Genetic association of primary nonresponse to anti-TNFα therapy in patients with inflammatory bowel disease.

OBJECTIVES: Primary nonresponse (PNR) to antitumor necrosis factor-α (TNFα) biologics is a serious concern in patients with inflammatory bowel disease (IBD). We aimed to identify the genetic variants associated with PNR. PATIENTS AND METHODS: Patients were recruited from outpatient GI clinics and PNR was determined using both clinical and endoscopic findings. A case-control genome-wide association study was performed in 589 IBD patients and associations were replicated in an independent cohort of 293 patients. Effect of the associated variant on gene expression and TNFα secretion was assessed by cell-based assays. Pleiotropic effects were investigated by Phenome-wide association study (PheWAS). RESULTS: We identified rs34767465 as associated with PNR to anti-TNFα therapy (odds ratio: 2.07, 95% CI, 1.46-2.94, P = 2.43 × 10-7, [replication odds ratio: 1.8, 95% CI, 1.04-3.16, P = 0.03]). rs34767465 is a multiple-tissue expression quantitative trait loci for FAM114A2. Using RNA-sequencing and protein quantification from HapMap lymphoblastoid cell lines (LCLs), we found a significant decrease in FAM114A2 mRNA and protein expression in both heterozygous and homozygous genotypes when compared to wild type LCLs. TNFα secretion was significantly higher in THP-1 cells [differentiated into macrophages] with FAM114A2 knockdown versus controls. Immunoblotting experiments showed that depletion of FAM114A2 impaired autophagy-related pathway genes suggesting autophagy-mediated TNFα secretion as a potential mechanism. PheWAS showed rs34767465 was associated with comorbid conditions found in IBD patients (derangement of joints [P = 3.7 × 10-4], pigmentary iris degeneration [P = 5.9 × 10-4], diverticulum of esophagus [P = 7 × 10-4]). CONCLUSIONS: We identified a variant rs34767465 associated with PNR to anti-TNFα biologics, which increases TNFα secretion through mechanism related to autophagy. rs34767465 may also explain the comorbidities associated with IBD.

Predictors of psychotropic medication adherence among HIV+ individuals living with bipolar disorder.

OBJECTIVE: HIV infection and bipolar disorder are highly comorbid and associated with frontostriatal disruption, emotional dysregulation, and neurocognitive impairment. Psychiatric and cognitive factors have been linked to antiretroviral nonadherence; however, predictors of psychotropic adherence among HIV+ individuals with psychiatric comorbidities have not been explored. We evaluated predictors of psychotropic adherence among individuals with HIV infection and bipolar disorder. METHOD: Psychiatric medication adherence of 50 participants with HIV infection and bipolar disorder was tracked for 30 days using Medication Event Monitoring Systems. Participants completed neurocognitive, neuromedical, and psychiatric batteries. RESULTS: Mean psychotropic adherence rate was 78%; 56% of participants achieved ≥90% adherence. Younger age and onset of depressive symptoms, more severe current depressive symptoms, number of previous psychiatric hospitalizations and suicide attempts, poorer neurocognition, and more negative attitudes and self-beliefs toward medications univariably predicted worse psychotropic adherence (p's < .10). A multivariable model demonstrated a combination of current depressive symptoms and more negative attitudes toward medications significantly predicting poorer adherence (R(2 )= 0.27, p < 0.003). Secondary analyses revealed an interaction between neurocognition and mood, such that individuals with HIV infection and bipolar disorder who had greater executive dysfunction and depressive symptoms evidenced the poorest psychotropic adherence (p < 0.001). CONCLUSIONS: Both psychiatric and neurocognitive factors contribute to poorer psychotropic adherence among HIV+ individuals with serious mental illness. Adherence interventions aimed at remediating these factors may be especially fruitful.