West African Genetic Ancestry Research Articles

West African Genetic Ancestry and Breast Cancer Outcomes Among Black Women.

Young Black women bear a disproportionate burden of breast cancer deaths compared with White women, yet they remain underrepresented in genomic studies. To evaluate the association of biological factors, including West African genetic ancestry, and nonbiological factors with disease-free survival (DFS) among young Black women with breast cancer. This observational cohort study included Black women diagnosed with invasive breast cancer between January 1, 2005, and December 31, 2016. Participants diagnosed with breast cancer at age 50 years or younger were recruited through the Florida and Tennessee state cancer registries. The final analysis was completed between June and September 2024. West African genetic ancestry. A multivariable model was developed to evaluate the association between West African genetic ancestry and breast cancer DFS, adjusting for immunohistochemistry subtype, lymph node (LN) status, and full-time employment. This study included 687 Black women with early-stage invasive breast cancer. Their median age at diagnosis was 44 years (IQR, 38-47 years), and the median follow-up was 10 years (IQR, 7-11 years). In multivariable analysis, triple-negative breast cancer (TNBC) and LN involvement were associated with shorter breast cancer DFS (hazard ratio, 1.81 [95% CI, 1.20-2.73] and 1.77 [95% CI, 1.30-2.41], respectively), whereas full-time employment was associated with improved outcomes (hazard ratio, 0.44 [95% CI, 0.30-0.63]). Among the 551 participants for whom global genetic ancestry could be assessed, having a higher percentage of West African genetic ancestry was associated with shorter breast cancer DFS among 246 participants in the hormone receptor (HR)-positive/human epidermal growth factor receptor 2 (ERBB2 [formerly HER2])-negative subgroup (hazard ratio, 1.45 [95% CI, 1.04-2.04]). Of the 369 participants (53.7%) with PAM50 data available, basal (133 [36.0%]) and luminal B (107 [29.0%]) subtypes were the most common. Among the 179 patients with HR-positive/ERBB2-negative disease and PAM50 data available, luminal B and basal subtypes combined were also overrepresented (81 [45.3%] and 24 [13.4%], respectively) compared with luminal A (70 [39.1%]). In this study of young Black women with breast cancer, having a higher percentage of West African genetic ancestry, TNBC, and LN involvement were associated with shorter breast cancer DFS. Interestingly, full-time employment was associated with improved breast cancer DFS. These findings highlight the importance of considering genetic ancestry beyond self-reported race and accounting for social determinants of health, in efforts to improve survival outcomes among Black women with breast cancer.

West African Genetic Ancestry, Neighborhood Deprivation, and Prostate Cancer

Racial disparities in prostate cancer are likely the result of complex relationships between both socioeconomic and environmental factors captured by the neighborhood environment and genetic factors, including West African genetic ancestry. However, few studies have examined the combined role of neighborhood environment and genetic ancestry in developing lethal prostate cancer. To examine the interactions between West African genetic ancestry and neighborhood deprivation in modifying prostate cancer risk and mortality. This case-control study was conducted in the Greater Baltimore area. Participants included men of African and European descent (617 cases with prostate cancer, 852 controls without prostate cancer) enrolled between January 2005 and January 2016. Follow-up was performed through December 31, 2020, using the National Death Index. Analysis was conducted from August 2023 to January 2024. Included exposures were West African genetic ancestry, derived from large-scale genotyping, and neighborhood deprivation, defined using 2000 census-tract-level Neighborhood Deprivation Index (NDI) score. Outcomes of interest were prostate cancer and all-cause mortality. Among a total of 1469 participants (mean [SD] age, 64.96 [7.95] years), there were 736 self-identified Black and 733 White men, and the mean (range) proportion of West African genetic ancestry was 0.27 (0.04-0.84) among participants residing in areas with low levels of deprivation and 0.48 (0.07-0.83) among participants residing in areas with high levels of deprivation. Multivariable logistic regression analysis revealed a significant multiplicative interaction of West African genetic ancestry and neighborhood deprivation with the odds of a prostate cancer diagnosis (P for interaction = .02). Among individuals living in neighborhoods with high NDI scores, West African genetic ancestry was associated with increased odds of a prostate cancer diagnosis (age-adjusted odds ratio [OR], 1.98; 95% CI, 1.23-3.19). In contrast, West African genetic ancestry was associated with reduced odds of this diagnosis among individuals residing in areas with medium to low levels of deprivation (age-adjusted OR, 0.22; 95% CI, 0.11-0.44). There was no significant multiplicative interaction between West African genetic ancestry and neighborhood deprivation for all-cause mortality (P for interaction = .44). The positive association of neighborhood deprivation with prostate cancer was independent of West African genetic ancestry (age- and West African ancestry-adjusted OR, 1,70; 95% CI, 1.50-1.94). This case-control study of men with West African and European ancestry found that West African genetic ancestry was associated with increased odds of prostate cancer among males who resided in neighborhoods with high deprivation but lower odds in more affluent neighborhoods. Thus, neighborhood environments may play a critical role in defining how genetic ancestry modulates prostate cancer risk.

Abstract 2149: West African genetic ancestry and origin of the BRCA1 locus in Jamaican men with high grade prostate cancer

Abstract Introduction: Men of West African (WA) ancestry are at higher risk for prostate cancer than men of European (EU) or Asian descent. Caribbean populations provide an opportunity to identify potential founder mutations that contribute to cancer risk. Jamaica has among the highest rates of prostate cancer incidence and mortality in the world and the majority of the population are of WA ancestry. However, there is a significant amount of genetic admixture of EU and Asian ancestry from historic migration patterns. Thus, the population provides a unique cohort for studying the complex interplay between genetic ancestry and prostate cancer. In this pilot study, we characterized the overall and gene locus-specific ancestry of Jamaican prostate cancer patients to explore potential associations with clinicopathologic disease features. We specifically focused this analysis on the BRCA1 locus based on its known association with inherited prostate cancer risk and also with breast cancer risk in patients from the Caribbean. Methods: A retrospective cohort of 31 Jamaican men (non-US citizens/residents) who travelled to the University of Miami (2015-2020) specifically for robotic prostatectomy were included in the analysis. DNA was prepared from normal prostate tissue and analyzed using the Illumina Global Screening Array version 3 with Multi-Disease Drop-In that includes more than 650,000 genetic markers. Both overall genetic ancestry and allele specific ancestries were determined for each study subject. Clinical and pathological features (age, PSA, stage, grade group (GG)) were also recorded and analyzed using descriptive statistics. Results: Median age was 67 years, median pre-op PSA was 6.7. The majority of patients were cT1c (91%) and GG 2 (29%) on biopsy. On final pathology most men were ≥pT3 (51%) and the proportion of GG 1, 2 and ≥ 3 was 3%, 52% and 45% respectively. The mean overall West African genetic ancestry was 51.2% (SD 28.4%). Overall % West African ancestry was not associated with pathological GG. In contrast, 50% of the men who were homozygous for African ancestry alleles at the BRCA1 locus had high-grade prostate cancer (GG 3, 4, 5) versus 37% of the men with non-African or heterozygous BRCA1 genotypes. Conclusions: In a select cohort of Jamaican men, we found that half of patients with BRCA1 alleles derived from West African ancestry also have high grade prostate cancer. BRCA1 of African ancestral origin may contribute to the relatively high prevalence of aggressive prostate cancer in men from Jamaica. Work in progress focuses on an expanded study of associations between allele-specific genetic ancestry and prostate cancer in high-risk populations. Citation Format: Sandra M. Gaston, Anthony J. Griswold, Oleksandr N. Kryvenko, Tianjie Gu, Guan-Nan Zhang, Nachiketh S. Prakash, Yuval Avda, Tarek Ajami, Chad R. Ritch. West African genetic ancestry and origin of the BRCA1 locus in Jamaican men with high grade prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2149.

Neuron-binding antibody responses are associated with Black ethnicity in multiple sclerosis during natalizumab treatment.

Multiple sclerosis is an inflammatory degenerative condition of the central nervous system that may result in debilitating disability. Several studies over the past twenty years suggest that multiple sclerosis manifests with a rapid, more disabling disease course among individuals identifying with Black or Latin American ethnicity relative to those of White ethnicity. However, very little is known about immunologic underpinnings that may contribute to this ethnicity-associated discordant clinical severity. Given the importance of B cells to multiple sclerosis pathophysiology, and prior work showing increased antibody levels in the cerebrospinal fluid of Black-identifying, compared to White-identifying multiple sclerosis patients, we conducted a cohort study to determine B cell subset dynamics according to both self-reported ethnicity and genetic ancestry over time. Further, we determined relationships between ethnicity, ancestry, and neuron-binding IgG levels. We found significant associations between Black ethnicity and elevated frequencies of class-switched B cell subsets, including memory B cells; double negative two B cells; and antibody-secreting cells. The frequencies of these subsets positively correlated with West African genetic ancestry. We also observed significant associations between Black ethnicity and increased IgG binding to neurons. Our data suggests significantly heightened T cell-dependent B cell responses exhibiting increased titres of neuron-binding antibodies among individuals with multiple sclerosis identifying with the Black African diaspora. Factors driving this immunobiology may promote the greater demyelination, central nervous system atrophy and disability more often experienced by Black-, and Latin American-identifying individuals with multiple sclerosis.

Genetic Factors Associated with Absolute and Relative Plasma Concentrations of Calcitriol.

Little is known regarding factors associated with calcitriol and a relative measure of calcitriol, the calcitriol-24,25-dihydroxyvitamin D3-calcifediol proportion ratio (C24CPR). Using a cross-sectional study design, healthy young adults of African and European descent, matched (1:1) on age (±5 years) provided a blood sample in non-summer months (N = 376). Vitamin D metabolites were measured in plasma with HPLC/MS-MS. West African genetic ancestry proportion (WGA) was estimated using STRUCTURE modeling of genetic ancestry-informative markers. Multivariable regression models were used to estimate the association of WGA and vitamin D-pathway gene variants with calcitriol and C24CPR, controlling for days from summer solstice, age, sex, blood pressure, body mass index, dietary vitamin D intake, oral contraceptive/medroxyprogesterone acetate use, smoking, tanning bed use, and time of day. Calcitriol and C24CPR were not highly correlated (rho = 0.14), although both were significantly, positively, and monotonically associated with WGA (Ptrend 0.025 and <0.001, respectively). In fully adjusted models, genetic factors explained a greater proportion of variability in C24CPR (R2 = 0.121 and 0.310, respectively). Variants in genes with associated with calcitriol (CALB1, CYP27B1, GC, and PPARGC1A) differed from those associated with C24CPR (CYP3A43, FGF23, KL, and VDR). Both absolute and relative measures of calcitriol were significantly higher among African Americans. Otherwise, these biomarkers appear to be genetically distinct. C24CPR may be better suited to personalized medicine, due to a higher proportion of population variability explained by genetic variation and a less skewed distribution.

The DARC Side of Inflamm-Aging: Duffy Antigen Receptor for Chemokines (DARC/ACKR1) as a Potential Biomarker of Aging, Immunosenescence, and Breast Oncogenesis among High-Risk Subpopulations.

The proclivity of certain pre-malignant and pre-invasive breast lesions to progress while others do not continues to perplex clinicians. Clinicians remain at a crossroads with effectively managing the high-risk patient subpopulation owing to the paucity of biomarkers that can adequately risk-stratify and inform clinical decisions that circumvent unnecessary administration of cytotoxic and invasive treatments. The immune system mounts the most important line of defense against tumorigenesis and progression. Unfortunately, this defense declines or "ages" over time-a phenomenon known as immunosenescence. This results in "inflamm-aging" or the excessive infiltration of pro-inflammatory chemokines, which alters the leukocyte composition of the tissue microenvironment, and concomitant immunoediting of these leukocytes to diminish their antitumor immune functions. Collectively, these effects can foster the sequelae of neoplastic transformation and progression. The erythrocyte cell antigen, Duffy antigen receptor for chemokines(DARC/ACKR1), binds and internalizes chemokines to maintain homeostatic levels and modulate leukocyte trafficking. A negative DARC status is highly prevalent among subpopulations of West African genetic ancestry, who are at higher risk of developing breast cancer and disease progression at a younger age. However, the role of DARC in accelerated inflamm-aging and malignant transformation remains underexplored. Herein, we review compelling evidence suggesting that DARC may be protective against inflamm-aging and, therefore, reduce the risk of a high-risk lesion progressing to malignancy. We also discuss evidence supporting that immunotherapeutic intervention-based on DARC status-among high-risk subpopulations may evade malignant transformation and progression. A closer look into this unique role of DARC could glean deeper insight into the immune response profile of individual high-risk patients and their predisposition to progress as well as guide the administration of more "cyto-friendly" immunotherapeutic intervention to potentially "turn back the clock" on inflamm-aging-mediated oncogenesis and progression.

Self-Identified African Americans and prostate cancer risk: West African genetic ancestry is associated with prostate cancer diagnosis and with higher Gleason sum on biopsy.

Concerns about overtreatment of clinically indolent prostate cancer (PrCa) have led to recommendations that men who are diagnosed with low‐risk PrCa be managed by active surveillance (AS) rather than immediate definitive treatment. However the risk of underestimating the aggressiveness of a patient's PrCa can be a significant source of anxiety and a barrier to patient acceptance of AS. The uncertainty is particularly keen for African American (AA) men who are about 1.7 times more likely to be diagnosed with PrCa than European American (EA) men and about 2.4 times more likely to die of this disease. The AA population, as many other populations in the Americas, is genetically heterogeneous with varying degrees of admixture from West Africans (WAs), Europeans, and Native Americans (NAs). Recommendations for PrCa screening and management rarely consider potential differences in risk within the AA population. We compared WA genetic ancestry in AA men undergoing standard prostate biopsy who were diagnosed with no cancer, low‐grade PrCa (Gleason Sum 6), or higher grade PrCa (Gleason Sum 7‐10). We found that WA genetic ancestry was significantly higher in men who were diagnosed with PrCa on biopsy, compared to men who were cancer‐negative, and highest in men who were diagnosed with higher grade PrCa (Gleason Sum 7‐10). Incorporating WA ancestry into the guidelines for making decisions about when to obtain a biopsy and whether to choose AS may allow AA men to personalize their approach to PrCa screening and management.

Abstract P109: Genetic Correlates of Resilience Among African American Families From the Jackson Heart Study

Background: Research has reported that measures of resilience, such as optimism, social support, and religious coping are positively associated with longevity, but there are limited studies on the genetic contribution of resilience among African Americans. Utilizing Jackson Heart Study (JHS) data, we examined the heritability estimates of markers of resilience and their association with proportion of West African genetic ancestry (pAfr) in order to understand familial patterns of resilience among African Americans. Hypothesis: We hypothesized that genetic variation would contribute significantly to variation in indicators of resilience, and that pAfr will be positively associated with greater resilience in African Americans. Methods: Resilience measures (optimism, social support, social networks, religious experiences, and religious practices and coping) were obtained from validated questionnaires. Scores were created for each resilience measure and then all measures were summed to create a total resilience score among 1,200 related and 1,456 unrelated individuals of the JHS cohort. We then analyzed the subset of related individuals to estimate polygenic heritability for resilience measures using Sequential Oligogenic Linkage Analysis Routines (SOLAR), and evaluated the subset of unrelated participants for the association between resilience and pAfr using a multiple linear regression model. The pAfr was estimated from more than 1,400 ancestry informative markers that differentiate West African genetic ancestry from European ancestry using HAPMIX genetic software. In both analyses, we controlled for age, sex, age-by-sex interaction, education, physical activity, smoking and depressive symptoms. Results: In related individuals, we found a significant proportion of variation (h 2 ±SE; p-value) due to familial correlation on religious practices and coping (0.15±0.09; p=0.0371); religious experience (0.26±0.09; p&lt;0.001); social networks (0.32±0.07; p&lt;0.001); and optimism (0.21±0.08; p&lt;0.001). Heritability estimates for total resilience and social support were not significant. In the subset of unrelated individuals, we found that pAfr was significantly associated (beta±SE; p-value) with total resilience (3.08±1.44; p=0.0327), religious experience (5.16±2.55; p=0.0437), and religious practices and coping (3.77±1.23; p=0.0023) in men but not in women. Conclusion: In this sample of African Americans, we found evidence that variation in markers of resilience are influenced by genetic ancestry and sex. West African genetic background was associated with markers of resilience in men only. Due to lack of household effects we could not account for influence of the common environment, which is a limitation of these findings. However, because we found genetic influences of resilience, future studies that explore associations with longevity loci are warranted.

West African Ancestry and Nocturnal Blood Pressure in African Americans: The Jackson Heart Study.

African Americans have a higher prevalence of nocturnal hypertension and nondipping blood pressure than European Americans, but the genetic contribution to these racial differences remains unclear. We assessed the association of the percentage West African genetic ancestry with nocturnal hypertension and nondipping blood pressure in 932 African Americans from the Jackson Heart Study. Using percentage West African ancestry determined from 389 ancestry informative markers, participants were categorized into tertiles (tertile 1 [low]: <79.3%, tertile 2: ≥79.3-86.3%, and tertile 3 [high]: >86.3%). Nocturnal hypertension was defined as mean nighttime (midnight-6 am) systolic (SBP)/diastolic blood pressure ≥120/70 mm Hg. Nondipping blood pressure was defined as mean nighttime-to-daytime (10 am-8 pm) SBP ratio >0.90. Nocturnal hypertension was present in 57.9% of participants; 66.6% had nondipping blood pressure. The mean age was 59.4 years, 32.8% were male, and 56.0% were taking antihypertensive medication. The prevalence ratios (95% confidence interval) adjusted for age, sex, cardiovascular disease risk factors, and socioeconomic and psychosocial factors comparing participants with moderate and high to those with low percentage West African ancestry for nocturnal hypertension were 0.98 (0.87-1.10) and 0.95 (0.84-1.08), respectively, and for nondipping blood pressure was 0.96 (0.86-1.07) and 0.98 (0.88-1.09), respectively. West African ancestry was not associated with nocturnal hypertension and nondipping blood pressure among African Americans. While rare genetic variants cannot be ruled out, these data highlight the need to better understand how environmental and behavioral factors contribute to differences in nocturnal blood pressure among African Americans compared with European Americans.

Ancestry-Adjusted Vitamin D Metabolite Concentrations in Association With Cytochrome P450 3A Polymorphisms.

We investigated the association between genetic polymorphisms in cytochrome P450 (CYP2R1, CYP24A1, and the CYP3A family) with nonsummer plasma concentrations of vitamin D metabolites (25-hydroxyvitamin D3 (25(OH)D3) and proportion 24,25-dihydroxyvitamin D3 (24,25(OH)2D3)) among healthy individuals of sub-Saharan African and European ancestry, matched on age (within 5 years; n = 188 in each ancestral group), in central suburban Pennsylvania (2006-2009). Vitamin D metabolites were measured using high-performance liquid chromatography with tandem mass spectrometry. Paired multiple regression and adjusted least-squares mean analyses were used to test for associations between genotype and log-transformed metabolite concentrations, adjusted for age, sex, proportion of West-African genetic ancestry, body mass index, oral contraceptive (OC) use, tanning bed use, vitamin D intake, days from summer solstice, time of day of blood draw, and isoforms of the vitamin D receptor (VDR) and vitamin D binding protein. Polymorphisms in CYP2R1, CYP3A43, vitamin D binding protein, and genetic ancestry proportion remained associated with plasma 25(OH)D3 after adjustment. Only CYP3A43 and VDR polymorphisms were associated with proportion 24,25(OH)2D3. Magnitudes of association with 25(OH)D3 were similar for CYP3A43, tanning bed use, and OC use. Significant least-squares mean interactions (CYP2R1/OC use (P = 0.030) and CYP3A43/VDR (P = 0.013)) were identified. A CYP3A43 genotype, previously implicated in cancer, is strongly associated with biomarkers of vitamin D metabolism. Interactive associations should be further investigated.

Abstract B01: Testing a multilevel risk prediction model in high risk men enrolled in a prostate cancer early detection program

Abstract Background: Health disparities play a major role in prostate cancer (PCa). African American (AA) compared to European American (EA) men are twice as likely to die of and be diagnosed with PCa. Multilevel factors from societal/neighborhood exposures down to genetics likely contribute to racial disparities, but few PCa risk prediction models include multilevel factors and consider race/ethnic differences. Objective: We sought to: 1) develop a multilevel risk prediction model for time to PCa diagnosis, that includes neighborhood variables, individual-level socioeconomic and clinical factors (education, race, digital rectal exam or DRE), and biologic variables (prostate specific antigen or PSA level, and percent West African genetic ancestry) in men at high risk for prostate cancer (defined as AA men and/or men with a PCa family history); 2) compare our multilevel model to a more standard prediction model that includes only age, race, PSA, and DRE (abnormal/normal). Methods: A total of 443 high risk, cancer-free men between 35 and 69 years of age with complete socioeconomic, racial, and genetic ancestry data were identified from the Prostate Risk Assessment Program (PRAP) at Fox Chase Cancer Center. Their data were geocoded and linked to 17 neighborhood variables at the census tract level (from the Year 2000 U.S. Census) that were previously associated with advanced PCa in EA men in a novel neighborhood-wide association study(NWAS) our study team developed. These variables generally represent neighborhood transportation, poverty, income, social support, immigration, renting/owning a house, and employment. Men were followed from time of program (PRAP) entry to PCa diagnosis or censoring, with annual follow-up visits that included PSA and DRE screening. Men with elevated PSA or other indications for PCa were referred to Urology for evaluation and potential biopsy according to PRAP protocols. Univariate analyses of neighborhood variables, and the interaction of each variable with PSA and race, were evaluated in Cox regression models, using robust standard errors to adjust for clustering by census tract, in order to inform the final multivariate, multilevel model. Harrell's C Index (C Statistic) was used to compare the multilevel risk prediction model to a standard prediction model. Results: With a median follow-up time of 71 months, PCa diagnosis occurred in 69 participants. The final multilevel risk prediction model included 3 neighborhood variables related to transportation, social support, and poverty, along with education, age, race, baseline PSA, baseline DRE, and PCa family history. Significant interactions between the top hit from the NWAS and PSA were noted in the full study population (neighborhood mode of transportation to work X PSA, p-value&amp;lt;0.001) and within racial subgroups (AA, p-value=0.03; EA, p-value&amp;lt;0.001). Genetic ancestry was not significant in multilevel models. Compared to standard prediction models, multilevel prediction models modestly improved for EA men (C-statistic: 0.80 vs 0.83) and remained relatively constant for AA men (0.86 vs 0.85) and the study population as a whole (0.82 vs. 0.83). Conclusion: This study is the first to investigate the role of neighborhood in PCa risk prediction. While risk prediction models show little change, significant neighborhood effects in multilevel models warrant additional study and could inform future health disparity studies. Citation Format: Shannon M. Lynch, Elizabeth Handorf, Elizabeth Blackman, Lisa Bealin, Shiju Daniel, Veda N. Giri, Elias Obeid, Camille Ragin, Mary B. Daly. Testing a multilevel risk prediction model in high risk men enrolled in a prostate cancer early detection program. [abstract]. In: Proceedings of the AACR Special Conference: Improving Cancer Risk Prediction for Prevention and Early Detection; Nov 16-19, 2016; Orlando, FL. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2017;26(5 Suppl):Abstract nr B01.

The Genetic Contribution of West-African Ancestry to Protection against Central Obesity in African-American Men but Not Women: Results from the ARIC and MESA Studies.

Over 80% of African-American (AA) women are overweight or obese. A large racial disparity between AA and European-Americans (EA) in obesity rates exists among women, but curiously not among men. Although socio-economic and/or cultural factors may partly account for this race-by-sex interaction, the potential involvement of genetic factors has not yet been investigated. Among 2814 self-identified AA in the Atherosclerosis Risk in Communities study, we estimated each individual's degree of West-African genetic ancestry using 3437 ancestry informative markers. We then tested whether sex modifies the association between West-African genetic ancestry and body mass index (BMI), waist-circumference (WC), and waist-to-hip ratio (WHR), adjusting for income and education levels, and examined associations of ancestry with the phenotypes separately in males and females. We replicated our findings in the Multi-Ethnic Study of Atherosclerosis (n = 1611 AA). In both studies, we find that West-African ancestry is negatively associated with obesity, especially central obesity, among AA men, but not among AA women (pinteraction = 4.14 × 10−5 in pooled analysis of WHR). In conclusion, our results suggest that the combination of male gender and West-African genetic ancestry is associated with protection against central adiposity, and suggest that the large racial disparity that exists among women, but not men, may be at least partly attributed to genetic factors.

Interaction of Alu Polymorphisms and Novel Measures of Discrimination in Association with Blood Pressure in African Americans Living in Tallahassee, Florida.

African Americans are 40% more likely to be afflicted with hypertension than are non-Hispanic, white Americans, resulting in a 30% higher instance of mortality due to cardiovascular disease. There is debate about the relative contributions of genetic and sociocultural risk factors to the racial disparity in hypertension. We assayed three Alu insertion polymorphisms located in the ACE (angiotensin 1 converting enzyme), PLAT (plasminogen activator, tissue), and WNK1 (lysine deficient protein kinase 1) genes. We also estimated West African genetic ancestry and developed novel measures of perceived discrimination to create a biocultural model of blood pressure among African American adults in Tallahassee, Florida (n = 158). When tested separately, the ACE Alu noninsertion allele was significantly associated with higher systolic and diastolic blood pressure. In multiple regression analyses, West African genetic ancestry was not associated with blood pressure and reduced the strength of all blood pressure models tested. A gene × environment interaction was identified between the ACE Alu genotype and a new measure of unfair treatment that includes experiences by individuals close to the study participant. Inclusion of the WNK1 Alu genotype further improved this model of blood pressure variation. Our results suggest an association of the ACE and WNK1 genotypes with blood pressure that is consistent with their proposed gene functions. Measures of perceived unfair treatment of others show a threshold effect, with increased blood pressure occurring at higher values. The interaction between the ACE genotype and unfair treatment highlights the benefits of including both genetic and cultural data to investigate complex disease.

Abstract B14: Population genetics analysis of prostate cancer GWAS SNPs to evaluate West African genetic ancestry as a risk factor

Abstract Background: Prostate cancer (Pca) is the most common cancer among men in the U.S., and African American (AA) men have higher incidence compared to European American men. Environmental and sociocultural factors may play a role for increasing Pca risk among AA men, but the causal relationship of any environmental and social/cultural factors with Pca risk is not well demonstrated. On the other hand, there is strong evidence for genetic factors that explain increased incidence in AAs. Admixture mapping identified loci at 8q24 region showing association between African genetic ancestry and Pca risk, and a genome-wide association study (GWAS) in AAs identified a novel locus at 17q21 associated with Pca. However, replication of variants identified in GWAS among European and Asian populations has been difficult in AAs. Here, we performed population genetics analyses of Pca GWAS identified single nucleotide polymorphisms (SNPs) to evaluate whether these SNPs are informative of genetic ancestry and whether West African genetic Ancestry (WAA) is a Pca risk factor. Samples and Methods: We accessed National Human Genome Research Institute GWAS catalog in December, 2012, and there were 80 SNPs reported in 17 studies. We downloaded genotype data of 76 SNPs in 1000 Genomes (1KG) Project Phase I May 2011 and 62 SNPs in Human Genome Diversity Project (HGDP) from SPSmart. We performed principal component analysis using Golden Helix SVS 7. STRUCTURE was also used to estimate genetic ancestry and examine population clustering patterns. Replication study subjects, 470 AA men from Washington, DC (220 Pca cases and 250 controls) were genotyped as a part of GWAS in AAs with Illumina Infinium 1M. Logistic regression analysis was performed adjusting for age and 5 principal components (PCs). Results: Mean heterozygosity of 76 Pca GWAS SNPs in the 1KG Project dataset was lower in African populations than in European populations, possibly due to ascertainment bias. The majority of Pca GWAS SNPs had FST less than 0.20, but rs9623117 on chromosome 22 was highly differentiated (FST=0.63). In the 1KG Project dataset, PC1 separated African populations from non-African populations, and PC2 reflects variation in non-African populations separating East Asian from European populations. AA (ASW) individuals fell between the African and European clusters. Fewer Pca GWAS SNPs were genotyped in HGDP dataset, but they successfully captured global human genome variation forming African and non-African population clusters. In the STRUCTURE analysis with the 1KG project dataset, K=2 separated African from non-African populations, and K=3 separated European from East Asian populations. WAA estimated using 76 Pca GWAS SNPs was significantly correlated with WAA estimated using ancestry informative markers. Only four Pca GWAS SNPs were replicated and three of them were independently associated (P&amp;lt;0.05) in our replication samples. The number of risk alleles were positively associated with Pca risk (PTREND=0.002), and AAs carrying ≥5 risk alleles had 3.5 times greater odds of Pca (95% C.I.; 1.36-9.17; P=0.009) compared to AAs with ≤ 2 risk alleles. Risk allele frequencies of the three independently associated SNPs were higher in West Africans than in Europeans and was positively correlated with WAA estimates (PANOVA&amp;lt;0.001). Conclusion: Results of our analyses provide evidence suggesting that WAA is a risk factor for Pca. Population genetics analyses show that Pca GWAS SNPs can successfully capture global human genome variation and are informative of genetic ancestry. AAs with high WAA are likely to carry more Pca risk alleles than AAs with low WAA. Citation Format: Ken Batai, Ebony Shah, Rick A. Kittles. Population genetics analysis of prostate cancer GWAS SNPs to evaluate West African genetic ancestry as a risk factor. [abstract]. In: Proceedings of the Sixth AACR Conference: The Science of Cancer Health Disparities; Dec 6–9, 2013; Atlanta, GA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2014;23(11 Suppl):Abstract nr B14. doi:10.1158/1538-7755.DISP13-B14

Genetic and environmental influences on plasma vitamin D binding protein concentrations

Recent studies suggest that low vitamin D-binding protein (VDBP aka group-specific complement or Gc) concentrations may be linked with inflammatory-mediated conditions, including asthma, chronic obstructive pulmonary disease, and cancer. However, these studies may be confounded by substantial racial and ethnic or genetic differences. The purpose of this study was to test the hypothesis that circulating VDBP concentrations are significantly associated with genetic ancestry. We used avalidated high-performance liquid chromatography tandem mass spectrometry assay of 25-hydroxyvitamin D3 and its downstream metabolite 24,25-dihydroxyvitamin D3. VDBP concentrations (milligrams per liter) were measured in duplicate using a commercial enzyme-linked immunosorbent assay among healthy African American (n=56) and Caucasian American (n=60) participants. Ancestry informative markers across the genome were used to estimate individual genetic ancestry proportions, designed to robustly distinguish between West African and European ancestry. Genotype-defined Gc isoforms were defined using rs7041 and rs4588 combination groups. VDBP concentration was correlated with both Gc isoform (r=0.93, P<0.001) and West African genetic ancestry (r=-0.66, P<0.001). In the final model, Gc isoform, the catabolic ratio of serum vitamin D, oral contraceptive use, and body mass index remained significantly associated with VDBP concentration, after adjustment for genetic ancestry. Failure to adjust for Gc isoform may lead to spurious associations in studies of VDBP concentration and disease risk, particularly when the condition of interest may also be associated with genetic ancestry. The higher circulating VDBP concentrations and higher vitamin D catabolic rate among Caucasian Americans observed here appear to be consistent with lower bone mineral density and racial and ethnic differences in vitamin D-inducing cytokines.

Identification of genetic risk associated with prostate cancer using ancestry informative markers.

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.

Abstract A67: IL-16 variants associated with prostate cancer risk in African Americans

Abstract Background: Prostate cancer (Pca) is the most common type of cancer among men in the United States, and its disproportionate incidence and mortality rates among ethnic groups are likely due to a combination of genes and environmental factors. While genome-wide association studies (GWASs) of European descents have identified candidate loci associated with Pca risk, including rs4072111 located in IL-16, the replication studies in African Americans (AAs) have been inconsistent, and GWASs have not yet produced many findings to resolve Pca health disparities. IL-16 is over-expressed in tumor cells possibly mediating expression of other cytokines that promote tumor growth. Here we explore SNP variation in IL-16 in AAs and test for association with Pca in AAs. Method: Two hundred and seventy-seven (277) tagging SNPs spanning IL-16 (79.20Mb to 79.45Mb on chromosome 15) were genotyped in 496 AA Pca cases and 501 controls from Washington, DC. In order to replicate our findings, 11 of the SNPs were also typed in additional 400 AA Pca cases and controls from Chicago, IL. One hundred (100) unlinked ancestry informative markers were also typed for each sample. West African genetic ancestry estimates were obtained using STRUCTURE. We tested for allelic association and calculated odds ratios using logistic regression, adjusting for West African ancestry and age. Empiric p-values were obtained by adaptive permutation. Results: Our first stage analyses revealed that a cluster of 20 IL-16 SNPs were significantly associated with Pca risk. The strongest association was found at rs7175701 (P=1.2 × 10−8), which lies within intron 26 of IL-16. In the replication population, two SNPs, slightly linked to rs7175701, but within the 3′UTR region were also strongly associated with Pca risk (P&amp;lt;0.005). Our study provides evidence that IL-16 polymorphisms likely play a role to Pca susceptibility in AAs. Many of the significantly associated SNPs are linked to rs11325 which is a candidate SNP for a miRNA target region in IL-16. Although the exact mechanism is unclear, additional functional studies are warranted. Impact: Our findings are significant given that there has been limited focus on the role of IL-16 genetic polymorphisms on Pca risk in AAs. Understanding the role of cytokines such as IL-16 in tumor growth in diverse populations is important, and could likely lead to the development of useful biomarkers for cancer screening and/or potential therapeutics. Citation Information: Cancer Epidemiol Biomarkers Prev 2011;20(10 Suppl):A67.

Abstract A93: Correlates of total testosterone and testosterone deficiency in African American men

Abstract Introduction: Elevated serum total testosterone (TT) levels have been associated with increased prostate cancer incidence and mortality faced by African American (AA) men. Testosterone deficiency (TD) is linked to several health outcomes including increased cancer and all-cause mortality. Several studies have examined the relationships between TT levels and biochemical and environmental factors, but few have examined these correlates in AA men. This study evaluated TT levels, TD and their correlates in AA men. Methods: Blood samples were collected from 191 controls recruited from 2000–2003 from the Urology clinic at the Howard University Hospital, along with demographic data, reported alcohol use, and BMI. Measurements of testosterone (total and free), prostate specific antigen (PSA), triglycerides (TG), total cholesterol, HDL, VLDL, LDL, IGF1 and IGFBP3 levels were obtained from the blood. Percentage west African genetic ancestry was determined using a panel of 100 ancestry informative markers. Results: On linear regression, age, HDL, LDL and IGFBP3 levels were associated with TT levels (p&amp;lt; 0.05). However, TT levels were not associated with degree of West African ancestry (p = 0.52). Using multivariate analysis, TD deficiency (TT &amp;lt; 300 ng/dL) was positively associated with TG levels (p &amp;lt; 0.05), alcohol use and elevated BMI (p = 0.018 for both). The highest quartile BMI (BMI &amp;gt; 31) was at 2.48 times higher risk for TD than the lowest quartile (&amp;lt; 25). The correlates of TT levels and risk factors for TD in AA men are similar to the established risk factors in European American men. Citation Information: Cancer Epidemiol Biomarkers Prev 2011;20(10 Suppl):A93.

126: Maternal and newborn West African genetic ancestry and the risk of early spontaneous preterm birth

126: Maternal and newborn West African genetic ancestry and the risk of early spontaneous preterm birth