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Identifying transcription factors (TFs) whose DNA bindings are altered by genetic variants that regulate susceptibility genes is imperative to understand transcriptional dysregulation in disease etiology. Here, we develop a statistical framework to analyze extensive ChIP-seq and GWAS data and identify 22 breast cancer risk-associated TFs. We find that, by analyzing genetic variations of TF-DNA bindings, the interaction of FOXA1 with co-factors such as ESR1 and E2F1, and the interaction of TFs with chromatin features (i.e., enhancers) play a key role in breast cancer susceptibility. Using genetic variants occupied by the 22 TFs, transcriptome-wide association analyses identify 52 previously unreported breast cancer susceptibility genes, including seven with evidence of essentiality from functional screens in breast relevant cell lines. We show that FOXA1 and co-factors form a core TF-transcriptional network regulating the susceptibility genes. Our findings provide additional insights into genetic variations of TF-DNA bindings (particularly for FOXA1) underlying breast cancer susceptibility. The identification of transcription factors (TFs) whose binding sites are affected by risk genetic variants remains crucial. Here, the authors develop a statistical framework to analyse ChIP-seq and GWAS data, identify 22 breast cancer risk-associated TFs and a core TF-transcriptional network for FOXA1 and co-factors.

Transcriptome-wide association studies (TWAS) have successfully discovered many putative disease susceptibility genes. However, TWAS may suffer from inaccuracy of gene expression predictions due to inclusion of non-regulatory variants. By integrating prior knowledge of susceptible transcription factor occupied elements, we develop sTF-TWAS and demonstrate that it outperforms existing TWAS approaches in both simulation and real data analyses. Under the sTF-TWAS framework, we build genetic models to predict alternative splicing and gene expression in normal breast, prostate and lung tissues from the Genotype-Tissue Expression project and apply these models to data from large genome-wide association studies (GWAS) conducted among European-ancestry populations. At Bonferroni-corrected P  < 0.05, we identify 354 putative susceptibility genes for these cancers, including 189 previously unreported in GWAS loci and 45 in loci unreported by GWAS. These findings provide additional insight into the genetic susceptibility of human cancers. Additionally, we show the generalizability of the sTF-TWAS on non-cancer diseases. Transcriptome-wide association studies can uncover genes involved in disease. Here, the authors extend the framework with a transcriptome-wide association study approach which incorporates transcription factor occupancy, adding tissue-specific mechanistic support to associations.

Introduction Cigarette smoking and alcohol drinking are well-known risk factors for various cancers. We aimed to determine a comprehensive profile of cancer risk associated with these lifestyle factors in predominantly low-income Americans. Methods We prospectively investigated the associations between cigarette smoking, alcohol drinking, and the risk of twelve cancer types among over 74 000 low-income Black and White adults from the Southern Community Cohort Study in the United States. We used the Cox proportional hazards models to estimate the hazard ratios (HRs) and corresponding 95% confidence intervals (CIs) for these associations. Results Compared to never smokers, current smokers had an increased HR for cancers of lung (HR: 14.14, 95% CI: 11.47-17.42), liver and bile duct (HR: 3.19, 95% CI: 2.40-4.25), kidney (HR: 1.47, 95% CI: 1.10-1.96), pancreas (HR: 1.88, 95% CI: 1.41-2.50), oral and pharynx (HR: 3.83, 95% CI: 2.70-5.42), and bladder (HR: 2.81, 95% CI: 1.92-4.11), and a reduced risk of prostate cancer (HR: 0.78, 95% CI: 0.68-0.89) and uterine cancer (HR: 0.45, 95% CI: 0.32-0.63); former smokers also exhibited elevated risks for cancers of lung, liver and bile duct, kidney, and bladder; however, a decreased risk for the lung, liver and bile duct, and bladder cancers was observed with longer durations of smoking cessation, with HRs from 9.71, 2.26, and 2.28 for a duration of <10 years down to 4.28, 1.58, and 1.42 for a duration of 10-19 years, respectively. Compared to never-drinkers, participants who consumed more than 2 drinks per day had increased risks of liver and bile duct cancer (HR: 1.66, 95% CI: 1.29-2.13) and oral and pharynx cancer (HR: 2.15, 95% CI: 1.58-2.91). Conclusion Cigarette smoking and alcohol drinking were associated with an increased risk of multiple cancers. Our findings support efforts to control cigarette and alcohol consumption for cancer prevention in low-income U.S. populations.

Background: Ginseng, an herbal remedy, has been commonly used in Asian countries to promote longevity and health for over 2,000 years. However, the association of ginseng consumption with all-cause and cause-specific mortality is still unclear. We analyzed the association of total and major cause-specific mortality (cardiovascular disease [CVD], cancer, and other death) with consumption of ginseng (primarily American and white ginseng).Methods: This study included 56,183 female participants with an average follow-up of 14.7 years in the Shanghai Women’s Health Study, an ongoing prospective cohort study. Data were assessed via an in-person interview conducted at baseline recruitment. Cox proportional hazards models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for ginseng-mortality associations after adjusting for confounders.Results: Compared with those who never used ginseng, regular ginseng use was associated with significantly reduced all-cause mortality (HR 0.92; 95% CI, 0.87–0.98). This inverse association was seen primarily among those who consumed ginseng for perceived general health benefit (HR 0.90; 95% CI, 0.85–0.96). A significant dose-response association was observed between duration of ginseng use and total mortality (HR 0.85, for using ≥6 years vs never use; P for trend <0.001), CVD mortality (HR 0.83; P for trend = 0.019), and other-cause mortality (HR 0.76; P for trend = 0.001). However, no dose-response association was observed between amount of ginseng consumption and mortality outcomes.Conclusion: Regular ginseng consumption, particularly over a long duration, was associated with decreased risk of all causes of death, death due to CVD, and death due to certain other diseases.

Yukinori Okada and colleagues report a genome-wide association study for body mass index (BMI) in east Asians. They identify genetic variants associated with BMI near CDKAL1 and KLF9 . Obesity is a disorder with a complex genetic etiology, and its epidemic is a worldwide problem. Although multiple genetic loci associated with body mass index, the most common measure of obesity, have been identified in European populations, few studies have focused on Asian populations. Here we report a genome-wide association study and replication studies with 62,245 east Asian subjects, which identified two new body mass index–associated loci in the CDKAL1 locus at 6p22 (rs2206734, P = 1.4 × 10 −11 ) and the KLF9 locus at 9q21 (rs11142387, P = 1.3 × 10 −9 ), as well as several previously reported loci (the SEC16B , BDNF, FTO , MC4R and GIPR loci, P < 5.0 × 10 −8 ). We subsequently performed gene-gene interaction analyses and identified an interaction ( P = 2.0 × 10 −8 ) between a SNP in the KLF9 locus (rs11142387) and one in the MSTN (also known as GDF8 ) locus at 2q32 (rs13034723). These findings should provide useful insights into the etiology of obesity.

Prostaglandins play a critical role in inflammatory response. To investigate the association of urinary PGE-M, a stable end-product of prostaglandin E2 (PGE 2 ) with overall and cause-specific mortality and examine potential effect modifiers, we obtained urinary PGE-M levels of 2927 non-cancerous adults from our previous case-control studies nested in the Shanghai Women’s Health Study and Shanghai Men’s Health Study, two cohort studies conducted in Shanghai, China. Mortality data and modifiable factors associated with urinary PGE-M were obtained from the parent cohort studies. Using linear regression models, we found that high urinary PGE-M levels were significantly associated with low education, heaving smoking, old age at urine collection, and abdominal obesity. Using Cox proportional hazards models, we found that increase (per standard deviation) of urinary PGE-M levels were significantly associated with overall mortality (adjusted hazard ratio = 1.19, 95% confidence interval: 1.07, 1.33) and particularly deaths from cardiometabolic diseases (adjusted hazard ratio = 1.27, 95% confidence interval: 1.11, 1.44). The increased death risks persisted across different time intervals during the follow-up and were stronger among participants who were younger than 60 ( P  = 0.0014 for all- cause mortality and P  = 0.007 for deaths from cardiometabolic diseases) at urine collection or perhaps among those who had higher education.

Purpose Limited studies have been conducted to evaluate pathogenetic mutations in breast cancer predisposition genes among Chinese women. To fully characterize germline mutations of these genes in this population, we used the whole-exome sequencing data in a population-based case–control study conducted in Shanghai, China. Methods We evaluated exonic, splicing, and copy number variants in 11 established and 14 candidate breast cancer predisposition genes in 831 invasive breast cancer cases and 839 controls. We identified 55 pathogenic variants, including 15 newly identified in this study. Results Approximately 8% of the cases and 0.6% of the cancer-free controls carried these pathogenetic variants ( P  = 3.05 × 10 −15 ). Among cases, 3.7% had a BRCA 2 pathogenic variant and 1.6% had a BRCA1 pathogenic variant, while 2.5% had a pathogenic variant in other genes including ATM, CHEK2, NBN, NF1, CDH1, PALB2, PTEN, TP53 as well as BARD1, BRIP, and RAD51D . Patients with BRCA 1/2 pathogenic variants were more likely to have a family history of breast cancer and hormone receptor negative tumors compared with patients without pathogenic variants. Conclusions This study highlighted the importance of hereditary breast cancer genes in the breast cancer etiology in this understudied population. Together with previous studies in East Asian women, this study suggested a relatively more prominent role of BRCA2 compared to BRCA1 . This study also provides additional evidence to design cost-efficient genetic testing among Chinese women for risk assessment and early detection of breast cancer.

Xiao-Ou Shu and colleagues report a meta-analysis of genome-wide association studies for body mass index (BMI) in east Asians. They identify three new genetic loci associated with BMI. Multiple genetic loci associated with obesity or body mass index (BMI) have been identified through genome-wide association studies conducted predominantly in populations of European ancestry. We performed a meta-analysis of associations between BMI and approximately 2.4 million SNPs in 27,715 east Asians, which was followed by in silico and de novo replication studies in 37,691 and 17,642 additional east Asians, respectively. We identified ten BMI-associated loci at genome-wide significance ( P < 5.0 × 10 −8 ), including seven previously identified loci ( FTO , SEC16B , MC4R , GIPR - QPCTL , ADCY3 - DNAJC27 , BDNF and MAP2K5 ) and three novel loci in or near the CDKAL1 , PCSK1 and GP2 genes. Three additional loci nearly reached the genome-wide significance threshold, including two previously identified loci in the GNPDA2 and TFAP2B genes and a newly identified signal near PAX6 , all of which were associated with BMI with P < 5.0 × 10 −7 . Findings from this study may shed light on new pathways involved in obesity and demonstrate the value of conducting genetic studies in non-European populations.

Wei Zheng and colleagues carried out a genome-wide association study of breast cancer in Chinese women and discovered risk variants on 6q25.1 located upstream of the gene encoding estrogen receptor 1 ( ESR1 ). They also found a similar association between the 6q25.1 locus and breast cancer in samples of European ancestry. We carried out a genome-wide association study among Chinese women to identify risk variants for breast cancer. After analyzing 607,728 SNPs in 1,505 cases and 1,522 controls, we selected 29 SNPs for a fast-track replication in an independent set of 1,554 cases and 1,576 controls. We further investigated four replicated loci in a third set of samples comprising 3,472 cases and 900 controls. SNP rs2046210 at 6q25.1, located upstream of the gene encoding estrogen receptor α ( ESR1 ), showed strong and consistent association with breast cancer across all three stages. Adjusted odds ratio (95% CI) were 1.36 (1.24–1.49) and 1.59 (1.40–1.82), respectively, for genotypes A/G and A/A versus G/G ( P for trend 2.0 × 10 −15 ) in the pooled analysis of samples from all three stages. We also found a similar, albeit weaker, association in an independent study comprising 1,591 cases and 1,466 controls of European ancestry ( P trend = 0.01). These results strongly implicate 6q25.1 as a susceptibility locus for breast cancer.