Background

Mitochondrial DNA (mtDNA) genetic variation is associated with neurocognitive (NC) impairment (NCI) in people with HIV (PWH). Other approaches use sequence conservation and protein structure to predict the impact of mtDNA variants on protein function. We examined predicted mtDNA variant pathogenicity in the CHARTER study using MutPred scores, hypothesizing that persons with higher scores (greater predicted pathogenicity) have more NCI.

Methods

CHARTER included NC testing in PWH from 2003 to 2007. MutPred scores were assigned to CHARTER participants with mtDNA sequence; any score > 0.5 was considered potentially deleterious. Outcomes at cohort entry were NCI, defined by global and seven NC domain deficit scores, and by mean global and domain NC performance T-scores. Univariate and multivariable regression analyses assessed associations between having a deleterious variant and NCI. Additional models included estimated peripheral blood cell mtDNA copy number.

Results

Data were available for 744 PWH (357 African ancestry; 317 European; 70 Hispanic). In the overall cohort, PWH having any potentially deleterious variant were less likely to have motor impairment (16 vs. 25 %, p = 0.001). In multivariable analysis, having a deleterious variant remained associated with lower likelihood of motor impairment (adjusted odds ratio 0.59 [95 % CI 0.41–0.88]; p = 0.009), and better motor performance by T-score (β 1.71 [0.31–3.10], p = 0.02). Associations persisted after adjustment for estimated mtDNA quantity.

Conclusions

In these PWH, having a potentially deleterious mtDNA variant was associated with less motor impairment. These unexpected findings suggest that potentially deleterious mtDNA variations may confer protection against impaired motor function by as yet unknown mechanisms.

中文翻译：

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HIV 感染者的线粒体 DNA 突变致病性评分和神经认知表现

背景

线粒体 DNA (mtDNA) 遗传变异与 HIV 感染者 (PWH) 的神经认知 (NC) 损伤 (NCI) 相关。其他方法使用序列保守性和蛋白质结构来预测 mtDNA 变异对蛋白质功能的影响。我们在 CHARTER 研究中使用 MutPred 评分检查了预测的 mtDNA 变异致病性，假设得分较高（预测致病性较高）的人有更多的 NCI。

方法

CHARTER 包括 2003 年至 2007 年在 PWH 中进行的 NC 测试。 MutPred 分数被分配给具有 mtDNA 序列的 CHARTER 参与者；任何> 0.5 的分数都被认为是潜在有害的。队列进入时的结果是 NCI，由全局和七个 NC 领域缺陷分数以及平均全局和领域 NC 表现 T 分数定义。单变量和多变量回归分析评估了有害变异与 NCI 之间的关联。其他模型包括估计的外周血细胞 mtDNA 拷贝数。

结果

可获得 744 名感染者的数据（357 名非洲裔；317 名欧洲裔；70 名西班牙裔）。在整个队列中，具有任何潜在有害变异的 PWH 出现运动障碍的可能性较小（16% vs. 25%，p = 0.001）。在多变量分析中，有害变异仍然与较低的运动障碍可能性相关（调整后的比值比 0.59 [95% CI 0.41–0.88]；p = 0.009），并且 T 评分更好的运动表现（β 1.71 [0.31–3.10] ]，p = 0.02）。在调整估计的线粒体 DNA 数量后，关联仍然存在。

结论

在这些 PWH 中，具有潜在有害的线粒体 DNA 变异与较少的运动障碍有关。这些意想不到的发现表明，潜在有害的 mtDNA 变异可能通过迄今未知的机制提供针对运动功能受损的保护。