Individuals Of African Ancestry Research Articles

African locus reduces the effect of ApoE ε4 allele in Alzheimer's disease.

Strong associations between ApoE ε4 and Alzheimer disease (AD) risk have been confirmed worldwide, but there is variability in the effect size across populations. African (AF)-descent populations have a lower risk from ApoE ε4 compared to other populations. Studies in admixed populations showed that the AF ancestral background surrounding the ApoE gene reduces the ε4 risk allele effect. Our aim in this study is to identify genetic loci that show a protective effect in AF ancestral background. Primary analyses included imputed data from 6,417 African American (AA) individuals (Kunkle et al. 2020). We estimated global ancestry using a PC-AiR approach that is robust to known and cryptic relatedness. To identify any protective factors interacting with ApoE in the AF local ancestry region, we performed association analyses using a logistic regression model with ApoE ε4 allele as an interaction term and adjusted for genome-wide ancestry, age, and sex. We performed replication analysis using Whole Genome Sequence (WGS) data on 837 African LA ancestry individuals from Ibadan/Nigeria. We identified a locus (rs10423769) that lies within a large cluster of pregnancy specific beta-1 glycoproteins on chromosome 19, ∼ 2 mB from ApoE, with a significant interaction with the ApoE ε4 allele (β=-0.53; SE=0.12;p-value=1.2x10-5 ; FDR adjusted p-value<0.05) in the logistic regression model in the imputed AA samples. We replicated the association in the Nigerian population (β=-1.35; SE=0.52;p-value=9.6x10-3 ). The epistatic interaction reduced the ApoE ε4 allele risk in AD individuals. This study identifies a new locus that reduces the risk effect of ApoE ε4 in AD in AF. rs10423769 is a common allele in AF-descent populations (minor allele frequency (MAF) = 0.12), rare in Europeans (MAF = 0.003) and monomorphic in East Asians. Our results confirm that the AF ancestral background surrounding the ApoE gene harbors protective factors that help mitigate the effect of the detrimental ε4 allele.

Association of low-frequency and rare coding variants with information processing speed

Measures of information processing speed vary between individuals and decline with age. Studies of aging twins suggest heritability may be as high as 67%. The Illumina HumanExome Bead Chip genotyping array was used to examine the association of rare coding variants with performance on the Digit-Symbol Substitution Test (DSST) in community-dwelling adults participating in the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium. DSST scores were available for 30,576 individuals of European ancestry from nine cohorts and for 5758 individuals of African ancestry from four cohorts who were older than 45 years and free of dementia and clinical stroke. Linear regression models adjusted for age and gender were used for analysis of single genetic variants, and the T5, T1, and T01 burden tests that aggregate the number of rare alleles by gene were also applied. Secondary analyses included further adjustment for education. Meta-analyses to combine cohort-specific results were carried out separately for each ancestry group. Variants in RNF19A reached the threshold for statistical significance (p = 2.01 × 10−6) using the T01 test in individuals of European descent. RNF19A belongs to the class of E3 ubiquitin ligases that confer substrate specificity when proteins are ubiquitinated and targeted for degradation through the 26S proteasome. Variants in SLC22A7 and OR51A7 were suggestively associated with DSST scores after adjustment for education for African-American participants and in the European cohorts, respectively. Further functional characterization of its substrates will be required to confirm the role of RNF19A in cognitive function.

Performance of polygenic risk scores for cancer prediction in a racially diverse academic biobank

PurposeGenome-wide association studies have identified hundreds of single nucleotide variations (formerly single nucleotide polymorphisms) associated with several cancers, but the predictive ability of polygenic risk scores (PRSs) is unclear, especially among non-Whites. MethodsPRSs were derived from genome-wide significant single-nucleotide variations for 15 cancers in 20,079 individuals in an academic biobank. We evaluated the improvement in discriminatory accuracy by including cancer-specific PRS in patients of genetically-determined African and European ancestry. ResultsAmong the individuals of European genetic ancestry, PRSs for breast, colon, melanoma, and prostate were significantly associated with their respective cancers. Among the individuals of African genetic ancestry, PRSs for breast, colon, prostate, and thyroid were significantly associated with their respective cancers. The area under the curve of the model consisting of age, sex, and principal components was 0.621 to 0.710, and it increased by 1% to 4% with the inclusion of PRS in individuals of European genetic ancestry. In individuals of African genetic ancestry, area under the curve was overall higher in the model without the PRS (0.723-0.810) but increased by <1% with the inclusion of PRS for most cancers. ConclusionPRS moderately increased the ability to discriminate the cancer status in individuals of European but not African ancestry. Further large-scale studies are needed to identify ancestry-specific genetic factors in non-White populations to incorporate PRS into cancer risk assessment.

Single-Cell and Bulk RNA-Sequencing Reveal Differences in Monocyte Susceptibility to Influenza A Virus Infection Between Africans and Europeans.

There is considerable inter-individual and inter-population variability in response to viruses. The potential of monocytes to elicit type-I interferon responses has attracted attention to their role in viral infections. Here, we use single-cell RNA-sequencing to characterize the role of cellular heterogeneity in human variation of monocyte responses to influenza A virus (IAV) exposure. We show widespread inter-individual variability in the percentage of IAV-infected monocytes. Notably, individuals with high cellular susceptibility to IAV are characterized by a lower activation at basal state of an IRF/STAT-induced transcriptional network, which includes antiviral genes such as IFITM3, MX1 and OAS3. Upon IAV challenge, we find that cells escaping viral infection display increased mRNA expression of type-I interferon stimulated genes and decreased expression of ribosomal genes, relative to both infected cells and those never exposed to IAV. We also uncover a stronger resistance of CD16+ monocytes to IAV infection, together with CD16+ -specific mRNA expression of IL6 and TNF in response to IAV. Finally, using flow cytometry and bulk RNA-sequencing across 200 individuals of African and European ancestry, we observe a higher number of CD16 + monocytes and lower susceptibility to IAV infection among monocytes from individuals of African-descent. Based on these data, we hypothesize that higher basal monocyte activation, driven by environmental factors and/or weak-effect genetic variants, underlies the lower cellular susceptibility to IAV infection of individuals of African ancestry relative to those of European ancestry. Further studies are now required to investigate how such cellular differences in IAV susceptibility translate into population differences in clinical outcomes and susceptibility to severe influenza.

Impact of genetic ancestry on viral infection response.

A study in Science reports the genetic determinants of differences in immune responses to viral infection between individuals of European and African ancestries.

Genetic and Genomic Epidemiology of Stroke in People of African Ancestry.

Stroke is one of the leading causes of disability and death worldwide and places a significant burden on healthcare systems. There are significant racial/ethnic differences in the incidence, subtype, and prognosis of stroke, between people of European and African ancestry, of which only about 50% can be explained by traditional stroke risk facts. However, only a small number of genetic studies include individuals of African descent, leaving many gaps in our understanding of stroke genetics among this population. This review article highlights the need for and significance of including African-ancestry individuals in stroke genetic studies and points to the efforts that have been made towards this direction. Additionally, we discuss the caveats, opportunities, and next steps in African stroke genetics—a field still in its infancy but with great potential for expanding our understanding of stroke biology and for developing new therapeutic strategies.

False-Negative Centromere 15 Probe Results in Association with African Ancestry in Plasma Cell Dyscrasias

Purpose:Multiple myeloma (MM) is a plasma cell (PC) malignancy with an increasing incidence in the United States. Fluorescence in situ hybridization (FISH) is currently the gold-standard diagnostic assay to detect recurrent genomic abnormalities of prognostic and therapeutic significance in MM. Hyperdiploid MM, a standard risk abnormality, is characterized by gains of odd-numbered chromosomes including chromosome 15. While gains of chromosome 15 have been reported in approximately 53% of standard risk MM patients (Chretien, Blood, 2015), losses of chromosome 15 are rarely reported. Enumeration of chromosome 15 centromere is detected using the alpha satellite FISH probe. We previously discovered ~9% of cases had false-negative chromosome 15 FISH results when compared to Mate Pair Sequencing (MPseq) (Smadbeck, BCJ, 2019). To our knowledge, no previous studies have reported a reduced performance of the alpha satellite D15Z4 FISH probe in PC FISH studies. A false-negative result for D15Z4 could result in an underreporting of trisomy 15 and overreporting of monosomy 15. Here, we investigated the incidence of false-negative D15Z4 FISH results by examining the presence of monosomy 15 from patients with a monoclonal gammopathy.Methods:We identified 1231 samples from patients with a monoclonal gammopathy who had undergone uniform testing to identify MM-specific cytogenetic abnormalities. DNA from bone marrow samples was genotyped on the Precision Medicine Research Array and biogeographical ancestry was assessed using the Geographic Population Structure Origins tool (Elhaik, Nat Commun, 2014; Home DNA 2016). FISH of immunoglobulin (cIg)-stained PCs was performed as described (Baughn, BCJ, 2018). Chromosome 15 centromere probe (Vysis CEP 15 D15Z4, Abbott Molecular, Abbott Park, IL) was used for chromosome 15 enumeration. Samples were divided into two groups: Cases with or without evidence of monosomy 15 by FISH. Mann-Whitney U test was applied to compare difference between groups for data deviating from normal distribution. A Chi-squared test evaluating the differences across these two groups was used.Results:We identified monosomy 15 in 31 cases (2.5% of cohort). Monosomy 15 was observed in nearly 100% of both the PC (cIg+) and non-PC (cIg-) populations, by contrast to the other recurrent PC-specific genomic abnormalities which were restricted to only the PC population. All samples with a banded analysis revealed most metaphases had two normal chromosome 15s demonstrating that the D15Z4 FISH probe failed to correctly enumerate the number of chromosome 15 centromere signals. Of the samples with a monosomy 15 result, the median African ancestry was 76.2% (95% percentiles: 77.5%-89.0%), while the median African ancestry of the non-monosomy 15 cohort was 2.3% (95% percentiles: 0%-87.7%) (). Although not all patients with >50% African ancestry had evidence of monosomy 15, 26/31 (83.9%) of patients with monosomy 15 had >50% African ancestry. Accordingly, patients with African ancestry (similarity ≥ 0.70) had 8.02-fold (95% confidence interval: 3.73-17.25, P = 9.92 X10 -8) increased possibility to have monosomy 15. Of cases with monosomy 15, 22 (71.0%) had an IGH rearrangement with the most prevalent IGH partner being CCND1. The incidence of t(11;14) was greater in the monosomy 15 group (13/31:41.9%), in contrast to the non-monosomy 15 group (330/1200=27.5%) (P = 0.12).Conclusions:We report a polymorphic variant of the chromosome 15 centromere resulting in a false-negative FISH result using the D15Z4 FISH probe. Surprisingly, the false-negative FISH result was not uniformly distributed among patients and was highly enriched in individuals of African ancestry. This may be due to a variation of the chromosome 15 alpha satellite in some individuals that prevents the D15Z4 FISH probe from sufficiently binding (O'Keefe, Genome Research, 2000). Although this study focused on identification of monosomy 15, the incidence of a false-negative result is likely greater than we have reported in this study since we did not evaluate cases that had a true trisomy 15 that was reported as normal chromosome 15 enumeration by FISH. This study highlights a critical need to ensure diagnostic reagents have equal performance for all patients independent of their ancestry. Evaluation of genomic events using unbiased approaches such as whole genome sequencing may circumvent some of these limitations. DisclosuresElhaik: DDC: Consultancy. Baird: DDC: Current Employment. Kumar: Antengene: Consultancy, Honoraria; Bluebird Bio: Consultancy; Beigene: Consultancy; BMS: Consultancy, Research Funding; Tenebio: Research Funding; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Research Funding; Novartis: Research Funding; Astra-Zeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Research Funding; KITE: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche-Genentech: Consultancy, Research Funding; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Oncopeptides: Consultancy; Carsgen: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Adaptive: Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Research Funding.

Dietary continuity and change at Panama Viejo from an interdisciplinary perspective, C. 600–1671

The study of food consumption during the colonial period in Panama Viejo traditionally has been based on chronicles and archival documentation. The present analysis reassesses the historical information about diet in this colonial enclave based on microbotanical, isotopic and bioanthropological evidence obtained from the excavations within and outside the remains of the old city’s Cathedral in two locations and four chronological periods to complement and contrast written sources. The ensuing data sets, once integrated, point to the consumption of native plants, particularly maize, among people of different ancestral origins from the settlement’s earliest years, as well as the consumption of wheat – which could not be grown in the region – plantains and rice, whose cultivation was introduced successfully. Stable isotope evidence indicates a shift from dietary strategies based on maize, seafood and terrestrial animal meat in pre-Hispanic and early colonial times to diets featuring more C3 plants, including rice, wheat, and plantains, as well beef and dairy products during the later colonial period. This gradual shift in dietary strategies appears among individuals of Indigenous American, African, European and mixed origins and ancestries, probably influenced by the nutritional and epidemiological stress registered in all of these populations.

APOL1 variants contribute to racial disparity in sepsis.

Genetic variants in apolipoprotein L1 (APOL1) — present only in individuals of African ancestry — contribute to increased susceptibility to sepsis and COVID-19. APOL1 variants impair mitophagy in endothelial cells, allowing the release of mitochondrial DNA that activates inflammasome and nucleotide sensing pathways.

Exome sequencing and analysis of 454,787 UK Biobank participants

A major goal in human genetics is to use natural variation to understand the phenotypic consequences of altering each protein-coding gene in the genome. Here we used exome sequencing1 to explore protein-altering variants and their consequences in 454,787 participants in the UK Biobank study2. We identified 12 million coding variants, including around 1 million loss-of-function and around 1.8 million deleterious missense variants. When these were tested for association with 3,994 health-related traits, we found 564 genes with trait associations at P ≤ 2.18 × 10−11. Rare variant associations were enriched in loci from genome-wide association studies (GWAS), but most (91%) were independent of common variant signals. We discovered several risk-increasing associations with traits related to liver disease, eye disease and cancer, among others, as well as risk-lowering associations for hypertension (SLC9A3R2), diabetes (MAP3K15, FAM234A) and asthma (SLC27A3). Six genes were associated with brain imaging phenotypes, including two involved in neural development (GBE1, PLD1). Of the signals available and powered for replication in an independent cohort, 81% were confirmed; furthermore, association signals were generally consistent across individuals of European, Asian and African ancestry. We illustrate the ability of exome sequencing to identify gene–trait associations, elucidate gene function and pinpoint effector genes that underlie GWAS signals at scale.

Associations of Serum Uric Acid Levels With Macrovascular and Renal Microvascular Dysfunction Among Individuals From Sub-Saharan Africa

Serum uric acid (SUA) level is associated with vascular dysfunction in Eurasian populations, but little is known about this association in individuals from sub-Saharan Africa, who have a high prevalence of both relatively high SUA levels and vascular dysfunction. To assess the associations of SUA levels with macrovascular and kidney microvascular dysfunction in individuals of sub-Saharan African ancestry and evaluate potential factors that could mediate these associations. Cross-sectional analyses of baseline data from the multicenter Research on Obesity and Diabetes Among African Migrants study, conducted from 2012 to 2015, were performed from January to March 2021. The population included Ghanaian individuals living in Ghana and Europe. Abnormal SUA levels. Logistic regression was used to examine the associations of SUA level quartiles with microvascular (albuminuria) and macrovascular (peripheral artery disease and coronary artery disease) dysfunction, with adjustments for age, sex, estimated glomerular filtration rate, site of residence, socioeconomic status, alcohol, smoking, diabetes, hypertension, waist-hip ratio, and total cholesterol level. Mediation analysis was performed to assess whether the association was via elevated blood pressure, hemoglobin A1c, and high-sensitivity C-reactive protein levels or via weight-hip ratio. The research questions were formulated after data collection. A total of 4919 Ghanaian individuals (3047 [61.9%] women) aged 25-75 years (mean [SD], 46.26 [11.08] years) were included. There was a significant positive association between SUA quartiles and albuminuria, but not coronary artery disease or peripheral artery disease, after adjustment for covariates. After full adjustment, individuals in the fourth SUA quartile had higher odds of albuminuria (adjusted odds ratio [aOR], 1.54; 95% CI, 1.07-2.21), but not peripheral artery disease (aOR, 1.35; 95% CI, 0.87-2.08) or coronary artery disease (aOR, 1.09; 95% CI, 0.77-1.55), compared with individuals in the first quartile. After full adjustment, systolic and diastolic blood pressure significantly mediated the association between SUA concentrations and albuminuria, accounting for 19.4% of the total association for systolic and 17.2% for diastolic blood pressure; hemoglobin A1c, high-sensitivity C-reactive protein, and waist-hip ratio did not mediate this association. In this cross-sectional study among a sub-Saharan African population, elevated SUA levels were significantly associated with kidney microvascular dysfunction and mediated partly through elevated blood pressure. These findings suggest that individuals from sub-Saharan Africa with elevated SUA levels may benefit from periodic screening for kidney microvascular dysfunction to aid early detection or treatment.

APOL1 risk variants in individuals of African genetic ancestry drive endothelial cell defects that exacerbate sepsis

The incidence and severity of sepsis is higher among individuals of African versus European ancestry. We found that genetic risk variants (RVs) in the trypanolytic factor apolipoprotein L1 (APOL1), present only in individuals of African ancestry, were associated with increased sepsis incidence and severity. Serum APOL1 levels correlated with sepsis and COVID-19 severity, and single-cell sequencing in human kidneys revealed high expression of APOL1 in endothelial cells. Analysis of mice with endothelial-specific expression of RV APOL1 and invitro studies demonstrated that RV APOL1 interfered with mitophagy, leading to cytosolic release of mitochondrial DNA and activation of the inflammasome (NLRP3) and the cytosolic nucleotide sensing pathways (STING). Genetic deletion or pharmacological inhibition of NLRP3 and STING protected mice from RV APOL1-induced permeability defects and proinflammatory endothelial changes in sepsis. Our studies identify the inflammasome and STING pathways as potential targets to reduce APOL1-associated health disparities in sepsis and COVID-19.

148 Fibrillin-rich microfibrils: Key components of dermal-epidermal junction architecture?

Understanding skin health and disease across global populations is of great importance yet the majority of studies focus primarily on individuals with lightly-pigmented skin. We obtained skin biopsies from photoprotected buttock of healthy, young (18-40 years; n = 33) individuals of black African, South Asian, Hispanic and white European ancestries. Our study cohort demonstrated diversity of pigmentation levels, with skin types ranging from lightest to darkest according to Individual Typology Angle (ITA) – an objective spectrophotometric skin colour classification consisting of 6 groups: ‘very light’; ‘light’; ‘intermediate’; ‘tan’; ‘brown’; and ‘dark’. In the ‘dark’ and ‘brown’ groups, epidermal thickness and dermal-epidermal junction (DEJ) convolution were significantly increased as compared to those in the ‘light’ and ‘very light’ groups, whereas measurements for the ‘tan’ and ‘intermediate’ groups were midway (P < 0.001). Fibrillin-rich microfibrils (FRM) are located at the DEJ in candelabra-like cascades, with concentration at the base of rete pegs. The distribution of FRM was assessed across all skin types; for individuals in ‘dark’ or ‘brown’ groups FRM were significantly more abundant (44.5% and 40.2%, respectively) than those in ‘light’ and ‘very light’ groups (28.6% and 26.9%, respectively), whereas those in the ‘tan’ or ‘intermediate’ groups were midway (33.7% and 30.8%, respectively; P < 0.001). A positive correlation exists between DEJ convolution and FRM abundance (r = 0.379; P < 0.001) suggesting that FRM may contribute to DEJ structure and integrity. This study demonstrates that fundamental differences exist in skin structure and composition in individuals of diverse geographical ancestry and suggest a role for FRM in DEJ architecture.

A randomized, double-blind, placebo-controlled trial of ondansetron for the treatment of cocaine use disorder with post hoc pharmacogenetic analysis

BackgroundCocaine use disorder (CUD) has significant consequences and there remain no FDA-approved pharmacotherapies. Ondansetron is an indirect dopaminergic modulator that has shown efficacy in alcohol use disorder, particularly in phenotypic and genotypic subgroups, and was found to be efficacious in a pilot dose-finding trial for CUD. MethodsOne-hundred eight (108) adults with CUD were randomized to ondansetron 4 mg twice daily or placebo for 9 weeks and assessed up to thrice weekly to evaluate self-reported cocaine use and urine benzoylecgonine. Participants received cognitive-behavioral therapy and brief behavioral compliance enhancement therapy. Consenting participants (N = 79) provided blood samples for exploratory pharmacogenetic analyses. ResultsParticipants in both arms reduced cocaine use over time, but there was no statistically significant difference on percentage of cocaine-free days (PCFD; p = 0.972) or percentage of cocaine-free urine samples (PCFU; p = 0.909). Participants with early-onset CUD had greater improvement regardless of study arm (p = 0.002). Post hoc pharmacogenetic analyses demonstrated an interaction effect between treatment and rs1176713 SNP on PCFU in the total sample (p = 0.040) and African ancestry subset (p = 0.03). Constipation, fatigue, and somnolence were more common among ondansetron-treated participants (Fisher exact p < 0.05). Those who developed constipation were mostly rs1176713:GG carriers (Fisher exact p = 0.029). ConclusionsOndansetron did not demonstrate efficacy in the treatment of CUD. However, these preliminary results suggest a genotype-based variance in response to ondansetron in African ancestry individuals with CUD. Further studies are needed to validate findings for developing a personalized genomic approach for CUD treatment in racially and ethnically diverse populations.

Surveillance for hepatocellular carcinoma in people of African ancestry with HIV and Hepatitis B.

Current guidelines recommend six-monthly ultrasound surveillance for hepatocellular carcinoma (HCC) in high risk, non-cirrhotic people with HIV and hepatitis B co-infection (HBV). African or Asian ethnicity is considered a risk factor for the development of HCC. Risk stratification scores for HCC have been generated in HBV mono-infected Caucasian and Asian populations, however they not been validated in people with HIV or those of African ancestry. We undertook an audit of HCC surveillance in HIV/HBV co-infected individuals of African ancestry who participated in the GEN-AFRICA study. Electronic patient records were reviewed for liver disease characteristics. REACH-B and PAGE-B scores were calculated to ascertain whether individuals at greatest risk of developing HCC were being targeted for ultrasound surveillance. 76 individuals (median age 51years, 96% HIV RNA < 200 copies/mL, 87% HBV DNA <20IU/mL) were included. 7% of participants had undergone six-monthly HCC surveillance by liver ultrasound (5% of those at low risk; 9% at intermediate or high risk). Adherence to HCC surveillance was poor and not targeted to those at highest risk. Lack of an evidence base for intensive HCC screening of non-cirrhotic, HIV/HBV co-infected individuals of African ancestry may have contributed to the poor uptake of biannual HCC ultrasound surveillance.

MP60-06 PROSTATE: INCORPORATING GENETIC ANCESTRY IN PROSTATE CANCER RISK SCORES FOR MEN OF AFRICAN DESCENT

You have accessJournal of UrologyProstate Cancer: Markers (MP60)1 Sep 2021MP60-06 PROSTATE: INCORPORATING GENETIC ANCESTRY IN PROSTATE CANCER RISK SCORES FOR MEN OF AFRICAN DESCENT Joshua Linscott, Meghana Pagadala, Hannah Carter, Matthew Hayn, Moritz Hansen, Jesse Sammon, Karim Kader, and Stephen Ryan Joshua LinscottJoshua Linscott More articles by this author , Meghana PagadalaMeghana Pagadala More articles by this author , Hannah CarterHannah Carter More articles by this author , Matthew HaynMatthew Hayn More articles by this author , Moritz HansenMoritz Hansen More articles by this author , Jesse SammonJesse Sammon More articles by this author , Karim KaderKarim Kader More articles by this author , and Stephen RyanStephen Ryan More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000002095.06AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Prostate cancer (PrCa) is the most heritable of the solid organ malignancies. In addition, incidence and aggressive phenotypes are higher in African American men. Prior research into genetic heritability has focused on ancestry as defined by the patient. We explored ancestral genetic backgrounds with forensic genetic tools to define and develop a polygenic risk score (PRS) in African Americans. METHODS: Single nucleotide polymorphisms (SNPs) were imputed from a PrCa case-control study of >99,000 men (ELLIPSE) using the Michigan Imputation Server, 1000 Genomes Project, Eaglev2.3. Ancestral likelihood ratios were calculated by Forensic Research Reference on Genetics (FROG)-kb based on a previously described 55-SNP panel and define genetically separate African and European cohorts. GWAS was performed to identify PrCa risk SNPs and PRSice 2.3.1 to develop a PRS. An 80:20 split training:testing groups was used with AUC and ROC analysis. RESULTS: FROG-kb identified 4,507 and 5,334 individuals of African and European ancestry, respectively (Figure 1). In the African group, 6 SNPs reached significance, 1 on chromosome 1, 4 on chromosome 8, and 1 on chromosome 11. Four SNPs unique to African ancestry, were used to create a PRS. Individually, family history (FH), age, and PRS achieved AUCs of 0.56, 0.54, and 0.60 respectively. Combined PRS, FH, and Age improved AUC to 0.64 (Figure 2). CONCLUSIONS: A 55-SNP panel identified genetic ancestral groups for GWAS analysis, which defined 4 PrCa associated SNPs specific to African genetic inheritance. The resulting PRS predicted PrCa better than FH and Age in African American men. A combined model performs similar to previously published studies in European cohorts. Here we have achieved comparable AUC using only 4 SNPs, in a group at higher risk for aggressive PrCa. Source of Funding: none © 2021 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 206Issue Supplement 3September 2021Page: e1043-e1043 Advertisement Copyright & Permissions© 2021 by American Urological Association Education and Research, Inc.MetricsAuthor Information Joshua Linscott More articles by this author Meghana Pagadala More articles by this author Hannah Carter More articles by this author Matthew Hayn More articles by this author Moritz Hansen More articles by this author Jesse Sammon More articles by this author Karim Kader More articles by this author Stephen Ryan More articles by this author Expand All Advertisement Loading ...

HIV Viremia Is Associated With APOL1 Variants and Reduced JC-Viruria.

Variants in the Apolipoprotein L1 (APOL1) gene (G1-rs60910145, rs73885319, G2-rs71785313) are common in Africans and in individuals of recent African ancestry and are associated with an increased risk of non-diabetic chronic kidney disease (CKD) and in particular of HIV associated nephropathy (HIVAN). In light of the significantly increased risk of HIVAN in carriers of two APOL1 risk alleles, a role in HIV infectivity has been postulated in the mechanism of APOL1 associated kidney disease. Herein, we aim to explore the association between HIV viremia and APOL1 genotype. In addition, we investigated interaction between BK and JC viruria, CKD and HIV viremia. A total of 199 persons living with HIV/AIDS (comprising 82 CKD cases and 117 controls) from among the participants in the ongoing Human Heredity and Health in Africa (H3Africa) Kidney Disease Research Network case control study have been recruited. The two APOL1 renal risk alleles (RRA) genotypes were associated with a higher risk of CKD (OR 12.6, 95% CI 3.89–40.8, p < 0.0001). Even a single APOL1 RRA was associated with CKD risk (OR 4.42, 95% CI 1.49–13.15, p = 0.007). The 2 APOL1 RRA genotypes were associated with an increased probability of having HIV viremia (OR 2.37 95% CI 1.0–5.63, p = 0.05). HIV viremia was associated with increased CKD risk (OR 7.45, 95% CI 1.66–33.35, P = 0.009) and with a significant reduction of JC virus urine shedding (OR 0.35, 95% CI 0.12–0.98, p = 0.046). In contrast to prior studies, JC viruria was not associated with CKD but was restricted in patients with HIV viremia, regardless of CKD status. These findings suggest a role of APOL1 variants in HIV infectivity and emphasize that JC viruria can serve as biomarker for innate immune system activation.

Congenital limb deficiency: Genetic investigation of 44 individuals presenting mainly longitudinal defects in isolated or syndromic forms.

Congenital limb deficiency (CLD), one of the most common congenital anomalies, is characterized by hypoplasia/aplasia of one or more limb bones and can be isolated or syndromic. The etiology in CLD is heterogeneous, including environmental and genetic factors. A fraction remains with no etiological factor identified. We report the study of 44 Brazilian individuals presenting isolated or syndromic CLD, mainly with longitudinal defects. Genetic investigation included particularly next-generation sequencing (NGS) and/or chromosomal microarray. The overall diagnostic yield was 45.7%, ranging from 60.9% in the syndromic to 16.7% in the non-syndromic group. In TAR syndrome, a common variant in 3´UTR of RBM8A, in trans with 1q21.1 microdeletion, was detected, corroborating the importance of this recently reported variant in individuals of African ancestry. NGS established a diagnosis in three individuals in syndromes recently reported or still under delineation (an acrofacial dysostosis, Coats plus and Verheij syndromes), suggesting a broader phenotypic spectrum in these disorders. Although a low rate of molecular detection in non-syndromic forms was observed, it is still possible that variants in non-coding regions and small CNVs, not detected by the techniques applied in this study, could play a role in the etiology of CLD.

Genetic underpinnings of regional adiposity distribution in African Americans: Assessments from the Jackson Heart Study.

African ancestry individuals with comparable overall anthropometric measures to Europeans have lower abdominal adiposity. To explore the genetic underpinning of different adiposity patterns, we investigated whether genetic risk scores for well-studied adiposity phenotypes like body mass index (BMI) and waist circumference (WC) also predict other, less commonly measured adiposity measures in 2420 African American individuals from the Jackson Heart Study. Polygenic risk scores (PRS) were calculated using GWAS-significant variants extracted from published studies mostly representing European ancestry populations for BMI, waist-hip ratio (WHR) adjusted for BMI (WHRBMIadj), waist circumference adjusted for BMI (WCBMIadj), and body fat percentage (BF%). Associations between each PRS and adiposity measures including BF%, subcutaneous adiposity tissue (SAT), visceral adiposity tissue (VAT) and VAT:SAT ratio (VSR) were examined using multivariable linear regression, with or without BMI adjustment. In non-BMI adjusted models, all phenotype-PRS were found to be positive predictors of BF%, SAT and VAT. WHR-PRS was a positive predictor of VSR, but BF% and BMI-PRS were negative predictors of VSR. After adjusting for BMI, WHR-PRS remained a positive predictor of BF%, VAT and VSR but not SAT. WC-PRS was a positive predictor of SAT and VAT; BF%-PRS was a positive predictor of BF% and SAT only. These analyses suggest that genetically driven increases in BF% strongly associate with subcutaneous rather than visceral adiposity and BF% is strongly associated with BMI but not central adiposity-associated genetic variants. How common genetic variants may contribute to observed differences in adiposity patterns between African and European ancestry individuals requires further study.

Advanced cancers amongst individuals of African ancestry exhibit an almost five-fold higher prevalence of high-risk HPV types not covered by the current 9-valent vaccine

<h3>Objectives:</h3> Among women with high-risk human papillomavirus (hrHPV) detected in cervical swabs, the distribution of hrHPV types is known to differ by racial/ethnic group, with East and West Africans and North Americans of African ancestry1 showing overrepresentation of hrHPV types that are not covered by the current 9-valent HPV vaccine. Possible downstream consequences in ethno-specific rates of aggressive hrHPV-related cancers, however, have not been systematically examined. Here, we surveyed a large, multiethnic database of aggressive cancers for non-9-valent-vaccine hrHPV types in association with individual ancestry data. <h3>Methods:</h3> Our archive of 290,311 unique advanced cancer samples underwent comprehensive genomic profiling (CGP) using a hybrid-capture-based DNA sequencing platform. We detected hrHPV genomic sequences in 1,690 cervical, 1,196 anogenital, and 1,380 head and neck cancers by <i>de novo</i> assembly of nonhuman reads, followed by alignment to the RefSeq database, which distinguishes hrHPV types. Patient ancestry was determined by classifying specific SNPs by CGP based on their known variation among populations in the 1000 Genomes Project. Quantitative data were analyzed using the Fisher exact test. A two-tailed P value of <.05 was considered statistically significant; the Bonferroni correction was applied for multiple simultaneous comparisons. <h3>Results:</h3> We identified four non-vaccine hrHPV types with >10 cancer cases each: HPV35 (n=71 cases), HPV51 (n=11), HPV59 (n=42), and HPV67 (n=12). Among patients whose cancers harbored hrHPV types that are covered by the 9-valent vaccine (here, HPV16, 18, 31, 33, 45, 52, and 58), 7.5% (308/4,131) were of African ancestry, lower than the overall representation of African ancestry in our database (9.1% [26,471/290,311]). In contrast, among cases with non-9-valent-vaccine hrHPV types, we identified several-fold enrichment for individuals of African ancestry (HPV35: 24% of African ancestry [17/71], HPV51: 27% [3/11], HPV59: 43% [18/42], HPV67: 25% [3/12]). In total, these four non-vaccine hrHPV types accounted for 11.4% (40/350) of all hrHPV-related advanced cancers in persons of African ancestry, but only 2.4% (95/3928) of hrHPV-related advanced cancers in individuals of other ancestries, a difference of nearly five-fold (p<0.00001, Table 1). Genomic alterations and tumor mutational burden showed no significant differences based on hrHPV type or patient ancestry, suggesting similar tumorigenic mechanisms. <h3>Conclusions:</h3> In our pan-hrHPV analysis of advanced cancers, hrHPV types not covered by the current 9-valent vaccine are strikingly increased in individuals of African ancestry. Our data strongly indicate a need to re-evaluate the choice of hrHPV types to include in the vaccine, as well as a need to re-evaluate the underlying process by which hrHPV types are chosen for inclusion.