Wei Zheng

Renji Hospital, Shanghai, Shanghai Shi, China

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Publications (596)3728.28 Total impact

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    Danxia Yu, William Blot, Wei Zheng
    PLoS Medicine 05/2015; 12(5):e1001830. · 14.00 Impact Factor
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    ABSTRACT: Clinical genetic testing is commercially available for rs61764370, an inherited variant residing in a KRAS 3′ UTR microRNA binding site, based on suggested associations with increased ovarian and breast cancer risk as well as with survival time. However, prior studies, emphasizing particular subgroups, were relatively small. Therefore, we comprehensively evaluated ovarian and breast cancer risks as well as clinical outcome associated with rs61764370.
    Gynecologic Oncology 05/2015; DOI:10.1016/j.ygyno.2015.04.034 · 3.69 Impact Factor
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    ABSTRACT: Coinciding with the increased incidence of non-Hodgkin's lymphoma (NHL) during the past decades, there has been a significant increase in the prevalence of diabetes mellitus in mainland China. We therefore evaluated whether type 2 diabetes (T2D) is associated with the risk of NHL using data from the Shanghai Men's Health Study (SMHS) and the Shanghai Women's Health Study (SWHS). The SMHS and SWHS are two on-going, prospective, population-based cohorts of more than 130 000 Chinese adults in urban Shanghai. Self-reported diabetes was recorded on the baseline questionnaire and updated in follow-up surveys. Cox regression models with T2D as a time-varying exposure were used to estimate hazard ratios and 95% confidence intervals, adjusting for covariates. After a median follow-up of 12.9 years for SWHS and 7.4 years for SMHS, 172 NHL cases were identified. Patients with T2D have a higher risk of incident NHL with a hazard ratio of 2.00 (95% confidence interval: 1.32-3.03) compared with those without diabetes. This positive association remained when the analysis was restricted to untreated diabetes or after excluding NHL cases that occurred within 3 years after the onset of diabetes. No interaction effect was found in the development of NHL between T2D and other potential risk factors. A linear inverse association was found between T2D duration and the risk of NHL in both men and women (Pfor linearity<0.01), with a highest risk of incident NHL in the first 5 years after the diagnosis of diabetes. Our study suggested that T2D might be associated with an increased risk of NHL.
    European journal of cancer prevention: the official journal of the European Cancer Prevention Organisation (ECP) 03/2015; DOI:10.1097/CEJ.0000000000000150 · 2.76 Impact Factor
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    ABSTRACT: Retinitis pigmentosa (RP), a heterogeneous group of inherited ocular diseases, is a genetic condition that causes retinal degeneration and eventual vision loss. Though some genes have been identified to be associated with RP, still a large part of the clinical cases could not be explained. Here we reported a four-generation Chinese family with RP, during which 6 from 9 members of the second generation affected the disease. To identify the genetic defect in this family, whole-exome sequencing together with validation analysis by Sanger sequencing were performed to find possible pathogenic mutations. After a pipeline of database filtering, including public databases and in-house databases, a novel missense mutation, c. 424 C > T transition (p.R142W) in OR2W3 gene, was identified as a potentially causative mutation for autosomal dominant RP. The mutation co-segregated with the disease phenotype over four generations. This mutation was validated in another independent three-generation family. RT-PCR analysis also identified that OR2W3 gene was expressed in HESC-RPE cell line. The results will not only enhance our current understanding of the genetic basis of RP, but also provide helpful clues for designing future studies to further investigate genetic factors for familial RP.
    Scientific Reports 03/2015; 5:9236. DOI:10.1038/srep09236 · 5.58 Impact Factor
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    ABSTRACT: Abnormalities in lipid levels have been associated with colorectal neoplasm risk; however, few studies have adjusted for use of cholesterol-lowering medications. The objective of this study was to determine the association of plasma lipid levels with adenoma risk while accounting for statin medication use. We included 254 subjects with advanced adenoma, 246 with single small adenoma, 179 with multiple small adenoma cases, and 403 control participants in the Tennessee Colorectal Polyp Study who also had plasma lipid measurements performed. Data on the use of statin medications were available for 83.4 % of these participants. The association between plasma lipids and adenoma risk was evaluated using logistic regression models. Participants in the highest quartile of HDL cholesterol (range 52-106 mg/dl) had an adjusted odds ratio of 0.49 (95 % CI 0.23, 1.07), 0.35 (95 % CI 0.13, 0.91), and 0.22 (95 % CI 0.09, 0.54) for single small, multiple small, and advanced adenomas compared to the lowest quartile (range 12-34 mg/dl), respectively. Participants with the highest quartile of triglyceride levels (range 178-721 mg/dl) had an adjusted odds ratio of 2.40 (95 % CI 1.26, 4.55), 1.67 (95 % CI 0.66, 4.23), and 2.79 (95 % CI 1.25, 6.23) for single small, multiple small, and advanced adenoma, respectively, compared to the lowest quartile (range 40-84 mg/dl). When restricted to individuals with known statin medication use, adjusting for statin use did not appreciably affect these results. We found a direct association between triglyceride plasma levels and an inverse association between plasma HDL cholesterol levels and adenoma risk. Both effects were not appreciably changed when accounting for the regular use of statin medication.
    Cancer Causes and Control 03/2015; 26(4). DOI:10.1007/s10552-015-0555-y · 2.96 Impact Factor
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    ABSTRACT: Genome-wide association studies (GWAS) and large-scale replication studies have identified common variants in 79 loci associated with breast cancer, explaining ∼14% of the familial risk of the disease. To identify new susceptibility loci, we performed a meta-analysis of 11 GWAS, comprising 15,748 breast cancer cases and 18,084 controls together with 46,785 cases and 42,892 controls from 41 studies genotyped on a 211,155-marker custom array (iCOGS). Analyses were restricted to women of European ancestry. We generated genotypes for more than 11 million SNPs by imputation using the 1000 Genomes Project reference panel, and we identified 15 new loci associated with breast cancer at P < 5 × 10(-8). Combining association analysis with ChIP-seq chromatin binding data in mammary cell lines and ChIA-PET chromatin interaction data from ENCODE, we identified likely target genes in two regions: SETBP1 at 18q12.3 and RNF115 and PDZK1 at 1q21.1. One association appears to be driven by an amino acid substitution encoded in EXO1.
    Nature Genetics 03/2015; DOI:10.1038/ng.3242 · 29.65 Impact Factor
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    ABSTRACT: The association between benzene exposure and non-Hodgkin lymphoma (NHL) has been the subject of debate as a result of inconsistent epidemiologic evidence. An IARC working group evaluated benzene in 2009 and noted evidence for a positive association between benzene exposure and NHL risk. To evaluate the association between occupational benzene exposure and non-Hodgkin lymphoma (NHL) among 73,087 women enrolled in the prospective population-based Shanghai Women's Health Study. Benzene exposure estimates were derived using a previously developed exposure assessment framework that combined ordinal job-exposure matrix intensity ratings with quantitative benzene exposure measurements from an inspection database of Shanghai factories collected between 1954-2000. Associations between benzene exposure metrics and NHL (n = 102 cases) were assessed using Cox proportional hazard models, with study follow-up occurring from December 1996 through December 2009. Women ever exposed to benzene had a significantly higher risk of NHL (Hazard Ratio (HR): 1.87, 95% C.I.: 1.19, 2.96). Compared to unexposed women, significant trends in NHL risk were observed for increasing years of benzene exposure (ptrend = 0.006) and increasing cumulative exposure levels (ptrend = 0.005), with the highest duration and cumulative exposure tertiles having a significantly higher association with NHL (HR: 2.07, 95% C.I.: 1.07, 4.01 and HR: 2.16, 95% C.I.: 1.17, 3.98, respectively). Our findings, using a population-based prospective cohort of women with diverse occupational histories, provide additional evidence that occupational exposure to benzene is associated with NHL risk.
    Environmental Health Perspectives 03/2015; DOI:10.1289/ehp.1408307 · 7.03 Impact Factor
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    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. Copyright © 2015 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.
    The American Journal of Human Genetics 03/2015; 96(3):487-97. DOI:10.1016/j.ajhg.2015.01.011 · 10.99 Impact Factor
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    ABSTRACT: The Shanghai Men's Health Study (SMHS) is a population-based cohort study of 61 480 men aged 40-74 years, launched in 2002 in urban Shanghai to investigate the contribution of lifestyle/environmental factors and genetic susceptibility to cancer and other non-communicable diseases (NCDs). At baseline, trained interviewers collected detailed information on personal and dietary habits, occupational/medical history and physical activity, and took anthropometric measurements (response rate: 74%). Blood, urine and DNA were collected from 75%, 89% and 89% of participants, respectively. The cohort has been followed up through a combination of in-person surveys every 3-4 years and annual record linkage with cancer and vital statistics registries. Response rates for in-person follow-up surveys were over 91% and coverage for mortality nearly 100%. SMHS participants have a high smoking rate (58.6%) and moderate alcohol-drinking rate (29.3%), but low obesity rate (2.6%). They have a low calorie intake from fat (16.2% of total calorie intake) and protein (16.4%), high calorie intake from carbohydrates (67.4%), and high intake of soy food, cruciferous vegetables and fish (156.5, 110.6 and 51.7 g/day, respectively). With its unique exposure pattern and wealth of data and biological samples, the SMHS is well positioned for long-term research into NCD aetiology and prognosis. Information about accessing the SMHS resources can be found at: http://www.mc.vanderbilt.edu/swhs-smhs/. © The Author 2015; all rights reserved. Published by Oxford University Press on behalf of the International Epidemiological Association.
    International Journal of Epidemiology 03/2015; DOI:10.1093/ije/dyv013 · 9.20 Impact Factor
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    ABSTRACT: High intake of nuts has been linked to a reduced risk of mortality. Previous studies, however, were primarily conducted among people of European descent, particularly those of high socioeconomic status. To examine the association of nut consumption with total and cause-specific mortality in Americans of African and European descent who were predominantly of low socioeconomic status (SES) and in Chinese individuals in Shanghai, China. Three large cohorts were evaluated in the study. One included 71 764 US residents of African and European descent, primarily of low SES, who were participants in the Southern Community Cohort Study (SCCS) in the southeastern United States (March 2002 to September 2009), and the other 2 cohorts included 134 265 participants in the Shanghai Women's Health Study (SWHS) (December 1996 to May 2000) and the Shanghai Men's Health Study (SMHS) (January 2002 to September 2006) in Shanghai, China. Self-reported nut consumption in the SCCS (approximately 50% were peanuts) and peanut-only consumption in the SMHS/SWHS were assessed using validated food frequency questionnaires. Deaths were ascertained through linkage with the National Death Index and Social Security Administration mortality files in the SCCS and annual linkage with the Shanghai Vital Statistics Registry and by biennial home visits in the SWHS/SMHS. Cox proportional hazards regression models were used to calculate hazard ratios (HRs) and 95% CIs. With a median follow-up of 5.4 years in the SCCS, 6.5 years in the SMHS, and 12.2 years in the SWHS, 14 440 deaths were identified. More than half of the women in the SCCS were ever smokers compared with only 2.8% in the SWHS. The ever-smoking rate for men was 77.1% in the SCCS and 69.6% in the SMHS. Nut intake was inversely associated with risk of total mortality in all 3 cohorts (all P < .001 for trend), with adjusted HRs associated with the highest vs lowest quintiles of intake being 0.79 (95% CI, 0.73-0.86) and 0.83 (95% CI, 0.77-0.88), respectively, for the US and Shanghai cohorts. This inverse association was predominantly driven by cardiovascular disease mortality (P < .05 for trend in the US cohort; P < .001 for trend in the Shanghai cohorts). When specific types of cardiovascular disease were examined, a significant inverse association was consistently seen for ischemic heart disease in all ethnic groups (HR, 0.62; 95% CI, 0.45-0.85 in blacks; HR, 0.60; 95% CI, 0.39-0.92 in whites; and HR, 0.70; 95% CI, 0.54-0.89 in Asians for the highest vs lowest quintile of nut intake). The associations for ischemic stroke (HR, 0.77; 95% CI, 0.60-1.00 for the highest vs lowest quintile of nut intake) and hemorrhagic stroke (HR, 0.77; 95% CI, 0.60-0.99 for the highest vs lowest quintile of nut intake) were significant only in Asians. The nut-mortality association was similar for men and women and for blacks, whites, and Asians and was not modified by the presence of metabolic conditions at study enrollment. Nut consumption was associated with decreased overall and cardiovascular disease mortality across different ethnic groups and among individuals from low SES groups. Consumption of nuts, particularly peanuts given their general affordability, may be considered a cost-effective measure to improve cardiovascular health.
    JAMA Internal Medicine 03/2015; 175(5). DOI:10.1001/jamainternmed.2014.8347 · 13.25 Impact Factor
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    ABSTRACT: Low bone mineral density (BMD) is common among breast cancer survivors due to acute estrogen deprivation. Soy food is a rich source of phytoestrogens, namely isoflavones, known to have both estrogenic and anti-estrogenic effects. The objective of the study was to assess the association between soy consumption and BMD in breast cancer survivors, which has not previously been evaluated. Forearm BMD was evaluated using dual-energy X-ray absorptiometry at 60 months post-diagnosis for 1,587 participants of the Shanghai Breast Cancer Survival Study. Soy intakes collected at 6, 18, and 36 months post-diagnosis were averaged, and the association with BMD, osteopenia, and osteoporosis was evaluated using linear and logistic regression. The mean (standard deviation) intake of isoflavones was 48.1 (28.0) mg/day. Soy intake was inversely associated with BMD and positively associated with osteoporosis. Compared with the lowest quartile, the highest quartile of soy isoflavone intake, ≥ 62.64 mg/day, was associated with a reduction of BMD by 1.95 % [95 % confidence interval (CI) -3.54, -0.36 %] and an increased odds ratio of 1.69 for osteoporosis (95 % CI 1.09, 2.61). The inverse association was predominantly seen among women who recently entered menopause (≤5 years). In contrast to observations from general populations, high soy intake (≥62.64 mg of soy isoflavone/day) was associated with lower proximal forearm BMD among breast cancer survivors, particularly during the early years of menopause. Our finding needs to be replicated, particularly in studies with more comprehensive bone density evaluation.
    Cancer Causes and Control 02/2015; 26(4). DOI:10.1007/s10552-015-0534-3 · 2.96 Impact Factor
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    ABSTRACT: Obesity is heritable and predisposes to many diseases. To understand the genetic basis of obesity better, here we conduct a genome-wide association study and Metabochip meta-analysis of body mass index (BMI), a measure commonly used to define obesity and assess adiposity, in up to 339,224 individuals. This analysis identifies 97 BMI-associated loci (P < 5 × 10(-8)), 56 of which are novel. Five loci demonstrate clear evidence of several independent association signals, and many loci have significant effects on other metabolic phenotypes. The 97 loci account for ∼2.7% of BMI variation, and genome-wide estimates suggest that common variation accounts for >20% of BMI variation. Pathway analyses provide strong support for a role of the central nervous system in obesity susceptibility and implicate new genes and pathways, including those related to synaptic function, glutamate signalling, insulin secretion/action, energy metabolism, lipid biology and adipogenesis
    Nature 02/2015; 518(7538). DOI:10.1038/nature14177 · 42.35 Impact Factor
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    ABSTRACT: We recently identified a novel susceptibility variant, rs865686, for estrogen-receptor positive breast cancer at 9q31.2. Here, we report a fine-mapping analysis of the 9q31.2 susceptibility locus using 43,160 cases and 42,600 controls of European ancestry ascertained from 52 studies and a further 5,795 cases and 6,624 controls of Asian ancestry from nine studies. Single nucleotide polymorphism (SNP) rs676256 was most strongly associated with risk in Europeans (OR=0.90 [0.88-0.92]; P-value=1.58 x 10(-25)). This SNP is one of a cluster of highly correlated variants, including rs865686, that spans approximately 14.5 Kb. We identified two additional independent association signals demarcated by SNPs rs10816625 (OR=1.12 [1.08-1.17]; P-value=7.89 x 10(-09)) and rs13294895 (OR=1.09 [1.06-1.12]; P-value=2.97 x 10(-11)). SNP rs10816625, but not rs13294895, was also associated with risk of breast cancer in Asian individuals (OR=1.12 [1.06-1.18]; P-value=2.77 x 10(-05)). Functional genomic annotation using data derived from breast cancer cell-line models indicates that these SNPs localise to putative enhancer elements that bind known drivers of hormone dependent breast cancer, including ER-α, FOXA1 and GATA-3. In vitro analyses indicate that rs10816625 and rs13294895 have allele-specific effects on enhancer activity and suggest chromatin interactions with the KLF4 gene locus. These results demonstrate the power of dense genotyping in large studies to identify independent susceptibility variants. Analysis of associations using subjects with different ancestry, combined with bioinformatic and genomic characterisation, can provide strong evidence for the likely causative alleles and their functional basis. © The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.
    Human Molecular Genetics 02/2015; DOI:10.1093/hmg/ddv035 · 6.68 Impact Factor
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    ABSTRACT: To evaluate the population attributable risks (PARs) between cigarette smoking and deaths of all causes, all cancers, lung cancer and other chronic diseases in urban Shanghai. In total, 61,480 men aged 40-74 years from 2002 to 2006 and 74,941 women aged 40-70 years from 1997 to 2000 were recruited to undergo baseline surveys in urban Shanghai, with response rates of 74.0% and 92.3%, respectively. A Cox proportional hazards regression model was used to estimate relative risks (RRs) and 95% confidence intervals (95% CIs) of deaths associated with cigarette smoking. PARs and 95% CIs for deaths were estimated from smoking exposure rates and the estimated RRs. Cigarette smoking was responsible for 23.9% (95% CI: 19.4-28.3%) and 2.4% (95% CI: 1.6-3.2%) of all deaths in men and women, respectively, in our study population. Respiratory disease had the highest PAR in men [37.5% (95% CI: 21.5-51.6%)], followed by cancer [31.3% (95% CI: 24.6-37.7%)] and cardiovascular disease (CVD) [24.1% (95% CI: 16.7-31.2%)]. While the top three PARs were 12.7% (95% CI: 6.1-19.3%), 4.0% (95% CI: 2.4-5.6%), and 1.1% (95% CI: 0.0-2.3%), for respiratory disease, CVD, and cancer, respectively in women. For deaths of lung cancer, the PAR of smoking was 68.4% (95% CI: 58.2-76.5%) in men. In urban Shanghai, 23.9% and 2.4% of all deaths in men and women could have been prevented if no people had smoked in the area. Effective control programs against cigarette smoking should be strongly advocated to reduce the increasing smoking-related death burden.
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    ABSTRACT: The number of effectively independent tests performed in genome-wide association studies (GWAS) varies by population, making a universal P-value threshold inappropriate. We estimated the number of independent SNPs in Phase 3 HapMap samples by: (1) the LD-pruning function in PLINK, and (2) an autocorrelation-based approach. Autocorrelation was also used to estimate the number of independent SNPs in whole genome sequences from 1000 Genomes. Both approaches yielded consistent estimates of numbers of independent SNPs, which were used to calculate new population-specific thresholds for genome-wide significance. African populations had the most stringent thresholds (1.49 × 10−7 for YRI at r2 = 0.3), East Asian populations the least (3.75 × 10−7 for JPT at r2 = 0.3). We also assessed how using population-specific significance thresholds compared to using a single multiple testing threshold at the conventional 5 × 10−8 cutoff. Applied to a previously published GWAS of melanoma in Caucasians, our approach identified two additional genes, both previously associated with the phenotype. In a Chinese breast cancer GWAS, our approach identified 48 additional genes, 19 of which were in or near genes previously associated with the phenotype. We conclude that the conventional genome-wide significance threshold generates an excess of Type 2 errors, particularly in GWAS performed on more recently founded populations.
    Annals of Human Genetics 01/2015; 79(2). DOI:10.1111/ahg.12095 · 1.93 Impact Factor
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    ABSTRACT: Epidemiologic and experimental studies have shown that a high intake of individual dietary antioxidants is associated with reduced risk of cancers. Few studies, however, have investigated the influences of a combination of antioxidants. We evaluated the association of two dietary antioxidant indices, the Dietary Antioxidant Quality Score (DAQS) and the Composite Dietary Antioxidant Index (CDAI), with 10 oxidative stress or inflammation biomarkers (urinary F2-isoprostanes-15-F2t-IsoP; urinary 15-F2t-IsoPM; urinary prostaglandin E2 metabolite-PGEM; C-reactive protein-CRP; interleukin-1beta-IL-1β; interleukin-6-IL-6; tumor necrosis factor-alpha-TNF-α; soluble TNF-receptor 1-sTNF-R1; soluble TNF-receptor 2-sTNF-R2; and soluble GP130- sGP130) in 3,853 participants of the Shanghai Women's Health Study (SWHS). We found the DAQS and CDAI to be highly correlated (r=0.72), and both inversely associated with levels of IL-1β (Ptrend=0.02 and 0.03, respectively) and TNF-α (Ptrend=0.005 and 0.003, respectively). Also, IL-6 and sTNF-R2 levels were inversely associated with the DAQS score; β-coefficient (±SE) for average-quality and high-quality group vs. low-quality group were -0.22(±0.13) and -0.30(±0.13) (Ptrend=0.06) for IL-6; -0.06(±0.04) and -0.10(±0.04) (Ptrend=0.01) for sTNF-R2. Neither the DAQS nor CDAI score was significantly associated with oxidative stress or other inflammatory biomarkers. Our observations lead us to hypothesize that these two indices offer a potential aggregate method of measuring dietary anti-inflammation, but not anti-oxidation properties.
    Antioxidants and Redox Signaling 01/2015; 22(11). DOI:10.1089/ars.2014.6212 · 7.67 Impact Factor
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    ABSTRACT: The chromosomal passenger complex (CPC) plays a pivotal role in the regulation of cell division. Therefore inherited CPC variability could influence tumor development. The present candidate gene approach investigates the relationship between single nucleotide polymorphisms (SNPs) in genes encoding key CPC components and breast cancer risk. Fifteen SNPs in four CPC genes (INCENP AURKB BIRC5 and CDCA8) were genotyped in 88,911 European women from 39 case-control studies of the Breast Cancer Association Consortium. Possible associations were investigated in fixed-effects meta-analyses. The synonymous SNP rs1675126 in exon 7 of INCENP was associated with overall breast cancer risk (per A allele OR 0.95 95% CI 1.02-1.10, p=0.0002). Two genotyped SNPs in BIRC5 were associated with familial breast cancer risk (top SNP rs2071214: per G allele OR 1.12, 95% CI 1.04-1.21, p=0.002). The data suggest that INCENP in the CPC pathway contributes to ER negative breast cancer susceptibility in the European population. In spite of a modest contribution of CPC inherited variants to the total burden of sporadic and familial breast cancer, their potential as novel targets for breast cancer treatment should be further investigated. © The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions please email: journals.permissions@oup.com.
    Carcinogenesis 01/2015; 36(2). DOI:10.1093/carcin/bgu326 · 5.27 Impact Factor
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    ABSTRACT: Genome-wide association studies (GWAS) have identified 12 epithelial ovarian cancer (EOC) susceptibility alleles. The pattern of association at these loci is consistent in BRCA1 and BRCA2 mutation carriers who are at high risk of EOC. After imputation to 1000 Genomes Project data, we assessed associations of 11 million genetic variants with EOC risk from 15,437 cases unselected for family history and 30,845 controls and from 15,252 BRCA1 mutation carriers and 8,211 BRCA2 mutation carriers (3,096 with ovarian cancer), and we combined the results in a meta-analysis. This new study design yielded increased statistical power, leading to the discovery of six new EOC susceptibility loci. Variants at 1p36 (nearest gene, WNT4), 4q26 (SYNPO2), 9q34.2 (ABO) and 17q11.2 (ATAD5) were associated with EOC risk, and at 1p34.3 (RSPO1) and 6p22.1 (GPX6) variants were specifically associated with the serous EOC subtype, all with P < 5 × 10(-8). Incorporating these variants into risk assessment tools will improve clinical risk predictions for BRCA1 and BRCA2 mutation carriers.
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    ABSTRACT: We previously carried out a multi-stage genome-wide association study (GWAS) on lung cancer among never smokers in the Female Lung Cancer Consortium in Asia (FLCCA) (6,609 cases, 7,457 controls) that identified novel susceptibility loci at 10q25.2, 6q22.2, and 6p21.32, and confirmed two previously identified loci at 5p15.33 and 3q28. Household air pollution (HAP) attributed to solid fuel burning for heating and cooking, is the leading cause of the overall disease burden in Southeast Asia, and is known to contain lung carcinogens. To evaluate the gene-HAP interactions associated with lung cancer in loci independent of smoking, we analyzed data from studies participating in FLCCA with fuel use information available (n = 3; 1,731 cases; 1,349 controls). Coal use was associated with a 30 % increased risk of lung cancer (OR 1.3, 95 % CI 1.0-1.6). Among the five a priori SNPs identified by our GWAS, two showed a significant interaction with coal use (HLA Class II rs2395185, p = 0.02; TP63 rs4488809 (rs4600802), p = 0.04). The risk of lung cancer associated with coal exposure varied with the respective alleles for these two SNPs. Our observations provide evidence that genetic variation in HLA Class II and TP63 may modify the association between HAP and lung cancer risk. The roles played in the cell cycle and inflammation pathways by the proteins encoded by these two genes provide biological plausibility for these interactions; however, additional replication studies are needed in other non-smoking populations.
    Human Genetics 01/2015; 134(3). DOI:10.1007/s00439-014-1528-z · 4.52 Impact Factor

Publication Stats

16k Citations
3,728.28 Total Impact Points


  • 2011–2015
    • Renji Hospital
      Shanghai, Shanghai Shi, China
    • Montreal Heart Institute
      Montréal, Quebec, Canada
    • Queensland Institute of Medical Research
      Brisbane, Queensland, Australia
    • University of Southern California
      • Department of Preventive Medicine
      Los Angeles, CA, United States
  • 2001–2015
    • Vanderbilt University
      • • Division of Epidemiology
      • • Department of Medicine
      • • Vanderbilt Epidemiology Center
      • • Vanderbilt Center for Evidence-based Medicine
      • • Center for Health Services Research
      Нашвилл, Michigan, United States
  • 2012–2014
    • University of Texas MD Anderson Cancer Center
      • Division of Cancer Prevention & Population Sciences
      Houston, Texas, United States
  • 1987–2014
    • Shanghai Cancer Institute
      Shanghai, Shanghai Shi, China
  • 2013
    • Johns Hopkins Medicine
      • Department of Pathology
      Baltimore, Maryland, United States
    • Imperial College London
      Londinium, England, United Kingdom
    • Harvard Medical School
      • Department of Medicine
      Boston, MA, United States
    • Institute of Cancer Research
      Londinium, England, United Kingdom
    • University of North Carolina at Chapel Hill
      • Department of Genetics
      North Carolina, United States
  • 2010–2013
    • Mayo Clinic - Rochester
      • Department of Health Science Research
      Rochester, Minnesota, United States
  • 2006–2013
    • Gateway-Vanderbilt Cancer Treatment Center
      Clarksville, Tennessee, United States
  • 1995–2012
    • Fred Hutchinson Cancer Research Center
      • Division of Public Health Sciences
      Seattle, WA, United States
  • 1992–2012
    • National Cancer Institute (USA)
      • Division of Cancer Epidemiology and Genetics
      Bethesda, MD, United States
  • 2009
    • Northwestern University
      • Department of Preventive Medicine
      Evanston, Illinois, United States
  • 2007
    • Fox Chase Cancer Center
      Filadelfia, Pennsylvania, United States
  • 1999–2006
    • University of South Carolina
      • Department of Epidemiology & Biostatistics
      Columbia, South Carolina, United States
  • 2005
    • National Institutes of Health
      Maryland, United States
  • 2004
    • Europaeische Akademie Bozen - Accademia Europea Bolzano
      Bozen, Trentino-Alto Adige, Italy
    • Northern Inyo Hospital
      BIH, California, United States
  • 2002–2003
    • Yale University
      New Haven, Connecticut, United States
    • Mayo Foundation for Medical Education and Research
      • Department of Health Sciences Research
      Scottsdale, AZ, United States
  • 1994–1997
    • University of Minnesota Duluth
      • Laboratory Medicine and Pathology
      Duluth, Minnesota, United States