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<2.27×10−9) 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.

A number of studies investigated the distribution of BMD values and the prevalence of osteoporosis in China, but their findings varied. Until now, a BMD reference database based on uniform measurements in a large-scale Chinese population has been lacking. A total of 75,321 Chinese adults aged 20 years and older were recruited from seven centers between 2008 and 2018. BMD values at the lumbar spine (L 1 -L 4 ), femoral neck, and total femur were measured by GE Lunar dual-energy X-ray absorptiometry systems. BMD values measured in each center were cross-calibrated by regression equations that were generated by scanning the same European spine phantom 10 times at every center. Cubic and multivariate linear regression were performed to assess associations between BMD values and demographic variables. Sex-specific prevalence of osteoporosis was age-standardized based on the year 2010 national census data for the Chinese population. The sex-specific BMD values at each site were negatively associated with age, positively associated with body mass index levels, and lower in the participants from southwest China than in those from other geographic regions after multivariate adjustment. Furthermore, BMD values at the femoral neck and total femur decreased with the year of BMD measurement. The peak BMD values at the lumbar spine, femoral neck, and total femur were 1.088 g/cm 2 , 0.966 g/cm 2 , and 0.973 g/cm 2 , respectively, for men, and 1.114 g/cm 2 , 0.843 g/cm 2 , and 0.884 g/cm 2 , respectively, for women. The age-standardized prevalence of osteoporosis at the spine or hip was 6.46% and 29.13% for men and women aged 50 years and older, respectively. Currently a total of 10.9 million men and 49.3 million women in China are estimated to have osteoporosis. In our national examination of BMD, we found that BMD values differed by demographic characteristics. We estimated the age-standardize prevalence of osteoporosis in China to be 6.46% and 29.13% respectively, for men and women aged 50 years and older. 2018, 75,546 participants were enrolled. After the exclusion of one participant with a description error of the BMD measurement site, one participant who was measured in 1998, 214 participants with missing data on BMD values, and nine participants with BMI <10 kg/m 2 or >50 kg/m 2 , a total of 75,321 ◼ 2 ZENG ET AL.

ObjectiveGlycans attached to the Fc portion of IgG are important modulators of IgG effector functions. Interindividual differences in IgG glycome composition are large and they associate strongly with different inflammatory and autoimmune diseases. IKZF1, HLA–DQ2A/B, and BACH2 genetic loci that affect IgG glycome composition show pleiotropy with systemic lupus erythematosus (SLE), indicating a potentially causative role of aberrant IgG glycosylation in SLE. We undertook this large multicenter case–control study to determine whether SLE is associated with altered IgG glycosylation.MethodsUsing ultra‐performance liquid chromatography analysis of released glycans, we analyzed the composition of the IgG glycome in 261 SLE patients and 247 matched controls of Latin American Mestizo origin (the discovery cohort) and in 2 independent replication cohorts of different ethnicity (108 SLE patients and 193 controls from Trinidad, and 106 SLE patients and 105 controls from China).ResultsMultiple statistically significant differences in IgG glycome composition were observed between patients and controls. The most significant changes included decreased galactosylation and sialylation of IgG (which regulate proinflammatory and antiinflammatory actions of IgG) as well as decreased core fucose and increased bisecting N‐acetylglucosamine (which affect antibody‐dependent cell‐mediated cytotoxicity).ConclusionThe IgG glycome in SLE patients is significantly altered in a way that decreases immunosuppressive action of circulating immunoglobulins. The magnitude of observed changes is associated with the intensity of the disease, indicating that aberrant IgG glycome composition or changes in IgG glycosylation may be an important molecular mechanism in SLE.

It has not been established which specific measures of obesity might be most appropriate for predicting CVD risk in Asians. The objectives of the present study were to determine the associations of BMI, waist circumference (WC) and waist:height ratio (WHtR) with CVD risk factors and to evaluate the optimal cut-off values to define overweight or obesity in Chinese adults. Data collected from seven nationwide health examination centres during 2008 and 2009 were analysed. The BMI, WC and WHtR of 244 266 Chinese adults aged $20 years included in the study were measured. Logistic regression models were fit to evaluate the OR of each CVD risk factor according to various anthropometric indices. Receiver operating characteristic (ROC) analyses were conducted to assess the optimal cut-off values to predict the risk of diabetes, hypertension, dyslipidaemia and the metabolic syndrome. WHtR had the largest areas under the ROC curve for all CVD risk factors in both sexes, followed by WC and BMI. The optimal cut-off values were approximately 24·0 and 23·0 kg/m 2 for BMI, 85·0 and 75·0 cm for WC, and 0·50 and 0·48 for WHtR for men and women, respectively. According to well-established cut-off values, BMI was found to be a more sensitive indicator of hypertension in both men and women, while WC and WHtR were found to be better indicators of diabetes and dyslipidaemia. A combination of BMI and central obesity measures was found to be associated with greater OR of CVD risk factors than either of them alone in both sexes. The present study demonstrated that WHtR and WC may be better indicators of CVD risk factors for Chinese people than BMI.