Catechol-O-methyltransferase polymorphism Val158Met is associated with distal neuropathic pain in HIV-associated sensory neuropathy

Abstract

Background: Many of those aging with HIV suffer from distal neuropathic pain (DNP) due to HIV-associated sensory neuropathy (HIV-SN). Prior studies have linked chronic pain conditions to a variant of the catechol-O-methyltransferase (COMT), Val 158 Met. This variant confers reduced enzymatic activity and results in higher synaptic dopamine levels. Here we examined the role of Val 158 Met as a predictor of DNP in HIV-SN. Methods: In 1044HIV-infected individuals enrolled in CNS HIV Antiretroviral Therapy Effects Research, an observational study across six US institutions, we characterized the relationship between Val 158 Met and DNP in HIV-SN. Participants underwent neurologic examination and genotyping. Stratification into genetic ancestry groups was employed to eliminate bias due to genetic background. Findings: Of 590 participants with HIV-SN, 38% endorsed DNP, 24% reported nonpainful symptoms of neuropathy (paresthesia and numbness), and 38% were asymptomatic. Compared with asymptomatic HIV-SN, Val 158 Met was associated with 2.3 higher odds of DNP. There were no increased odds of nonpainful symptoms. The association remained significant after controlling for other risk factors for DNP: lifetime diagnosis of depression, older age, ancestry, cumulative exposure to dideoxynucleoside antiretrovirals, diabetes, and nadir CD4 + . Stratified by genetic ancestry, the association between Val 158 Met and DNP was significant in European and African genetic ancestry.

Genetic Polymorphism of Delta Aminolevulinic Acid Dehydratase (ALAD) Gene and Symptoms of Chronic Mercury Exposure in Munduruku Indigenous Children within the Brazilian Amazon

“…Since it was the village with the lowest level of mercury and cases exceed the reference limit (≥6.0 µg/g), we hypothesize that the presence of the variant ALAD allele influences the occurrence of these disturbances by increasing the association between ALAD protein and Hg molecules and, consequently, raising blood Hg levels. Nevertheless, in addition to the ALAD polymorphism, there may be other genetic influences, making individuals more predisposed to certain conditions influencing the occurrence of neurological symptoms [38][39][40][41][42]. Visual field defects, for instance, have already been associated with a mutation on the OPA 1 (OPA1 Mitochondrial Dynamin Like GTPase) gene [39] and a polymorphism near the TGFBR3 (Transforming Growth Factor Beta Receptor (3) gene [38].…”

“…Visual field defects, for instance, have already been associated with a mutation on the OPA 1 (OPA1 Mitochondrial Dynamin Like GTPase) gene [39] and a polymorphism near the TGFBR3 (Transforming Growth Factor Beta Receptor (3) gene [38]. Another example is the COMT gene (Catechol-O-Methyltransferase), whose SNPs have been associated with lower chances of developing memory impairment [41] and higher odds of developing distal neuropathic pain [40]. A review study published in 2020 showed that epigenetic alterations such as miRNA expression and DNA methylation could cause impaired memory and neuronal development, depression-like behavior, visual deficits, and hyperactivity, in experimental models [42].…”

Joint European Academy of Neurology–European Pain Federation–Neuropathic Pain Special Interest Group of the International Association for the Study of Pain guidelines on neuropathic pain assessment

“…There have been several candidate genes, GCH1 [77], IL6 [78], IL10 and IL1R2 [79], TNFA [80], SCN9A [81], CACNG2 [82], SLC6A4 [83], ACO1 , B2M , BMP6 , TF , CP , TFRC , FXN , and SLC11A2 [84], and HTR2A [85,86] found to be associated with neuropathic pain susceptibility in a single study each. Studies have also reported the association of COMT [74], OPRM1 [86], MMP1 [87], KCNS1 [88], TNFA [89], and P2RX7 [90] harbouring variants with increased pain intensity. The most recent study replicated only one variant in P2RX7 associated with neuropathic pain in patients with herpes zoster [91].…”

Neuropathic pain in the community: prevalence, impact, and risk factors

“…[91] However, a recent study (n=590) reported that a COMT variant confers an increased risk of distal neuropathic pain in HIV-SN patients of European and African ancestry. [96] Moreover, COMT variants were also associated with pain intensity in patients who underwent lumbar discectomy. [71] Similarly, studies have reported the association of OPRM1 variants with neuropathic pain susceptibility inconsistently in different populations.…”