Inflammatory Cytokine Gene Polymorphisms and Increased Risk of Parkinson Disease

Abstract

Background:The proinflammatory cytokines tumor necrosis factor ␣ (TNF-␣) and IL-1␤ (interleukin 1␤) have a role in neuroinflammation, and functional polymorphisms in the TNF-α and IL-1β genes may affect susceptibility to Parkinson disease (PD).Objective: To investigate whether functional DNA polymorphisms of the TNF-α and IL-1β genes affect the risk of PD.Design: Population-based case-control study.Setting: Three rural California counties (Fresno, Tulare, and Kern).Participants: Two hundred eighty-nine incident idiopathic PD cases and 269 population control subjects, marginally matched by age, sex, and race/ethnicity. Main Outcome Measures:Genotypes of IL-1β-511 and TNF-α-308. Results:We observed a greater than 2-fold increased risk of PD among carriers of the homozygous variant genotype of IL-1β-511 (odds ratio [OR], 2.26; 95% confidence interval [CI], 1.27-4.02) and the homozygous variant genotype of TNF-α-308 (OR, 2.49; 95% CI, 0.90-6.85) and an almost 3-fold increased risk among carriers of the homozygous variant genotype for either or both polymorphisms (OR, 2.92; 95% CI, 1.66-5.16). Conclusions:A smaller magnitude of PD risk increase among carriers of the heterozygous genotype for either or both polymorphisms suggests a gene-dosing effect (OR, 1.45; 95% CI, 0.97-2.16; PϽ.001 for trend). Results were not sensitive to exclusion of all nonwhite subjects or to adjustment for nonsteroidal anti-inflammatory drug use or smoking.

Association of NQO1 and TNF polymorphisms with Parkinson’s disease: A meta-analysis of 15 genetic association studies

“…This result is consistent with the majority of previous studies (22)(23)(24)(25)(26)(27), and only one study presented an opposing conclusion (21). In comparison to the former studies, the meta-analysis showed a stronger power and involved subgroup analyses by genetic models and ethnicity, which allowed for a more stable and comprehensive conclusion.…”

“…A study was also found from the references in the retrieved literature. Finally, 15 eligible studies (16 stages) (13,14,(16)(17)(18)(19)(21)(22)(23)(24)(25)(26)(27)(28)(29) were included in the meta-analyses (Table I).…”

Estrogen anti-inflammatory activity in brain: A therapeutic opportunity for menopause and neurodegenerative diseases

“…In addition, a number of proinflammatory mediators, such as cytokines, and inflammatory-associated factors such as cyclooxygenase-2 (COX-2) and inducible-nitric oxide synthase (iNOS) are elevated in the CNS or cerebrospinal fluid of neurodegenerative disease patients. Furthermore, recent epidemiological studies indicate that the chronic use of nonsteroidal anti-inflammatory agents (NSAIDs) reduces the risk of PD and AD ( [39,152,154,225]) and inheritance of polymorphisms resulting in enhanced expression of various inflammatory mediators was reported to increase the risk of these two pathologies ( [32,246]). Importantly, activated microglia were found at the histopathological sites of several brain disorders, including neurodegenerative diseases such as AD, MS, PD, ALS (amyotrophic lateral sclerosis) and AIDS-associated dementia ( [56,93,116,153] and [192]).…”

Progress and prospects: Immunobiology of gene therapy for neurodegenerative disease: prospects and risks

“…PD, Alzheimer's disease, multiple sclerosis, Huntington's disease, amyotrophic lateral sclerosis, tauopathies and age-related macular degeneration are all associated with chronic neuroinflammation and elevated levels of several cytokines. 12,[31][32][33][34][35][36][37][38][39][40] In addition, there are several recent reports that show normal aging is accompanied by progressive alterations in immune function. 41 Increased innate immune activity, microglial and immune cell activation and increased pro-inflammatory cytokine expression/release are found in brains of patients with PD and inflammation is thought to be a major contributor to the ongoing neurodegeneration and disease progression.…”