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1.  Diacylglycerol Kinase K Variants Impact Hypospadias in a California Study Population 
The Journal of urology  2012;189(1):305-311.
A recent genome-wide association study reported the novel finding that variants in diacylglycerol kinase kappa (DGKK) were associated with hypospadias. Our objectives were to determine whether this finding could be replicated in a more racially-ethnically diverse study population of California births and to provide a more comprehensive investigation of variants.
We examined the association of 27 DGKK SNPs with hypospadias, relative to population-based non-malformed controls born in selected California counties from 1990-2003. Analyses included a maximum of 928 controls and 665 cases (91 mild, 336 moderate, 221 severe, 17 undetermined). Results for mild and moderate cases were similar so they were grouped together.
For mild and moderate cases, odds ratios (OR) for 15 of the 27 SNPs had p-values <0.05; two were <1, and the others ranged from 1.3 to 1.8. Among severe cases, ORs tended to be closer to one and none of the p-values were <0.05. Due to high LD across the SNPs, haplotype analyses were conducted, and two blocks were generated. These analyses identified a set of eight variants that was associated with a three- to four- fold increased risk, relative to the most common haplotype, regardless of severity of the phenotype (the OR was 4.1, p<10-4 for mild to moderate cases and 3.3, p=0.001 for severe cases).
This study confirms that DGKK variants are associated with hypospadias. Further studies are needed to enable a more thorough investigation of DGKK variability and to delineate the mechanism by which DGKK contributes to urethral development.
PMCID: PMC3973486  PMID: 23177175
2.  HOXB13 Mutation and Prostate Cancer: Studies of Siblings and Aggressive Disease 
Recent work detected for the first time a high-risk prostate cancer mutation, in homeobox B13 (HOXB13) among European-Americans.
We further evaluated this G84E missense mutation (rs138213197) in two genetic association studies of prostate cancer: a family-based study of brothers and a case-control study of more aggressive disease (N=2,665 total). We then calculated overall impact of this mutation by pooling all published studies of European-Americans.
In our studies the mutation was found exclusively among men with prostate cancer (carrier frequency=1.48%) or unaffected brothers of cases carrying the mutation (frequency=0.34%), and carrying the mutation gave an odds ratio for disease=4.79 (P=0.01). The G84E mutation was more common among men with an earlier age of onset (≤55 years) or a family history of prostate cancer. We also observed for the first time an African-American case carrying the G84E mutation, although at HOXB13 both of his chromosomes were of European-American ancestry. The pooled analysis also indicated that carrying the G84E mutation results in an almost five-fold increase in risk of prostate cancer (P=3.5×10−17), and this risk is even higher among cases with an early age of prostate cancer onset (≤55 years) or a family history of disease: a test of heterogeneity across these strata gives P<1×10−5.
The HOXB13 mutation substantially increases risk of early onset, familial prostate cancer in European-American men. Impact: Testing for the G84E mutation in men with a positive family history may help distinguish those who merit more regular screening for prostate cancer.
PMCID: PMC3617049  PMID: 23396964
Familial Cancer; Genetic Association; Homeobox; Functional Mutation; Prostate Cancer
3.  The Future of Clinical Trials: A panel discussion 
Statistics in medicine  2012;31(25):10.1002/sim.5484.
A panel discussion on the future of clinical trials addressed several issues raised in the course of the first day of the Workshop. The chair posed questions in six areas which the panel and audience addressed. This paper summarizes the panel discussion.
PMCID: PMC3864589  PMID: 22806631
4.  Mechanistic Phenotypes: An Aggregative Phenotyping Strategy to Identify Disease Mechanisms Using GWAS Data 
PLoS ONE  2013;8(12):e81503.
A single mutation can alter cellular and global homeostatic mechanisms and give rise to multiple clinical diseases. We hypothesized that these disease mechanisms could be identified using low minor allele frequency (MAF<0.1) non-synonymous SNPs (nsSNPs) associated with “mechanistic phenotypes”, comprised of collections of related diagnoses. We studied two mechanistic phenotypes: (1) thrombosis, evaluated in a population of 1,655 African Americans; and (2) four groupings of cancer diagnoses, evaluated in 3,009 white European Americans. We tested associations between nsSNPs represented on GWAS platforms and mechanistic phenotypes ascertained from electronic medical records (EMRs), and sought enrichment in functional ontologies across the top-ranked associations. We used a two-step analytic approach whereby nsSNPs were first sorted by the strength of their association with a phenotype. We tested associations using two reverse genetic models and standard additive and recessive models. In the second step, we employed a hypothesis-free ontological enrichment analysis using the sorted nsSNPs to identify functional mechanisms underlying the diagnoses comprising the mechanistic phenotypes. The thrombosis phenotype was solely associated with ontologies related to blood coagulation (Fisher's p = 0.0001, FDR p = 0.03), driven by the F5, P2RY12 and F2RL2 genes. For the cancer phenotypes, the reverse genetics models were enriched in DNA repair functions (p = 2×10−5, FDR p = 0.03) (POLG/FANCI, SLX4/FANCP, XRCC1, BRCA1, FANCA, CHD1L) while the additive model showed enrichment related to chromatid segregation (p = 4×10−6, FDR p = 0.005) (KIF25, PINX1). We were able to replicate nsSNP associations for POLG/FANCI, BRCA1, FANCA and CHD1L in independent data sets. Mechanism-oriented phenotyping using collections of EMR-derived diagnoses can elucidate fundamental disease mechanisms.
PMCID: PMC3861317  PMID: 24349080
5.  A Genome-Wide Association Study Identifies Novel Loci for Paclitaxel-Induced Sensory Peripheral Neuropathy in CALGB 40101 
Sensory peripheral neuropathy is a common and sometimes debilitating toxicity associated with paclitaxel therapy. This study aims to identify genetic risk factors for development of this toxicity.
Experimental Design
A prospective pharmacogenetic analysis of primary breast cancer patients randomized to the paclitaxel arm of CALGB 40101 was used to identify genetic predictors of the onset and severity of sensory peripheral neuropathy. A genome-wide association study in 855 subjects of European ancestry was performed and findings were replicated in additional European (n = 154) and African American (n = 117) subjects.
A single nucleotide polymorphism in FGD4 was associated with the onset of sensory peripheral neuropathy in the discovery cohort (rs10771973; HR, 1.57; 95% CI, 1.30–1.91; P = 2.6 × 10−6) and in a European (HR, 1.72; 95% CI, 1.06–2.80; P = 0.013) and African American (HR, 1.93; 95% CI, 1.13-3.28; P = 6.7 × 10−3) replication cohort. There is also evidence that markers in additional genes, including EPHA5 (rs7349683) and FZD3 (rs10771973), were associated with the onset or severity of paclitaxel-induced sensory peripheral neuropathy.
A genome-wide association study has identified novel genetic markers of paclitaxel-induced sensory peripheral neuropathy, including a common polymorphism in FGD4, a congenital peripheral neuropathy gene. These findings suggest that genetic variation may contribute to variation in development of this toxicity. Validation of these findings may allow for the identification of patients at increased risk of peripheral neuropathy and inform the use of an alternative to paclitaxel and/or the clinical management of this toxicity.
PMCID: PMC3445665  PMID: 22843789
paclitaxel; peripheral neuropathy; breast cancer; pharmacogenetics; genome-wide association study
6.  Rare Genetic Variants and Treatment Response: Sample Size and Analysis Issues 
Statistics in medicine  2012;31(25):3041-3050.
Incorporating information about common genetic variants may help improve the design and analysis of clinical trials. For example, if genes impact response to treatment, one can pre-genotype potential participants to screen out genetically determined non-responders and substantially reduce the sample size and duration of a trial. Genetic associations with response to treatment are generally much larger than those observed for development of common diseases, as highlighted here by findings from genome-wide association studies. With the development and decreasing cost of next generation sequencing, more extensive genetic information—including rare variants—is becoming available on individuals treated with drugs and other therapies. We can use this information to evaluate whether rare variants impact treatment response. The sparseness of rare variants, however, raises issues of how the resulting data should be best analyzed. As shown here, simply evaluating the association between each rare variant and treatment response one-at-a-time will require enormous sample sizes. Combining the rare variants together can substantially reduce the required sample sizes, but require a number of assumptions about the similarity among the rare variants’ effects on treatment response. We have developed an empirical approach for aggregating and analyzing rare variants that limit such assumptions and work well under a range of scenarios. Such analyses provide a valuable opportunity to more fully decipher the genomic basis of response to treatment.
PMCID: PMC3766744  PMID: 22736504
aggregation; clinical trials; GWAS; pharmacogenomics; rare variants; treatment response
7.  Non-Steroidal Anti-Inflammatory Drugs, Variation in Inflammatory Genes, and Aggressive Prostate Cancer 
Pharmaceuticals (Basel, Switzerland)  2010;3(10):3127-3142.
Increasing evidence suggests that prostatic inflammation plays a key role in the development of prostate cancer. It remains controversial whether non-steroidal anti-inflammatory drugs (NSAIDs) reduce the risk of prostate cancer. Here, we investigate how a previously reported inverse association between NSAID use and the risk of aggressive prostate cancer is modulated by variants in several inflammatory genes. We found that NSAIDs may have differential effects on prostate cancer development, depending on one’s genetic makeup. Further study of these inflammatory pathways may clarify the mechanisms through which NSAIDs impact prostate cancer risk.
PMCID: PMC3766748  PMID: 24023525
prostatic neoplasms; non-steroidal anti-inflammatory agents; aspirin; genetic variation; single nucleotide polymorphism
8.  Segmentation and Estimation for SNP Microarrays: a Bayesian Multiple Change Point Approach 
Biometrics  2010;66(3):675-683.
High-density SNP microarrays provide a useful tool for the detection of copy number variants (CNVs). The analysis of such large amounts of data is complicated, especially with regard to determining where copy numbers change and their corresponding values. In this paper, we propose a Bayesian multiple change point model (BMCP) for segmentation and estimation of SNP microarray data. Segmentation concerns separating a chromosome into regions of equal copy number differences between the sample of interest and some reference, and involves the detection of locations of copy number difference changes. Estimation concerns determining true copy number for each segment. Our approach not only gives posterior estimates for the parameters of interest, namely locations for copy number difference changes and true copy number estimates, but also useful confidence measures. In addition, our algorithm can segment multiple samples simultaneously, and infer both common and rare CNVs across individuals. Finally, for studies of CNVs in tumors, we incorporate an adjustment factor for signal attenuation due to tumor heterogeneity or normal contamination that can improve copy number estimates.
PMCID: PMC3766751  PMID: 19764955
Bayesian multiple change points; copy number variant; estimation; segmentation; signal attenuation; SNP microarrays
9.  Evaluation of Polymorphisms in EWSR1 and Risk of Ewing Sarcoma: A Report from the Childhood Cancer Survivor Study 
Pediatric blood & cancer  2011;59(1):52-56.
Ewing sarcoma is a malignant bone tumor characterized by a high frequency of somatic EWSR1 translocations. Ewing sarcoma is less common in people of African or African-American ancestry, suggesting a genetic etiology.
Germline DNA from white patients with Ewing sarcoma (n = 135), white controls with Wilms tumor (n = 200), and African-American controls (n = 285) was genotyped at 21 SNPs in the EWSR1 gene. Intron 7 of EWSR1, the most common site of translocation, was also sequenced in all subjects. Genetic variation between groups was evaluated statistically using exact logistic regression and Fisher exact tests.
One SNP in EWSR1 (rs2857461) showed a low level of statistical association with the diagnosis of Ewing sarcoma compared to Wilms tumor. The odds ratio for having Ewing sarcoma in people with at least one copy of the minor allele of rs2857461 was 3.57 (95% confidence interval 0.79 – 21.7; p = 0.07). No other SNPs or variations in intron 7 of EWSR1 were associated with Ewing sarcoma. The median relative difference in minor allele frequencies between white subjects with Ewing sarcoma and African-American controls at the evaluated EWSR1 SNPs was 45%.
Variations in EWSR1 at known SNPs or across intron 7 are not associated with the diagnosis of Ewing sarcoma. EWSR1 does not appear to be a Ewing sarcoma susceptibility gene. The genetic basis for this disease remains unknown.
PMCID: PMC3204324  PMID: 21793187
Ewing sarcoma; EWSR1; single nucleotide polymorphism; genetic epidemiology
10.  Global Patterns of Prostate Cancer Incidence, Aggressiveness, and Mortality in Men of African Descent 
Prostate Cancer  2013;2013:560857.
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.
PMCID: PMC3583061  PMID: 23476788
11.  Next Generation Analytic Tools for Large Scale Genetic Epidemiology Studies of Complex Diseases 
Genetic epidemiology  2011;36(1):22-35.
Over the past several years, genome-wide association studies (GWAS) have succeeded in identifying hundreds of genetic markers associated with common diseases. However, most of these markers confer relatively small increments of risk and explain only a small proportion of familial clustering. To identify obstacles to future progress in genetic epidemiology research and provide recommendations to NIH for overcoming these barriers, the National Cancer Institute sponsored a workshop entitled “Next Generation Analytic Tools for Large-Scale Genetic Epidemiology Studies of Complex Diseases” on September 15–16, 2010. The goal of the workshop was to facilitate discussions on (1) statistical strategies and methods to efficiently identify genetic and environmental factors contributing to the risk of complex disease; and (2) how to develop, apply, and evaluate these strategies for the design, analysis, and interpretation of large-scale complex disease association studies in order to guide NIH in setting the future agenda in this area of research. The workshop was organized as a series of short presentations covering scientific (gene-gene and gene-environment interaction, complex phenotypes, and rare variants and next generation sequencing) and methodological (simulation modeling and computational resources and data management) topic areas. Specific needs to advance the field were identified during each session and are summarized.
PMCID: PMC3368075  PMID: 22147673
gene-gene interactions; gene-environment interactions; rare variants; next generation sequencing; complex phenotypes; simulations; computational resources
12.  Copy Number Alterations in Prostate Tumors and Disease Aggressiveness 
Genes, chromosomes & cancer  2011;51(1):66-76.
Detecting genomic alterations that result in more aggressive prostate cancer may improve clinical treatment and our understanding of the biology underlying this common but complex disease. To this end, we undertook a genome-wide copy number alterations (CNAs) study of clinicopathological characteristics of 62 prostate tumors using the Illumina 1M SNP array. The highest overall frequencies of CNAs were on chromosomes 8q (gains), 8p (loss and copy-neutral) and 6q (copy-loss). Combined loss and copy-neutral events were associated with increasing disease grade (p=0.03), stage (p=0.01), and diagnostic PSA (p=0.01). Further evaluation of CNAs using gene ontology identified pathways involved with disease aggressiveness. The ‘regulation of apoptosis’ pathway was associated with stage of disease (p=0.004), while the ‘reproductive cellular process’ pathway was associated with diagnostic PSA (p=0.00038). Specific genes within these pathways exhibited strong associations with clinical characteristics; for example, in the apoptosis pathway BNIP3L was associated with increasing prostate tumor stage (p=0.007). These findings confirm known regions of CNAs in prostate cancer, and localize additional regions and possible genes (e.g., BNIP3L, WWOX, and GATM) that may help clarify the genetic basis of prostate cancer aggressiveness.
PMCID: PMC3209417  PMID: 21965145
13.  Association of the Innate Immunity and Inflammation Pathway with Advanced Prostate Cancer Risk 
PLoS ONE  2012;7(12):e51680.
Prostate cancer is the most frequent and second most lethal cancer in men in the United States. Innate immunity and inflammation may increase the risk of prostate cancer. To determine the role of innate immunity and inflammation in advanced prostate cancer, we investigated the association of 320 single nucleotide polymorphisms, located in 46 genes involved in this pathway, with disease risk using 494 cases with advanced disease and 536 controls from Cleveland, Ohio. Taken together, the whole pathway was associated with advanced prostate cancer risk (P = 0.02). Two sub-pathways (intracellular antiviral molecules and extracellular pattern recognition) and four genes in these sub-pathways (TLR1, TLR6, OAS1, and OAS2) were nominally associated with advanced prostate cancer risk and harbor several SNPs nominally associated with advanced prostate cancer risk. Our results suggest that the innate immunity and inflammation pathway may play a modest role in the etiology of advanced prostate cancer through multiple small effects.
PMCID: PMC3522730  PMID: 23272139
14.  The Covariate's Dilemma 
PLoS Genetics  2012;8(11):e1003096.
PMCID: PMC3497901  PMID: 23162385
15.  Variations in the heme oxygenase-1 microsatellite polymorphism are associated with plasma CD14 and viral load in HIV-infected African Americans 
Genes and Immunity  2011;13(3):258-267.
Heme oxygenase-1 (HO-1) is an anti-inflammatory enzyme that maintains homeostasis during cellular stress. Given previous findings that shorter length variants of a HO-1 promoter-region GTn microsatellite polymorphism are associated with increased HO-1 expression in cell lines, we hypothesized that shorter variants would also be associated with increased levels of HO-1 expression, less inflammation, and lower levels of inflammation-associated viral replication in HIV-infected subjects. Healthy donors (n=20) with shorter GTn repeats had higher HO-1 mRNA transcript in peripheral blood mononuclear cells stimulated with lipopolysaccharide (LPS) (r= −0.38, p=0.05). The presence of fewer GTn repeats in subjects with untreated HIV disease was associated with higher HO-1 mRNA levels in peripheral blood (r= −0.41, p=0.02); similar observations were made in CD14+ monocytes from antiretroviral-treated subjects (r= −0.36, p=0.04). In African-Americans, but not Caucasians, greater GTn repeats were correlated with higher soluble CD14 (sCD14) levels during highly active antiretroviral therapy (HAART) (r= 0.38, p=0.007) as well as higher mean viral load off-therapy (r= 0.24, p=0.04). These data demonstrate that the HO-1 GTn microsatellite polymorphism is associated with higher levels of HO-1 expression and that this pathway may have important effects on the association between inflammation and HIV replication.
PMCID: PMC3330188  PMID: 22048453
Heme oxygenase-1; microsatellite; polymorphism; HIV; soluble CD14; monocytes
16.  Impact of consumption of vegetable, fruit, grain, and high glycemic index foods on aggressive prostate cancer risk 
Nutrition and cancer  2011;63(6):860-872.
Prostate cancer is a common but complex disease, and distinguishing modifiable risk factors such as diet for more aggressive disease is extremely important. Previous work has detected intriguing associations between vegetable, fruit, and grains and more aggressive prostate cancer, although these remain somewhat unclear. Here we further investigate such potential relationships with a case-control study of 982 men (470 more aggressive prostate cancer cases and 512 control subjects). Comparing the highest to lowest quartiles of intake, we found that increasing intakes of leafy vegetables were inversely associated with risk of aggressive prostate cancer (adjusted odds ratio (OR) =0.66, 95% CI: 0.46, 0.96, P-trend=0.02), as was higher consumption of high carotenoid vegetables (OR=0.71, 95% CI: 0.48, 1.04; P-trend=0.04). Conversely, increased consumption of high glycemic index foods were positively associated with risk of aggressive disease (OR=1.64, 95% CI: 1.05, 2.57; P-trend=0.02). These results were driven by a number of specific foods within the food groups. Our findings support the hypothesis that diets high in vegetables and low in high glycemic index foods decrease risk of aggressive prostate cancer.
PMCID: PMC3209415  PMID: 21774611
Diet; aggressive prostate cancer
17.  Polygenic Modeling of Genome-Wide Association Studies: An Application to Prostate and Breast Cancer 
Genome-wide association studies (GWAS) have successfully detected and replicated associations with numerous diseases, including cancers of the prostate and breast. These findings are helping clarify the genomic basis of such diseases, but appear to explain little of disease heritability. This limitation might reflect the focus of conventional GWAS on a small set of the most statistically significant associations with disease. More information might be obtained by analyzing GWAS using a polygenic model, which allows for the possibility that thousands of genetic variants could impact disease. Furthermore, there may exist common polygenic effects between potentially related phenotypes (e.g., prostate and breast cancer). Here we present and apply a polygenic model to GWAS of prostate and breast cancer. Our results indicate that the polygenic model can explain an increasing—albeit low—amount of heritability for both of these cancers, even when excluding the most statistically significant associations. In addition, nonaggressive prostate cancer and breast cancer appear to share a common polygenic model, potentially reflecting a similar underlying biology. This supports the further development and application of polygenic models to genomic data.
PMCID: PMC3125548  PMID: 21348634
18.  National Cancer Institute Prostate Cancer Genetics Workshop 
Cancer research  2011;71(10):3442-3446.
Compelling evidence supports a genetic component to prostate cancer (PC) susceptibility and aggressiveness. Recent genome-wide association studies (GWAS) have identified >30 single nucleotide polymorphisms associated with PC susceptibility. It remains unclear, however, whether such genetic variants are associated with disease aggressiveness—one of the most important questions in PC research today. To help clarify this and substantially expand research in the genetic determinants of PC aggressiveness, the first National Cancer Institute Prostate Cancer Genetics Workshop assembled researchers to develop plans for a large new research consortium and patient cohort. The workshop reviewed the prior work in this area and addressed the practical issues in planning future studies. With new DNA sequencing technology, the potential application of sequencing information to patient care is emerging. The workshop, therefore, included state-of-the-art presentations by experts on new genotyping technologies, including sequencing and associated bioinformatics issues, which are just beginning to be applied to cancer genetics.
PMCID: PMC3096727  PMID: 21558387
19.  Fine Mapping of Prostate Cancer Aggressiveness Loci on Chromosome 7q22-35 
The Prostate  2010;71(7):682-689.
Deciphering the genetic basis of prostate cancer aggressiveness could provide valuable information for the screening and treatment of this common but complex disease. We previously detected linkage between a broad region on chromosome 7q22-35 and Gleason score—a strong predictor of prostate cancer aggressiveness. To further clarify this finding and focus on the potentially causative gene, we undertook a fine-mapping study across the 7q22-35 region.
Our study population encompassed 698 siblings diagnosed with prostate cancer. 3,072 single nucleotide polymorphisms (SNPs) spanning the chromosome 7q22-35 region were genotyped using the Illumina GoldenGate assay. The impact of SNPs on Gleason scores were evaluated using affected sibling pair linkage and family-based association tests.
We confirmed the previous linkage signal and narrowed the 7q22-35 prostate cancer aggressiveness locus to a 370 kb region. Centered under the linkage peak is the gene KLRG2 (killer cell lectin-like receptor subfamily G, member 2). Association tests indicated that the potentially functional non-synonymous SNP rs17160911 in KLRG2 was significantly associated with Gleason score (p = 0.0007).
These findings suggest that genetic variants in the gene KLRG2 may affect Gleason score at diagnosis and hence the aggressiveness of prostate cancer.
PMCID: PMC3027848  PMID: 20945404
prostate cancer; Gleason Score; siblings; SNP
20.  VALID: Visualization of Association Study Results and Linkage Disequilibrium 
Genetic Epidemiology  2009;33(7):599-603.
Promising findings from genetic association studies are commonly presented with two distinct figures: one gives the association study results and the other indicates linkage disequilibrium (LD) between genetic markers in the region(s) of interest. Fully interpreting the results of such studies requires synthesizing the information in these figures, which is generally done in a subjective and unsystematic manner. Here we present a method to formally combine association results and LD and display them in the same figure; we have developed a freely available web-based application that can be used to generate figures to display the combined data. To demonstrate this approach we apply it to fine mapping data from the prostate cancer 8q24 loci. Combining these two sources of information in a single figure allows one to more clearly assess patterns of association, facilitating the interpretation of genome-wide and fine mapping data and improving our ability to localize causal variants.
PMCID: PMC3258024  PMID: 19197947
21.  Genome-wide association study of prostate cancer in men of African ancestry identifies a susceptibility locus at 17q21 
Nature genetics  2011;43(6):570-573.
In search of common risk alleles for prostate cancer that could contribute to high rates of the disease in men of African ancestry, we conducted a genome-wide association study (GWAS), with 1,047,986 single nucleotide polymorphism (SNP) markers examined in 3,425 African American prostate cancer cases and 3,290 African American male controls. The most significant 17 novel associations in stage 1 were followed-up in 1,844 cases and 3,269 controls of African ancestry. We identified a novel risk variant on chromosome 17q21 (rs7210100; odds ratio per allele=1.51; p=3.4×10−13). The frequency of the risk allele is ~5% in men of African descent while it is rare in other populations (<1%). Further studies are needed to investigate the biological contribution of this allele to prostate cancer risk. These findings emphasize the importance of conducting GWAS in diverse populations.
PMCID: PMC3102788  PMID: 21602798
22.  A Genetic Signature of Spina Bifida Risk from Pathway-Informed Comprehensive Gene-Variant Analysis 
PLoS ONE  2011;6(11):e28408.
Despite compelling epidemiological evidence that folic acid supplements reduce the frequency of neural tube defects (NTDs) in newborns, common variant association studies with folate metabolism genes have failed to explain the majority of NTD risk. The contribution of rare alleles as well as genetic interactions within the folate pathway have not been extensively studied in the context of NTDs. Thus, we sequenced the exons in 31 folate-related genes in a 480-member NTD case-control population to identify the full spectrum of allelic variation and determine whether rare alleles or obvious genetic interactions within this pathway affect NTD risk. We constructed a pathway model, predetermined independent of the data, which grouped genes into coherent sets reflecting the distinct metabolic compartments in the folate/one-carbon pathway (purine synthesis, pyrimidine synthesis, and homocysteine recycling to methionine). By integrating multiple variants based on these groupings, we uncovered two provocative, complex genetic risk signatures. Interestingly, these signatures differed by race/ethnicity: a Hispanic risk profile pointed to alterations in purine biosynthesis, whereas that in non-Hispanic whites implicated homocysteine metabolism. In contrast, parallel analyses that focused on individual alleles, or individual genes, as the units by which to assign risk revealed no compelling associations. These results suggest that the ability to layer pathway relationships onto clinical variant data can be uniquely informative for identifying genetic risk as well as for generating mechanistic hypotheses. Furthermore, the identification of ethnic-specific risk signatures for spina bifida resonated with epidemiological data suggesting that the underlying pathogenesis may differ between Hispanic and non-Hispanic groups.
PMCID: PMC3227667  PMID: 22140583
23.  Use of principal components to aggregate rare variants in case-control and family-based association studies in the presence of multiple covariates 
BMC Proceedings  2011;5(Suppl 9):S29.
Rare variants may help to explain some of the missing heritability of complex diseases. Technological advances in next-generation sequencing give us the opportunity to test this hypothesis. We propose two new methods (one for case-control studies and one for family-based studies) that combine aggregated rare variants and common variants located within a region through principal components analysis and allow for covariate adjustment. We analyzed 200 replicates consisting of 209 case subjects and 488 control subjects and compared the results to weight-based and step-up aggregation methods. The principal components and collapsing method showed an association between the gene FLT1 and the quantitative trait Q1 (P<10−30) in a fraction of the computation time of the other methods. The proposed family-based test has inconclusive results. The two methods provide a fast way to analyze simultaneously rare and common variants at the gene level while adjusting for covariates. However, further evaluation of the statistical efficiency of this approach is warranted.
PMCID: PMC3287864  PMID: 22373382
24.  Impact of Meat Consumption, Preparation, and Mutagens on Aggressive Prostate Cancer 
PLoS ONE  2011;6(11):e27711.
The association between meat consumption and prostate cancer remains unclear, perhaps reflecting heterogeneity in the types of tumors studied and the method of meat preparation—which can impact the production of carcinogens.
We address both issues in this case-control study focused on aggressive prostate cancer (470 cases and 512 controls), where men reported not only their meat intake but also their meat preparation and doneness level on a semi-quantitative food-frequency questionnaire. Associations between overall and grilled meat consumption, doneness level, ensuing carcinogens and aggressive prostate cancer were assessed using multivariate logistic regression.
Higher consumption of any ground beef or processed meats were positively associated with aggressive prostate cancer, with ground beef showing the strongest association (OR = 2.30, 95% CI:1.39–3.81; P-trend = 0.002). This association primarily reflected intake of grilled or barbequed meat, with more well-done meat conferring a higher risk of aggressive prostate cancer. Comparing high and low consumptions of well/very well cooked ground beef to no consumption gave OR's of 2.04 (95% CI:1.41–2.96) and 1.51 (95% CI:1.06–2.14), respectively. In contrast, consumption of rare/medium cooked ground beef was not associated with aggressive prostate cancer. Looking at meat mutagens produced by cooking at high temperatures, we detected an increased risk with 2-amino-3,8-Dimethylimidazo-[4,5-f]Quinolaxine (MelQx) and 2-amino-3,4,8-trimethylimidazo(4,5-f)qunioxaline (DiMelQx), when comparing the highest to lowest quartiles of intake: OR = 1.69 (95% CI:1.08–2.64;P-trend = 0.02) and OR = 1.53 (95% CI:1.00–2.35; P-trend = 0.005), respectively.
Higher intake of well-done grilled or barbequed red meat and ensuing carcinogens could increase the risk of aggressive prostate cancer.
PMCID: PMC3223211  PMID: 22132129
25.  National Cancer Institute Prostate Cancer Genetics Workshop 
Cancer research  2011;71(10):3442-3446.
Compelling evidence supports a genetic component to prostate cancer (PC) susceptibility and aggressiveness. Recent genome-wide association studies (GWAS) have identified >30 single nucleotide polymorphisms associated with PC susceptibility. It remains unclear, however, whether such genetic variants are associated with disease aggressiveness—one of the most important questions in PC research today. To help clarify this and substantially expand research in the genetic determinants of PC aggressiveness, the first National Cancer Institute Prostate Cancer Genetics Workshop assembled researchers to develop plans for a large new research consortium and patient cohort. The workshop reviewed the prior work in this area and addressed the practical issues in planning future studies. With new DNA sequencing technology, the potential application of sequencing information to patient care is emerging. The workshop, therefore, included state-of-the-art presentations by experts on new genotyping technologies, including sequencing and associated bioinformatics issues, which are just beginning to be applied to cancer genetics.
PMCID: PMC3096727  PMID: 21558387

Results 1-25 (46)