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Genome-wide association study of lung adenocarcinoma in East Asia and comparison with a European population.
Shi, J, Shiraishi, K, Choi, J, Matsuo, K, Chen, TY, Dai, J, Hung, RJ, Chen, K, Shu, XO, Kim, YT, et al
Nature communications. 2023;(1):3043
Abstract
Lung adenocarcinoma is the most common type of lung cancer. Known risk variants explain only a small fraction of lung adenocarcinoma heritability. Here, we conducted a two-stage genome-wide association study of lung adenocarcinoma of East Asian ancestry (21,658 cases and 150,676 controls; 54.5% never-smokers) and identified 12 novel susceptibility variants, bringing the total number to 28 at 25 independent loci. Transcriptome-wide association analyses together with colocalization studies using a Taiwanese lung expression quantitative trait loci dataset (n = 115) identified novel candidate genes, including FADS1 at 11q12 and ELF5 at 11p13. In a multi-ancestry meta-analysis of East Asian and European studies, four loci were identified at 2p11, 4q32, 16q23, and 18q12. At the same time, most of our findings in East Asian populations showed no evidence of association in European populations. In our studies drawn from East Asian populations, a polygenic risk score based on the 25 loci had a stronger association in never-smokers vs. individuals with a history of smoking (Pinteraction = 0.0058). These findings provide new insights into the etiology of lung adenocarcinoma in individuals from East Asian populations, which could be important in developing translational applications.
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A Network Meta-Analysis of the Dose-Response Effects of Dapagliflozin on Efficacy and Safety in Adults With Type 1 Diabetes.
Li, Y, Li, H, Dong, L, Lin, D, Xu, L, Lou, P, Zang, D, Wang, K, Ma, L
Frontiers in endocrinology. 2022;:923376
Abstract
BACKGROUND Most patients with type 1 diabetes (T1DM) do not reach the blood glucose goal with treatment of insulin. In our research, we intended to estimate the therapeutic effect and safety of additional different doses of dapagliflozin on insulin treatment in T1DM. METHODS We performed direct and indirect network meta-analysis using Bayesian models and graded different dosages of dapagliflozin by mixed therapy contrasts. We retrieved information from the PubMed, Embase, The Cochrane Library, Web of Science, China Biology Medicine (CBM) disc, China National Knowledge Infrastructure (CNKI), Wanfang Data, and WEIPU Data. Our research included randomized controlled trials (RCTs) including T1DM treated with insulin and additional dapagliflozin 5 mg or dapagliflozin 10 mg from January 2012 to June 2021. Thirteen RCTs with 10,701 participants were divided into three groups as below: insulin alone, dapagliflozin 5 mg + insulin, and dapagliflozin 10 mg + insulin. RESULTS Dapagliflozin dose-dependently exhibited reductions in glycated hemoglobin (HbA1c), total insulin daily dose (TDD), and body weight. Neither dapagliflozin 5 mg nor 10 mg could induce hypoglycemia or severe hypoglycemia. However, both doses of dapagliflozin increased the incidence of diabetic ketoacidosis (DKA) and genital infection. CONCLUSIONS Dapagliflozin 10 mg could achieve a better outcome in efficacy and could not increase the risk of hypoglycemia. Although it may induce a higher risk of DKA and genital infection, there was no significant difference between dapagliflozin 10 mg and 5 mg. Our outcomes indicate that dapagliflozin 10mg has a high reliability of being graded prior as a supplementary treatment to insulin in T1DM.
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Specific alterations of gut microbiota in diabetic microvascular complications: A systematic review and meta-analysis.
Hong, J, Fu, T, Liu, W, Du, Y, Min, C, Lin, D
Frontiers in endocrinology. 2022;:1053900
Abstract
BACKGROUND The role of gut microbiota in diabetes mellitus (DM) and its complications has been widely accepted. However, the alternation of gut microbiota in diabetic microvascular complications (DC) remains to be determined. METHODS Publications (till August 20th, 2022) on gut microbiota in patients with DC were retrieved from PubMed, Web of Science, Embase and Cochrane. Review Manager 5.3 was performed to estimate the standardized mean difference (SMD) and 95% confidence interval (CI) and calculate alpha diversity indices and the relative abundance of gut microbiota between patients in DC v.s. DM and DC v.s. healthy controls (HC). RESULTS We included 13 studies assessing 329 patients with DC, 232 DM patients without DC, and 241 HC. Compared to DM, patients with DC shared a significantly lower Simpson index (SMD = -0.59, 95% CI [-0.82, -0.36], p < 0.00001), but a higher ACE index (SMD = 0.42, 95% CI[0.11, 0.74], p = 0.009). Compared to HC, DC patients held a lower ACE index (SMD = -0.61, 95% CI[-1.20, -0.02], p = 0.04). The relative abundances of phylum Proteobacteria (SMD = 0.03, 95% CI[0.01, 0.04], p = 0.003, v.s. HC) and genus Klebsiella (SMD = 0.00, 95% CI[0.00, 0.00], p < 0.00001, v.s. HC) were enriched, accompanying with depleted abundances of phylum Firmicutes (SMD = -0.06, 95% CI[-0.11, -0.01], p = 0.02, v.s. HC), genera Bifidobacterium (SMD = -0.01, 95% CI[-0.02,-0.01], p < 0.0001, v.s. DM), Faecalibacterium (SMD = -0.01, 95% CI[-0.02, -0.00], p = 0.009, v.s. DM; SMD = -0.02, 95% CI[-0.02, -0.01], p < 0.00001, v.s. HC) and Lactobacillus (SMD = 0.00, 95% CI[-0.00, -0.00], p < 0.00001, v.s. HC) in DC. CONCLUSIONS Gut microbiota perturbations with the depletion of alpha diversity and certain short-chain fatty acids (SCFAs)-producing bacteria were associated with the pathology of DC. Therefore, gut microbiota might serve as a promising approach for the diagnosis and treatment of DC. Further investigations are required to study the mechanisms by which gut dysbiosis acts on the onset and progression of DC.
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Association of antenatal corticosteroids with morbidity and mortality among preterm multiple gestations: meta-analysis of observational studies.
Lin, D, Fan, D, Chen, G, Luo, C, Guo, X, Liu, Z
BMJ open. 2021;(9):e047651
Abstract
OBJECTIVE This meta-analysis aimed to assess the efficacy of antenatal corticosteroids (ACS) on morbidity and mortality among preterm multiple pregnancies. METHODS The PubMed, Embase, Web of Science and Cochrane Library databases were searched for studies investigating the outcomes among preterm multiple gestations following to ACS, from their inception to 1 November 2020. Two authors independently performed the study selection, risk of bias assessment and data extraction. The primary outcomes were respiratory distress syndrome (RDS) and mortality and secondary outcomes included intraventricular haemorrhage (IVH), periventricular leukomalacia (PVL), necrotising enterocolitis, retinopathy of prematurity and bronchopulmonary dysplasia. Pooled ORs were obtained using random effects models. Subgroup analyses were performed to explain heterogeneity by ACS completeness, administration-to-delivery intervals (≤7 days) and single or multicentre. RESULTS A total of 16 observational studies with 36 973 newborns were included in the meta-analysis. ACS treatment was associated with a reduction in RDS (OR 0.66; 95% CI 0.54 to 0.82; I2=91.4%; p<0.001), mortality (OR 0.64; 95% CI 0.50 to 0.81; I2=85.9%; p<0.001), IVH (OR 0.67; 95% CI 0.54 to 0.83; I2=77.4%; p<0.001) and PVL (OR 0.65; 95% CI 0.47 to 0.92; I2=75.5%; p<0.001). Subgroup analyses showed ACS completeness, administration-to-delivery interval and multicentre study affected these associations. DISCUSSION ACS may be beneficial for reducing the risks of RDS, mortality, IVH and PVL among preterm multiple gestations. The efficacy of ACS could be affected by ACS completeness and administration-to-delivery. More robust evidence on the efficacy of ACS treatment among multiple gestations is warranted.
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Metabolome-wide association study identified the association between a circulating polyunsaturated fatty acids variant rs174548 and lung cancer.
Wang, C, Qin, N, Zhu, M, Chen, M, Xie, K, Cheng, Y, Dai, J, Liu, J, Xia, Y, Ma, H, et al
Carcinogenesis. 2017;(11):1147-1154
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Abstract
Quantitative trait loci (QTLs) are widely used as instruments to infer causal risk factors of diseases based on the idea of mendelian randomization. Plasma metabolites can serve as risk factors of cancer, and the heritability of many circulating metabolites was high. We conducted a metabolome-wide association study (MWAS) to systematically investigate the effects of genetic variants on metabolites and lung cancer based on published genome-wide association study (GWASs) and metabolic-QTL (mQTL) study. Then we confirmed the results by subsequent genetic and metabolic validations and inferred the causal relationship between identified metabolites and lung cancer through genetic variant(s). We firstly identified six polyunsaturated fatty acids (PUFAs) represented by rs174548-linked haplotype were significantly associated with lung cancer risk in a Chinese GWAS (2311 cases and 3077 controls). Rs174548 was further confirmed to be associated with lung cancer in 13 821 Europeans and 18 471 Asians (ORmeta = 0.87, Pmeta = 1.76 × 10-15) and the effect was much stronger in females (Pinteraction = 6.00 × 10-4). We next validated rs174548-plasma PUFA association in 253 Chinese subjects (β = -0.57, P = 1.68 × 10-3). Rs174548 was also found associated with FADS1 (the major fatty acid desaturase of identified PUFAs) expression in liver tissues. Taken together, we found that rs174548 was associated with both PUFAs and lung cancer. Because rs174548 was the only mQTL variant of PUFAs reported by previous GWASs and explained a large proportion of heritability, we proposed that plasma PUFAs could be causally associated with lung cancer based on the idea of mendelian randomization. These findings provide a diet-related risk factor and may have important implications for prevention on lung cancer.
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The gene polymorphisms of IL-8(-251T/A) and IP-10(-1596C/T) are associated with susceptibility and progression of type 2 diabetic retinopathy in northern Chinese population.
Dong, L, Bai, J, Jiang, X, Yang, MM, Zheng, Y, Zhang, H, Lin, D
Eye (London, England). 2017;(4):601-607
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Abstract
PurposeThe aim of the present study is to investigate the association of the polymorphism of two genes in CXC chemokine family, interleukin-8 (IL-8) and interferon-inducible protein 10 (IP-10), with both susceptibility and progression of DR in T2D population of northern China.Patients and methodsA total of 1043 eligible type 2 diabetic patients from Heilongjiang of northern China were recruited for this study. They were grouped into: with diabetic retinopathy (DR, 528 cases) and without diabetic retinopathy (DNR, 515 cases). Single nucleotide polymorphism (SNP) genotyping of IL-8(-251T/A) and IP-10(-1596C/T) was performed by polymerase chain reaction. Multivariate analysis and stepwise multiple logistic progression analysis were conducted to evaluate the association between gene SNP and DR susceptibility and progression. Pooled odds ratio (OR) with 95% confidence interval (CI) was applied to assess the strength of the association among study groups.ResultsThe occurring of IL-8(-251) AA genotype was correlated with susceptibility (OR: 2.286, 95% CI: 1.382-3.782, P=0.001) and progression of high-risk proliferative diabetic retinopathy (PDR) (OR: 0.354, 95% CI: 0.162-0.770, P=0.009). Reversely, T allele of IP-10 (-1596) C/T was correlated with a reduced risk of DR (OR: 0.341, 95% CI: 0.249-0.466, P<0.001). However, gene polymorphisms of IL-8-251T/A and IP-10-1596C/T were not associated with diabetic macular edema (DME)(P>0.05).ConclusionsAA genotype of IL-8-251T/A was closely correlated to DR and high-risk proliferative diabetic retinopathy (PDR). -1596T allele of the IP-10 is a beneficial genotype for DR.
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Meta-analysis of genome-wide association studies identifies multiple lung cancer susceptibility loci in never-smoking Asian women.
Wang, Z, Seow, WJ, Shiraishi, K, Hsiung, CA, Matsuo, K, Liu, J, Chen, K, Yamji, T, Yang, Y, Chang, IS, et al
Human molecular genetics. 2016;(3):620-9
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Abstract
Genome-wide association studies (GWAS) of lung cancer in Asian never-smoking women have previously identified six susceptibility loci associated with lung cancer risk. To further discover new susceptibility loci, we imputed data from four GWAS of Asian non-smoking female lung cancer (6877 cases and 6277 controls) using the 1000 Genomes Project (Phase 1 Release 3) data as the reference and genotyped additional samples (5878 cases and 7046 controls) for possible replication. In our meta-analysis, three new loci achieved genome-wide significance, marked by single nucleotide polymorphism (SNP) rs7741164 at 6p21.1 (per-allele odds ratio (OR) = 1.17; P = 5.8 × 10(-13)), rs72658409 at 9p21.3 (per-allele OR = 0.77; P = 1.41 × 10(-10)) and rs11610143 at 12q13.13 (per-allele OR = 0.89; P = 4.96 × 10(-9)). These findings identified new genetic susceptibility alleles for lung cancer in never-smoking women in Asia and merit follow-up to understand their biological underpinnings.
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Genome-wide association studies in East Asians identify new loci for waist-hip ratio and waist circumference.
Wen, W, Kato, N, Hwang, JY, Guo, X, Tabara, Y, Li, H, Dorajoo, R, Yang, X, Tsai, FJ, Li, S, et al
Scientific reports. 2016;:17958
Abstract
Sixty genetic loci associated with abdominal obesity, measured by waist circumference (WC) and waist-hip ratio (WHR), have been previously identified, primarily from studies conducted in European-ancestry populations. We conducted a meta-analysis of associations of abdominal obesity with approximately 2.5 million single nucleotide polymorphisms (SNPs) among 53,052 (for WC) and 48,312 (for WHR) individuals of Asian descent, and replicated 33 selected SNPs among 3,762 to 17,110 additional individuals. We identified four novel loci near the EFEMP1, ADAMTSL3 , CNPY2, and GNAS genes that were associated with WC after adjustment for body mass index (BMI); two loci near the NID2 and HLA-DRB5 genes associated with WHR after adjustment for BMI, and three loci near the CEP120, TSC22D2, and SLC22A2 genes associated with WC without adjustment for BMI. Functional enrichment analyses revealed enrichment of corticotropin-releasing hormone signaling, GNRH signaling, and/or CDK5 signaling pathways for those newly-identified loci. Our study provides additional insight on genetic contribution to abdominal obesity.
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Meta-analysis of genome-wide association studies of adult height in East Asians identifies 17 novel loci.
He, M, Xu, M, Zhang, B, Liang, J, Chen, P, Lee, JY, Johnson, TA, Li, H, Yang, X, Dai, J, et al
Human molecular genetics. 2015;(6):1791-800
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Human height is associated with risk of multiple diseases and is profoundly determined by an individual's genetic makeup and shows a high degree of ethnic heterogeneity. Large-scale genome-wide association (GWA) analyses of adult height in Europeans have identified nearly 180 genetic loci. A recent study showed high replicability of results from Europeans-based GWA studies in Asians; however, population-specific loci may exist due to distinct linkage disequilibrium patterns. We carried out a GWA meta-analysis in 93 926 individuals from East Asia. We identified 98 loci, including 17 novel and 81 previously reported loci, associated with height at P < 5 × 10(-8), together explaining 8.89% of phenotypic variance. Among the newly identified variants, 10 are commonly distributed (minor allele frequency, MAF > 5%) in Europeans, with comparable frequencies with in Asians, and 7 single-nucleotide polymorphisms are with low frequency (MAF < 5%) in Europeans. In addition, our data suggest that novel biological pathway such as the protein tyrosine phosphatase family is involved in regulation of height. The findings from this study considerably expand our knowledge of the genetic architecture of human height in Asians.
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Characterization of large structural genetic mosaicism in human autosomes.
Machiela, MJ, Zhou, W, Sampson, JN, Dean, MC, Jacobs, KB, Black, A, Brinton, LA, Chang, IS, Chen, C, Chen, C, et al
American journal of human genetics. 2015;(3):487-97
Abstract
Analyses of genome-wide association study (GWAS) data have revealed that detectable genetic mosaicism involving large (>2 Mb) structural autosomal alterations occurs in a fraction of individuals. We present results for a set of 24,849 genotyped individuals (total GWAS set II [TGSII]) in whom 341 large autosomal abnormalities were observed in 168 (0.68%) individuals. Merging data from the new TGSII set with data from two prior reports (the Gene-Environment Association Studies and the total GWAS set I) generated a large dataset of 127,179 individuals; we then conducted a meta-analysis to investigate the patterns of detectable autosomal mosaicism (n = 1,315 events in 925 [0.73%] individuals). Restricting to events >2 Mb in size, we observed an increase in event frequency as event size decreased. The combined results underscore that the rate of detectable mosaicism increases with age (p value = 5.5 × 10(-31)) and is higher in men (p value = 0.002) but lower in participants of African ancestry (p value = 0.003). In a subset of 47 individuals from whom serial samples were collected up to 6 years apart, complex changes were noted over time and showed an overall increase in the proportion of mosaic cells as age increased. Our large combined sample allowed for a unique ability to characterize detectable genetic mosaicism involving large structural events and strengthens the emerging evidence of non-random erosion of the genome in the aging population.