Gene Therapy in Primary Immunodeficiencies Primary immunodeficiencies (PIDs) result from inherited mutations in genes involved in the production, function or survival of specific elements of the immune system (T, B, NK lymphocytes, neutrophils, antigen-presenting cells). Knowing that these elements derive from pluripotent hematopoietic stem cells, it has been tried to use allogeneic hematopoietic stem cell transplantation (HSCT) as an alternative for patients with a PID, which has proven to be an effective therapeutic approach leading to immune restoration.
Vitamin D affects gene expression, but its downstream effects on the proteome are unclear. Hormonal contraceptives (HC), which affect vitamin D metabolism and have widespread effects on the plasma proteome, may confound the association between vitamin D and the proteome. We determined whether HC use modified the association between 25-hydroxyvitamin D (25D) and a panel of 54 high-abundance plasma proteins. Cross-sectional analyses were conducted in healthy, nonsmoking female HC users (n = 216), female HC nonusers (n = 502), and men (n = 301) from Toronto, Canada. Plasma 25D was measured by HPLC-MS/MS, and proteins were measured by LC-multiple-reaction-monitoring (MRM)-MS. The 54 proteins clustered into four distinct proteomic profiles. A positive association was observed between Profile 1, containing positive acute phase proteins, and 25D. In female HC users, a J-shaped association existed between Profile 1 and 25D, but no associations existed in female HC nonusers and men. Twelve proteins were individually associated with 25D in female HC users, but only two were associated with 25D in female HC nonusers and no associations were observed in men. After accounting for hormone dose, only three proteins were associated with 25D. In summary, HC use is an important confounder of the association between circulating 25D and numerous plasma proteins.
Rationale: The mechanisms underlying the various acute effects of caffeine are not clear. Some of the physiological effects of caffeine may be mediated through increased catecholamines, which are metabolized by catechol-O-methyltransferase (COMT). A Val158Met polymorphism in COMT affects enzyme activity with Val/Val homozygotes having a 3–4-fold greater activity than Met/Met homozygotes. Objective: To determine whether the self-reported acute effects of caffeine are associated with the COMT Val158Met polymorphism (rs4680). Methods: Subjects were men (n=344) and women (n=801) aged 20–29 years who were participants of the Toronto Nutrigenomics and Health Study. Acute effects were assessed by questionnaire, and caffeine intake was assessed using a semiquantitative food frequency questionnaire. Odds ratios (OR) and 95% confidence intervals (CI) were calculated to determine if the likelihood of reporting an acute effect was associated with COMT genotype. Results: Among individuals consuming more than 200 mg/day of caffeine, COMT genotype was associated with self-reported increased heart rate. Compared to the Val/Val genotype, the adjusted OR (95% CI) of reporting increased heart rate for the Val/Met and the Met/Met genotypes was 1.43 (0.64, 3.20) and 2.98 (1.04, 8.51), respectively. Conclusions: These findings show that the Met/Met genotype, conferring slow COMT activity, is associated with self-reported increased heart rate after caffeine intake. This observation suggests that caffeine may increase heart rate in a genetic subset of the population who have an impaired ability to breakdown catecholamines such as epinephrine and norepinephrine.
