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Variation in PPP3CC Genotype Is Associated with Long-Term Recovery after Severe Brain Injury.

ABSTRACT: After experimental traumatic brain injury (TBI), calcineurin is upregulated; blocking calcineurin is associated with improved outcomes. In humans, variation in the calcineurin A-gamma gene (PPP3CC) has been associated with neuropsychiatric disorders, though any role in TBI recovery remains unknown. This study examines associations between PPP3CC genotype and mortality, as well as gross functional status assessed at admission using the Glasgow Coma Scale (GCS) and at 3, 6, and 12 months after severe TBI using the Glasgow Outcome Score (GOS). The following tagging single nucleotide polymorphisms (tSNPs) in PPP3CC were genotyped: rs2443504, rs2461491, rs2469749, and rs10108011. The rs2443504 AA genotype was univariately associated with GCS (p?=?0.022), GOS at 3, 6, and 12 months (p?=?0.002, p?=?0.034, and p?=?0.004, respectively), and mortality (p?=?0.007). In multivariate analysis controlling for age, sex, and GCS, the AA genotype of rs2443504 was associated with GOS at 3 (p?=?0.02), and 12 months (p?=?0.01), with a trend toward significance at 6 months (p?=?0.05); the AA genotype also was associated with mortality in the multivariate model (p?=?0.04). Further work is warranted to better understand the role of calcineurin, as well as the genes encoding it and their relevance to outcomes after brain injury.

SUBMITTER: Osier ND

PROVIDER: S-EPMC5198144 | biostudies-literature | 2017 Jan

REPOSITORIES: biostudies-literature

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Variation in PPP3CC Genotype Is Associated with Long-Term Recovery after Severe Brain Injury.

Osier Nicole D ND Bales James W JW Pugh Bunny B Shin Samuel S Wyrobek Julie J Puccio Ava M AM Okonkwo David O DO Ren Dianxu D Alexander Sheila S Conley Yvette P YP Dixon C Edward CE

Journal of neurotrauma 20160627 1

After experimental traumatic brain injury (TBI), calcineurin is upregulated; blocking calcineurin is associated with improved outcomes. In humans, variation in the calcineurin A-gamma gene (PPP3CC) has been associated with neuropsychiatric disorders, though any role in TBI recovery remains unknown. This study examines associations between PPP3CC genotype and mortality, as well as gross functional status assessed at admission using the Glasgow Coma Scale (GCS) and at 3, 6, and 12 months after sev ...[more]

PMID: 27225880

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Project description:Background and aims: Severe traumatic brain injury is a leading cause of acquired persistent disabilities, and represents an important health and economic burden. However, the determinants of long-term outcome have rarely been systematically studied in a prospective longitudinal study of a homogeneous group of patients suffering exclusively from severe TBI Methods: Prospective observational study of an inception cohort of adult patients with severe traumatic brain injury in the Parisian area (PariS-TBI). Outcome was assessed with face-to-face interview 8 years after Traumatic Brain Injury, focusing on impairments, activity limitations, and participation restriction. Results: Five hundred and four patients were included between 2005 and 2007. At 8-year follow-up, 261 patients were deceased, 128 were lost to follow-up, 22 refused to participate, and 86 were finally evaluated. Age, gender, initial injury severity did not significantly differ between evaluated patients and lost to follow-up, but the latter were more frequently students or unemployed. Mean age was 41.9 (SD 13.6), 79% were male, median initial Glasgow Coma Scale Score was 6. The most frequent somatic complaints concerned balance (47.5%), motricity (31%), and headaches (36%), but these were less frequent than cognitive complaints (Memory 71%, Slowness 68%, Concentration 67%). According to the Hospital Anxiety and Depression Scale (HADS), 25 % had a score >8 for anxiety and 23.7% for depression. According to the Extended Glasgow Outcome Scale, 19.8% remained severely disabled, 46.5% moderately disabled, 33.7% had a good recovery. Older age, longer education duration, lower functional status upon intensive care discharge, and more severe 8-year dysexecutive problems were significantly associated with a lower Extended Glasgow Outcome Scale score in multivariable analysis. At 8 years, 48.7% of patients were employed in a productive job. Of those, 38% declared a salary loss since traumatic brain injury. Unemployment was significantly associated with lower 1-year GOSE score and more severe 8-year dysexecutive problems. Conclusions: These results from an inception cohort study highlight the fact that long-term outcome after severe TBI is determined by a complex combination of injury-related, demographic and neuropsychological factors. Long after the injury, persisting impairments still interfere with social integration, and participation.

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Dataset Information

Variation in PPP3CC Genotype Is Associated with Long-Term Recovery after Severe Brain Injury.

Publications

Variation in PPP3CC Genotype Is Associated with Long-Term Recovery after Severe Brain Injury.

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