Objective Systemic lupus erythematosus (SLE), an autoimmune disorder, has been associated with nearly 100 susceptibility loci. Nevertheless, these loci only partially explain SLE heritability and their putative causal variants are rarely prioritised, which make challenging to elucidate disease biology. To detect new SLE loci and causal variants, we performed the largest genome-wide meta-analysis for SLE in East Asian populations. Methods We newly genotyped 10 029 SLE cases and 180 167 controls and subsequently meta-analysed them jointly with 3348 SLE cases and 14 826 controls from published studies in East Asians. We further applied a Bayesian statistical approach to localise the putative causal variants for SLE associations. Results We identified 113 genetic regions including 46 novel loci at genome-wide significance (p<5×10⁻⁸). Conditional analysis detected 233 association signals within these loci, which suggest widespread allelic heterogeneity. We detected genome-wide associations at six new missense variants. Bayesian statistical fine-mapping analysis prioritised the putative causal variants to a small set of variants (95% credible set size ≤10) for 28 association signals. We identified 110 putative causal variants with posterior probabilities ≥0.1 for 57 SLE loci, among which we prioritised 10 most likely putative causal variants (posterior probability ≥0.8). Linkage disequilibrium score regression detected genetic correlations for SLE with albumin/globulin ratio (r_g=−0.242) and non-albumin protein (r_g=0.238). Conclusion This study reiterates the power of large-scale genome-wide meta-analysis for novel genetic discovery. These findings shed light on genetic and biological understandings of SLE.

Although substantial evidence reveals that healthy lifestyle behaviors are associated with a lower risk of rheumatoid arthritis (RA), the underlying metabolic mechanisms remain unclear. This study aimed to identify the metabolic signature reflecting a healthy lifestyle and investigate its observational and genetic linkage with RA risk. This study included 87,258 UK Biobank participants (557 cases with incident RA) aged 37-73 y with complete lifestyle, genotyping, and nuclear magnetic resonance (NMR) metabolomics data. A healthy lifestyle was assessed based on 5 factors: healthy diet, regular exercise, not smoking, moderate alcohol consumption, and normal body mass index. The metabolic signature was developed by summing the selected metabolites' concentrations weighted by the coefficients using elastic net regression. We used the multivariate Cox model to assess the associations between metabolic signatures and RA risk, and examined the mediating role of the metabolic signature in the impact of a healthy lifestyle on RA. We performed genome-wide association analysis (GWAS) to obtain genetic variants associated with the metabolic signature and then conducted Mendelian randomization (MR) analyses to detect causality. The metabolic signature comprised 81 metabolites, robustly correlated with a healthy lifestyle (r = 0.45, P = 4.2 × 10^-15). The metabolic signature was inversely associated with RA risk (HR per standard deviation (SD) increment: 0.76; 95% CI: 0.70-0.83), and largely explained the protective effects of healthy lifestyle on RA with 64% (95% CI: 50.4-83.3) mediation proportion. 1- and 2-sample MR analyses also consistently showed the associations of genetically inferred per SD increment in metabolic signature with a reduction in RA risk (HR: 0.84; 95% CI: 0.75-0.94; and P = 0.002 and OR: 0.84; 95% CI: 0.73-0.97; and P = 0.02, respectively). Our findings implicate that the metabolic signature reflecting healthy lifestyle is a potential causal mediator in the development of RA, highlighting the importance of early lifestyle intervention and metabolic status tracking for precise prevention of RA. Am J Clin Nutr 2023;xxx:xx-xx.

Mitochondrial dysfunction fuels vascular inflammation and atherosclerosis. Mitochondrial calcium uptake 1 (MICU1) maintains mitochondrial Ca ²⁺ homeostasis. However, the role of MICU1 in vascular inflammation and atherosclerosis remains unknown. Here, we report that endothelial MICU1 prevents vascular inflammation and atherosclerosis by maintaining mitochondrial homeostasis. We observed that vascular inflammation was aggravated in endothelial cell–specific Micu1 knockout mice ( Micu1 ^ECKO ) and attenuated in endothelial cell–specific Micu1 transgenic mice ( Micu1 ^ECTg ). Furthermore, hypercholesterolemic Micu1 ^ECKO mice also showed accelerated development of atherosclerosis, while Micu1 ^ECTg mice were protected against atherosclerosis. Mechanistically, MICU1 depletion increased mitochondrial Ca ²⁺ influx, thereby decreasing the expression of the mitochondrial deacetylase sirtuin 3 (SIRT3) and the ensuing deacetylation of superoxide dismutase 2 (SOD2), leading to the burst of mitochondrial reactive oxygen species (mROS). Of clinical relevance, we observed decreased MICU1 expression in the endothelial layer covering human atherosclerotic plaques and in human aortic endothelial cells exposed to serum from patients with coronary artery diseases (CAD). Two-sample Wald ratio Mendelian randomization further revealed that increased expression of MICU1 was associated with decreased risk of CAD and coronary artery bypass grafting (CABG). Our findings support MICU1 as an endogenous endothelial resilience factor that protects against vascular inflammation and atherosclerosis by maintaining mitochondrial Ca ²⁺ homeostasis.

Objective Genome-wide association studies (GWAS) have identified >100 risk loci for systemic lupus erythematosus (SLE), but the disease genes at most loci remain unclear, hampering translation of these genetic discoveries. We aimed to prioritise genes underlying the 110 SLE loci that were identified in the latest East Asian GWAS meta-analysis. Methods We built gene expression predictive models in blood B cells, CD4⁺ and CD8⁺ T cells, monocytes, natural killer cells and peripheral blood cells of 105 Japanese individuals. We performed a transcriptome-wide association study (TWAS) using data from the latest genome-wide association meta-analysis of 208 370 East Asians and searched for candidate genes using TWAS and three data-driven computational approaches. Results TWAS identified 171 genes for SLE (p<1.0×10^–5); 114 (66.7%) showed significance only in a single cell type; 127 (74.3%) were in SLE GWAS loci. TWAS identified a strong association between CD83 and SLE (p<7.7×10^–8). Meta-analysis of genetic associations in the existing 208 370 East Asian and additional 1498 cases and 3330 controls found a novel single-variant association at rs72836542 (OR=1.11, p=4.5×10^–9) around CD83. For the 110 SLE loci, we identified 276 gene candidates, including 104 genes at recently-identified SLE novel loci. We demonstrated in vitro that putative causal variant rs61759532 exhibited an allele-specific regulatory effect on ACAP1, and that presence of the SLE risk allele decreased ACAP1 expression. Conclusions Cell-level TWAS in six types of immune cells complemented SLE gene discovery and guided the identification of novel genetic associations. The gene findings shed biological insights into SLE genetic associations.