A meta-analysis of genome-wide association studies of multiple myeloma among men and women of African ancestry.

Persons of African ancestry (AA) have a twofold higher risk for multiple myeloma (MM) compared with persons of European ancestry (EA). Genome-wide association studies (GWASs) support a genetic contribution to MM etiology in individuals of EA. Little is known about genetic risk factors for MM in individuals of AA. We performed a meta-analysis of 2 GWASs of MM in 1813 cases and 8871 controls and conducted an admixture mapping scan to identify risk alleles. We fine-mapped the 23 known susceptibility loci to find markers that could better capture MM risk in individuals of AA and constructed a polygenic risk score (PRS) to assess the aggregated effect of known MM risk alleles. In GWAS meta-analysis, we identified 2 suggestive novel loci located at 9p24.3 and 9p13.1 at P < 1 × 10-6; however, no genome-wide significant association was noted. In admixture mapping, we observed a genome-wide significant inverse association between local AA at 2p24.1-23.1 and MM risk in AA individuals. Of the 23 known EA risk variants, 20 showed directional consistency, and 9 replicated at P < .05 in AA individuals. In 8 regions, we identified markers that better capture MM risk in persons with AA. AA individuals with a PRS in the top 10% had a 1.82-fold (95% confidence interval, 1.56-2.11) increased MM risk compared with those with average risk (25%-75%). The strongest functional association was between the risk allele for variant rs56219066 at 5q15 and lower ELL2 expression (P = 5.1 × 10-12). Our study shows that common genetic variation contributes to MM risk in individuals with AA.

Imatinib treatments have long-term impact on placentation and embryo survival.

Imatinib is an oral chemotherapeutic used primarily to treat chronic myeloid leukemia (CML) and gastrointestinal stromal tumors (GIST). The potential effects of cancer treatments on a patient's future fertility  are a major concern affecting the quality of life for cancer survivors. The effects of imatinib on future fertility are unknown. It is teratogenic. Therefore, patients are advised to stop treatment before pregnancy. Unfortunately, CML and GIST have high rates of recurrence in the absence of the drug, therefore halting imatinib during pregnancy endangers the mother. Possible long-term (post-treatment) effects of imatinib on reproduction have not been studied. We have used a mouse model to examine the effects of imatinib on the placenta and implantation after long-term imatinib exposure. We found significant changes in epigenetic markers of key imprinted genes in the placenta. There was a significant decrease in the labyrinth zone and vasculature of the placenta, which could impact fetal growth later in pregnancy. These effects on placental growth occurred even when imatinib was stopped prior to pregnancy. These results indicate potential long-term effects of imatinib on pregnancy and implantation. A prolonged wash-out period prior to pregnancy or extra monitoring for possible placental insufficiency may be advisable.

Circulating Metabolic Biomarkers of Screen-Detected Prostate Cancer in the ProtecT Study.

BACKGROUND: Whether associations between circulating metabolites and prostate cancer are causal is unknown. We report on the largest study of metabolites and prostate cancer (2,291 cases and 2,661 controls) and appraise causality for a subset of the prostate cancer-metabolite associations using two-sample Mendelian randomization (MR). METHODS: The case-control portion of the study was conducted in nine UK centers with men ages 50-69 years who underwent prostate-specific antigen screening for prostate cancer within the Prostate Testing for Cancer and Treatment (ProtecT) trial. Two data sources were used to appraise causality: a genome-wide association study (GWAS) of metabolites in 24,925 participants and a GWAS of prostate cancer in 44,825 cases and 27,904 controls within the Association Group to Investigate Cancer Associated Alterations in the Genome (PRACTICAL) consortium. RESULTS: Thirty-five metabolites were strongly associated with prostate cancer (P < 0.0014, multiple-testing threshold). These fell into four classes: (i) lipids and lipoprotein subclass characteristics (total cholesterol and ratios, cholesterol esters and ratios, free cholesterol and ratios, phospholipids and ratios, and triglyceride ratios); (ii) fatty acids and ratios; (iii) amino acids; (iv) and fluid balance. Fourteen top metabolites were proxied by genetic variables, but MR indicated these were not causal. CONCLUSIONS: We identified 35 circulating metabolites associated with prostate cancer presence, but found no evidence of causality for those 14 testable with MR. Thus, the 14 MR-tested metabolites are unlikely to be mechanistically important in prostate cancer risk. IMPACT: The metabolome provides a promising set of biomarkers that may aid prostate cancer classification.

Micro-RNAs involved in cellular proliferation have altered expression profiles in granulosa of young women with diminished ovarian reserve.

PURPOSE: The study aims to determine differences in micro-RNA (miRNA) expression in granulosa (GC) and cumulus cells (CC) between young women with diminished ovarian reserve (DOR) or normal ovarian reserve (NOR). Secondary objective was to identify downstream signaling pathways that could ultimately indicate causes of lower developmental competence of oocytes from young women with DOR. METHODS: The method of the study is prospective cohort study. RESULTS: Of the miRNA, 125 are differentially expressed in GC between DOR and NOR. Only nine miRNA were different in CC; therefore, we focused analysis on GC. In DOR GC, miR-100-5p, miR-16-5p, miR-30a-3p, and miR-193a-3p were significantly downregulated, while miR-155-5p, miR-192-5p, miR-128-3p, miR-486-5p, miR130a-3p, miR-92a-3p, miR-17-3p, miR-221-3p, and miR-175p were increased. This pattern predicted higher cell proliferation in the DOR GC. The primary pathways include MAPK, Wnt, and TGFbeta. CONCLUSIONS: The miRNA pattern identified critical functions in cell proliferation and survival associated with DOR. GC in women with DOR seems to respond differently to the LH surge.

Gene-Centric Analysis of Preeclampsia Identifies Maternal Association at PLEKHG1.

The genetic susceptibility to preeclampsia, a pregnancy-specific complication with significant maternal and fetal morbidity, has been poorly characterized. To identify maternal genes associated with preeclampsia risk, we assembled 498 cases and 1864 controls of European ancestry from preeclampsia case-control collections in 5 different US sites (with additional matched population controls), genotyped samples on a cardiovascular gene-centric array composed of variants from ≈2000 genes selected based on prior genetic studies of cardiovascular and metabolic diseases and performed case-control genetic association analysis on 27 429 variants passing quality control. In silico replication testing of 9 lead signals with P<10-4 was performed in independent European samples from the SOPHIA (Study of Pregnancy Hypertension in Iowa) and Inova cohorts (212 cases, 456 controls). Multiethnic assessment of lead signals was then performed in samples of black (26 cases, 136 controls), Hispanic (132 cases, 468 controls), and East Asian (9 cases, 80 controls) ancestry. Multiethnic meta-analysis (877 cases, 3004 controls) revealed a study-wide statistically significant association of the rs9478812 variant in the pleiotropic PLEKHG1 gene (odds ratio, 1.40 [1.23-1.60]; Pmeta=5.90×10-7). The rs9478812 effect was even stronger in the subset of European cases with known early-onset preeclampsia (236 cases diagnosed <37 weeks, 1864 controls; odds ratio, 1.59 [1.27-1.98]; P=4.01×10-5). PLEKHG1 variants have previously been implicated in genome-wide association studies of blood pressure, body weight, and neurological disorders. Although larger studies are required to further define maternal preeclampsia heritability, this study identifies a novel maternal risk locus for further investigation.

Perinatal outcomes after natural conception versus in vitro fertilization (IVF) in gestational surrogates: a model to evaluate IVF treatment versus maternal effects.

OBJECTIVE: To study the perinatal outcomes between singleton live births achieved with the use of commissioned versus spontaneously conceived embryos carried by the same gestational surrogate. DESIGN: Retrospective cohort study. SETTING: Academic in vitro fertilization center. PATIENT(S): Gestational surrogate. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Pregnancy outcome, gestational age at birth, birth weight, perinatal complications. RESULT(S): We identified 124 gestational surrogates who achieved a total of 494 pregnancies. Pregnancy outcomes for surrogate and spontaneous pregnancies were significantly different (P<.001), with surrogate pregnancies more likely to result in twin pregnancies: 33% vs. 1%. Miscarriage and ectopic rates were similar. Of these pregnancies, there were 352 singleton live births: 103 achieved from commissioned embryos and 249 conceived spontaneously. Surrogate births had lower mean gestational age at delivery (38.8 ± 2.1 vs. 39.7 ± 1.4), higher rates of preterm birth (10.7% vs. 3.1%), and higher rates of low birth weight (7.8% vs. 2.4%). Neonates from surrogacy had birth weights that were, on average, 105 g lower. Surrogate births had significantly higher obstetrical complications, including gestational diabetes, hypertension, use of amniocentesis, placenta previa, antibiotic requirement during labor, and cesarean section. CONCLUSION(S): Neonates born from commissioned embryos and carried by gestational surrogates have increased adverse perinatal outcomes, including preterm birth, low birth weight, hypertension, maternal gestational diabetes, and placenta previa, compared with singletons conceived spontaneously and carried by the same woman. Our data suggest that assisted reproductive procedures may potentially affect embryo quality and that its negative impact can not be overcome even with a proven healthy uterine environment.

Differential gene expression by 1,25(OH)2D3 in an endometriosis stromal cell line.

Endometriosis is a common female reproductive disease characterized by invasion of endometrial cells into other organs, frequently causing pelvic pain and infertility. Alterations of the vitamin D system have been linked to endometriosis incidence and severity. To shed light on the potential mechanism for these associations, we examined the effects of 1,25(OH)2D3 on gene expression in endometriosis cells. Stromal cell lines derived from endometriosis tissue were treated with 1,25(OH)2D3, and RNA-seq was used to identify genes differentially expressed between treated and untreated cells. Gene ontology and pathway analyses were carried out using Partek Flow and Ingenuity software suites, respectively. We identified 1627 genes that were differentially expressed (886 down-regulated and 741 up-regulated) by 1,25(OH)2D3. Only one gene, CYP24A1, was strongly up-regulated (369-fold). Many genes were strongly down-regulated. 1,25(OH)2D3 treatment down-regulated several genetic pathways related to neuroangiogenesis, cellular motility, and invasion, including pathways for axonal guidance, Rho GDP signaling, and matrix metalloprotease inhibition. These findings support a role for vitamin D in the pathophysiology of endometriosis, and provide new targets for investigation into possible causes and treatments.

Pilot Study of Intensive Chemotherapy With Peripheral Hematopoietic Cell Support for Children Less Than 3 Years of Age With Malignant Brain Tumors, the CCG-99703 Phase I/II Study. A Report From the Children's Oncology Group.

BACKGROUND: The primary goals of the Children's Cancer Group 99703 study were to assess the feasibility and tolerability of-as well as the response rate to-a novel dose-intensive chemotherapy regimen. METHODS: Between March 1998 and October 2004, 92 eligible patients were enrolled. Following biopsy/resection, patients received three identical cycles of Induction chemotherapy (vincristine, cyclophosphamide, etoposide, and cisplatin) administered every 21-28 days. Patients without tumor progression then received three consolidation cycles of marrow-ablative chemotherapy (thiotepa and carboplatin) followed by autologous hematopoietic cell rescue. RESULTS: The maximum tolerated dose of thiotepa was 10 mg/kg/day × 2 days per cycle. The toxic mortality rate was zero during induction and 2.6% during consolidation. Centrally evaluated response rates to induction and consolidation in evaluable patients with residual tumor were 73.3% and 66.7%, respectively. Disease progression rates on induction and consolidation were 4%. Five-year event-free survival and overall survival were 43.9 ± 5.2% and 63.6 ± 5% respectively. Gross total resection versus less than gross total resection were the only significant outcome comparisons: 5-year maximum tolerated dose and overall survival of 54.4 ± 7% versus 28.9 ± 7% (P = 0.0065) and 75.9 ± 8% versus 48.7 ± 8% (P = 0.0034), respectively. The 5-year maximum tolerated dose for localized (M0) versus metastatic (M1+) medulloblastoma was 67.5 ± 9.5% versus 30 ± 14.5% (P = 0.007). The 5-year maximum tolerated dose and overall survival for desmoplastic medulloblastoma patients versus other medulloblastoma were 78.6 ± 11% versus 50.5 ± 12% (P = 0.038) and 85.7 ± 9.4% versus 60.6 ± 11.6% (P = 0.046), respectively. CONCLUSIONS: This phase I dose-escalation study of marrow-ablative thiotepa regimen determined a maximum tolerated dose that had acceptable toxicity. Overall survival data justify this strategy for current Children's Oncology Group studies.

Genetic variants and non-genetic factors predict circulating vitamin D levels in Hispanic and non-Hispanic White women: the Breast Cancer Health Disparities Study.

Genome-wide association studies (GWAS) have identified common polymorphisms in or near GC, CYP2R1, CYP24A1, and NADSYN1/DHCR7 genes to be associated with circulating levels of 25-hydroxyvitamin D [25(OH)D] in European populations. To replicate these GWAS findings, we examined six selected polymorphisms from these regions and their relation with circulating 25(OH)D levels in 1,605 Hispanic women (629 U.S. Hispanics and 976 Mexicans) and 354 non-Hispanic White (NHW) women. We also assessed the potential interactions between these variants and known non-genetic predictors of 25(OH)D levels, including body mass index (BMI), sunlight exposure and vitamin D intake from diet and supplements. The minor alleles of the two GC polymorphisms (rs7041 and rs2282679) were significantly associated with lower 25(OH)D levels in both Hispanic and NHW women. The CYP2R1 polymorphism, rs2060793, also was significantly associated with 25(OH)D levels in both groups. We found no significant associations for the polymorphisms in the CYP24A1. In Hispanic controls, 25(OH)D levels were significantly associated with the rs12785878T and rs1790349G haplotype in the NADSYN1/DHCR7 region. Significant interactions between GC rs2282679 and BMI and between rs12785878 and time spent in outdoor activities were observed. These results provide further support for the contribution of common genetic variants to individual variability in circulating 25(OH)D levels. The observed interactions between SNPs and non-genetic factors warrant confirmation.

Influence of vitamin D levels on in vitro fertilization outcomes in donor-recipient cycles.

OBJECTIVE: To elucidate the role of vitamin D in reproduction by examining the relationship between recipient vitamin D levels and pregnancy rates in donor-recipient IVF cycles. DESIGN: Retrospective cohort study. SETTING: Academic tertiary care center. PATIENT(S): Ninety-nine recipients of egg donation at University of Southern California Fertility. INTERVENTION(S): Serum was collected from egg donor recipients before ET and was tested for vitamin D levels [25(OH)D]. MAIN OUTCOME MEASURE(S): Clinical pregnancy as defined by sonographic presence of a heartbeat at 7-8 weeks of gestation. RESULT(S): In a diverse population of 99 recipients (53% Caucasian, 20% Asian, 16% Hispanic, 7% African American), adjusted clinical pregnancy rates were lower among vitamin D-deficient recipients than among vitamin D-replete recipients (37% vs. 78%). Live-birth rates were 31% among vitamin D-deficient recipients, compared with 59% among vitamin D-replete recipients. There were no differences in adjusted clinical pregnancy and live-birth rates among recipients who were vitamin D deficient [25(OH)D<20 ng/mL] vs. among those who were vitamin D insufficient [20 ng/mL ≤ 25(OH)D<30 ng/mL]. CONCLUSION(S): Nonreplete vitamin D status [25(OH)D<30 ng/mL] was associated with lower pregnancy rates in recipients of egg donation. Since the oocyte donor-recipient model is able to separate the impact of vitamin D on oocyte vs. endometrium, these data suggest that the effects of vitamin D may be mediated through the endometrium.

Immediate post-abortion insertion of intrauterine contraceptives (IUC) in a diverse urban population.

Ethnic minority women have a higher incidence of unintended pregnancy and abortion than Caucasian women, with significant individual and social implications. Post-abortion intrauterine contraceptive (IUC) use may reduce future unintended pregnancy. This was a retrospective review of 265 women undergoing abortion at a Los Angeles County Reproductive Options Clinic. Demographic factors, reproductive history, and post-abortion contraceptive choice were evaluated and analyzed. The population was predominantly Latina (73%) and single, with a mean age of 27. Immediate post-abortion IUC insertion was chosen by 48% overall and more frequently by Latinas (55%) than by African Americans (33%) or Asians (43%) (p = 0.02). IUC use increased with age, undesired future fertility, increasing gravidity, and history of previous abortion in univariate analysis. In multivariate analysis, IUC use increased with Latina ethnicity and increasing gravidity. In a clinic serving low-income urban women in Los Angeles, post-abortal IUC uptake is highest among Latinas and those with prior pregnancies. Future research should examine reasons for and barriers to IUC uptake in diverse communities and methods to improve post-abortion IUC uptake to prevent subsequent unintended pregnancies.

LHRH and LHR genotypes and prostate cancer incidence and survival.

Despite their crucial role in initiating steroid-hormone synthesis, the hypothalamic and pituitary hormones (LH, LHRH) and their receptors have received scant attention in genetic studies of hormone-related diseases. This study included 1,170 men diagnosed with prostate cancer (PC) in Los Angeles County between 1999 and 2003. LHRH and LH receptor genotypes were examined for association with PC survival. Additionally, associations with PC incidence were examined by comparing PC cases to control men of similar age and race/ethnicity. The LHR 312 G allele was found to be associated with increased PC mortality (p=0.01). Ten years after diagnosis, 16% of men carrying two copies of the G allele (genotype GG) had died of PC, compared to 11% of those with genotype AG and 9% of those with AA. In a case-control comparison, this same allele was significantly associated with decreased PC risk: OR=0.68 (95% CI: 0.49, 0.93) for genotype GG vs. AA. These results suggest that androgens may play opposing roles in PC initiation and progression, and highlight the need to include these important but overlooked genes in future studies of PC etiology, prognosis, and treatment.

Global patterns of prostate cancer incidence, aggressiveness, and mortality in men of african descent.

Prostate cancer (CaP) is the leading cancer among men of African descent in the USA, Caribbean, and Sub-Saharan Africa (SSA). The estimated number of CaP deaths in SSA during 2008 was more than five times that among African Americans and is expected to double in Africa by 2030. We summarize publicly available CaP data and collected data from the men of African descent and Carcinoma of the Prostate (MADCaP) Consortium and the African Caribbean Cancer Consortium (AC3) to evaluate CaP incidence and mortality in men of African descent worldwide. CaP incidence and mortality are highest in men of African descent in the USA and the Caribbean. Tumor stage and grade were highest in SSA. We report a higher proportion of T1 stage prostate tumors in countries with greater percent gross domestic product spent on health care and physicians per 100,000 persons. We also observed that regions with a higher proportion of advanced tumors reported lower mortality rates. This finding suggests that CaP is underdiagnosed and/or underreported in SSA men. Nonetheless, CaP incidence and mortality represent a significant public health problem in men of African descent around the world.

Protective effects of low calcium intake and low calcium absorption vitamin D receptor genotype in the California Collaborative Prostate Cancer Study.

BACKGROUND: High calcium intake is consistently associated with increased prostate cancer risk in epidemiologic studies. We previously reported that the positive association between calcium intake and risk of aggressive prostate cancer was modified by the single-nucleotide polymorphism (SNP) in the CDX-2 binding site of the vitamin D receptor (VDR) gene, among African American men. METHODS: We expanded our previous study to include White men, a population with a higher calcium intake and a higher prevalence of the low absorption allele. We also examined VDR polymorphisms at other loci unrelated to calcium absorption. The study included 1,857 prostate cancer cases (1,140 with advanced stage at diagnosis, 717 with localized stage) and 1,096 controls. OR were estimated using conditional logistic regression. RESULTS: Among both Blacks and Whites, we observed a threshold for calcium intake (604 mg/d) below which prostate cancer risk declined sharply. Low calcium intake was most strongly associated with decreased risk among men with the VDR Cdx2 low calcium absorption genotype (P for interaction = 0.001 and P = 0.06 for Whites and African Americans, respectively). Among all men with this genotype, those in the lowest quartile of calcium intake (≤604 mg/d) had a 50% reduction in risk as compared with those in the upper three quartiles [OR = 0.49; 95% confidence interval (CI), 0.36-0.67]. The association between calcium intake and prostate cancer risk was not modified by genotype at other VDR loci. CONCLUSIONS: Our findings support the hypothesis that genetic determinants of calcium absorption influence prostate cancer risk. IMPACT: The differences between African Americans and Whites in calcium absorption and dietary calcium intake may contribute to racial disparities in prostate cancer incidence and mortality rates.

Calcium intake and prostate cancer among African Americans: effect modification by vitamin D receptor calcium absorption genotype.

High dietary intake of calcium has been classified as a probable cause of prostate cancer, although the mechanism underlying the association between dietary calcium and prostate cancer risk is unclear. The vitamin D receptor (VDR) is a key regulator of calcium absorption. In the small intestine, VDR expression is regulated by the CDX-2 transcription factor, which binds a polymorphic site in the VDR gene promoter. We examined VDR Cdx2 genotype and calcium intake, assessed by a food frequency questionnaire, in 533 African-American prostate cancer cases (256 with advanced stage at diagnosis, 277 with localized stage) and 250 African-American controls who participated in the California Collaborative Prostate Cancer Study. We examined the effects of genotype, calcium intake, and diet-gene interactions by conditional logistic regression. Compared with men in the lowest quartile of calcium intake, men in the highest quartile had an approximately twofold increased risk of localized and advanced prostate cancer (odds ratio [OR] = 2.20, 95% confidence interval [CI] = 1.40, 3.46), with a significant dose-response. Poor absorbers of calcium (VDR Cdx2 GG genotype) had a significantly lower risk of advanced prostate cancer (OR = 0.41, 95% CI = 0.19, 0.90). The gene-calcium interaction was statistically significant (p = 0.03). Among men with calcium intake below the median (680 mg/day), carriers of the G allele had an approximately 50% decreased risk compared with men with the AA genotype. These findings suggest a link between prostate cancer risk and high intestinal absorption of calcium.

A fetal variant in the GCM1 gene is associated with pregnancy induced hypertension in a predominantly hispanic population.

The aim of the study was to determine whether polymorphism in the GCM1 gene is associated with pregnancy induced hypertension (PIH) in a case-control study of mother-baby dyads. Predominantly Hispanic women, ages 15-45, with (n=136) and without (n=169) PIH were recruited. We genotyped four polymorphisms in the GCM1 gene and examined the association with PIH using both logistic regression and likelihood expectation maximization (LEM) to adjust for intra-familial correlation between genotypes. Maternal genotype was not associated with PIH for any polymorphisms examined. Fetal genotype, however, was associated with maternal risk of PIH. Mothers carrying a fetus with ≥1 copy of the minor (C) allele for rs9349655 were less likely to develop PIH than women carrying a fetus with the GG genotype (parity-adjusted OR=0.44, 95% Cl: 0.21, 0.94). The trend of decreasing risk with increasing C alleles was also statistically significant (OR(trend)=0.41 95% Cl: 0.20, 0.85). The minor alleles for the other three SNPs also appear to be associated with protection. Multilocus analyses of fetal genotypes showed that the protective effect of carrying minor alleles at rs9349655 and rs13200319 (non-significant) remained unchanged when adjusting for genotypes at the other loci. However, the apparent (non-significant) effect of rs2816345 and rs2518573 disappeared when adjusting for rs9349655. In conclusion, we found that a fetal GCM1 polymorphism is significantly associated with PIH in a predominantly Hispanic population. These results suggest that GCM1 may represent a fetal-effect gene, where risk to the mother is conferred only through carriage by the fetus.

Aromatase (CYP19) promoter gene polymorphism and risk of nonviral hepatitis-related hepatocellular carcinoma.

BACKGROUND: Experimental studies suggest that sex hormones may induce or promote the development of hepatocellular carcinoma (HCC). Androgens are converted to estrogens by the CYP19 gene product, aromatase. Hepatic aromatase level and activity have been shown to be markedly elevated in HCC. Aromatase expression in liver tumors is driven by a promoter upstream of CYP19 exon I.6. METHODS: First, the authors identified an A/C polymorphism in the exon I.6 promoter of the CYP19 gene. To determine whether allelic variants in the CYP19 I.6 promoter differ in their ability to drive gene expression, we carried out an in vitro reporter gene assay. Then, the authors studied the association between this polymorphism and HCC risk in 2 complementary case-control studies: 1 in high-risk southern Guangxi, China, and another in low-risk US non-Asians of Los Angeles County. RESULTS: Transcriptional activity was 60% higher for promoter vectors carrying the rs10459592 C allele compared with those carrying an A allele (P = .007). In both study populations, among subjects negative for at-risk serologic markers of hepatitis B or C, there was a dose-dependent association between number of high activity C allele and risk of HCC (P(trend) = .014). Risk of HCC was significantly higher (odds ratio [OR], 2.25; 95% confidence interval (CI), 1.18-4.31) in subjects homozygous for the C allele compared with those homozygous for the A allele. CONCLUSIONS: This study provides epidemiologic evidence for the role of hepatic aromatization of androgen into estrogen in the development of nonviral hepatitis-related HCC.

Validation of genome-wide prostate cancer associations in men of African descent.

BACKGROUND: Genome-wide association studies (GWAS) have identified numerous prostate cancer susceptibility alleles, but these loci have been identified primarily in men of European descent. There is limited information about the role of these loci in men of African descent. METHODS: We identified 7,788 prostate cancer cases and controls with genotype data for 47 GWAS-identified loci. RESULTS: We identified significant associations for SNP rs10486567 at JAZF1, rs10993994 at MSMB, rs12418451 and rs7931342 at 11q13, and rs5945572 and rs5945619 at NUDT10/11. These associations were in the same direction and of similar magnitude as those reported in men of European descent. Significance was attained at all reported prostate cancer susceptibility regions at chromosome 8q24, including associations reaching genome-wide significance in region 2. CONCLUSION: We have validated in men of African descent the associations at some, but not all, prostate cancer susceptibility loci originally identified in European descent populations. This may be due to the heterogeneity in genetic etiology or in the pattern of genetic variation across populations. IMPACT: The genetic etiology of prostate cancer in men of African descent differs from that of men of European descent.

Maternal and fetal variants in the TGF-beta3 gene and risk of pregnancy-induced hypertension in a predominantly Latino population.

OBJECTIVE: We sought to determine whether polymorphisms in the transforming growth factor (TGF)-beta3 gene are associated with risk of pregnancy-induced hypertension (PIH) in case-control mother-baby dyads. STUDY DESIGN: Patients (n = 136) and control subjects (n = 169) were recruited from our hospital. We genotyped 4 TGF-beta3 polymorphisms and examined association with PIH using logistic regression, adjusting for parity, maternal age, gestational age at delivery, fetal (or maternal) genotypes for the polymorphism in question, and the 3 other polymorphisms within the TGF-beta3 gene. RESULTS: Only 1 of the TGF-beta3 polymorphisms (rs11466414) was associated with PIH. Mothers who carried a baby with a minor allele were at decreased risk (odds ratio(multi-locus adj), 0.32; 95% confidence interval, 0.14-0.77). Maternal TGF-beta3 variants had no effect on risk of PIH. CONCLUSION: A fetal TGF-beta3 polymorphism (rs11466414) is associated with PIH in a predominantly Hispanic population.

5-lipoxygenase and 5-lipoxygenase-activating protein gene polymorphisms, dietary linoleic acid, and risk for breast cancer.

The n-6 polyunsaturated fatty acid 5-lipoxygenase pathway has been shown to play a role in the carcinogenesis of breast cancer. We conducted a population-based case-control study among Latina, African-American, and White women from the San Francisco Bay area to examine the association of the 5-lipoxygenase gene (ALOX5) and 5-lipoxygenase-activating protein gene (ALOX5AP) with breast cancer risk. Three ALOX5AP polymorphisms [poly(A) microsatellite, -4900 A>G (rs4076128), and -3472 A>G (rs4073259)] and three ALOX5 polymorphisms [Sp1-binding site (-GGGCGG-) variable number of tandem repeat polymorphism, -1279 G>T (rs6593482), and 760 G>A (rs2228065)] were genotyped in 802 cases and 888 controls. We did not find significant main effects of ALOX5 and ALOX5AP genotypes on breast cancer risk that were consistent across race or ethnicity; however, there was a significant interaction between the ALOX5AP -4900 A>G polymorphism and dietary linoleic acid intake (P=0.03). Among women consuming a diet high in linoleic acid (top quartile of intake, >17.4 g/d), carrying the AA genotype was associated with higher breast cancer risk (age- and race-adjusted odds ratio, 1.8; 95% confidence interval, 1.2-2.9) compared with carrying genotypes AG or GG. Among women consuming