Takayasu arteritis (TAK) is an immune-mediated vasculitis affecting large arteries first reported in 1908 from Japan. Case reports of familial onset of TAK from Japan and other countries indicated ...genetic contribution to TAK onset beyond ethnicity. Genetic studies of TAK have been performed mainly addressing the human leukocyte antigen (HLA) locus. HLA genetic studies of TAK that have previously been reported are reviewed in this manuscript. HLA-B*52:01 is associated with TAK beyond population. Many of the associations other than HLA-B*52:01 can be explained by a haplotype with HLA-B*52:01. HLA-B*67:01 is a novel susceptibility HLA-B allele to TAK confirmed in the Japanese population. Further independent associations are suggested in the HLA locus. Involvement of the 171st and 67th amino acid residues with TAK onset has been indicated. The 67th amino acid may explain the difference in susceptibility effects to TAK and Behçet's disease between HLA-B*52:01 and *51:01. HLA-B*52:01 is associated not only with TAK susceptibility but also with clinical phenotypes. Recent genome-wide association studies of TAK revealed multiple non-HLA susceptibility genes. In particular, the IL12B region seems to have a central role in TAK onset and its progression. Whether TAK and giant cell arteritis (GCA), the other vasculitis affecting large arteries, are the same disease is an interesting question to address in spite of different clinical manifestations between the two diseases. GCA is associated with HLA-DR4, which is not associated with TAK. GCA is not associated with HLA-Bw52. These two diseases seem not to share non-HLA susceptibility loci based on the recent genetic studies.
Structural variations (SVs) or copy number variations (CNVs) greatly impact the functions of the genes encoded in the genome and are responsible for diverse human diseases. Although a number of ...existing SV detection algorithms can detect many types of SVs using whole genome sequencing (WGS) data, no single algorithm can call every type of SVs with high precision and high recall.
We comprehensively evaluate the performance of 69 existing SV detection algorithms using multiple simulated and real WGS datasets. The results highlight a subset of algorithms that accurately call SVs depending on specific types and size ranges of the SVs and that accurately determine breakpoints, sizes, and genotypes of the SVs. We enumerate potential good algorithms for each SV category, among which GRIDSS, Lumpy, SVseq2, SoftSV, Manta, and Wham are better algorithms in deletion or duplication categories. To improve the accuracy of SV calling, we systematically evaluate the accuracy of overlapping calls between possible combinations of algorithms for every type and size range of SVs. The results demonstrate that both the precision and recall for overlapping calls vary depending on the combinations of specific algorithms rather than the combinations of methods used in the algorithms.
These results suggest that careful selection of the algorithms for each type and size range of SVs is required for accurate calling of SVs. The selection of specific pairs of algorithms for overlapping calls promises to effectively improve the SV detection accuracy.
Rare autoimmune diseases are difficult to conduct researches in spite of present era with advanced scientific progress. Research using genetic approach is a promising way since genetic findings ...implicate causality of diseases. Still, there are multiple obstacles preventing genetic studies of rare diseases. Here, we list up the problems and propose solutions for them with detailed examples. The biggest problem is that it is difficult to collect a substantial number of DNA samples from patients with rare diseases. We propose to collaborate not only with academic institutions and hospitals but with patients' groups. Detailed examples include studies about Takayasu arteritis (TAK), relapsing polychondritis, and systemic sclerosis. In TAK, we identified IL12B, a key gene which seems to play a central role in the disease. After getting evidence of IL12p40 encoded by IL12B as a possible therapeutic target by showing similarities of the genetic background between TAK and ulcerative colitis, we performed a pilot clinical study of ustekinumab, a monoclonal antibody against IL12p40 for patients with refractory TAK and obtained good response. This is a good example of how genetic findings in a rare disease lead to development of new therapeutic option.
Rheumatoid arthritis (RA) is an autoimmune disease characterized by chronic inflammation and subsequent proliferation of synovial tissues, which eventually leads to cartilage and bone destruction ...without effective treatments. Anti-citrullinated cyclic peptide/protein antibody (ACPA) and rheumatoid factor (RF) are two main characteristic autoantibodies found in RA patients and are associated with unfavorable disease outcomes. Although etiologies and causes of the disease have not been fully clarified yet, it is likely that interactive contributions of genetic and environmental factors play a main role in RA pathology. Previous works have demonstrated several genetic and environmental factors as risks of RA development and/or autoantibody productions. Among these, cigarette smoking and
are the well-established environmental and genetic risks, respectively. In this narrative review, we provide a recent update on genetic contributions to RA and the environmental risks of RA with a special focus on cigarette smoking and its impacts on RA pathology. We also describe gene-environmental interaction in RA pathogenesis with an emphasis on cigarette smoking and
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Mosaic chromosomal alterations (mCAs) are frequently observed in cancer cells and are regarded as one of the common features of cancers. Strikingly, accumulating studies demonstrated that mCAs are ...also prevalent in elderly individuals without cancer, implying mCA could be a feature of aging and not necessarily a cancerous state. However, the genetic basis of mCA has been mostly unknown. Recent studies of autosomal mCA based on biobank-scale datasets, including UK Biobank and Biobank Japan, provided a glimpse into the underlying genetic mechanism. In this concise review, we briefly introduced mCA, its link with cancer and aging, and the emerging genetic mechanisms of this phenomenon. We highlighted the following aspects: (1) the interplay between somatic and inherited germline mutations in generating mosaicism; (2) monogenic and polygenic architectures of mCA; and (3) population-specific profiles of mCA. We provided a future perspective emphasizing the need to understand the connection between mCA and other characteristics of aging, in particular, the epigenetic and immunologic features.
Poor trans-ancestry portability of polygenic risk scores is a consequence of Eurocentric genetic studies and limited knowledge of shared causal variants. Leveraging regulatory annotations may improve ...portability by prioritizing functional over tagging variants. We constructed a resource of 707 cell-type-specific IMPACT regulatory annotations by aggregating 5,345 epigenetic datasets to predict binding patterns of 142 transcription factors across 245 cell types. We then partitioned the common SNP heritability of 111 genome-wide association study summary statistics of European (average n ≈ 189,000) and East Asian (average n ≈ 157,000) origin. IMPACT annotations captured consistent SNP heritability between populations, suggesting prioritization of shared functional variants. Variant prioritization using IMPACT resulted in increased trans-ancestry portability of polygenic risk scores from Europeans to East Asians across all 21 phenotypes analyzed (49.9% mean relative increase in R
). Our study identifies a crucial role for functional annotations such as IMPACT to improve the trans-ancestry portability of genetic data.
IgG4-related disease (IgG4-RD) is an emerging concept of a novel clinical entity, characterized by the swelling of the affected organs, increase in serum total IgG and IgG4 levels, infiltration of ...plasmacyte and eosinophil, fibrosis of the affected lesions and good response to corticosteroid. IgG4-RD includes diseases with organ-specific fibrosis and infiltration of IgG4-positive plasmacyte, previously known as type 1 autoimmune pancreatitis (AIP), Mikulicz's disease and others. Although the precise mechanisms of the pathogenesis of IgG4-RD are not yet understood, some studies have suggested genetic components contributing to the onset of IgG4-RD or its subgroup. The recent emergence of the concept of IgG4-RD has made it difficult to conduct genetic analyses of IgG4-RD as a whole. When the analyses are restricted to the various subgroups of IgG4-RD, they require a large number of DNA samples from patients satisfying IgG4-RD diagnostic criteria not completely overlapping the criteria in type 1 AIP, Mikulicz's disease and others. Not only HLA but also non-HLA genes have been described as IgG4-RD risk genes, particularly in type 1 AIP. In this mini-review article, we will explore previous studies analyzing genetic associations with IgG4-RD and its subgroups, and discuss the future direction of the research addressing the existing problems.
The extent to which the biology of oncogenesis and ageing are shaped by factors that distinguish human populations is unknown. Haematopoietic clones with acquired mutations become common with ...advancing age and can lead to blood cancers
. Here we describe shared and population-specific patterns of genomic mutations and clonal selection in haematopoietic cells on the basis of 33,250 autosomal mosaic chromosomal alterations that we detected in 179,417 Japanese participants in the BioBank Japan cohort and compared with analogous data from the UK Biobank. In this long-lived Japanese population, mosaic chromosomal alterations were detected in more than 35.0% (s.e.m., 1.4%) of individuals older than 90 years, which suggests that such clones trend towards inevitability with advancing age. Japanese and European individuals exhibited key differences in the genomic locations of mutations in their respective haematopoietic clones; these differences predicted the relative rates of chronic lymphocytic leukaemia (which is more common among European individuals) and T cell leukaemia (which is more common among Japanese individuals) in these populations. Three different mutational precursors of chronic lymphocytic leukaemia (including trisomy 12, loss of chromosomes 13q and 13q, and copy-neutral loss of heterozygosity) were between two and six times less common among Japanese individuals, which suggests that the Japanese and European populations differ in selective pressures on clones long before the development of clinically apparent chronic lymphocytic leukaemia. Japanese and British populations also exhibited very different rates of clones that arose from B and T cell lineages, which predicted the relative rates of B and T cell cancers in these populations. We identified six previously undescribed loci at which inherited variants predispose to mosaic chromosomal alterations that duplicate or remove the inherited risk alleles, including large-effect rare variants at NBN, MRE11 and CTU2 (odds ratio, 28-91). We suggest that selective pressures on clones are modulated by factors that are specific to human populations. Further genomic characterization of clonal selection and cancer in populations from around the world is therefore warranted.
Age is the dominant risk factor for infectious diseases, but the mechanisms linking age to infectious disease risk are incompletely understood. Age-related mosaic chromosomal alterations (mCAs) ...detected from genotyping of blood-derived DNA, are structural somatic variants indicative of clonal hematopoiesis, and are associated with aberrant leukocyte cell counts, hematological malignancy, and mortality. Here, we show that mCAs predispose to diverse types of infections. We analyzed mCAs from 768,762 individuals without hematological cancer at the time of DNA acquisition across five biobanks. Expanded autosomal mCAs were associated with diverse incident infections (hazard ratio (HR) 1.25; 95% confidence interval (CI) = 1.15-1.36; P = 1.8 × 10
), including sepsis (HR 2.68; 95% CI = 2.25-3.19; P = 3.1 × 10
), pneumonia (HR 1.76; 95% CI = 1.53-2.03; P = 2.3 × 10
), digestive system infections (HR 1.51; 95% CI = 1.32-1.73; P = 2.2 × 10
) and genitourinary infections (HR 1.25; 95% CI = 1.11-1.41; P = 3.7 × 10
). A genome-wide association study of expanded mCAs identified 63 loci, which were enriched at transcriptional regulatory sites for immune cells. These results suggest that mCAs are a marker of impaired immunity and confer increased predisposition to infections.
Short- and long-read sequencing technologies are routinely used to detect DNA variants, including SNVs, indels, and structural variations (SVs). However, the differences in the quality and quantity ...of variants detected between short- and long-read data are not fully understood. In this study, we comprehensively evaluated the variant calling performance of short- and long-read-based SNV, indel, and SV detection algorithms (6 for SNVs, 12 for indels, and 13 for SVs) using a novel evaluation framework incorporating manual visual inspection. The results showed that indel-insertion calls greater than 10 bp were poorly detected by short-read-based detection algorithms compared to long-read-based algorithms; however, the recall and precision of SNV and indel-deletion detection were similar between short- and long-read data. The recall of SV detection with short-read-based algorithms was significantly lower in repetitive regions, especially for small- to intermediate-sized SVs, than that detected with long-read-based algorithms. In contrast, the recall and precision of SV detection in nonrepetitive regions were similar between short- and long-read data. These findings suggest the need for refined strategies, such as incorporating multiple variant detection algorithms, to generate a more complete set of variants using short-read data.
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