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Effective clinical trials are meant to provide the safest and fastest way to find new treatments to improve health. The FDA affirms that because people may respond differently to treatments, it is imperative to test drugs and medical products in a variety of populations ( https://www.fda.gov/patients/clinical-trials-what-patients-need-know/basics-about-clinical-trials ). Unfortunately, clinical trial enrollment in the US remains largely homogeneous, with the majority of participants being non-Hispanic white men. Despite efforts to increase diversity in recruitment for clinical trials, enrollment of racial/ethnic minorities in this nation has decreased over the past two decades. 1

Research to understand human genomic variation and its implications in health has great potential to contribute in the reduction of health disparities. Biological anthropology can play important roles in genomics and health disparities research using a biocultural approach. This paper argues that racial/ethnic categories should not be used as a surrogate for sociocultural factors or global genomic clusters in biomedical research or clinical settings, because of the high genetic heterogeneity that exists within traditional racial/ethnic groups. Genetic ancestry is used to show variation in ancestral genomic contributions to recently admixed populations in the United States, such as African Americans and Hispanic/Latino Americans. Genetic ancestry estimates are also used to examine the relationship between ancestry‐related biological and sociocultural factors affecting health disparities. To localize areas of genomes that contribute to health disparities, admixture mapping and genome‐wide association studies (GWAS) are often used. Recent GWAS have identified many genetic variants that are highly differentiated among human populations that are associated with disease risk. Some of these are population‐specific variants. Many of these variants may impact disease risk and help explain a portion of the difference in disease burden among racial/ethnic groups. Genetic ancestry is also of particular interest in precision medicine and disparities in drug efficacy and outcomes. By using genetic ancestry, we can learn about potential biological differences that may contribute to the heterogeneity observed across self‐reported racial groups., Special Issue: Race reconciled II: Interpreting and communicating biological variation and race in 2021

Prostate cancer (PCa) is the second most frequently diagnosed malignancy and the second leading cause of death in men worldwide, after adjusting for age. According to the International Agency for Research on Cancer, continents such as North America and Europe report higher incidence of PCa; however, mortality rates are highest among men of African ancestry in the western, southern, and central regions of Africa and the Caribbean. The American Cancer Society reports, African Americans (AAs), in the United States, have a 1.7 increased incidence and 2.4 times higher mortality rate, compared to European American’s (EAs). Hence, early population history in west Africa and the subsequent African Diaspora may play an important role in understanding the global disproportionate burden of PCa shared among Africans and other men of African descent. Nonetheless, disparities involved in diagnosis, treatment, and survival of PCa patients has also been correlated to socioeconomic status, education and access to healthcare. Although recent studies suggest equal PCa treatments yield equal outcomes among patients, data illuminates an unsettling reality of disparities in treatment and care in both, developed and developing countries, especially for men of African descent. Yet, even after adjusting for the effects of the aforementioned factors; racial disparities in mortality rates remain significant. This suggests that molecular and genomic factors may account for much of PCa disparities.

Background: Given the scarcity of cell lines from underrepresented populations, it is imperative that genetic ancestry for these cell lines is characterized. Consequences of cell line mischaracterization include squandered resources and publication retractions. Methods: We calculated genetic ancestry proportions for 15 cell lines to assess the accuracy of previous race/ethnicity classification and determine previously unknown estimates. DNA was extracted from cell lines and genotyped for ancestry informative markers representing West African (WA), Native American (NA), and European (EUR) ancestry. Results: Of the cell lines tested, all previously classified as White/Caucasian were accurately described with mean EUR ancestry proportions of 97%. Cell lines previously classified as Black/African American were not always accurately described. For instance, the 22Rv1 prostate cancer cell line was recently found to carry mixed genetic ancestry using a much smaller panel of markers. However, our more comprehensive analysis determined the 22Rv1 cell line carries 99% EUR ancestry. Most notably, the E006AA-hT prostate cancer cell line, classified as African American, was found to carry 92% EUR ancestry. We also determined the MDA-MB-468 breast cancer cell line carries 23% NA ancestry, suggesting possible Afro-Hispanic/Latina ancestry. Conclusions: Our results suggest predominantly EUR ancestry for the White/Caucasian-designated cell lines, yet high variance in ancestry for the Black/African American–designated cell lines. In addition, we revealed an extreme misclassification of the E006AA-hT cell line. Impact: Genetic ancestry estimates offer more sophisticated characterization leading to better contextualization of findings. Ancestry estimates should be provided for all cell lines to avoid erroneous conclusions in disparities literature.

Cervical cancer adversely impacts African American communities. While disparities in incidence remain unclear, communities continue to use forums to increase cervical cancer education. The purpose of this paper is to examine the efficacy of using community forums to increase human papillomavirus vaccine (HPVV) and cervical cancer knowledge in African American communities. This study is a one-group pretest-posttest study design using a 17-item questionnaire to collect data from 412 participants in diverse communities. Our analyses revealed perceived knowledge increased significantly after the forums for African American participants. For African Americans, perceived knowledge prior to the forums was explained by gender, access to care, and trust in clinical trials. After the forum, perceived knowledge was associated with access to care and trust in vaccines. Participants who had health insurance reported higher perceived HPV and cervical cancer knowledge and greater trust in vaccines. This study found community forums that address the cultural and historical context of research mistreatment related to HPVV development and include diverse racial/ethnic representation of stakeholders may be a useful strategy to increase HPVV, and cervical cancer knowledge in African American communities.

Red blood cell (RBC) transfusion remains a critical therapeutic intervention in sickle cell disease (SCD); however, the apparent propensity of some patients to regularly develop RBC alloantibodies after transfusion presents a significant challenge to finding compatible blood for so-called alloimmunization responders. Predisposing genetic loci have long been thought to contribute to the responder phenomenon, but to date, no definitive loci have been identified. We undertook a genome-wide association study of alloimmunization responder status in 267 SCD multiple transfusion recipients, using genetic estimates of ancestral admixture to bolster our findings. Analyses revealed single nucleotide polymorphisms (SNPs) on chromosomes 2 and 5 approaching genome-wide significance (minimum P = 2.0 × 10−8 and 8.4 × 10−8, respectively), with local ancestry analysis demonstrating similar levels of admixture in responders and nonresponders at implicated loci. Association at chromosome 5 was nominally replicated in an independent cohort of 130 SCD transfusion recipients, with meta-analysis surpassing genome-wide significance (rs75853687, Pmeta = 6.6 × 10−9), and this extended to individuals forming multiple (>3) alloantibodies (Pmeta = 9.4 × 10−5). The associated variant is rare outside of African populations, and orthogonal genome-wide haplotype analyses, contingent on local ancestry, revealed genome-wide significant sharing of a ∼60-kb haplotype of African ancestry at the chromosome 5 locus (Bayes Factor = 4.95). This locus overlaps a putative cis-acting enhancer predicted to regulate transcription of ADRA1B and the lncRNA LINC01847, both members of larger ontologies associated with immune regulation. Our findings provide potential insights to the pathophysiology underlying the development of alloantibodies and implicate non-RBC ancestry-limited loci in the susceptibility to alloimmunization.

Prostate cancer (PCa) incidence and mortality is nearly twice that in Black men than any other race (Non-Hispanic White, Asian/Pacific Islander, American Indian/Alaska Native, Hispanic (any race)). Characterization of the underlying biological factors that contribute to this cancer health disparity (CHD) is required to close the gap and improve patient outcome for Black men. In vitro PCa research tools which reflect the racial/ethnic diversity of this patient population are urgently needed, as most PCa cell lines are of Non-Hispanic White-origin. PCa patient-derived xenografts (PDXs) retain many of the characteristics of patient tumors and can be isolated from specific racial/ethnic groups to address this concern. Rodent PDX models provide a valuable resource for studying human cancer, however recent trends in reducing animal usage have instituted a search for alternative methods for studying PDXs that also maintain their complexity. While 2D in vitro culture of PCa PDXs has been largely unsuccessful, recent evidence suggests 3D in vitro culture of PCa PDXs may enable better long-term culture of the tumor cells. Here, we present a racially/ethnically diverse PCa PDX library of specimens (Black, Non-Hispanic White, Hispanic) developed at MD Anderson Cancer Center (the MDA PCa PDX series) compatible with 3D in vitro culture. In order to confirm self-reported race/ethnicity, each PCa PDX was characterized by whole-exome sequencing and compared to reference populations for a genetic ancestry estimation. For 3D in vitro culture, we utilized a high throughput microfluidic culture platform with 96 chips, the MIMETAS OrganoPlate® 2-lane. This platform suits both 3D tissue/cell model development and throughput needs required for drug discovery. MDA-PCa PDX cell clusters were suspended in hyaluronic acid-based hydrogel solutions, seeded into the OrganoPlate, and cultured under continuous perfusion. Genetic ancestry estimation studies revealed that patient-reported race/ethnicity often aligned with the same racial/ethnic population genetic signatures. For example, two self-reported Black PDXs were primarily of West African origin (74.6-84.6%). When cultured in 3D, PCa PDX cultures were stable and viable for at least 7 days, as determined by high content fluorescence imagining coupled with cell viability dyes. By immunofluorescent staining, PCa PDX cultures exhibited appropriate expression of phenotypic prostate-specific antigen (PSA) and androgen receptor (AR) which was maintained over the life of the culture. Studies are ongoing to screen a panel of chemotherapy drugs and determine the predictivity of the platform. This well characterized racially/ethnically diverse PCa PDX library, together with the 3D in vitro platform and methods is a valuable resource for evaluating population-based tumor response. Citation Format: Peter Shepherd, Andrei Bonteanu, Stanley Hooker, Kristin Bircsak, Divya Iyer, Dwayne Dexter, Daniel A. Harrington, Rick Kittles, Nora M. Navone. 3D in vitro prostate cancer PDX resource for studying cancer health disparities [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2625.

Given the scarcity of human cell lines from under-represented populations available for study, it is crucial that these cell lines be accurately characterized regarding their genetic ancestry so findings can be properly contextualized. Mischaracterization of a cell line's race/ethnicity can lead to wasted time and resources and potentially publication retractions. Here we calculated genetic ancestry proportions for 22 commercially available cell lines to test the accuracy of the “race/ethnicity” categorization assigned to these cells and to provide previously unknown genetic ancestry estimates to the scientific community. To determine cellular genetic ancestry proportions, DNA was extracted from the cell lines and genotyped for ancestry informative markers using the Agena MassARRAY platform with iPLEX chemistry. Genotypes for each cell line were analyzed with STRUCTURE software using settings of 30,000 for burn-in length, 70,000 replications, and K = 3 ancestral populations, representing West African (WA), Native American (NA), and European (EA) input genotype data. Commercially available cell lines designated as “Caucasian” in ethnicity were accurately described with mean European ancestry proportions of 97% (range 92-99%). Recently, using a much smaller panel of markers, the 22Rv1 cell line was found to have 41% WA ancestry. Our genetic ancestry analysis found the 22Rv1 cell line to have mostly EA ancestry, 91% EA, while also containing a non-negligible proportion of WA ancestry (8%). Three of the commercially available cell lines ascribed “Black” race appear to be accurate (HeLa, MDA-MB-PCa2, MDA-MB-468), although two of the three, HeLa and MDA-MBPCa2, fall far below the mean of ~80% WA ancestry for US-born African Americans with 60% and 66% WA ancestry, respectively. Interestingly, the MDA-MB-468 “Black” cell line had an appreciable amount of NA ancestry, 23% NA and 77% WA ancestry, which could suggest possible Afro-Caribbean ethnicity. Most notably, the E006 cell line, designated as “Black,” is as European as the previously mentioned cell lines ascribed Caucasian ethnicity with > 92% EA genetic ancestry. Cell lines with unassigned ethnicity varied widely in genetic ancestry with ranges of WA, NA, and EA ancestry proportions of 1%-92%, 0%-30%, and 2%-96%, respectively. Our results suggest predominantly European ancestry for the Caucasian-designated cell lines and high variance in genetic ancestry proportions for the Black-designated cell lines. However, the E006 cell line is an example of extreme misclassification, which has led to erroneous findings in the disparities literature and leave open the possibility of mischaracterization of other unanalyzed cell lines. Genetic ancestry estimates add more advanced and detailed ancestral characterization to these cell lines and allow for better contextualization of comparisons, applicability, and significant findings. We suggest robust genetic ancestry estimates as a requirement for all current and novel cell lines used in research. Citation Format: Stanley E. Hooker Jr., Madhavi Bathina, Stacy Lloyd, Priyatham Gorjala, Ranjana Mitra, Kevin S. Kimbro, Rick A. Kittles. Estimating genetic ancestry of commonly used cancer cell lines [abstract]. In: Proceedings of the Eleventh AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2018 Nov 2-5; New Orleans, LA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(6 Suppl):Abstract nr B073.

African Americans (AAs) are an admixed population of West African (WA) and European ancestry (EA). Crohn's disease (CD) susceptibility genes have not been established. We therefore evaluated the contribution of European admixture and major established risk genes to AA CD.Ninety-seven admixture informative markers were genotyped for ancestry estimates using STRUCTURE. Overall, 354 AA CD cases and 354 ethnicity-matched controls were genotyped for total 21 single nucleotide polymorphisms (SNPs) in ATG16L1, NOD2, IBD5, IL23R and IRGM by TaqMan or direct sequencing. Association was evaluated by logistic regression, adjusted for ancestry.Mean EA was similar among the CD cases and controls (20.9% and 20.4%, respectively, P = 0.58). No significant admixture differences were observed among 211 to 227 cases stratified by phenotypic subclassifications including onset, surgery, site, and behavior. CD was associated with NOD2 carrier (6.93% CD, 2.15% Controls, P = 0.007), ATG16L1 Thr300Ala (36.1% CD, 29.3% Controls, P = 0.003), SLC22A4 and SLC22A5 (IBD5 locus) functional SNPs (Leu503Phe [10.5% CD, 7.6% Controls, P = 0.05] and g-207c [41.3% CD, 35.7% Controls, P = 0.03], respectively), and IL23R rs2201841 (18.2% CD, 13.8% Controls, P = 0.03), but not IRGM variants, nor three African ancestral NOD2 nonsynonymous variants. IBD5 risk was recessive. An all-minor allele IBD5 haplotype from EA was associated (P = 0.05), whereas a more common haplotype isolating g-207c was not.Specific functional gene variations contribute significantly to AA CD risk. Established NOD2, SLC22A4-A5, and ATG16L1 variants show increased CD risk, with IBD5 recessive. Although CD is more common in whites, European admixture is similar among AA cases and controls.

Prostate cancer (PCa) is a common malignancy and a leading cause of cancer death among men in the United States with African-American (AA) men having the highest incidence and mortality rates. Given recent results from admixture mapping and genome-wide association studies for PCa in AA men, it is clear that many risk alleles are enriched in men with West African genetic ancestry. A total of 77 ancestry informative markers (AIMs) within surrounding candidate gene regions were genotyped and haplotyped using Pyrosequencing in 358 unrelated men enrolled in a PCa genetic association study at the Howard University Hospital between 2000 and 2004. Sequence analysis of promoter region single-nucleotide polymorphisms (SNPs) to evaluate disruption of transcription factor-binding sites was conducted using in silico methods. Eight AIMs were significantly associated with PCa risk after adjusting for age and West African ancestry. SNP rs1993973 (intervening sequences) had the strongest association with PCa using the log-additive genetic model (P=0.002). SNPs rs1561131 (genotypic, P=0.007), rs1963562 (dominant, P=0.01) and rs615382 (recessive, P=0.009) remained highly significant after adjusting for both age and ancestry. We also tested the independent effect of each significantly associated SNP and rs1561131 (P=0.04) and rs1963562 (P=0.04) remained significantly associated with PCa development. After multiple comparisons testing using the false discovery rate, rs1993973 remained significant. Analysis of the rs156113–, rs1963562–rs615382l and rs1993973–rs585224 haplotypes revealed that the least frequently found haplotypes in this population were significantly associated with a decreased risk of PCa (P=0.032 and 0.0017, respectively). The approach for SNP selection utilized herein showed that AIMs may not only leverage increased linkage disequilibrium in populations to identify risk and protective alleles, but may also be informative in dissecting the biology of PCa and other health disparities.

Four independent regions within 8q24 near the MYC gene are associated with risk for prostate cancer. Here we investigated allelic imbalance at 8q24 risk variants and MYC gene DNA copy number (CN) in 27 primary prostate cancers. Heterozygotes were observed in 24 of 27 patients at one or more 8q24 markers and 27% of the loci exhibited AI in tumor DNA. 8q24 risk alleles were preferentially favored in the tumors. Increased MYC gene CN was observed in 33% of tumors, and the co-existence of increased MYC gene CN with AI at risk loci was observed in 86% (P

BACKGROUND Prostate cancer (Pca) is a common malignancy that disproportionately affects African American men (AA). Recently there have been several genome-wide association studies (GWAS) implicating new prostate cancer risk loci along chromosomes 2, 3, 6, 7, 8, 10, 11, 12, 17, 19, and X in populations of European ancestry. Given the higher incidence and mortality for AAs, and differences in allele frequencies and haplotype structures between African and European descent populations, it is important to assess the impact of these candidate risk loci in AAs. METHODS Here we evaluated 20 single nucleotide polymorphisms (SNPs) associated with prostate cancer risk in recent GWAS studies, in AA prostate cancer cases and controls. RESULTS We replicated five of the SNPs in our AA population, rs10896449 on 11q13.2 (P = 0.009), rs2735839 on 19q33.33 region, (P = 0.04), rs443076 on chromosome 17q12 (P = 0.008), rs5945572 on Xp11.22 (P = 0.05), as well as the rare variant specific to west African ancestry, bd11934905 in region 2 of 8q24 (P = 1 × 10−4). CONCLUSIONS While we were able to replicate a few of the previous GWAS SNPs, we were not able to confirm the vast majority of these associations in our AA population. This finding further supports the need to perform GWAS and additional fine mapping in AAs to locate additional susceptibility loci. Prostate 70: 270–275, 2010. © 2009 Wiley-Liss, Inc.

Regions on chromosome 8q24 harbor susceptibility alleles for multiple cancers including colorectal (region 3) and prostate cancer (regions 1–4). The objectives of the present study were (i) to test whether single-nucleotide polymorphisms (SNPs) in region 4 are associated with colorectal cancer (CRC) in European or African Americans; (ii) to test whether 8q24 SNPs previously shown to be associated with colorectal and prostate cancer also show association in our multiethnic series and (iii) to test for association between 100 ancestry informative markers (AIMs) and CRC in both the African American and European American cohorts. In total, we genotyped nine markers on 8q24 and 100 unlinked AIMs in 569 CRC cases and 439 controls (490 European Americans and 518 African Americans) obtained retrospectively from a hospital-based sample. We found rs7008482 in 8q24 region 4 to be significantly associated with CRC in European Americans (P = 0.03). Also in region 4, we found that a second SNP, rs16900305, trended toward association with CRC in African Americans. The rs6983267 in region 3, previously implicated in CRC risk, trended toward association with disease in European Americans but not in African Americans. Finally, none of the 100 AIMs tested for association reached statistical significance after correction for multiple hypothesis testing. In summary, these results are evidence that 8q24 region 4 contains novel CRC-associated alleles in European and African Americans.

Prostate cancer is a common complex disease that disproportionately affects men of African descent. Recently, several different common variants on chromosome 8q24 have been shown to be associated with prostate cancer in multiple studies and ethnic groups. The objective of this study was to confirm the association of 8q24 markers with prostate cancer in African Americans. We genotyped 24 markers along 8q24 and 80 unlinked ancestry informative markers in a hospital-based case-control sample of 1057 African American men (490 prostate cancer cases and 567 controls). Association analyses of 8q24 markers with prostate cancer risk were adjusted for both global and local 8q24 admixture stratification using estimates from ancestry informative markers. We report that rs7008482, which maps to the 8q24.13 region, is an additional independent prostate cancer risk variant (P = 5 × 10−4), and we also replicate the association of rs16901979 with prostate cancer (P = 0.002). Other published risk variants in the region such as rs1447295 and rs6983267 showed a similar direction and magnitude of effect, but were not significant in our population. Both rs7008482 and rs16901979 independently predicted risk and remained significant (P < 0.001) after controlling for each other. Our data combined with additional replications of 8q24 markers provide compelling support for multiple regions of risk for prostate cancer on 8q24.

To determine whether there were differential quit rates between African Americans (AA) and European Americans with the experimental treatment naltrexone, and examine the role of genetic ancestry on these outcomes among AAs.Data from a previous randomized trial of 315 smokers to naltrexone versus placebo were reanalyzed using West African (WA) genetic ancestry to define subpopulations. Logistic regression models were used to estimate treatment effects on early and end of treatment quit rates, by race and WA ancestry.Among European Americans (n=136), naltrexone significantly increased quit rates at 4 weeks (62 vs. 43%, P=0.03) with directional, but not statistically significant effects at 12 weeks (30 vs. 18%, P=0.12). In contrast, among the AAs (n=95), quit rates did not differ between naltrexone and placebo groups at either interval (4 weeks: 43 vs. 32%, P=0.27; 12 weeks: 22 vs. 18%, P=0.60). A median split was conducted in AAs for WA ancestry. Among AAs with low WA ancestry, quit rates were significantly higher with naltrexone compared with placebo (60 vs. 27%, P=0.03). There was no advantage in quit rates with naltrexone for the high WA ancestry group.Naltrexone efficacy for smoking cessation varies across AA individuals with different levels of WA ancestry. These results suggest that genetic background may partially explain racial differences in drug response.

Waist-to-hip ratio (WHR), a relative comparison of waist and hip circumferences, is an easily accessible measurement of body fat distribution, in particular central abdominal fat. A high WHR indicates more intra-abdominal fat deposition and is an established risk factor for cardiovascular disease and type 2 diabetes. Recent genome-wide association studies have identified numerous common genetic loci influencing WHR, but the contributions of rare variants have not been previously reported. We investigated rare variant associations with WHR in 1510 European-American and 1186 African-American women from the National Heart, Lung, and Blood Institute-Exome Sequencing Project. Association analysis was performed on the gene level using several rare variant association methods. The strongest association was observed for rare variants in IKBKB (P=4.0 × 10(-8)) in European-Americans, where rare variants in this gene are predicted to decrease WHRs. The activation of the IKBKB gene is involved in inflammatory processes and insulin resistance, which may affect normal food intake and body weight and shape. Meanwhile, aggregation of rare variants in COBLL1, previously found to harbor common variants associated with WHR and fasting insulin, were nominally associated (P=2.23 × 10(-4)) with higher WHR in European-Americans. However, these significant results are not shared between African-Americans and European-Americans that may be due to differences in the allelic architecture of the two populations and the small sample sizes. Our study indicates that the combined effect of rare variants contribute to the inter-individual variation in fat distribution through the regulation of insulin response.

Background Uruguay exhibits one of the highest rates of breast cancer in Latin America, similar to those of developed nations, the reasons for which are not completely understood. In this study we investigated the effect that ancestral background has on breast cancer susceptibility among Uruguayan women. Methods We carried out a case–control study of 328 (164 cases, 164 controls) women enrolled in public hospitals and private clinics across the country. We estimated ancestral proportions using a panel of nuclear and mitochondrial ancestry informative markers (AIMs) and tested their association with breast cancer risk. Results Nuclear individual ancestry in cases was (mean ± SD) 9.8 ± 7.6% African, 13.2 ± 10.2% Native American and 77.1 ± 13.1% European, and in controls 9.1 ± 7.5% African, 14.7 ± 11.2% Native American and 76.2 ± 14.2% European. There was no evidence of a difference in nuclear or mitochondrial ancestry between cases and controls. However, European mitochondrial haplogroup H was associated with breast cancer (OR = 2.0; 95% CI 1.1, 3.5). Conclusions We have not found evidence that overall genetic ancestry differs between breast cancer patients and controls in Uruguay but we detected an association of the disease with a European mitochondrial lineage, which warrants further investigation. Electronic supplementary material The online version of this article (doi:10.1186/s12905-015-0171-8) contains supplementary material, which is available to authorized users.

Low vitamin D levels are associated with an increased incidence of colorectal cancer (CRC) and higher mortality from the disease. In the US, African Americans (AAs) have the highest CRC incidence and mortality and the lowest levels of vitamin D. Single nucleotide polymorphisms (SNPs) in the vitamin D receptor (VDR) gene have been previously associated with CRC, but few studies have included AAs. We studied 795 AA CRC cases and 985 AA controls from Chicago and North Carolina as well as 1324 Caucasian cases and 990 Caucasian controls from Chicago and Spain. We genotyped 54 tagSNPs in VDR (46586959 to 46521297 Mb) and tested for association adjusting for West African ancestry, age, gender, and multiple testing. Untyped markers were imputed using MACH1.0. We analyzed associations by gender and anatomic location in the whole study group as well as by vitamin D intake in the North Carolina AA group. In the joint analysis, none of the SNPs tested was significantly associated with CRC. For four previously tested restriction fragment length polymorphisms, only one (referred to as ApaI), tagged by the SNP rs79628898, had a nominally significant p-value in AAs; none of these polymorphisms were associated with CRC in Caucasians. In the North Carolina AAs, for whom we had vitamin D intake data, we found a significant association between an intronic SNP rs11574041 and vitamin D intake, which is evidence for a VDR gene-environment interaction in AAs. In summary, using a systematic tagSNP approach, we have not found evidence for significant associations between VDR and CRC in AAs or Caucasians.

Prostate cancer (PCa) is a complex disease that disproportionately affects African Americans and other individuals of African descent. A number of regions across the genome have been associated to PCa, most of them with moderate effects. A few studies have reported chromosomal changes on 12p and 12q that occur during the onset and development of PCa but to date no consistent association of the disease with chromosome 12 polymorphic variation has been identified. In order to unravel genetic risk factors that underlie PCa health disparities we investigated chromosome 12 using ancestry informative markers (AIMs), which allow us to distinguish genomic regions of European or West African origin, and tested them for association with PCa. Additional SNPs were genotyped in those areas where significant signals of association were detected. The strongest signal was discovered at the SNP rs12827748, located upstream of the PAWR gene, a tumor suppressor, which is amply expressed in the prostate. The most frequent allele in Europeans was the risk allele among African Americans. We also examined vitamin D related genes, VDR and CYP27B1, and found a significant association of PCa with the TaqI polymorphism (rs731236) in the former. Although our results warrant further investigation we have uncovered a genetic susceptibility factor for PCa in a likely candidate by means of an approach that takes advantage of the differential contribution of parental groups to an admixed population.

BACKGROUND & AIMS: Genome-wide association studies of colorectal cancer (CRC) have identified risk variants in 10 genomic regions. None of these studies included African Americans, who have the highest incidence and mortality from CRC in the United States. For the 10 genomic regions, we performed an association study of Americans of African and European descent. METHODS: We genotyped 22 single nucleotide polymorphisms (SNPs) in DNA samples from 1194 patients with CRC (795 African Americans and 399 European Americans) and 1352 controls (985 African Americans and 367 European Americans). At chromosome 8q24.21 region 3, we analyzed 6 SNPs from 1000 African American cases and 1393 controls. Association testing was done using multivariate logistic regression controlling for ancestry, age, and sex. RESULTS: Among African Americans, the SNP rs6983267 at 8q24.21 was not associated with CRC (odds ratio, 1.18; P .12); instead, the 8q24.21 SNP rs7014346 (odds ratio, 1.15; P .03) was associated with CRC in this population. At 15q13.3, rs10318 was associated with CRC in both populations. At 11q23.1, rs3802842 was significantly associated with rectal cancer risk only among African Americans (odds ratio, 1.34; P .01); this observation was made in previous studies. Among European Americans, SNPs at 8q24.21, 11q23.1, and 16q22.1 were significantly associated with CRC, and the odds ratios were of the same magnitude and direction for all SNPs tested, consistent with previously published studies. In contrast, in African Americans, the opposite allele of rs10795668 at 10p14 was associated with colorectal cancer (odds ratio, 1.35; P .04), and altogether the odds ratios were in the opposite direction for 9 of the 22 SNPs tested. CONCLUSIONS: There is genetic heterogeneity in CRC associations in Americans of African versus European descent.

Little is known about the lay public’s awareness and attitudes concerning genetic testing and what factors influence their perspectives. The existing literature focuses mainly on ethnic and socioeconomic differences; however, here we focus on how awareness and attitudes regarding genetic testing differ by geographical regions in the US. We compared awareness and attitudes concerning genetic testing for disease risk and ancestry among 452 adults (41% Black and 67% female) in four major US cities, Norman, OK; Cincinnati, OH; Harlem, NY; and Washington, DC; prior to their participation in genetic ancestry testing. The OK participants reported more detail about their personal ancestries (p = 0.02) and valued ancestry testing over disease testing more than all other sites (p < 0.01). The NY participants were more likely than other sites to seek genetic testing for disease (p = 0.01) and to see benefit in finding out more about one’s ancestry (p = 0.02), while the DC participants reported reading and hearing more about genetic testing for African ancestry than all other sites (p < 0.01). These site differences were not better accounted for by sex, age, education, self-reported ethnicity, religion, or previous experience with genetic testing/counseling. Regional differences in awareness and attitudes transcend traditional demographic predictors, such as ethnicity, age and education. Local sociocultural factors, more than ethnicity and socioeconomic status, may influence the public’s awareness and belief systems, particularly with respect to genetics.

Prostate cancer (Pca) is a common malignancy that disproportionately affects African American men (AA). Recently there have been several genome-wide association studies (GWAS) implicating new prostate cancer risk loci along chromosomes 2, 3, 6, 7, 8, 10, 11, 12, 17, 19, and X in populations of European ancestry. Given the higher incidence and mortality for AAs, and differences in allele frequencies and haplotype structures between African and European descent populations, it is important to assess the impact of these candidate risk loci in AAs.Here we evaluated 20 single nucleotide polymorphisms (SNPs) associated with prostate cancer risk in recent GWAS studies, in AA prostate cancer cases and controls.We replicated five of the SNPs in our AA population, rs10896449 on 11q13.2 (P = 0.009), rs2735839 on 19q33.33 region, (P = 0.04), rs443076 on chromosome 17q12 (P = 0.008), rs5945572 on Xp11.22 (P = 0.05), as well as the rare variant specific to west African ancestry, bd11934905 in region 2 of 8q24 (P = 1 x 10(-4)).While we were able to replicate a few of the previous GWAS SNPs, we were not able to confirm the vast majority of these associations in our AA population. This finding further supports the need to perform GWAS and additional fine mapping in AAs to locate additional susceptibility loci.

Prostate cancer is a common malignancy that disproportionately affects African-American men. Environmental factors and variation in genes responsible for chemical and dietary carcinogen metabolism and DNA damage repair may modulate risk. Fourteen single nucleotide polymorphisms in NAT2 and four NER genes (ERCC1, XPF/ERCC4, XPG/ERCC5 and CSB/ERCC6) were genotyped in a case-control study of 254 African-American prostate cancer cases and 301 healthy controls from Washington, DC. Smoking status, BMI, age and genetic ancestry were included as covariates in the association analyses. We found that individuals homozygous for the XPG/ERCC5 -72C/T promoter polymorphism had a significant reduction in risk, for prostate cancer (OR=0.12; 95% CI=0.03-0.48). A haplotype trend regression test also revealed a protective effect for the haplotype bearing the T allele (P=0.003). In silica analyses suggest a functional implication for the promoter variant since it deletes a GCF transcriptional factor-binding site responsible for the downregulation of transcription. The protective effect of the promoter SNP on risk for prostate cancer was independent of smoking. In contrast, none of the SNPs typed for NAT2, ERCC1, ERCC4 and ERCC6 showed significant association with risk. Additional tests for genotype interactions were not significant. We note that there may be other factors, such as dietary exposures, which may modulate prostate cancer risk in combination with genetic variation within the NAT2 and NER genes. Our results, in combination with previous observations of LOH for ERCC5 in prostate tumors, provide further evidence for a role of XPG/ERCC5 in the etiology of prostate cancer.

Background: Genome-wide association studies (GWAS) of colorectal cancer (CRC) have identified risk variants in candidate genes involved in TGF-ß signaling including BMP4, GREM1, CDH1, RHPN2 and SMAD7. We previously replicated the association with a 3′-UTR SNP in GREM1 (rs10318) in African Americans but did not find evidence of associations in the other genes. This finding could be explained by different genomic structure in African Americans. Therefore, we sought to fine-map these genes to identify CRC risk variants in African Americans who are at highest risk of CRC in the US. Methods: DNA from cases and controls was obtained from two US institutions. In total, we included DNA from 795 AA cases and 985 AA controls. TagSNPs with minor allele frequencies >5% and pairwise r2 >0.8 were identified in five genes using YRI Hapmap data. A total of 81 SNPs were genotyped in cases and controls using Sequenom MassARRAY. We calculated odds ratios and 95% confidence intervals using logistic regression controlling for ancestry, age, gender and multiple testing in PLINK. Results: Association analysis was completed for four genes: BMP4, GREM1, CDH1 and RHPN2. The top tagSNP associations for each gene are shown in the Table. None of the SNPs were significant after permutation testing. In GREM1, the strongest SNP associations were found at the 3′ end of the gene. In BMP4, we identified two SNPs (rs1957852 and rs7146040) that are in LD with rs4444235 previously identified in a European GWAS. In CDH1, rs12931189 is located in the same LD block as the strongest association signal (rs7199991) in a recent fine-mapping study in Europeans. Finally, we have no evidence for associations in RHPN2 in African Americans. Conclusion: These results provide preliminary evidence of associations in African American colorectal cancer patients in BMP4, GREM1 and CDH1 identified by GWAS in Europeans. Ongoing work is testing associations in SMAD7 and further fine-mapping by imputation and resequencing in these regions. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1661. doi:1538-7445.AM2012-1661

Background: Genome-wide association studies have identified several colorectal cancer (CRC) genetic risk factors. However, these studies have been performed primarily in individuals of European descent and none include African Americans (AAs). Determining CRC genetic risk factors in AAs is important because CRC incidence and mortality rates are highest of all US populations. Aim: To validate genome-wide CRC genetic risk factors, we tested single nucleotide polymorphism (SNP) associations in ten chromosome (chr) regions in AAs and European-Americans (EAs). Methods: We genotyped 22 SNPs in 1725 AA and 883 EA CRC cases and controls using Sequenom iPLEX. Ancestry estimates were obtained using STRUCTURE 2.1. We tested for allelic association and calculated odds ratios and confidence intervals using logistic regression adjusting for ancestry, age and gender. Results: Association results are shown in the Table. In AAs, rs10795668 (chr 10) and rs10318 (chr 15) were significantly associated with CRC. rs7014346 (chr 8) and rs355527 (chr 20) trended toward significant associations. In EAs, three SNPs on chr 8 were significantly associated with CRC. In addition, two chr 11 SNPs (rs3802842 & rs1074997) and rs1862748 (chr 16) were significantly associated with disease in EAs. SNPs on chr 15 and chr 16 are located in or near genes GREM1 and CDH1 respectively. SNPs on chr 8, 10, 11 and 20 are in gene deserts. Conclusion: This is the first study to validate genome-wide SNP associations in AAs. We also confirm several associations in EAs. SNPs on chr 15 & 16 are located in genes involved in TGFβ signaling (GREM1 & CDH1) which has been implicated in CRC pathogenesis, while those on chr 8, 10, 11 and 20 are in gene deserts. Future fine-mapping in these regions is warranted to identify functional variants.Genome-wide SNP associations in African- and European-AmericansChr (gene)SNPReference alleleAllele frequency casesAllele frequency controlsOR [95% CI]p*African Americans 8rs7014346A0.420.391.14 [0.99-1.31]0.0710rs10795668A0.080.061.41 [1.07-1.87]0.0415 (GREM1)rs10318T0.050.031.45 [1.02-2.05]0.0520rs355527A0.180.200.87 [0.73-1.04]0.09European Americans 8rs6983626T0.120.091.38 [1.00-1.91]0.058rs6983267G0.520.471.24 [1.01-1.51]0.048rs7837328A0.430.371.30 [1.06-1.60]0.0111rs3802842C0.330.281.26 [1.02-1.57]0.0211rs10749971G0.410.331.42 [1.15-1.74]0.000216 (CDH1)rs1862748T0.280.320.80 [0.64-0.99]0.04 Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4734.

In the USA, African American (AA) men are at higher risk of developing and dying from prostate cancer (Pca). Strong and replicable associations between prostate cancer risk and regions 1, 2, and 3 of 8q24 among cohorts of European ancestry have been found but few for those of African ancestry. Recently, we discovered in a study of AAs, a fourth region of Pca risk at 126 Mb of 8q24.13 surrounding SNP rs7008482. Region 4 is 2 Mb upstream of the other three regions on 8q24 and contains two interesting candidate genes for Pca risk. To further interrogate region 4, we performed fine-mapping within a 500-Kb region (126.1Mb-126.6Mb). SNPs were selected for fine-mapping of the region based on the following characteristics: tagging SNPs from Yoruba HAPMAP data and non-synonymous or potential regulatory SNPs. We genotyped 250 SNPs in 263 AA Pca cases and 562 AA healthy controls. A structured-association analysis taking into account African ancestry, (local 8q24 ancestry and genomic ancestry) revealed that several SNPs within two genes KIAA0196 and NSMCE2 were significantly associated with Pca risk. The majority of the associated SNPs were common and exhibited low to moderate risk which may contribute to high population attributable risk in African Americans. Among these, rs16900305, located in an intronic region of KIAA0196, exhibited the strongest association (P=0.0003). KIAA0196 has been shown to be over-expressed in clinical prostate carcinomas and in approximately 30% of hormone-refractory tumors. Our findings strongly support region 4 in 8q24.13 as a candidate locus influencing prostate cancer risk among African Americans. Given the two interesting genes in this region and strong associations in a high risk group for Pca, further attention to this region is warranted. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4725.

T cost of the development and production of strikefighter aircraft increased rapidly in the 1950s because of the ever-increasing sophistication of the electronics and the bombs or missiles carried, together with the demand for supersonic performance of at least Mach 2. In a forlorn attempt to reverse this tendency in England, W.E.W. Fetter, designer of the famed Canberra bomber, proposed the Gnat fighter, weighing less than 10,000 Ib ancf limited to high subsonic performance, in the hope that such an aircraft would be inexpensive and easy to produce. Gen. Norstadt of the U.S. Air Force, Supreme Commander of NATO, supported the concept, but added that it should be capable of taking off and landing on 2000 ft grass strips, which he described as "cow pastures." The specifications of the NATO Light Fighter, as it came to be known, closely followed those of the Gnat, except that this aircraft was to have high-pressure tires and thus could not operate from grass fields. Fetter, being the obstinate fellow he was, steadfastly refused to change and, therefore, opened the field to D'Assault, Breguet, and Fiat; thus, the lightweight fighter competition began. In the background, Col. John O'Driscoll of the U.S. Air Force was the driving force behind the competition and had inspired Gen. Norstadt to issue his requirements. At the time, O'Driscoll was the executive head of the Mutual Weapons Development Program (MWDP) in Paris, and had funding available for development projects of interest to NATO. He was also a man of great vision and experience, and the resuscitation of the German and Italian aircraft industries and air forces owes much to the vigor with which he pursued both the competition and selection of the lightweight fighter. He also held the purse strings and dealt most effectively with the competitors, despite the enormous pressures to which he was subjected. The Bristol Engine Company had proposed the Orpheus engine as the powerplant for the Gnat. This engine had an air mass flow of 80 Ib/s, a compression ratio of 4.5/1, a thrust of 4850 Ib for a weight of 800 Ib. As such, it was easily the lightest engine available and was subsequently adopted by all the aircraft competitors as the desired powerplant. Thus, Col. O'Driscoll had few problems in the choice of the engine, and after the technical details had been scrutinized at WrightPatterson Air Force Base and Theodore von Karman, he was able to give immediate financial support for the development of the engine. The arrangement was that MWDP would pay 15% of the development cost and the Bristol Engine Company fund the remainder. A cross-sectional drawing of the Orpheus is shown in Fig. 1. It had a seven-stage axial compressor, an annular combustion chamber, and a single-stage turbine (the compression ratio having been chosen for this purpose). The basic new feature was the large-diameter, thin shaft connecting the turbine and compressor, which eliminated all whirling problems and enabled two main bearings to be used—one at the front of the compressor and the other at the rear of the turbine. Hitherto, axial engines had always had a three-bearing arrangement, which necessitated a coupling in the center of the compressor-turbine shaft where the third bearing was situated. The Orpheus was the first jet engine to avoid this complication, weight, and cost. Additionally, the turbine was mounted on the shaft by Firth couplings. This simple device proved to be a very accurate centering mechanism, allowing the turbine to be removed and replaced without the need for dynamic rebalancing. All of these features have now become standard design techniques in modern engines, but were initiated on the Orpheus and made a substantial contribution to its low cost, light weight, and reliability. The engine met all of its performance requirements, and ran like a "watch." In the meantime, the aircraft competition had been won by Fiat, where Gabrielli had designed the G91. Hundreds of this aircraft were produced in both Germany and Italy, and the Orpheus engine was likewise produced by Fiat in Italy and Klockner-Humboldt Deutz in Germany. In fact, in the postwar era, the first 100,000 h of flying by the Luftwaffe were all with the G91 and the Orpheus. Col. O'Driscoll had always considered short takeoff and landing to be a prime requirement in the European theater, which at that time was very short of concrete runways, all of which were highly vulnerable. Having launched the G91 and the Orpheus, he thus turned his attention to vertical takeoff and landing (VTOL). In Paris at the time, was a famous French aircraft designer, Michele Wibault, who was unattached to any aircraft company and was being supported by Winthrop Rockefeller. Wibault had an idea for a vertical takeoff fighter, which consisted of a turbine engine (in his case the Bristol Orion engine) driving through gearboxes and cross shafts four centrifugal compressors, two on each side of the aircraft (see Fig. 2). The volutes could be rotated through 90 deg, so the

Many population-based rare-variant (RV) association tests, which aggregate variants across a region, have been developed to analyze sequence data. A drawback of analyzing population-based data is that it is difficult to adequately control for population substructure and admixture, and spurious associations can occur. For RVs, this problem can be substantial, because the spectrum of rare variation can differ greatly between populations. A solution is to analyze parent-child trio data, by using the transmission disequilibrium test (TDT), which is robust to population substructure and admixture. We extended the TDT to test for RV associations using four commonly used methods. We demonstrate that for all RV-TDT methods, using proper analysis strategies, type I error is well-controlled even when there are high levels of population substructure or admixture. For trio data, unlike for population-based data, RV allele-counting association methods will lead to inflated type I errors. However type I errors can be properly controlled by obtaining p values empirically through haplotype permutation. The power of the RV-TDT methods was evaluated and compared to the analysis of case-control data with a number of genetic and disease models. The RV-TDT was also used to analyze exome data from 199 Simons Simplex Collection autism trios and an association was observed with variants in ABCA7. Given the problem of adequately controlling for population substructure and admixture in RV association studies and the growing number of sequence-based trio studies, the RV-TDT is extremely beneficial to elucidate the involvement of RVs in the etiology of complex traits.