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Dengue, a viral infection transmitted by Aedes mosquitoes, is an emerging global health threat exacerbated by climate change. Rising temperatures and altered precipitation patterns create favourable conditions for vector proliferation and extended transmission periods, increasing the risk of dengue in endemic regions and facilitating its spread to non-endemic areas. Understanding the interplay between critical genetic factors and dengue susceptibility is crucial for developing effective public health strategies. The Human Leukocyte Antigen (HLA) genes encode proteins essential for an effective immune response against pathogens, and their genetic variations influence susceptibility to severe dengue. In this study, we conducted a comprehensive meta-analysis of HLA alleles associated with dengue infection and dengue severity. We analysed 19 case-control studies on dengue infections in populations worldwide to infer HLA associations with various pathological forms of dengue and to examine differences across different populations. Our findings indicate that HLA-A*02 increases susceptibility to dengue fever (DF), while HLA-A*03 increases the risk of Dengue Haemorrhagic Fever (DHF), with these increased susceptibilities primarily observed in Southeast Asian populations. Additionally, HLA-A*24 is associated with DHF and all symptomatic dengue infections (DEN), contributing to dengue risk in both Southeast Asia and the Caribbean. Conversely, HLA-A*33 and HLA-B*44 show a protective effect against DHF but show significant regional heterogeneity, highlighting divergent, population-specific susceptibility profiles. This study underscores the importance of population-specific genetic risk assessments for dengue infection and emphasizes the need for targeted medical interventions and improved predictive models to mitigate dengue’s impact, especially as climate change accelerates disease spread.

The Jomon and the Yayoi are considered to be the two major ancestral populations of the modern mainland Japanese. The Jomon people, who inhabited mainland Japan, admixed with Yayoi immigrants from the Asian continent. To investigate the population history in the Jomon period (14,500–2,300 years before present [YBP]), we analyzed whole Y-chromosome sequences of 345 Japanese males living in mainland Japan. A phylogenetic analysis of East Asian Y chromosomes identified a major clade (35.4% of mainland Japanese) consisting of only Japanese Y chromosomes, which seem to have originated from indigenous Jomon people. A Monte Carlo simulation indicated that ~70% of Jomon males had Y chromosomes in this clade. The Bayesian skyline plots of 122 Japanese Y chromosomes in the clade detected a marked decrease followed by a subsequent increase in the male population size from around the end of the Jomon period to the beginning of the Yayoi period (2,300 YBP). The colder climate in the Late to Final Jomon period may have resulted in critical shortages of food for the Jomon people, who were hunter-gatherers, and the rice farming introduced by Yayoi immigrants may have helped the population size of the Jomon people to recover.

Individual differences have been observed in side effects after vaccination for COVID-19, and host genetic factors have been suggested as a contributing factor. Here, we conducted a genome-wide association study (GWAS) involving 2,554 Japanese corporate employees who received a third booster dose of BNT162b2/Pfizer or mRNA-1273/Moderna vaccine. Although no genome-wide significant association was found for the presence of adverse symptoms, the GWAS for severity revealed six associated loci. The most significant association was observed between the severity of swelling of lymph nodes and chromosome 2q12 locus, including the IL1RL1 , IL18R1 , and IL18RAP genes (lead variant: rs76152249; P  = 1.46 × 10 −9 ). Pathway analysis suggested associations between immune pathways related to the MHC locus, including HLA genes, and the occurrence and severity of fever, and the NF-κB binding pathway and those of itching at the injection site. In addition, a meta-analysis of previous GWAS studies for the primary first or second dose of COVID-19 vaccine revealed 818 variants from 72 loci that demonstrated genome-wide significant associations with any of 12 symptoms, and pathway analysis identified immune pathways related to the MHC locus, suggesting shared genetic risks among primary and booster vaccinations. These results may help control side effects following COVID-19 vaccination.

There are ten leukocyte immunoglobulin (Ig)-like receptor ( LILR ) genes, i.e., five genes encoding activating receptors ( LILRA1, LILRA2, LILRA4, LILRA5 , and LILRA6 ) characterized by their truncated cytoplasmic tails, and five genes encoding inhibitory receptors ( LILRB1, LILRB2, LILRB3, LILRB4 , and LILRB5 ) characterized by their extended cytoplasmic tails containing immunoreceptor tyrosine-based inhibitory motifs (ITIMs). Among these, LILRB3 , LILRA6 , and LILRA3 are known for harboring high frequencies of copy number variations (CNVs). However, the presence of CNVs in the leukocyte receptor complex (LRC) region complicates single nucleotide polymorphism (SNP) association analysis within commercially available SNP microarray datasets. This study introduces LILR Genotype Imputation with Attribute Bagging (LIBAG), a novel method for determining CNVs in LILRB3, LILRA6 , and LILRA3 from commercially available SNP genotyping array datasets. LILRA6 CNV imputation accuracy peaked at 98.0% for the Infinium Japanese Screening Array, followed by 97.4% for Axiom Japonica V2, 97.3% for Axiom Japonica Array NEO, and 94.3% for Axiom Japonica V1, with the lowest recorded accuracy of 93.6% for the Axiom Genome-wide ASI1 array. For the 1000 Genomes Project (1kGP) dataset, LILRA6 CNV imputation achieved peak accuracies of 94.5% for 1kGP-EAS (East Asian), 86.6% for 1kGP-AMR (Admixed American), 83.8% for 1kGP-EUR European), and 75.0% for 1kGP-AFR (African), particularly after the 20 kb flanking region. Similarly, imputation accuracy for LILRA3 CNV progressively increased, peaking at the 80 kb flanking region. Accuracy reached 1kGP-AMR, reaching 99.2% and 98.9% for 1kGP-AFR, 98.7% for 1kGP-EUR, and 97.5% for 1kGP-EAS. Investigating the LILR copy number (CN) in diseases associated with HLA class I molecules will provide further insights into disease pathogenesis.

CD58 plays roles in cell adhesion and co-stimulation with antigen presentation from major histocompatibility complex class II on antigen-presenting cells to T-cell antigen receptors on naïve T cells. CD58 reportedly contributes to the development of various human autoimmune diseases. Recently, genome-wide association studies (GWASs) identified CD58 as a susceptibility locus for autoimmune diseases such as systemic lupus erythematosus (SLE), multiple sclerosis (MS), and primary biliary cholangitis (PBC). However, the primary functional variant and molecular mechanisms of susceptibility to autoimmune diseases in the CD58 locus were not clarified. Here, rs10924104, located in the ZNF35-binding motif within the gene expression regulatory motif, was identified as the primary functional variant for SLE, MS, and PBC among genetic variants showing stronger linkage disequilibrium (LD) with GWAS-lead variants in the CD58 locus. Expression-quantitative trait locus (e-QTL) data for each distinct blood cell type and in vitro functional analysis using the CRISPR/Cas9 system corroborated the functional role of rs10924104 in the upregulation of CD58 transcription by the disease-risk allele. Additionally, the strength of disease susceptibility observed in the CD58 locus could be accounted for by the strength of LD between rs10924104 and each GWAS-lead variant. In conclusion, the present study demonstrated for the first time the existence of a shared autoimmune disease-related primary functional variant (i.e., rs10924104) that regulates the expression of CD58. Clarifying the molecular mechanism of disease susceptibility derived from such a shared genetic background is important for understanding human autoimmune diseases and human immunology.

Primary biliary cholangitis (PBC) is a chronic, progressive cholestatic liver disease in which intrahepatic bile ducts are destroyed by an autoimmune reaction. Our previous genome-wide association study (GWAS) identified chromosome 11q23.1 as a susceptibility gene locus for PBC in the Japanese population. Here, high-density association mapping based on single nucleotide polymorphism (SNP) imputation and in silico/in vitro functional analyses identified rs1944919 as the primary functional variant. Expression-quantitative trait loci analyses showed that the PBC susceptibility allele of rs1944919 was significantly associated with increased COLCA1 / COLCA2 expression levels. Additionally, the effects of rs1944919 on COLCA1 / COLCA2 expression levels were confirmed using genotype knock-in versions of cell lines constructed using the CRISPR/Cas9 system and differed between rs1944919-G/G clones and -T/T clones. To our knowledge, this is the first study to demonstrate the contribution of COLCA1/COLCA2 to PBC susceptibility.

Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are life-threatening acute inflammatory vesiculobullous reactions of the skin and mucous membranes. These severe cutaneous drug reactions are known to be caused by inciting drugs and infectious agents. Previously, we have reported the association of  HLA-A*02:06  and  HLA-B*44:03  with cold medicine (CM)-related SJS/TEN with severe ocular complications (SOCs) in the Japanese population. However, the conventional HLA typing method (PCR-SSOP) sometimes has ambiguity in the final HLA allele determination. In this study, we performed HLA-disease association studies in CM-SJS/TEN with SOCs at 3- or 4-field level. 120 CM-SJS/TEN patients with SOCs and 817 Japanese healthy controls are HLA genotyped using the high-resolution next-generation sequencing (NGS)-based HLA typing of HLA class I genes, including  HLA-A ,  HLA-B , and  HLA-C . Among the alleles of HLA class I genes,  HLA-A*02:06:01  was strongly associated with susceptibility to CM-SJS/TEN ( p  = 1.15 × 10 −18 , odds ratio = 5.46). Four other alleles ( HLA-A*24:02:01 ,  HLA-B*52:01:01 ,  HLA-B*46:01:01 , and  HLA-C*12:02:02 ) also demonstrated significant associations. HLA haplotype analyses indicated that  HLA-A*02:06:01  is primarily associated with susceptibility to CM-SJS/TEN with SOCs. Notably, there were no specific disease-causing rare variants among the high-risk HLA alleles. This study highlights the importance of higher resolution HLA typing in the study of disease susceptibility, which may help to elucidate the pathogenesis of CM-SJS/TEN with SOCs.

An imputation algorithm for human leukocyte antigen (HLA) is helpful for exploring novel disease associations. However, population-specific HLA imputation references are essential for achieving high imputation accuracy. In this study, a subset of 1012 individuals from the Taiwan Biobank (TWB) who underwent both whole-genome SNP array and NGS-based HLA typing were used to establish Taiwanese HLA imputation references. The HIBAG package was used to generate the imputation references for eight HLA loci at a two- and three-field resolution. Internal validation was carried out to evaluate the call threshold and accuracy for each HLA gene. HLA class II genes found to be associated with rheumatoid arthritis (RA) were validated in this study by the imputed HLA alleles. Our Taiwanese population-specific references achieved average HLA imputation accuracies of 98.11% for two-field and 98.08% for three-field resolution. The frequency distribution of imputed HLA alleles among 23,972 TWB subjects were comparable with PCR-based HLA alleles in general Taiwanese reported in the allele frequency net database. We replicated four common HLA alleles (HLA-DRB1*03:01, DRB1*04:05, DQA1*03:03, and DQB1*04:01) significantly associated with RA. The population-specific references provide an informative tool to investigate the associations of HLA variants and human diseases in large-scale population-based studies.

Food allergy is an increasingly important health problem in the world. Several genome-wide association studies (GWAS) focused on European ancestry samples have identified food allergy-specific loci in the HLA class II region. We conducted GWAS of self-reported reactivity with common foods using the data from 11011 Japanese women and identified shrimp and peach allergy-specific loci in the HLA-DR/DQ gene region tagged by rs74995702 ( P  = 6.30 × 10 −17 , OR  = 1.91) and rs28359884 ( P  = 2.3 × 10 −12 , OR  = 1.80), respectively. After HLA imputation using a Japanese population-specific reference, the most strongly associated haplotype was HLA-DRB1*04:05-HLA-DQB1*04:01 for shrimp allergy ( P  = 3.92 × 10 −19 , OR  = 1.99) and HLA-DRB1*09:01-HLA-DQB1*03:03 for peach allergy ( P  = 1.15 × 10 −7 , OR  = 1.68). Additionally, both allergies’ associated variants were eQTLs for several HLA genes, with HLA-DQA 2 the single eQTL gene shared between the two traits. Our study suggests that allergy to certain foods may be related to genetic differences that tag both HLA alleles having particular epitope binding specificities as well as variants modulating expression of particular HLA genes. Investigating this further could increase our understanding of food allergy aetiology and potentially lead to better therapeutic strategies for allergen immunotherapies.

We have performed a genome-wide association study (GWAS) including 473 Japanese HBV (hepatitis B virus)-positive HCC (hepatocellular carcinoma) patients and 516 HBV carriers including chronic hepatitis and asymptomatic carrier individuals to identify new host genetic factors associated with HBV-derived HCC in Japanese and other East Asian populations. We identified 65 SNPs with P values < 10 −4 located within the HLA class I region and three SNPs were genotyped in three independent population-based replication sets. Meta-analysis confirmed the association of the three SNPs (rs2523961: OR = 1.73, P = 7.50 × 10 −12 ; rs1110446: OR = 1.79, P = 1.66 × 10 −13 ; and rs3094137: OR = 1.73, P = 7.09 × 10 −9 ). We then performed two-field HLA genotype imputation for six HLA loci using genotyping data to investigate the association between HLA alleles and HCC. HLA allele association testing revealed that HLA-A * 33:03 (OR = 1.97, P = 4.58 × 10 −4 ) was significantly associated with disease progression to HCC. Conditioning analysis of each of the three SNPs on the HLA class I region abolished the association of HLA-A * 33:03 with disease progression to HCC. However, conditioning the HLA allele could not eliminate the association of the three SNPs, suggesting that additional genetic factors may exist in the HLA class I region.