Loci associated with N-glycosylation of human immunoglobulin G show pleiotropy with autoimmune diseases and haematological cancers

Contains fulltext : 118733.pdf (publisher's version ) (Open Access)Glycosylation of immunoglobulin G (IgG) influences IgG effector function by modulating binding to Fc receptors. To identify genetic loci associated with IgG glycosylation, we quantitated N-linked IgG glycans using two approaches. After isolating IgG from human plasma, we performed 77 quantitative measurements of N-glycosylation using ultra-performance liquid chromatography (UPLC) in 2,247 individuals from four European discovery populations. In parallel, we measured IgG N-glycans using MALDI-TOF mass spectrometry (MS) in a replication cohort of 1,848 Europeans. Meta-analysis of genome-wide association study (GWAS) results identified 9 genome-wide significant loci (P<2.27 x 10(-9)) in the discovery analysis and two of the same loci (B4GALT1 and MGAT3) in the replication cohort. Four loci contained genes encoding glycosyltransferases (ST6GAL1, B4GALT1, FUT8, and MGAT3), while the remaining 5 contained genes that have not been previously implicated in protein glycosylation (IKZF1, IL6ST-ANKRD55, ABCF2-SMARCD3, SUV420H1, and SMARCB1-DERL3). However, most of them have been strongly associated with autoimmune and inflammatory conditions (e.g., systemic lupus erythematosus, rheumatoid arthritis, ulcerative colitis, Crohn's disease, diabetes type 1, multiple sclerosis, Graves' disease, celiac disease, nodular sclerosis) and/or haematological cancers (acute lymphoblastic leukaemia, Hodgkin lymphoma, and multiple myeloma). Follow-up functional experiments in haplodeficient Ikzf1 knock-out mice showed the same general pattern of changes in IgG glycosylation as identified in the meta-analysis. As IKZF1 was associated with multiple IgG N-glycan traits, we explored biomarker potential of affected N-glycans in 101 cases with SLE and 183 matched controls and demonstrated substantial discriminative power in a ROC-curve analysis (area under the curve = 0.842). Our study shows that it is possible to identify new loci that control glycosylation of a single plasma protein using GWAS. The results may also provide an explanation for the reported pleiotropy and antagonistic effects of loci involved in autoimmune diseases and haematological cancer

Traffic-related air pollution exposures and changes in heart rate variability in Mexico City: A panel study

Abstract Background While air pollution exposures have been linked to cardiovascular outcomes, the contribution from acute gas and particle traffic-related pollutants remains unclear. Using a panel study design with repeated measures, we examined associations between personal exposures to traffic-related air pollutants in Mexico City and changes in heart rate variability (HRV) in a population of researchers aged 22 to 56 years. Methods Participants were monitored for approximately 9.5 hours for eight days while operating a mobile laboratory van designed to characterize traffic pollutants while driving in traffic and &#8220;chasing&#8221; diesel buses. We examined the association between HRV parameters (standard deviation of normal-to-normal intervals (SDNN), power in high frequency (HF) and low frequency (LF), and the LF/HF ratio) and the 5-minute maximum (or average in the case of PM2.5) and 30-, 60-, and 90-minute moving averages of air pollutants (PM2.5, O3, CO, CO2, NO2, NOx, and formaldehyde) using single- and two-pollutant linear mixed-effects models. Results Short-term exposure to traffic-related emissions was associated with statistically significant acute changes in HRV. Gaseous pollutants &#8211; particularly ozone &#8211; were associated with reductions in time and frequency domain components (&#945; = 0.05), while significant positive associations were observed between PM2.5 and SDNN, HF, and LF. For ozone and formaldehyde, negative associations typically increased in magnitude and significance with increasing averaging periods. The associations for CO, CO2, NO2, and NOx were similar with statistically significant associations observed for SDNN, but not HF or LF. In contrast, PM2.5 increased these HRV parameters. Conclusions Results revealed an association between traffic-related PM exposures and acute changes in HRV in a middle-aged population when PM exposures were relatively low (14 &#956;g/m3) and demonstrate heterogeneity in the effects of different pollutants, with declines in HRV &#8211; especially HF &#8211; with ozone and formaldehyde exposures, and increases in HRV with PM2.5 exposure. Given that exposure to traffic-related emissions is associated with increased risk of cardiovascular morbidity and mortality, understanding the mechanisms by which traffic-related emissions can cause cardiovascular disease has significant public health relevance.Massachusetts Institute of Technology. Mexico City Projec