from 17,960 participants across 11 collection sites were analysed. In logistic regression, there was no strong evidence of association between STR length and severe malaria (Odds Ratio, OR: 0.96, 95% confidence intervals 0.91-1.02 per ten GT(n) repeats), although there did appear to be an association at some sites (e.g., Kenya, OR 0.90, 95% CI 0.82-0.99). There was no evidence of an interaction with any clinical variables.
Meta-analysis suggested that increasing HMOX1 STR length is unlikely to be reliably associated with severe malaria. It cannot be ruled out that repeat length may alter risk in specific populations, although whether this is due to chance variation, or true variation due to underlying biology (e.g., gene vs environment interaction) remains unanswered.
诱导型血红素加氧酶-1（由基因 HMOX1 编码）的表达可能决定了其对疟疾感染期间释放的血红素的保护作用。在一些研究中，HMOX1 中的一个短串联 GT(n)重复（STR）长度可变，可能会影响基因表达，与人类疟疾的结果有关。在这项研究中，在一个大型前瞻性收集的数据集（MalariaGEN）中，对 HMOX1 上的 STR 与严重疟疾和严重疟疾亚型之间的关联进行了分析。
使用最近开发的用于 STR 的参考单倍型面板对 HMOX1 STR 进行了推断。根据重复长度的观察到的三峰分布，将 STR 按总长度分类，并分为三个等位基因。使用逻辑回归评估该重复与严重疟疾和严重疟疾亚型（脑型疟疾和严重疟疾性贫血）病例之间的关联。对每个 MalariaGEN 收集地点进行个体分析，并进行荟萃分析。一个地点（肯尼亚）有详细的临床元数据，允许评估 STR 对临床变量（例如寄生虫计数、血小板计数）的影响，并进行回归分析以调查 STR 是否与任何临床变量相互作用。
对来自 11 个收集地点的 17960 名参与者的数据进行了分析。在逻辑回归中，STR 长度与严重疟疾之间没有强烈的关联证据（比值比，OR：每 10 个 GT(n)重复 0.96，95%置信区间 0.91-1.02），尽管在某些地点似乎存在关联（例如，肯尼亚，OR 0.90，95%CI 0.82-0.99）。没有证据表明与任何临床变量存在相互作用。
荟萃分析表明，增加 HMOX1 STR 长度不太可能与严重疟疾可靠相关。不能排除重复长度可能会改变特定人群的风险，尽管这是由于偶然变异还是由于潜在生物学（例如基因与环境相互作用）的真正变异仍未得到解答。
