Large-scale genetic study in East Asians identifies six new loci associated with colorectal cancer risk

Known genetic loci explain only a small proportion of the familial relative risk of colorectal cancer (CRC). We conducted the largest genome-wide association study in East Asians with 14,963 CRC cases and 31,945 controls and identified six new loci associated with CRC risk (P = 3.42 × 10−8 to 9.22 × 10−21) at 10q22.3, 10q25.2, 11q12.2, 12p13.31, 17p13.3 and 19q13.2. Two of these loci map to genes (TCF7L2 and TGFB1) with established roles in colorectal tumorigenesis. Four other loci are located in or near genes involved in transcription regulation (ZMIZ1), genome maintenance (FEN1), fatty acid metabolism (FADS1 and FADS2), cancer cell motility and metastasis (CD9) and cell growth and differentiation (NXN). We also found suggestive evidence for three additional loci associated with CRC risk near genome-wide significance at 8q24.11, 10q21.1 and 10q24.2. Furthermore, we replicated 22 previously reported CRC loci. Our study provides insights into the genetic basis of CRC and suggests new biological pathways

The Polymorphism rs2725220 Is Associated with Hyperuricemia in the Korean Population

Elevated serum uric acid levels are associated with a variety of adverse health outcomes, including gout, hypertension, diabetes mellitus, metabolic syndrome, and cardiovascular diseases. Several genome-wide association studies on uric acid levels have implicated the ATP-binding cassette, subfamily G, member 2 (ABCG2) gene as being possibly causal. We investigated an association between the single-nucleotide polymorphism (SNP) rs2725220 in the ABCG2 gene and uric acid levels in the Korean population. A total of 991 subjects in Seoul City were used for a replication study with ABCG2 SNP rs2725220. The rs2725220 SNP in the ABCG2 gene was associated with mean uric acid levels (effect per allele 0.25 mg/dL, p < 0.0001). Subjects with the GC/CC genotype had a 1.78-fold (range, 1.22- to 2.62-fold) higher risk of having abnormal uric acid levels (≥7.0 mg/dL) than subjects with the GG genotype. When analyzed by gender, the association with ABCG2 was stronger in men than in women. The association with ABCG2 was much stronger in male subjects with body mass index (BMI) ≥ 26.4 (odds ratio, 5.09; 95% confidence interval, 2.41 to 10.8) than in male subjects with BMI < 26.4. This study clearly demonstrates that genetic variations in ABCG2 influence uric acid levels in Korean adults

Genome-Wide Association Study Identifies Eight Novel Loci for Susceptibility of Scrub Typhus and Highlights Immune-Related Signaling Pathways in Its Pathogenesis

Scrub typhus is a fatal zoonotic disease caused by Orientia tsutsugamushi. This disease is accompanied by systemic vasculitis, lymphadenopathy, headache, myalgia, and eschar. In recent studies, a novel strain that is resistant to current medical treatment was identified in Thailand. Thus, the development of new specific drugs for scrub typhus is needed. However, the exact molecular mechanism governing the progression of scrub typhus has not been fully elucidated. To understand disease-related genetic factors and mechanisms associated with the progression of scrub typhus, we performed a genome-wide association study (GWAS) in scrub typhus-infected patients and found a scrub typhus-related signaling pathway by molecular interaction search tool (MIST) and PANTHER. We identified eight potent scrub typhus-related single nucleotide polymorphisms (SNPs) located on the PRMT6, PLGLB2, DTWD2, BATF, JDP2, ONECUT1, WDR72, KLK, MAP3K7, and TGFBR2 genes using a GWAS. We also identified 224 genes by analyzing protein-protein interactions among candidate genes of scrub typhus and identified 15 signaling pathways associated with over 10 genes by classifying these genes according to signaling pathways. The signaling pathway with the largest number of associated genes was the gonadotropin-releasing hormone receptor pathway, followed by the TGF-beta signaling pathway and the apoptosis signaling pathway. To the best of our knowledge, this report describes the first GWAS in scrub typhus

Additional file 2: Figure S2. of Gene-gene interaction analysis identifies a new genetic risk factor for colorectal cancer

Linkage disequilibrium of six SNPs of the adiponectin gene (APN). (TIFF 599 kb

Additional file 1: Figure S1. of Gene-gene interaction analysis identifies a new genetic risk factor for colorectal cancer

Overall study population design. (TIFF 1061 kb

Obstructive sleep apnoea and long-term risk of incident diabetes in the middle-aged and older general population

Background Obstructive sleep apnoea (OSA) is associated with increased risk of type 2 diabetes. However, results from large population-based prospective cohort studies are rare. The main aim of the present study was to investigate the relative risk of 8-year incident type 2 diabetes in relation to OSA severity in a prospective cohort study of middle-aged and older adults. Methods A total of 2918 participants (mean age 59 years) of the Korean Genome and Epidemiology Study (KoGES), who underwent home-based overnight polysomnography at baseline examination between 2011 and 2014, were followed up 4-yearly between 2015–2018 and 2019–2021. A total of 1697 participants were present in both follow-ups. After excluding participants who had diabetes at baseline (n=481), a total of 1216 participants were eligible for the analyses. Results OSA at baseline was categorised by apnoea–hypopnoea index levels as non-OSA (0–4.9 events·h−1), mild OSA (5.0–14.9 events·h−1) and moderate–severe OSA (≥15.0 events·h−1). Incident type 2 diabetes was identified at each follow-up. Compared with non-OSA, participants with moderate–severe OSA had 1.5 times higher risk of developing type 2 diabetes at the end of the 8-year follow-up after adjusting for potential covariates (relative risk 1.50, 95% CI 1.02–2.21). In the same analytical models for 4-year relative risk of incident type 2 diabetes, none of the OSA groups were at significantly higher risk compared with the non-OSA group. Conclusion Moderate–severe OSA, a modifiable risk factor, poses a higher risk of incident type 2 diabetes compared with non-OSA over an 8-year period in general middle-aged and older adults

Heritability Analyses Uncover Shared Genetic Effects of Lung Function and Change over Time

Genetic influence on lung functions has been identified in previous studies; however, the relative longitudinal effects of genetic factors and their interactions with smoking on lung function remain unclear. Here, we identified the longitudinal effects of genetic variants on lung function by determining single nucleotide polymorphism (SNP) heritability and genetic correlations, and by analyzing interactions with smoking. Subject-specific means and annual change rates were calculated for eight spirometric measures obtained from 6622 Korean adults aged 40-69 years every two years for 14 years, and their heritabilities were estimated separately. Statistically significant (p &lt; 0.05) heritability for the subject-specific means of all spirometric measures (8 similar to 32%) and change rates of forced expiratory volume in 1 s to forced vital capacity ratio (FEV1/FVC; 16%) and post-bronchodilator FEV1/FVC (17%) were detected. Significant genetic correlations of the change rate with the subject-specific mean were observed for FEV1/FVC (rho(g) = 0.64) and post-bronchodilator FEV1/FVC (rho(g) = 0.47). Furthermore, post-bronchodilator FEV1/FVC showed significant heritability of SNP-by-smoking interaction (hGXS2 = 0.4) for the annual change rate. The GWAS also detected genome-wide significant SNPs for FEV1 (rs4793538), FEV1/FVC (rs2704589, rs62201158, and rs9391733), and post-bronchodilator FEV1/FVC (rs2445936). We found statistically significant evidence of heritability role on the change in lung function, and this was shared with the effects on cross-sectional measurements. We also found some evidence of interaction with smoking for the change of lung function.N