Objective
Systemic lupus erythematosus (SLE) is a highly heritable complex disorder with heterogeneous clinical manifestations. In this study, we aimed to identify the genetic risk load using ...clinical and serological manifestations in SLE patients.
Methods
We genotyped a total of 1,655 Korean patients with SLE (n = 1,243 as a discovery set and n = 412 as a replication set) using a customized genome‐wide single‐nucleotide polymorphism (SNP) array, KoreanChip. A weighted genetic risk score (wGRS) for an individual was calculated from 112 well‐validated non‐HLA SNPs and HLA haplotypes of SLE‐risk loci. We analyzed associations between individual wGRS and clinical SLE subphenotypes and autoantibodies using multivariable linear or logistic regression adjusted by onset age, sex, and disease duration.
Results
Childhood‐onset SLE (<16 years) conferred the highest genetic risk compared with adult‐onset (16–50 years) or late‐onset (>50 years) SLE (P = 6.8 × 10−6). High wGRS significantly increased associations with SLE manifestations, regardless of onset age, sex, and disease duration. Individual wGRS significantly correlated positively with more clinical American College of Rheumatology criteria (β = 0.143, P = 1.8 × 10−6). Subphenotype analysis revealed significant associations between the highest and lowest wGRS quartile with risk of renal disorder (hazard ratio HR 1.74, P = 2.2 × 10−8) and anti–Sm antibody production (HR 1.85, P = 2.8 × 10−5). Higher wGRS markedly modulated the pathogenesis of proliferative and membranous lupus nephritis class III or IV (HR 1.98, P = 1.6 × 10−5) and class V (HR 2.79, P = 1.0 × 10−3), but especially lupus nephritis class V in anti–Sm‐positive SLE (area under the curve 0.68, P = 1.8 × 10−4).
Conclusion
Patients with SLE and high wGRS tended to have earlier age of SLE onset, higher anti–Sm antibody positivity, and more diverse clinical phenotypes. Genetic profiling may predict high risk for lupus nephritis and a diverse clinical course in SLE patients.
Genome-wide association studies (GWAS) in rheumatoid arthritis (RA) have discovered over 100 RA loci, explaining patient-relevant RA pathogenesis but showing a large fraction of missing heritability. ...As a continuous effort, we conducted GWAS in a large Korean RA case-control population.
We newly generated genome-wide variant data in two independent Korean cohorts comprising 4068 RA cases and 36 487 controls, followed by a whole-genome imputation and a meta-analysis of the disease association results in the two cohorts. By integrating publicly available omics data with the GWAS results, a series of bioinformatic analyses were conducted to prioritise the RA-risk genes in RA loci and to dissect biological mechanisms underlying disease associations.
We identified six new RA-risk loci (
,
,
,
,
and
) with p
<5×10
and consistent disease effect sizes in the two cohorts. A total of 122 genes were prioritised from the 6 novel and 13 replicated RA loci based on physical distance, regulatory variants and chromatin interaction. Bioinformatics analyses highlighted potentially RA-relevant tissues (including immune tissues, lung and small intestine) with tissue-specific expression of RA-associated genes and suggested the immune-related gene sets (such as CD40 pathway, IL-21-mediated pathway and citrullination) and the risk-allele sharing with other diseases.
This study identified six new RA-associated loci that contributed to better understanding of the genetic aetiology and biology in RA.
Human genetic studies into rheumatoid arthritis (RA) have uncovered more than 100 genetic loci associated with susceptibility to RA and have refined the RA-association model for HLA variants. The ...majority of RA-risk variants are highly shared across multiple ancestral populations and are located in noncoding elements that might have allele-specific regulatory effects in relevant tissues. Emerging multi-omics data, high-density genotype data and bioinformatic approaches are enabling researchers to use RA-risk variants to identify functionally relevant cell types and biological pathways that are involved in impaired immune processes and disease phenotypes. This Review summarizes reported RA-risk loci and the latest insights from human genetic studies into RA pathogenesis, including how genetic data has helped to identify currently available drugs that could be repurposed for patients with RA and the role of genetics in guiding the development of new drugs.
This study aimed to analyze pregnancy outcomes based on biologic agents use in women using the nationwide population-based database.
The study used the claims database to identify women of ...childbearing age with several rheumatic (rheumatoid arthritis, juvenile idiopathic arthritis, ankylosing spondylitis, psoriatic arthritis) and inflammatory bowel diseases (Crohn's disease and ulcerative colitis) who had pregnancy-related codes between January 2010 and December 2019. We analyzed live births and adverse pregnancy outcomes based on the previous use of biologics. We also stratified the patients according to duration of biologic agent exposure before pregnancy and the use of biologics during pregnancy to analyze the pregnancy outcomes by subgroups.
We identified 4,787 patients with pregnancy events. Among them, 1,034 (21.6%) used biologics before pregnancy. Live birth rate was not different between the biologics group and biologics naïve group (75.0% vs. 75.2%). Multivariate analyses showed that biologics use was associated with higher risk of intrauterine growth retardation (odds ratio OR, 1.780) and lower risk of gestational diabetes mellitus (OR, 0.776) compared with biologics naïve. Biologics use during pregnancy was associated with higher risk of preterm delivery (OR, 1.859), preeclampsia/eclampsia (OR, 1.762), intrauterine growth retardation (OR, 3.487), and cesarean section (OR, 1.831), but lower risk of fetal loss (OR, 0.274) compared with biologics naïve.
Although there was no difference in live birth rate between the biologics group and biologics naïve group, biologics use seems to be associated with several adverse pregnancy outcomes, especially in patients with biologics during pregnancy. Therefore, patients with biologics during pregnancy need to be carefully observed for adverse pregnancy outcomes.
The association of HLA-B*27 with AS is amongst the strongest of any known association of a common variant with any human disease. Nonetheless, there is strong evidence indicating that other HLA-B ...alleles are involved in the disease. European ethnicity studies have demonstrated risk associations with HLA-B*40 and multiple other HLA-B, HLA-A, and HLA class II alleles, and demonstrated that in that ethnic group, the amino acid sequence at position 97 in HLA-B is the key determinant of HLA associations with AS. A recent study in Korean AS cases and controls additionally identified association at HLA-C*15:02. In the current study, we examined the MHC associations of AS in an expanded East Asian cohort.
A total of 1637 Chinese, Taiwanese, and Korean AS cases meeting the modified New York Criteria for AS, and 1589 ethnically matched controls, were genotyped with the Illumina Immunochip, including a dense coverage of the MHC region. HLA genotypes and amino acid composition were imputed using the SNP2HLA programme using the Han-MHC reference panel based on the data of Han Chinese subjects (n = 9689), and association tested using logistic regression controlling for population stratification effects.
A strong association was seen with HLA-B*27 (odds ratio (OR) = 205.3, P = 5.76 × 10
). Controlling for this association, the strongest risk association is seen with HLA-C*15 at genome-wide significant level (OR = 7.62, P = 9.30 × 10
), and confirmed association is also seen with HLA-B*40 at suggestive level (OR = 1.65, P = 2.54 × 10
). At amino acid level, the strongest association seen in uncontrolled analysis was with histidine at position 114 in HLA-B (P = 7.24 × 10
), but conditional analyses suggest that the primary amino acid associations are with lysine at position 70 and asparagine at position 97. Restriction of the ERAP1 association with HLA-B27-positive AS, previously reported in European subjects, was confirmed in East Asians.
This study confirms in East Asians that the HLA associations of AS are multiple, including previously reported associations at HLA-B*27, HLA-B*40, and HLA-C*15, as well as novel association with HLA-DQB1*04. The HLA-B associations are driven by the amino acids at positions 70 and 97, in the B pocket of HLA-B.
Objective
HLA association fine‐mapping studies have shown the effects of missense variants in HLA–DRB1 on rheumatoid arthritis (RA) susceptibility, prognosis, and autoantibody production. However, ...the phenotypic effects of expression changes in HLA–DRB1 remain poorly understood. Therefore, we investigated the allele‐specific expression of HLA–DRB1 and its effect on an HLA–DRβ1 structure–associated trait in RA.
Methods
We quantified the allele‐specific expression of each HLA–DRB1 3‐field classic allele in 48 Korean RA patients with anti–citrullinated protein antibodies (ACPAs) and 319 healthy European subjects by using both RNA sequencing and HLA–DRB1 genotype data to calculate the relative expression strength of multiple HLA–DRB1 alleles (n = 14 in Koreans and n = 25 in Europeans) in each population. The known association between ACPA level and alanine at position 74 of HLA–DRβ1 in ACPA‐positive RA was revisited to understand the phenotypic effect of allele‐specific expression of HLA–DRB1 by modeling multivariate logistic regression with the genomic dosage or relative expression dosage of Ala‐74 in 2 independent sets of 1,723 Korean RA patients with ACPA.
Results
The relative expression strength was highly allele‐specific, causing imbalanced allelic expression in HLA–DRB1 heterozygotes. The association between HLA‐DRβ1 Ala‐74 and ACPA level in RA was better explained by relative expression dosage of Ala‐74 than by the genomic dosage (change in Akaike's information criterion = −6.98). Moreover, the expression variance of Ala‐74 in Ala‐74 heterozygotes with no genomic variance of Ala‐74 was significantly associated with ACPA level (P = 2.26 × 10−3).
Conclusion
Our findings illustrate the advantage of integrating quantitative and qualitative changes in HLA–DRB1 into a single model for understanding HLA–DRB1 associations.
Diabetic macular edema (DME), a complication of diabetes mellitus, is a leading cause of adult-onset blindness worldwide. Recently, intravitreal anti-VEGF injection has been used as a first-line ...treatment. This study analyzed the association between the genetic profile of patients with DME and their response to treatment. Intravitreal anti-VEGF injections were administered monthly for three months to Korean patients diagnosed with DME, who were classified into two groups depending on whether they responded to anti-VEGF therapy or showed recurrence within six months. Peripheral blood samples were used for genetic analyses. Genome-wide association analysis results sowed that the genes DIRC3 on chromosome 2 (rs16857280, p = 1.2 × 10
), SLCO3A1 on chromosome 15 (rs12899055, p = 2.5 × 10
), and RAB2A on chromosome 8 (rs2272620, p = 4.6 × 10
) were associated with treatment response to intravitreal anti-VEGF injection. SLC35F1, TMEM132D, KIAA0368, HPCAL1, IGF2BP3, SPN2S, COL23A1, and CREB5 were also related to treatment response (p < 5.0 × 10
). Using the KEGG pathway analysis, RAB2A and CREB5 were found to be associated with AMPK signaling related to VEGF (p = 0.018). The identified genetic biomarkers can elucidate the factors affecting patient response to intravitreal anti-VEGF injection and help select appropriate therapeutic strategy.
PDF
