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1.  Genetic variation in Transforming Growth Factor beta 1 and mammographic density in Singapore Chinese women 
Cancer research  2013;73(6):1876-1882.
Transforming growth factor-beta (TGF-β) plays a critical role in normal mammary development and morphogenesis. Decreased TGF-β signaling has been associated with increased mammographic density. Percent mammographic density (PMD) adjusted for age and body mass index (BMI) is a strong risk factor and predictor of breast cancer risk. PMD is highly heritable, but few genetic determinants have been identified. We investigated the association between genetic variation in TGFB1 and PMD using a cross-sectional study of 2,038 women who were members of the population-based Singapore Chinese Health Study cohort. We assessed PMD using a computer-assisted method. We used linear regression to examine the association between 9 tagging SNPs of TGFB1 and PMD and their interaction with parity, adjusting for age, BMI, and dialect group. We calculated ‘P-values adjusted for correlated tests’ (PACT) to account for multiple testing. The strongest association was observed for rs2241716. Adjusted PMD was higher by 1.5% per minor allele (PACT =0.04). When stratifying by parity, this association was limited to nulliparous women. For nulliparous women, adjusted PMD was higher by 8.6% per minor allele (PACT=0.003; P for interaction with parity=0.002). Three additional TGFB1 tagging SNPs, which were in linkage disequilibrium with rs2241716, were statistically significantly associated with adjusted PMD (PACT<0.05) for nulliparous women. However, none of these three SNPs showed statistically significant association after adjusting for rs2241716. Our data support that TGFB1 genetic variation may be an important genetic determinant of mammographic density measure that predicts breast cancer risk, particularly in nulliparous women.
doi:10.1158/0008-5472.CAN-12-1870
PMCID: PMC3740538  PMID: 23333936
TGFB1; polymorphism; mammographic density; Chinese
2.  Underlying genetic structure impacts the association between CYP2B6 polymorphisms and response to efavirenz and nevirapine 
AIDS (London, England)  2012;26(16):2097-2106.
Objective
CYP2B6 variation predicts pharmacokinetic characteristics of its substrates. Consideration for underlying genetic structure is critical to protect against spurious associations with the highly polymorphic CYP2B6 gene.
Design
The effect of CYP2B6 variation on response to its substrates, nonnucleoside reverse transcriptase inhibitors (NNRTIs), was explored in the Women's Interagency HIV Study.
Methods
Five putative functional polymorphisms were tested for associations with virologic suppression within one year after NNRTI initiation in women naïve to antiretroviral agents (n=91). Principal components (PCs) were generated to control for population substructure. Logistic regression was used to test the joint effect of rs3745274 and rs28399499, which together indicate slow, intermediate, and extensive metabolizers.
Results
Rs3745274 was significantly associated with virologic suppression (OR=3.61, 95% CI 1.16-11.22, p trend=0.03); the remaining polymorphisms tested were not significantly associated with response. Women classified as intermediate and slow metabolizers were 2.90 (95% CI 0.79-12.28) and 13.44 (95% CI 1.66-infinity) times as likely to achieve virologic suppression compared to extensive metabolizers after adjustment for PCs (p trend=0.005). Failure to control for genetic ancestry resulted in substantial confounding of the relationship between the metabolizer phenotype and treatment response.
Conclusion
The CYP2B6 metabolizer phenotype was significantly associated with virologic response to NNRTIs; this relationship would have been masked by simple adjustment for self-reported ethnicity. Given the appreciable genetic heterogeneity that exists within self-reported ethnicity, these results exemplify the importance of characterizing underlying genetic structure in pharmacogenetic studies. Further follow-up of the CYP2B6 metabolizer phenotype is warranted given the potential clinical importance of this finding.
doi:10.1097/QAD.0b013e3283593602
PMCID: PMC3940150  PMID: 22951632
CYP2B6; population substructure; women; NNRTIs; confounding
3.  A multi-site single blind clinical study to compare the effects of prolonged exposure, eye movement desensitization and reprocessing and waiting list on patients with a current diagnosis of psychosis and co morbid post traumatic stress disorder: study protocol for the randomized controlled trial Treating Trauma in Psychosis 
Trials  2013;14:151.
Background
Trauma contributes to psychosis and in psychotic disorders post-traumatic stress disorder (PTSD) is often a comorbid disorder. A problem is that PTSD is underdiagnosed and undertreated in people with psychotic disorders. This study’s primary goal is to examine the efficacy and safety of prolonged exposure and eye movement desensitization and reprocessing (EMDR) for PTSD in patients with both psychotic disorders and PTSD, as compared to a waiting list. Secondly, the effects of both treatments are determined on (a) symptoms of psychosis, in particular verbal hallucinations, (b) depression and social performance, and (c) economic costs. Thirdly, goals concern links between trauma exposure and psychotic symptomatology and the prevalence of exposure to traumatic events, and of PTSD. Fourthly predictors, moderators, and mediators for treatment success will be explored. These include cognitions and experiences concerning treatment harm, credibility and burden in both participants and therapists.
Methods/Design
A short PTSD-screener assesses the possible presence of PTSD in adult patients (21- to 65- years old) with psychotic disorders, while the Clinician Administered PTSD Scale interview will be used for the diagnosis of current PTSD. The M.I.N.I. Plus interview will be used for diagnosing lifetime psychotic disorders and mood disorders with psychotic features. The purpose is to include consenting participants (N = 240) in a multi-site single blind randomized clinical trial. Patients will be allocated to one of three treatment conditions (N = 80 each): prolonged exposure or EMDR (both consisting of eight weekly sessions of 90 minutes each) or a six-month waiting list. All participants are subjected to blind assessments at pre-treatment, twomonths post treatment, and six monthspost treatment. In addition, participants in the experimental conditions will have assessments at mid treatment and at 12 months follow-up.
Discussion
The results from the post treatment measurement can be considered strong empirical indicators of the safety and effectiveness of prolonged exposure and EMDR. The six-month and twelve-month follow-up data have the potential of reliably providing documentation of the long-term effects of both treatments on the various outcome variables. Data from pre-treatment and midtreatment can be used to reveal possible pathways of change.
Trial registration
Trial registration: ISRCTN79584912
doi:10.1186/1745-6215-14-151
PMCID: PMC3667059  PMID: 23702050
Psychosis; PTSD; Trauma; Schizophrenia; Hallucinations; Working memory; Prolonged exposure; EMDR; Economic evaluation; Moderators; Mediators
4.  Variations in Sex Hormone Metabolism Genes, Postmenopausal Hormone Therapy, and Risk of Endometrial Cancer 
We investigated whether variants in sex steroid hormone metabolism genes modify the effect of hormone therapy (HT) on endometrial cancer risk in postmenopausal non-Hispanic white women. A nested-case control study was conducted within the California Teachers Study (CTS). We genotyped htSNPs in six genes involved in the hormone metabolism in 286 endometrial cancer cases and 488 controls. Odds ratio (OR) and 95% confidence interval (CI) were estimated for each haplotype using unconditional logistic regression, adjusting for age. The strongest interaction was observed between duration of estrogen therapy (ET) use and haplotype 1A in CYP11A1 (Pinteraction=0.0027; Pinteraction=0.027 after correcting for multiple testing within each gene). The OR for endometrial cancer per copy of haplotype 1A was 2.00 (95%CI: 1.05-3.96) for long-term ET users and 0.90 (95% CI: 0.69-1.18) for never users. The most significant interaction with estrogen-progestin therapy (EPT) was found for two haplotypes on CYP19A1 and EPT use (haplotype 4A, Pinteraction=0.024 and haplotype 3B, Pinteraction=0.043. However, neither this interaction, nor the ET or EPT interactions for any other genes, was statistically significant after correction for multiple testing. Variations in CYP11A1 may modify the effect of ET use on risk of postmenopausal endometrial cancer; however, larger studies are needed to explore these findings further.
doi:10.1002/ijc.26163
PMCID: PMC3267886  PMID: 21544810
menopausal hormone therapy; genetic polymorphism; hormone metabolism gene; endometrial cancer
5.  Genetic variation in peroxisome proliferator-activated receptor gamma, soy, and mammographic density in Singapore Chinese women 
Background
Peroxisome proliferator-activated receptor gamma (PPARγ) is a transcription factor important for adipogenesis and adipocyte differentiation. Data from animal studies suggest that PPARγ may be involved in breast tumorigenesis, but results from epidemiologic studies on the association between PPARγ variation and breast cancer risk have been mixed. Recent data suggest that soy isoflavones can activate PPARγ. We investigated the inter-relations of soy, PPARγ, and mammographic density (MD), a biomarker of breast cancer risk in a cross-sectional study of 2,038 women who were members of the population-based Singapore Chinese Health Study Cohort.
Methods
We assessed MD using a computer-assisted method. We used linear regression to examine the association between 26 tagging SNPs of PPARγ and their interaction with soy intake and MD. To correct for multiple testing, we calculated P-values adjusted for multiple correlated tests (PACT).
Results
Out of the 26 tested SNPs in the PPARγ, 6 SNPs were individually shown to be statistically significantly associated with MD (PACT=0.004∼0.049). A stepwise regression procedure identified that only rs880663 was independently associated with MD which decreased by 1.89% per minor allele (PACT=0.008).This association was significantly stronger in high soy consumers as MD decreased by 3.97% per minor allele of rs880663 in high soy consumers (PACT=0.006; P for interaction with lower soy intake=0.017).
Conclusions
Our data support that PPARγ genetic variation may be important in determining MD, particularly in high soy consumers.
Impact
Our findings may help to identify molecular targets and lifestyle intervention for future prevention research.
doi:10.1158/1055-9965.EPI-11-1042
PMCID: PMC3408217  PMID: 22301832
PPARγ; PPARG; polymorphism; soy; mammographic density; Chinese
6.  Low-level processing of Illumina Infinium DNA Methylation BeadArrays 
Nucleic Acids Research  2013;41(7):e90.
We propose a novel approach to background correction for Infinium HumanMethylation data to account for technical variation in background fluorescence signal. Our approach capitalizes on a new use for the Infinium I design bead types to measure non-specific fluorescence in the colour channel opposite of their design (Cy3/Cy5). This provides tens of thousands of features for measuring background instead of the much smaller number of negative control probes on the platforms (n = 32 for HumanMethylation27 and n = 614 for HumanMethylation450, respectively). We compare the performance of our methods with existing approaches, using technical replicates of both mixture samples and biological samples, and demonstrate that within- and between-platform artefacts can be substantially reduced, with concomitant improvement in sensitivity, by the proposed methods.
doi:10.1093/nar/gkt090
PMCID: PMC3627582  PMID: 23476028
7.  Genetic polymorphisms of epidermal growth factor in relation to risk of hepatocellular carcinoma: two case-control studies 
BMC Gastroenterology  2013;13:32.
Background
Earlier, we reported a highly statistically significant association between T-helper 1 (Th1) and Th2 cytokine genotypes and hepatocellular carcinoma (HCC) risk among natives of southern Guangxi, China, a hyperendemic region for HCC. Epidermal growth factor (EGF) plays a critical role in malignant transformation of hepatocytes and tumor progression. A polymorphism in the EGF gene (61A > G) results in elevation of EGF in liver tissues and blood. Epidemiological data are sparse on the possible association between EGF genetic polymorphism and HCC risk.
Methods
The EGF 61A > G polymorphism, multiple Th1 and Th2 genotypes, and environmental risk factors for HCC were determined on 117 HCC cases and 225 healthy control subjects among non-Asians of Los Angeles County, California, a low-risk population for HCC, and 250 HCC cases and 245 controls of southern Guangxi, China.
Results
Following adjustment for all known or suspected HCC risk factors, non-Asians in Los Angeles who possessed at least one copy of the high activity 61*G allele of the EGF gene showed a statistically non-significant, 78% increased risk of HCC compared with those possessing the EGF A/A genotype. This EGF-HCC risk association significantly strengthened among heavy users of alcohol [odds ratio (OR) = 3.44, 95% confidence interval (CI) = 0.93–12.76, P = 0.065)], and among individuals carrying the high-risk Th1/Th2 genotypes for HCC (OR = 3.34, 95% CI = 1.24-9.03, P = 0.017). No association between EGF genotype and HCC risk was observed among Chinese in southern Guangxi, China.
Conclusion
Genetic polymorphism in the EGF gene resulting in elevated level of EGF, may contribute to HCC risk among low-risk non-Asians in Los Angeles.
doi:10.1186/1471-230X-13-32
PMCID: PMC3621500  PMID: 23419149
Epidermal growth factor; T-helper; Cytokines; Hepatocellular carcinoma
8.  Genetic Determinants for Promoter Hypermethylation in the Lungs of Smokers: A Candidate Gene-Based Study 
Cancer Research  2011;72(3):707-715.
The detection of tumor suppressor gene promoter methylation in sputum-derived exfoliated cells predicts early lung cancer. Here we identified genetic determinants for this epigenetic process and examined their biological effects on gene regulation. A two-stage approach involving discovery and replication was employed to assess the association between promoter hypermethylation of a 12-gene panel and common variation in 40 genes involved in carcinogen metabolism, regulation of methylation, and DNA damage response in members of the Lovelace Smokers Cohort (n=1434). Molecular validation of three identified variants was conducted using primary bronchial epithelial cells. Association of study-wide significance (P<8.2×10−5) was identified for rs1641511, rs3730859, and rs1883264 in TP53, LIG1, and BIK, respectively. These SNPs were significantly associated with altered expression of the corresponding genes in primary bronchial epithelial cells. In addition, rs3730859 in LIG1 was also moderately associated with increased risk for lung cancer among Caucasian smokers. Together, our findings suggest that genetic variation in DNA replication and apoptosis pathways impacts the propensity for gene promoter hypermethylation in the aerodigestive tract of smokers. The incorporation of genetic biomarkers for gene promoter hypermethylation with clinical and somatic markers may improve risk assessment models for lung cancer.
doi:10.1158/0008-5472.CAN-11-3194
PMCID: PMC3271143  PMID: 22139380
DNA damage response; promoter hypermethylation; single nucleotide polymorphism; sputum; smoker
9.  Characteristics of Triple-Negative Breast Cancer in Patients With a BRCA1 Mutation: Results From a Population-Based Study of Young Women 
Journal of Clinical Oncology  2011;29(33):4373-4380.
Purpose
Triple-negative breast cancers (TNBCs) are tumors with low or no expression of estrogen receptor, progesterone receptor, or human epidermal growth factor receptor 2. These tumors have a poor prognosis, remain a clinical challenge, and are more common among women with BRCA1 mutations. We tested whether there are distinguishing features of TNBC after BRCA1 mutation status has been taken into account.
Patients and Methods
We sequenced BRCA1 and BRCA2 genes in a population-based sample of 1,469 patients with incident breast cancer age 20 to 49 years from Los Angeles County (California). Information on tumor receptor status was available for 1,167 women. Clinical, pathologic, and hormone-related lifestyle characteristics were compared across patient subgroups defined by BRCA1 mutation status and triple-negative receptor status.
Results
Forty-eight percent of BRCA1 mutation carriers had TNBC compared with only 12% of noncarriers. Within BRCA1 mutation carriers, as well as within noncarriers, triple-negative receptor status was associated with younger age at diagnosis and higher tumor grade. Among women without a BRCA1 mutation, we observed that women with TNBC had higher premenopausal body mass index and earlier age at first full-term pregnancy than those with non-TNBC. Age at menarche and other reproductive factors were not associated with triple-negative status regardless of BRCA1 mutation status. Within BRCA1 mutation carriers, Ashkenazi Jewish women were about five times more likely to have TNBC than non–Ashkenazi Jewish women.
Conclusion
Our results suggest that among BRCA1 mutation carriers, as among noncarriers, there are unique characteristics associated with the triple-negative subtype. The findings in Ashkenazi Jewish BRCA1 mutation carriers should be confirmed.
doi:10.1200/JCO.2010.33.6446
PMCID: PMC3221522  PMID: 22010008
10.  Glutathione S-transferase (GST) gene polymorphisms, cigarette smoking and colorectal cancer risk among Chinese in Singapore 
Carcinogenesis  2011;32(10):1507-1511.
Cigarette smoking is a risk factor for colorectal cancer. Putative colorectal procarcinogens in tobacco smoke include polycyclic aromatic hydrocarbons and heterocyclic aromatic amines that are known substrates of glutathione S-transferases (GSTs). This study examined the influence of functional GST gene polymorphisms on the smoking–colorectal cancer association in a population known to be minimally exposed to dietary sources of these procarcinogens. Incident cases of colorectal cancer (n = 480) and matched controls (n = 1167) were selected from the Singapore Chinese Health Study, a population-based prospective cohort of 63 257 men and women who have been followed since 1993. We determined the deletion polymorphisms of GSTM1 and GSTT1 and the functional polymorphism at codon 105 of GSTP1 for each subject. A three level composite GST index was used to examine if GST profile affected a smoker’s risk of developing colorectal cancer. While there was no statistically significant association between cigarette smoking and colorectal cancer risk among subjects absent of any at-risk GST genotypes, smokers possessing two to three at-risk GST genotypes exhibited a statistically significant increased risk of colorectal cancer compared with non-smokers (P = 0.0002). In this latter stratum, heavy smokers exhibited a >5-fold increased risk relative to never-smokers (odds ratio, 5.43; 95% confidence interval, 2.22–13.23). Subjects with one at-risk GST genotype displayed a statistically significant but weaker association with smoking. These findings suggest that GST gene polymorphisms influence interindividual susceptibility to smoking-associated colorectal cancer. Our data indicate an important role for GST enzymes in the detoxification of colorectal carcinogens in tobacco smoke.
doi:10.1093/carcin/bgr175
PMCID: PMC3179426  PMID: 21803734
12.  Risk of Urinary Bladder Cancer Is Associated with 8q24 Variant rs9642880[T] in Multiple Racial/Ethnic Groups: Results from the Los Angeles–Shanghai Case–Control Study 
Background
Multiple chromosome 8q24 genotypic variants are strongly implicated in several cancers. Recent genome-wide association studies of urinary bladder cancer report risk to be associated with the T allele of rs9642880 on 8q24 among individuals of European descent.
Methods
We examined associations between bladder cancer risk and genotypes defined by rs9642880 and each of 8 additional 8q24 variants associated with risk of other cancers, in both high-risk non-Hispanic white and low-risk Chinese participants enrolled in a large population-based case–control study conducted in Los Angeles County and Shanghai.
Results
We confirmed association of rs9642880 T with bladder cancer risk not only among non-Hispanic whites but also among Chinese participants [overall per-allele relative risk estimate 1.32 (95% CI, 1.16–1.50; P = 0.000024)]. Subgroup analyses suggested that effects of rs9642880 are largely confined to nonsmokers and former smokers, and may be particularly important in the etiology of noninvasive papillary tumors. There was little indication that 8q24 SNPs associated with other cancer types—rs7008482, rs7000448, rs6983561, rs6983267, rs13281615, rs13254738, or rs10090154—are associated with bladder cancer risk.
Conclusions
Bladder cancer risk is associated specifically with variation in the discrete 8q24 region containing rs9642880. Factors other than rs9642880 genotypes seem to underlie differences in bladder cancer risk between non-Hispanic whites and Chinese.
Impact
Characterization of functional consequences of genetic variation in the discrete region including rs9642880 is needed to understand biological basis of this bladder cancer-specific 8q24 association in these racial/ethnic groups characterized by both high and low risk of bladder cancer.
doi:10.1158/1055-9965.EPI-10-0763
PMCID: PMC3417222  PMID: 21051319
13.  Combined effects of MDM2 SNP309 and TP53 R72P polymorphisms, and soy isoflavones on breast cancer risk among Chinese women in Singapore 
Breast Cancer Research and Treatment  2011;130(3):1011-1019.
The MDM2 oncoprotein regulates the p53 pathway and, while functional polymorphisms of the MDM2 and p53 genes have been investigated for association with breast cancer risk, results are largely null or non-conclusive. We have earlier reported that the increased intake of soy isoflavones reduces risk of postmenopausal breast cancer, and experimental studies suggest that dietary isoflavones can down-regulate the expression of the MDM2 oncoprotein. In this study, we investigated the association between the MDM2 SNP309 and TP53 R72P polymorphisms and breast cancer risk using a case–control study of 403 cases and 662 controls nested among 35,303 women in The Singapore Chinese Health Study, a population-based, prospective cohort of middle-aged and elderly men and women who have been continuously followed since 1993. The G allele of the TP53 R72P polymorphism and T allele of the MDM2 SNP309 polymorphism were putative high-risk alleles and exhibited a combined gene–dose-dependent joint effect on breast cancer risk that was more clearly observed in postmenopausal women. Among postmenopausal women, the simultaneous presence of G allele in TP53 and T allele in MDM2 polymorphisms was associated with an odds ratio (OR) of 2.42 [95% confidence interval (CI) 1.06–5.50]. Furthermore, the protective effect of dietary soy isoflavones on postmenopausal breast cancer was mainly confined to women homozygous for the high activity MDM2 allele (GG genotype). In this genetic subgroup, women consuming levels of soy isoflavones above the median level exhibited risk that was half of those with below median intake (OR 0.52; 95% CI 0.28–0.99). Our findings support experimental data implicating combined effects of MDM2 protein and the p53-mediated pathway in breast carcinogenesis, and suggest that soy isoflavones may exert protective effect via down-regulation of the MDM2 protein.
doi:10.1007/s10549-011-1680-2
PMCID: PMC3404431  PMID: 21833626
MDM2; p53; Soy isoflavones; Breast cancer; Chinese
14.  Genetic variation in insulin-like growth factor 2 may play a role in ovarian cancer risk 
Human Molecular Genetics  2011;20(11):2263-2272.
The insulin-like growth factor (IGF) signaling axis plays an important role in cancer biology. We hypothesized that genetic variation in this pathway may influence risk of ovarian cancer. A three-center study of non-Hispanic whites including 1880 control women, 1135 women with invasive epithelial ovarian cancer and 321 women with borderline epithelial ovarian tumors was carried out to test the association between tag single-nucleotide polymorphisms (tSNPs) (n=58) in this pathway and risk of ovarian cancer. We found no association between variation in IGF1, IGFBP1 or IGFBP3 and risk of invasive disease, whereas five tSNPs in IGF2 were associated with risk of invasive epithelial ovarian cancer at P<0.05 and followed-up one of the associated SNPs. We conducted genotyping in 3216 additional non-Hispanic white cases and 5382 additional controls and were able to independently replicate our initial findings. In the combined set of studies, rs4320932 was associated with a 13% decreased risk of ovarian cancer per copy of the minor allele carried (95% confidence interval 0.81–0.93, P-trend=7.4 × 10−5). No heterogeneity of effect across study centers was observed (phet=0.25). IGF2 is emerging as an important gene for ovarian cancer; additional genotyping is warranted to further confirm these associations with IGF2 and to narrow down the region harboring the causal SNP.
doi:10.1093/hmg/ddr087
PMCID: PMC3090188  PMID: 21422097
15.  Association of the Calcyon Neuron-Specific Vesicular Protein Gene (CALY) With Adolescent Smoking Initiation in China and California 
American Journal of Epidemiology  2011;173(9):1039-1048.
Although previous investigations have indicated a role for genetic factors in smoking initiation, the underlying genetic mechanisms are still unknown. In 2,339 adolescents from a Chinese Han population in the Wuhan Smoking Prevention Trial (Wuhan, China, 1998–1999), the authors explored the association of 57 genes in the dopamine pathway with smoking initiation. Using a conservative approach for declaring significance, positive findings were further examined in an independent sample of 603 Caucasian adolescents followed for up to 10 years as part of the Children's Health Study (Southern California, 1993–2009). The authors identified 1 single nucleotide polymorphism (rs2298122) in the calcyon neuron-specific vesicular protein gene (CALY) that was positively associated with smoking initiation in females (odds ratio = 2.21, 95% confidence interval: 1.49, 3.27; P = 8.4 × 10−5) in the Wuhan Smoking Prevention Trial cohort, and they replicated the association in females from the Children's Health Study cohort (hazard rate ratio = 2.05, 95% confidence interval: 1.27, 3.31; P = 0.003). These results suggest that the CALY gene may influence smoking initiation in adolescents, although the potential roles of underlying psychological characteristics that may be components of the smoking-initiation phenotype, such as impulsivity or novelty-seeking, remain to be explored.
doi:10.1093/aje/kwq471
PMCID: PMC3121219  PMID: 21415033
adolescent; dopamine; genetic association studies; smoking
16.  Genetic variations on chromosomes 5p15 and 15q25 and bladder cancer risk: findings from the Los Angeles–Shanghai bladder case–control study 
Carcinogenesis  2010;32(2):197-202.
Genome-wide association studies have associated common variations at chromosomes 5p15 and 15q25 with lung cancer risk. The 5p15 locus has also been associated with increased bladder cancer risk in a recent report. The 15q25 locus has been associated with nicotine dependence and self-reported number of cigarettes smoked per day in some studies and it was proposed that its association with lung cancer may be mediated through differences in smoking behavior. Here, we investigated the roles of variations at 5p15 (rs401681, rs402710, rs2736098 and rs2736100) and 15q25 (rs1051730 and rs8034191) in bladder cancer etiology in two case–control studies conducted separately in Los Angeles County, CA, USA (498 cases and 588 controls) and in Shanghai, China (506 cases and 530 controls). We replicated the association between the 5p15 locus and bladder cancer among non-Hispanic whites (NHW) in Los Angeles [for rs2736100, per C allele odds ratio (OR) = 1.23; 95% confidence interval (CI), 1.02–1.48; P = 0.029] and among Chinese in Shanghai (OR = 1.22; 95% CI, 1.02–1.47; P = 0.033). Both rs1051730 and rs8034191 at 15q25 were rare among Chinese. Among NHW, a significant association was found between rs8034191 and bladder cancer which persisted after adjustment for cigarette smoking status, number of cigarettes smoked per day and number of years of smoking (per C allele OR = 1.26; 95% CI, 1.04–1.54; P = 0.017). Our results support 5p15 and 15q25 as susceptibility regions for bladder cancer risk.
doi:10.1093/carcin/bgq233
PMCID: PMC3026841  PMID: 21081471
17.  Progesterone Receptor Gene Polymorphisms and Risk of Endometriosis: Results from an International Collaborative Effort 
Fertility and sterility  2010;95(1):40-45.
Objective
To investigate the association between self-reported endometriosis and the putative functional promoter +331C/T single nucleotide polymorphism (SNP) and the PROGINS allele.
Design
Control subjects from ovarian cancer case-control studies participating in the international Ovarian Cancer Association Consortium. The majority of controls are drawn from population-based studies.
Setting
An international ovarian cancer consortium including studies from the Australia, Europe and the United States,
Patients
5,812 White female controls, of whom 348 had endometriosis, from eight ovarian cancer case-control studies.
Interventions
None.
Main Outcome Measures
Genotypes for the +331C/T SNP and PROGINS allele and a history of endometriosis.
Results
The occurrence of endometriosis was reduced in women carrying one or more copies of the +331 T allele (OR=0.65; 95% CI: 0.43–0.98, p=0.042), whereas there was no association between the PROGINS allele and endometriosis (OR=0.94, 95% CI 0.76, 1.16).
Conclusions
Additional studies of the +331C/T variant are warranted given the current finding and the equivocal results of previous studies. The +331 T allele has been shown to result in a reduced PR-A to PR-B ratio and if the observed association with endometriosis is confirmed it would suggest that this ratio is important for this disease.
doi:10.1016/j.fertnstert.2010.06.059
PMCID: PMC3176720  PMID: 20719308
Endometriosis; progesterone receptor; ovarian cancer; PROGINS
18.  Common alleles in candidate susceptibility genes associated with risk and development of epithelial ovarian cancer 
Common germline genetic variation in the population is associated with susceptibility to epithelial ovarian cancer. Microcell-mediated chromosome transfer and expression microarray analysis identified nine genes associated with functional suppression of tumorogenicity in ovarian cancer cell lines; AIFM2, AKTIP, AXIN2, CASP5, FILIP1L, RBBP8, RGC32, RUVBL1 and STAG3. Sixty-three tagging single nucleotide polymorphisms (tSNPs) in these genes were genotyped in 1,799 invasive ovarian cancer cases and 3,045 controls to look for associations with disease risk. Two SNPs in RUVBL1, rs13063604 and rs7650365, were associated with increased risk of serous ovarian cancer [HetOR = 1.42 (1.15–1.74) and the HomOR = 1.63 (1.10–1.42), p-trend = 0.0002] and [HetOR = 0.97 (0.80–1.17), HomOR = 0.74 (0.58–0.93), p-trend = 0.009], respectively. We genotyped rs13063604 and rs7650365 in an additional 4,590 cases and 6,031 controls from ten sites from the United States, Europe and Australia; however, neither SNP was significant in Stage 2. We also evaluated the potential role of tSNPs in these nine genes in ovarian cancer development by testing for allele-specific loss of heterozygosity (LOH) in 286 primary ovarian tumours. We found frequent LOH for tSNPs in AXIN2, AKTIP and RGC32 (64, 46 and 34%, respectively) and one SNP, rs1637001, in STAG3 showed significant allele-specific LOH with loss of the common allele in 94% of informative tumours (p = 0.015). Array comparative genomic hybridisation indicated that this nonrandom allelic imbalance was due to amplification of the rare allele. In conclusion, we show evidence for the involvement of a common allele of STAG3 in the development of epithelial ovarian cancer.
doi:10.1002/ijc.25554
PMCID: PMC3098608  PMID: 20635389
risk of ovarian cancer; polymorphism; association studies
19.  Genetic variation in the progesterone receptor gene and risk of endometrial cancer: a haplotype-based approach 
Carcinogenesis  2010;31(8):1392-1399.
Background: It is well established that estrogen increases endometrial cancer risk, whereas progesterone opposes the estrogen effects. The PROGINS allele of the progesterone receptor (PGR) gene reduces the function of PGR and has been associated with increased risk of the endometrioid type ovarian cancer. We investigated whether genetic variation in PGR is also associated with endometrial cancer risk using a haplotype-based approach. Methods: We pooled data from two endometrial cancer case–control studies that were nested within two prospective cohorts, the Multiethnic Cohort Study and the California Teachers Study. Seventeen haplotype-tagging single nucleotide polymorphisms (SNPs) across four linkage disequilibrium (LD) blocks spanning the PGR locus were genotyped in 583 incident cases and 1936 control women. Odds ratios (ORs) and 95% confidence intervals (CIs) associated with each haplotype were estimated using conditional logistic regression, stratified by age and ethnicity. Results: Genetic variation in LD block 3 of the PGR locus was associated with endometrial cancer risk (Pglobal test = 0.002), with haplotypes 3C, 3D and 3F associated with 31–34% increased risk. Among whites (383 cases/840 controls), genetic variation in all four blocks was associated with increased endometrial cancer risk (Pglobal test = 0.010, 0.013, 0.005 and 0.020). Haplotypes containing the PROGINS allele and several haplotypes in blocks 1, 3 and 4 were associated with 34–77% increased risk among whites. SNP analyses for whites suggested that rs608995, partially linked to the PROGINS allele (r2 = 0.6), was associated with increased risk (OR = 1.30, 95% CI = 1.06–1.59). Conclusions: Our results suggest that genetic variation in the PGR region is associated with endometrial cancer risk.
doi:10.1093/carcin/bgq113
PMCID: PMC2915632  PMID: 20547493
20.  Common variants at 19p13 are associated with susceptibility to ovarian cancer 
Bolton, Kelly L. | Tyrer, Jonathan | Song, Honglin | Ramus, Susan J. | Notaridou, Maria | Jones, Chris | Sher, Tanya | Gentry-Maharaj, Aleksandra | Wozniak, Eva | Tsai, Ya-Yu | Weidhaas, Joanne | Paik, Daniel | Van Den Berg, David J. | Stram, Daniel O. | Pearce, Celeste Leigh | Wu, Anna H. | Brewster, Wendy | Anton-Culver, Hoda | Ziogas, Argyrios | Narod, Steven A. | Levine, Douglas A. | Kaye, Stanley B. | Brown, Robert | Paul, Jim | Flanagan, James | Sieh, Weiva | McGuire, Valerie | Whittemore, Alice S. | Campbell, Ian | Gore, Martin E. | Lissowska, Jolanta | Yang, Hannah | Medrek, Krzysztof | Gronwald, Jacek | Lubinski, Jan | Jakubowska, Anna | Le, Nhu D. | Cook, Linda S. | Kelemen, Linda E. | Brook-Wilson, Angela | Massuger, Leon F.A.G. | Kiemeney, Lambertus A. | Aben, Katja K.H. | van Altena, Anne M. | Houlston, Richard | Tomlinson, Ian | Palmieri, Rachel T. | Moorman, Patricia G. | Schildkraut, Joellen | Iversen, Edwin S. | Phelan, Catherine | Vierkant, Robert A. | Cunningham, Julie M. | Goode, Ellen L. | Fridley, Brooke L. | Kruger-Kjaer, Susan | Blaeker, Jan | Hogdall, Estrid | Hogdall, Claus | Gross, Jenny | Karlan, Beth Y. | Ness, Roberta B. | Edwards, Robert P. | Odunsi, Kunle | Moyisch, Kirsten B. | Baker, Julie A. | Modugno, Francesmary | Heikkinenen, Tuomas | Butzow, Ralf | Nevanlinna, Heli | Leminen, Arto | Bogdanova, Natalia | Antonenkova, Natalia | Doerk, Thilo | Hillemanns, Peter | Dürst, Matthias | Runnebaum, Ingo | Thompson, Pamela J. | Carney, Michael E. | Goodman, Marc T. | Lurie, Galina | Wang-Gohrke, Shan | Hein, Rebecca | Chang-Claude, Jenny | Rossing, Mary Anne | Cushing-Haugen, Kara L. | Doherty, Jennifer | Chen, Chu | Rafnar, Thorunn | Besenbacher, Soren | Sulem, Patrick | Stefansson, Kari | Birrer, Michael J. | Terry, Kathryn L. | Hernandez, Dena | Cramer, Daniel W. | Vergote, Ignace | Amant, Frederic | Lambrechts, Diether | Despierre, Evelyn | Fasching, Peter A. | Beckmann, Matthias W. | Thiel, Falk C. | Ekici, Arif B. | Chen, Xiaoqing | Johnatty, Sharon E. | Webb, Penelope M. | Beesley, Jonathan | Chanock, Stephen | Garcia-Closas, Montserrat | Sellers, Tom | Easton, Douglas F. | Berchuck, Andrew | Chenevix-Trench, Georgia | Pharoah, Paul D.P. | Gayther, Simon A.
Nature genetics  2010;42(10):880-884.
Epithelial ovarian cancer (EOC) is the leading cause of death from gynecological malignancy in the developed world accounting for 4 percent of deaths from cancer in women1. We performed a three-phase genome-wide association study of EOC survival in 8,951 EOC cases with available survival time data, and a parallel association analysis of EOC susceptibility. Two SNPs at 19p13.11, rs8170 and rs2363956, showed evidence of association with survival (overall P=5×10−4 and 6×10−4), but did not replicate in phase 3. However, the same two SNPs demonstrated genome-wide significance for risk of serous EOC (P=3×10−9 and 4×10−11 respectively). Expression analysis of candidate genes at this locus in ovarian tumors supported a role for the BRCA1 interacting gene C19orf62, also known as MERIT40, which contains rs8170, in EOC development.
doi:10.1038/ng.666
PMCID: PMC3125495  PMID: 20852633
21.  A multi-stage genome-wide association study of bladder cancer identifies multiple susceptibility loci 
Rothman, Nathaniel | Garcia-Closas, Montserrat | Chatterjee, Nilanjan | Malats, Nuria | Wu, Xifeng | Figueroa, Jonine | Real, Francisco X | Van Den Berg, David | Matullo, Giuseppe | Baris, Dalsu | Thun, Michael | Kiemeney, Lambertus A | Vineis, Paolo | De Vivo, Immaculata | Albanes, Demetrius | Purdue, Mark P | Rafnar, Thorunn | Hildebrandt, Michelle A T | Kiltie, Anne E | Cussenot, Olivier | Golka, Klaus | Kumar, Rajiv | Taylor, Jack A | Mayordomo, Jose I | Jacobs, Kevin B | Kogevinas, Manolis | Hutchinson, Amy | Wang, Zhaoming | Fu, Yi-Ping | Prokunina-Olsson, Ludmila | Burdette, Laurie | Yeager, Meredith | Wheeler, William | Tardón, Adonina | Serra, Consol | Carrato, Alfredo | García-Closas, Reina | Lloreta, Josep | Johnson, Alison | Schwenn, Molly | Karagas, Margaret R | Schned, Alan | Andriole, Gerald | Grubb, Robert | Black, Amanda | Jacobs, Eric J | Diver, W Ryan | Gapstur, Susan M | Weinstein, Stephanie J | Virtamo, Jarmo | Cortessis, Victoria K | Gago-Dominguez, Manuela | Pike, Malcolm C | Stern, Mariana C | Yuan, Jian-Min | Hunter, David | McGrath, Monica | Dinney, Colin P | Czerniak, Bogdan | Chen, Meng | Yang, Hushan | Vermeulen, Sita H | Aben, Katja K | Witjes, J Alfred | Makkinje, Remco R | Sulem, Patrick | Besenbacher, Soren | Stefansson, Kari | Riboli, Elio | Brennan, Paul | Panico, Salvatore | Navarro, Carmen | Allen, Naomi E | Bueno-de-Mesquita, H Bas | Trichopoulos, Dimitrios | Caporaso, Neil | Landi, Maria Teresa | Canzian, Federico | Ljungberg, Borje | Tjonneland, Anne | Clavel-Chapelon, Francoise | Bishop, David T | Teo, Mark T W | Knowles, Margaret A | Guarrera, Simonetta | Polidoro, Silvia | Ricceri, Fulvio | Sacerdote, Carlotta | Allione, Alessandra | Cancel-Tassin, Geraldine | Selinski, Silvia | Hengstler, Jan G | Dietrich, Holger | Fletcher, Tony | Rudnai, Peter | Gurzau, Eugen | Koppova, Kvetoslava | Bolick, Sophia C E | Godfrey, Ashley | Xu, Zongli | Sanz-Velez, José I | García-Prats, María D | Sanchez, Manuel | Valdivia, Gabriel | Porru, Stefano | Benhamou, Simone | Hoover, Robert N | Fraumeni, Joseph F | Silverman, Debra T | Chanock, Stephen J
Nature genetics  2010;42(11):978-984.
We conducted a multi-stage, genome-wide association study (GWAS) of bladder cancer with a primary scan of 589,299 single nucleotide polymorphisms (SNPs) in 3,532 cases and 5,120 controls of European descent (5 studies) followed by a replication strategy, which included 8,381 cases and 48,275 controls (16 studies). In a combined analysis, we identified three new regions associated with bladder cancer on chromosomes 22q13.1, 19q12 and 2q37.1; rs1014971, (P=8×10−12) maps to a non-genic region of chromosome 22q13.1; rs8102137 (P=2×10−11) on 19q12 maps to CCNE1; and rs11892031 (P=1×10−7) maps to the UGT1A cluster on 2q37.1. We confirmed four previous GWAS associations on chromosomes 3q28, 4p16.3, 8q24.21 and 8q24.3, validated previous candidate associations for the GSTM1 deletion (P=4×10−11) and a tag SNP for NAT2 acetylation status (P=4×10−11), as well as demonstrated smoking interactions with both regions. Our findings on common variants associated with bladder cancer risk should provide new insights into mechanisms of carcinogenesis.
doi:10.1038/ng.687
PMCID: PMC3049891  PMID: 20972438
22.  Rapid testing versus karyotyping in Down's syndrome screening: cost-effectiveness and detection of clinically significant chromosome abnormalities 
In all, 80% of antenatal karyotypes are generated by Down's syndrome screening programmes (DSSP). After a positive screening, women are offered prenatal foetus karyotyping, the gold standard. Reliable molecular methods for rapid aneuploidy diagnosis (RAD: fluorescence in situ hybridization (FISH) and quantitative fluorescence PCR (QF-PCR)) can detect common aneuploidies, and are faster and less expensive than karyotyping.
In the UK, RAD is recommended as a standalone approach in DSSP, whereas the US guidelines recommend that RAD be followed up by karyotyping. A cost-effectiveness (CE) analysis of RAD in various DSSP is lacking. There is a debate over the significance of chromosome abnormalities (CA) detected with karyotyping but not using RAD. Our objectives were to compare the CE of RAD versus karyotyping, to evaluate the clinically significant missed CA and to determine the impact of detecting the missed CA. We performed computer simulations to compare six screening options followed by FISH, PCR or karyotyping using a population of 110 948 pregnancies. Among the safer screening strategies, the most cost-effective strategy was contingent screening with QF-PCR (CE ratio of $24 084 per Down's syndrome (DS) detected). Using karyotyping, the CE ratio increased to $27 898. QF-PCR missed only six clinically significant CA of which only one was expected to confer a high risk of an abnormal outcome. The incremental CE ratio (ICER) to find the CA missed by RAD was $66 608 per CA. These costs are much higher than those involved for detecting DS cases. As the DSSP are mainly designed for DS detection, it may be relevant to question the additional costs of karyotyping.
doi:10.1038/ejhg.2010.138
PMCID: PMC3039505  PMID: 20842178
Down's syndrome; prenatal diagnosis; chromosome abnormalities
23.  Genetic Association Between the COMT Genotype and Urinary Levels of Tea Polyphenols and Their Metabolites among Daily Green Tea Drinkers 
Available in vitro and animal studies have shown cancer protective effects of tea polyphenols. Recent study suggests a greater protective effect of green tea intake on breast cancer risk among women possessing the low-activity associated genotype of the catechol-O-methyltransferase (COMT), which may modulate the metabolism and excretion of tea polyphenols through urine. To determine the effect of COMT genotype on urinary excretion of tea polyphenol metabolites of daily green tea drinkers, a cross-sectional analysis was performed within the Shanghai Cohort Study, a population-based, prospective investigation of diet and cancer in 18,244men. In addition to an in-person interview, each participant provided a blood and urine sample at baseline. In the present study, COMT genotype (rs4680) and five urinary metabolites of tea polyphenols were determined in 660 cohort subjects who self-identified as daily drinkers of green tea. All urinary tea polyphenol measurements were expressed in units of urinary creatinine. Men possessing the homozygous low-activity associated COMT genotype (LL) exhibited statistically significantly lower urinary levels of individual as well as all of the five tea polyphenol metabolites under study relative to individuals possessing the wild type high-activity associated COMT genotype (HH)or the heterozygous variant genotype (HL). Levels of urinary tea polyphenol metabolites were comparable between men possessing the HH and HL genotypes. The present study demonstrated that men carrying low-activity associated COMT genotype excreted less tea polyphenols from urine, which suggests that they may retain more tea polyphenols in their bodies and derive greater health benefits from green tea intake.
PMCID: PMC3010377  PMID: 21191472
urinary tea polyphenols; green tea; COMT genotype
24.  Isothiocyanates, glutathione S-transferase M1 and T1 polymorphisms and gastric cancer risk: a prospective study of men in Shanghai, China 
Isothiocyanates (ITC) in cruciferous vegetables may be chemopreventive against gastric cancer development. Glutathione S-transferases (GSTs) may modify the chemopreventive effect of ITC. The relationship between urinary total ITC and risk of gastric cancer was prospectively examined. Between 1986 and 1989, 18,244 middle-aged men in Shanghai, China were enrolled in a prospective study of diet and cancer and donated baseline urine and blood samples. Urinary ITC was quantified for 307 incident cases of gastric cancer that occurred during the first 16 years of follow-up, and 911 matched control subjects. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using logistic regression methods. Seropositivity for antibodies to Helicobacter pylori and homozygous deletions of GSTM1 and GSTT1 were determined. Compared with the first tertile, ORs (95% CIs) of gastric cancer for the second and third tertiles of urinary total ITC were 0.83 (0.61–1.15) and 0.66 (0.47–0.94) (Ptrend=0.02). A stronger protective effect of ITC against gastric cancer development was seen among men with homozygous deletion of GSTM1 (third tertile versus first tertile, OR = 0.50, 95% CI = 0.27–0.93) or GSTT1 (third tertile versus first tertile, OR = 0.47, 95% CI = 0.25–0.88), and particularly with deletions of both GSTM1 and GSTT1 (second and third tertiles versus first tertile, OR = 0.44, 95% CI = 0.21–0.93). In this cohort of Chinese men at high risk for gastric cancer, isothiocyanates may protect against the development of gastric cancer. The protection may be stronger for individuals genetically deficient in enzymes that metabolize these chemopreventive compounds.
doi:10.1002/ijc.24583
PMCID: PMC2757456  PMID: 19610060
cruciferous vegetables; ITC; GST polymorphisms; urinary biomarkers; gastric cancer
25.  Sequence Variant on 3q28 and Urinary Bladder Cancer Risk: Findings from the Los Angeles-Shanghai Bladder Case-Control Study 
Recently, the first genome wide association study of bladder cancer identified an association of genome-wide significance between SNP rs715021 and urinary bladder cancer risk among European individuals. This SNP is in a haplotype block in linkage disequilibrium with the TP63 gene. We investigated the role of this SNP among 1,042 cases and 1,123 controls among non-Latino whites in Los Angeles County, California, USA, and among Chinese in Shanghai, China. We confirmed an association between the A allele and bladder cancer risk (log-additive per A allele OR = 1.24; 95% CI = 1.02–1.52, p = 0.032) in Los Angeles County and a similar association in Shanghai (log-additive per A allele OR = 1.21; 95% CI = 0.98–1.49, p = 0.080). These estimates did not differ by study site, smoking status, or gender. However, the effects were greater in older individuals. Analysis within non-Latino whites for whom we had histological results, revealed that this association was restricted to low risk tumors (OR = 1.49, 95% CI = 1.17–1.92, p = 0.002) and absent among high-risk tumors (OR = 1.03, 95% CI = 0.80–1.33, p = 0.790; heterogeneity p = 0.019). A positive association (OR = 1.56; 95% CI = 0.93–2.62, p = 0.089) was only observed among high-risk tumors from individuals older than 56 years old (interaction p = 0.045). Our results suggest that a TP63 gene variant may increase susceptibility for the development of urinary bladder tumors with low risk of progression.
doi:10.1158/1055-9965.EPI-09-0492
PMCID: PMC2783174  PMID: 19843673

Results 1-25 (51)