San Diego Joint Doctoral Program in Clinical Psychology, San Diego State University/University of California, San Diego, CA.
Department of Psychiatry, University of California, San Diego, CA.
J Acquir Immune Defic Syndr. 2019 Aug 15;81(5):e148-e157. doi: 10.1097/QAI.0000000000002083.
The Val allele of the Val158Met single-nucleotide polymorphism of the catechol-o-methyltransferase gene (COMT) results in faster metabolism and reduced bioavailability of dopamine (DA). Among persons living with HIV, Val carriers display neurocognitive deficits relative to Met carriers, presumably due to exacerbation of HIV-related depletion of DA. COMT may also impact neurocognition by modulating cardiometabolic function, which is often dysregulated among persons living with HIV. We examined the interaction of COMT, cardiometabolic risk, and nadir CD4 on neurocognitive impairment (NCI) among HIV+ men.
Three hundred twenty-nine HIV+ men underwent COMT genotyping and neurocognitive and neuromedical assessments. Cohort-standardized z scores for body mass index, systolic blood pressure, glucose, triglycerides, and high-density lipoprotein cholesterol were averaged to derive a cardiometabolic risk score (CMRS). NCI was defined as demographically adjusted global deficit score of ≥0.5. Logistic regression modeled NCI as a function of COMT, CMRS, and their interaction, covarying for estimated premorbid function, race/ethnicity, and HIV-specific characteristics. Follow-up analysis included the 3-way interaction of COMT, CMRS, and nadir CD4.
Genotypes were 81 (24.6%) Met/Met, 147 (44.7%) Val/Met, and 101 (30.7%) Val/Val. COMT interacted with CMRS (P = 0.02) such that higher CMRS increased risk of NCI among Val/Val [odds ratio (OR) = 2.13, P < 0.01], but not Val/Met (OR = 0.93, P > 0.05) or Met/Met (OR = 0.92, P > 0.05) carriers. Among Val/Val, nadir CD4 moderated the effect of CMRS (P < 0.01) such that higher CMRS increased likelihood of NCI only when nadir CD4 <180.
Results suggest a tripartite model by which genetically driven low DA reserve, cardiometabolic dysfunction, and historical immunosuppression synergistically enhance risk of NCI among HIV+ men, possibly due to neuroinflammation and oxidative stress.
儿茶酚-O-甲基转移酶（COMT）基因的 Val158Met 单核苷酸多态性的 Val 等位基因导致多巴胺（DA）代谢加快，生物利用度降低。在感染 HIV 的人群中，与 Met 携带者相比，Val 携带者表现出神经认知缺陷，可能是由于 HIV 相关的 DA 耗竭加剧。COMT 还可能通过调节心血管代谢功能来影响神经认知，而心血管代谢功能在感染 HIV 的人群中常常失调。我们研究了 COMT、心血管代谢风险和 CD4 最低点对 HIV 阳性男性神经认知障碍（NCI）的相互作用。
329 名 HIV 阳性男性接受了 COMT 基因分型和神经认知及神经医学评估。将体重指数、收缩压、血糖、甘油三酯和高密度脂蛋白胆固醇的队列标准化 z 分数平均，得出心血管代谢风险评分（CMRS）。NCI 的定义为经过人口统计学调整后的全球缺陷评分≥0.5。Logistic 回归模型将 NCI 作为 COMT、CMRS 及其相互作用的函数进行建模，同时考虑了估计的发病前功能、种族/民族和 HIV 特异性特征。后续分析包括 COMT、CMRS 和 CD4 最低点的 3 重相互作用。
基因型为 81（24.6%）Met/Met、147（44.7%）Val/Met 和 101（30.7%）Val/Val。COMT 与 CMRS 相互作用（P=0.02），即较高的 CMRS 增加了 Val/Val 患者发生 NCI 的风险（比值比[OR]为 2.13，P<0.01），但 Val/Met（OR=0.93，P>0.05）或 Met/Met（OR=0.92，P>0.05）患者的风险没有增加。在 Val/Val 患者中，CD4 最低点调节了 CMRS 的作用（P<0.01），即只有当 CD4 最低点<180 时，较高的 CMRS 才会增加发生 NCI 的可能性。
结果表明，一个三方模型，即遗传驱动的低 DA 储备、心血管代谢功能障碍和历史免疫抑制协同增强了 HIV 阳性男性发生 NCI 的风险，这可能是由于神经炎症和氧化应激所致。
