C-reactive protein (CRP) is a hallmark acute-phase reactant and is widely used as a blood marker for inflammation. Substantial roles of serum CRP levels in the pathogenesis of diseases have been ...suggested, and investigation of the mechanisms that regulate serum CRP levels would have a substantial clinical impact. Here, through genome-wide association and replication studies performed using 12 854 Japanese subjects, we identified a significant association between serum CRP levels and a single nucleotide polymorphism in the promoter region of interleukin-6 (IL6) (rs2097677, P = 4.1 × 10(-11)), a typical pleiotropic pro-inflammatory cytokine. Our study also replicated the associations in the CRP (rs3093059, P = 3.5 × 10(-21)) and HNF1A loci (rs7310409, P = 2.7 × 10(-8)). Pleiotropic association analysis with hematological and biochemical traits using 30 466 Japanese subjects demonstrated that the CRP-increasing allele of rs2097677 in the IL6 locus was significantly associated with an increased white blood cell count, platelet count and serum globulin and a decreased mean corpuscular hemoglobin and mean corpuscular hemoglobin concentration (P < 5.0 × 10(-4)), although no pleiotropic association was observed in the CRP or HNF1A locus (α = 0.01). Our study demonstrated the pivotal role of the IL6 locus in the regulation of serum CRP levels and inflammatory pathways.
Genome-wide association studies (GWASs) have revealed relationships between over 57,000 genetic variants and diseases. However, unlike Mendelian diseases, complex diseases arise from the interplay of ...multiple genetic and environmental factors. Natural selection has led to a high tendency of risk alleles to be enriched in minor alleles in Mendelian diseases. Therefore, an allele that was previously advantageous or neutral may later become harmful, making it a risk allele.
Using data in the NHGRI-EBI Catalog and the VARIMED database, we investigated whether (1) GWASs more easily detect risk alleles and (2) facilitate evolutionary insights by comparing risk allele frequencies of different diseases. We conducted computer simulations of P-values for association tests when major and minor alleles were risk alleles. We compared the expected proportion of SNVs whose risk alleles were minor alleles with the observed proportion.
Our statistical results revealed that risk alleles were enriched in minor alleles, especially for variants with low minor allele frequencies (MAFs < 0.1). Our computer simulations revealed that > 50% risk alleles were minor alleles because of the larger difference in the power of GWASs to differentiate between minor and major alleles, especially with low MAFs or when the number of controls exceeds the number of cases. However, the observed ratios between minor and major alleles in low MAFs (< 0.1) were much larger than the expected ratios of GWAS's power imbalance, especially for diseases whose average risk allele frequencies were low, such as myopia, sudden cardiac arrest, and systemic lupus erythematosus.
Minor alleles are more likely to be risk alleles in the published GWASs on complex diseases. One reason is that minor alleles are more easily detected as risk alleles in GWASs. Even when correcting for the GWAS's power imbalance, minor alleles are more likely to be risk alleles, especially in some diseases whose average risk allele frequencies are low. These analyses serve as a starting point for future studies on quantifying the degree of negative natural selection in various complex diseases.
Pancreatic cancer shows very poor prognosis and is the fifth leading cause of cancer death in Japan. Previous studies indicated some genetic factors contributing to the development and progression of ...pancreatic cancer; however, there are limited reports for common genetic variants to be associated with this disease, especially in the Asian population. We have conducted a genome-wide association study (GWAS) using 991 invasive pancreatic ductal adenocarcinoma cases and 5,209 controls, and identified three loci showing significant association (P-value<5x10(-7)) with susceptibility to pancreatic cancer. The SNPs that showed significant association carried estimated odds ratios of 1.29, 1.32, and 3.73 with 95% confidence intervals of 1.17-1.43, 1.19-1.47, and 2.24-6.21; P-value of 3.30x10(-7), 3.30x10(-7), and 4.41x10(-7); located on chromosomes 6p25.3, 12p11.21 and 7q36.2, respectively. These associated SNPs are located within linkage disequilibrium blocks containing genes that have been implicated some roles in the oncogenesis of pancreatic cancer.
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
, OR = 1.91) and rs28359884 (P = 2.3 × 10
, 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
, OR = 1.99) and HLA-DRB1*09:01-HLA-DQB1*03:03 for peach allergy (P = 1.15 × 10
, OR = 1.68). Additionally, both allergies' associated variants were eQTLs for several HLA genes, with HLA-DQA2 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.
Impaired renal uric acid excretion is the major mechanism of hyperuricemia in patients with primary gout. This review highlights recent advances in the knowledge of normal mechanisms of renal uric ...acid handling and derangement of these mechanisms in uric acid underexcretion.
The discovery of URAT1 has facilitated identification of other molecules potentially involved in uric acid transport in the renal tubules. Some of these molecules show gender differential expression in animal experiments. Sodium-dependent monocarboxylate cotransporters have been shown to transport lactate and butyrate, and may have roles in hyperuricemia associated with diabetic ketoacidosis and alcohol ingestion. Certain polymorphisms in SLC22A12 may be associated with the development of hyperuricemia or gout, although confirmation is needed. Mechanisms of hyperuricemia associated with uric acid underexcretion in patients with familial juvenile hyperuricemic nephropathy also remain to be clarified. Distal tubular salt wasting and compensatory upregulation of the resorption of sodium and uric acid in the proximal tubule may explain the hyperuricemia associated with this disorder.
Much progress has been made in understanding the mechanisms of renal uric acid handling. Elucidation of the mechanisms of hyperuricemia in patients with familial juvenile hyperuricemic nephropathy will shed light on the function of uromodulin, functional impairment of which eventually results in diminished uric acid excretion.
ChatGPT, a large language model released in late 2022, shocked the world with its human-like response capabilities. ChatGPT can generate grammatically correct sentences and respond to prompts ...accurately; however, it sometimes provides incorrect information. The latest version of ChatGPT is also capable of recognizing and interpreting images and pointing out errors in table calculations. AI has demonstrated capabilities surpassing those of humans in various fields, such as Go and Shogi, autonomous driving taxis, and medical research, with medical diagnostics reaching levels comparable to those of specialists. Generative AI like ChatGPT is characterized by its ability to create not only text but also images and sounds, thus generating new original content. Doctors and medical professionals must understand its principles as much as possible for usage.Information systems have evolved through a Tri-Core Information Model consisting of genes, brains, and AI. Each shares the structure of input, information processing, and output, functioning based on the principles of maximizing probability and incorporating randomness. However, there are differences among genes, brains, and AI in terms of parameter update intervals, number of parameters, and energy consumption. The brain's system has evolved to develop reasoning capabilities, language, and painting functions to maximize the probabilities of survival and reproduction. Generative AI features probability maximization and performs randomization based on this probability.ChatGPT calculates the probability of the next word from past sentences and generates new sentences using optimized parameters. While AI's evolution could pose a threat to humanity, understanding the threat and preventing AI from running amok requires not only knowledge of AI's technology and performance but also an understanding of its principles and theoretical basis. In the medical field, as the application of AI advances, it is necessary to consider not only technical knowledge but also ethical, legal, and social issues.
Rheumatoid arthritis is a multifactorial disease characterized by chronic inflammation of the joints. Both genetic and environmental factors are involved in the pathogenesis leading to joint ...destruction and ultimately disability. In the inflamed RA joint the synovium is highly infiltrated by CD4⁺ T cells, B cells and macrophages, and the intimal lining becomes hyperplastic owing to the increased number of macrophage-like and fibroblast-like synoviocytes. This hyperplastic intimal synovial lining forms an aggressive front, called pannus, which invades cartilage and bone structures, leading to the destruction and compromised function of affected joints. This process is mediated by a number of cytokines (tumor necrosis factor-α, interleukin-1, interleukin-6, interleukin-17 interferon-γ, etc.), chemokines (monocyte chemoattractant protein-1, monocyte chemoattractant protein-4 CCL18, etc.), cell adhesion molecules (intercellular adhesion molecule-1, vascular cell adhesion molecule-1, etc.) and matrix metalloproteinases. Expression of these molecules is controlled at the transcription level and activation of a limited number of transcription factors is involved in this process.
For single-cell experiments, it is important to accurately count the number of viable cells in a nanoliter well. We used a deep learning-based convolutional neural network (CNN) on a large amount of ...digital data obtained as microscopic images. The training set consisted of 103 019 samples, each representing a microscopic grayscale image. After extensive training, the CNN was able to classify the samples into four categories, i.e., 0, 1, 2, and more than 2 cells per well, with an accuracy of 98.3% when compared to determination by two trained technicians. By analyzing the samples for which judgments were discordant, we found that the judgment by technicians was relatively correct although cell counting was often difficult by the images of discordant samples. Based on the results, the system was further enhanced by introducing a new algorithm in which the highest outputs from CNN were used, increasing the accuracy to higher than 99%. Our system was able to classify the data even from wells with a different shape. No other tested machine learning algorithm showed a performance higher than that of our system. The presented CNN system is expected to be useful for various single-cell experiments, and for high-throughput and high-content screening.
Previous reports including genome-wide association studies (GWASs) have described associations of serum lipids with genomic variations. In the present study, we examined the association of ∼2.5 ...million single-nucleotide polymorphisms (SNPs) from 3041 Japanese healthy volunteers obtained from the Japan Pharmacogenomics Data Science Consortium (JPDSC) database with serum lipids. We confirmed the previously reported associations of 14 SNPs in 5 regions for low-density lipoprotein (LDL) cholesterol, 23 SNPs in 12 regions for high-density lipoprotein (HDL) cholesterol, 16 SNPs in 6 regions for triglyceride and 5 SNPs in 1 region for phospholipid. Furthermore, we identified 16 possible novel candidate genes associated with LDL cholesterol, HDL cholesterol or triglycerides, where SNPs had P-values of <1 × 10(-5). Further replication analyses of these genes with Korean data revealed significant associations of SNPs located within the PCSK7 gene and triglyceride (Pmeta=7.98 × 10(-9) and 1.91 × 10(-8) for rs508487 and rs236911, respectively). These associations remained significant even by the conditional analysis adjusting for three neighboring variations associated with triglyceride. Our present data suggest that PCSK7 as well as PCSK9 may be associated with lipids, especially triglyceride, and may serve as a candidate for a new drug target to treat lipid abnormality syndromes.
Gallbladder cancer (GC) is a relatively uncommon cancer with higher incidence in certain areas including Japan. Because of the difficulty in diagnosis, prognosis of GC is very poor. To identify ...genetic determinants of GC, we conducted a genome-wide association study (GWAS) in 41 GC patients and 866 controls. Association between each single-nucleotide polymorphism (SNP) with GC susceptibility was evaluated by multivariate logistic regression analysis conditioned on age and gender of subjects. SNPs that showed suggestive association (P<1 × 10(-4)) with GC were further examined in 30 cases and 898 controls. SNP rs7504990 in the DCC (deleted in colorectal cancer, 18q21.3) that encodes a netrin 1 receptor achieved a combined P-value of 7.46 × 10(-8) (OR=6.95; 95% CI=3.43-14.08). Subsequent imputation analysis identified multiple SNPs with similarly strong associations in an adjacent genomic region, where loss of heterozygosity was reported in GC and other cancers. Reduced expression of DCC was indicated to be associated with the poorly differentiated histological type, increased proliferation and metastasis through loss of adhesiveness. However, due to the limited sample size investigated here, further replication study and functional analysis would be necessary to further confirm the result of the association.
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