scholarly journals Two genetic variants explain the association of European ancestry with multiple sclerosis risk in African-Americans

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Nathan Nakatsuka ◽  
Nick Patterson ◽  
Nikolaos A. Patsopoulos ◽  
Nicolas Altemose ◽  
Arti Tandon ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
African American ◽  
African Americans ◽  
Odds Ratio ◽  
African Ancestry ◽  
Epidemiological Studies ◽  
Chromosome 1 ◽  
European Ancestry ◽  
Increased Risk ◽  
West Africans

Abstract Epidemiological studies have suggested differences in the rate of multiple sclerosis (MS) in individuals of European ancestry compared to African ancestry, motivating genetic scans to identify variants that could contribute to such patterns. In a whole-genome scan in 899 African-American cases and 1155 African-American controls, we confirm that African-Americans who inherit segments of the genome of European ancestry at a chromosome 1 locus are at increased risk for MS [logarithm of odds (LOD) = 9.8], although the signal weakens when adding an additional 406 cases, reflecting heterogeneity in the two sets of cases [logarithm of odds (LOD) = 2.7]. The association in the 899 individuals can be fully explained by two variants previously associated with MS in European ancestry individuals. These variants tag a MS susceptibility haplotype associated with decreased CD58 gene expression (odds ratio of 1.37; frequency of 84% in Europeans and 22% in West Africans for the tagging variant) as well as another haplotype near the FCRL3 gene (odds ratio of 1.07; frequency of 49% in Europeans and 8% in West Africans). Controlling for all other genetic and environmental factors, the two variants predict a 1.44-fold higher rate of MS in European-Americans compared to African-Americans.

scholarly journals Vitamin D deficiency increases prostatic megalin expression and globulin-bound testosterone import, increasing prostatic androgens in African American men

2021 ◽  
Author(s):  
Jason Garcia ◽  
Kirsten Krieger ◽  
Candice Loitz ◽  
Lillian M Perez ◽  
Zachary A Richards ◽  
...  
Keyword(s):  
Vitamin D ◽  
African American ◽  
African Americans ◽  
Vitamin D Deficiency ◽  
African American Men ◽  
African Ancestry ◽  
Serum Vitamin ◽  
Vitamin D Metabolites ◽  
Increased Risk ◽  
Vitamin D Levels

Vitamin D deficiency associates with an increased risk of prostate cancer (PCa) mortality and is hypothesized to contribute to PCa aggressiveness and disparities in African Americans. We reported a relationship between African-ancestry, circulating and intraprostatic vitamin D metabolites and prostatic expression of megalin, an endocytic membrane receptor that internalizes globulin-bound hormones. Here, we show that megalin imports sex hormone-binding globulin (SHBG)-bound testosterone, potentially regulating intraprostatic hormone levels. Vitamin D levels regulated megalin expression in cell lines, patient-derived prostate epithelial cells, and prostate tissue explants, and mice with prostatic knockout of Lrp2 (megalin) showed reduced prostatic testosterone. Notably, prostatic 5α-dihydrotestosterone levels were higher in African American men and correlated inversely with serum vitamin D status, while megalin protein levels were reduced in PCa tissue. Our findings highlight the negative impact of vitamin D deficiency on PCa and the potential link to PCa disparities observed in African Americans.

Abstract 16819: Sequencing of Genetic Loci Associated With Leukocyte Telomere Length Reveals New Intronic Variants in African Americans

Circulation ◽  
2015 ◽  
Vol 132 (suppl_3) ◽  
Author(s):  
Rasika Mathias ◽  
Kruthika Iyer ◽  
Margaret Taub ◽  
Lisa Yanek ◽  
Diane Becker ◽  
...  
Keyword(s):  
African Americans ◽  
Telomere Length ◽  
Risk Score ◽  
Genetic Risk Score ◽  
African Ancestry ◽  
Whole Genome Sequence ◽  
European Ancestry ◽  
Leukocyte Telomere Length ◽  
Increased Risk ◽  
Intronic Variants

Background: Shorter telomere length is associated with an increased risk of coronary artery disease (CAD). A prior genomewide association study (GWAS) on 37,684 European ancestry individuals identified seven loci determining leukocyte telomere length (LTL). A genetic risk score across all 7 loci showed an association with CAD. In this study we sequenced these loci to determine whether the same risk variants could be replicated in African admixed individuals. Methods: We used whole genome sequence data (WGS) in 127 healthy African American subjects from GeneSTAR, a family study of early-onset CAD. LTL was calculated from WGS raw bam data (>30x coverage on the Illumina HiSeq platform) for 7 contiguous repeats of the telomere motif (TTAGGG or CCCTAA, Ding et al., 2014). Tests for association for LTL adjusting for age and sex were performed for a total of 55,821 called variants from ~1Mb subset regions of WGS genotype data centered on each of the 7 European peak GWAS SNPs. Results: We identified a total of 17 variants with p<5x10 -4 mapping to 6 of the 7 regions examined; none of the prior European GWAS peak SNPs were significant. The peak SNP per region in the African Americans included intronic variants rs77138331 in ACYP2 (p=0.0005, MAF = 7%), rs149577640 in NAF1 (p=0.002, MAF=1%), rs35387865 in TERT (p=0.003, MAF = 1%) and rs186486116 in OBFC1 (p=0.004, MAF=1%). Additionally, novel intronic variants not previously observed in dbSNP located at chr19: 22190184 (p=0.005, MAF=1%) and chr2:62445438 (0.005, MAF=2%), mapping to ZNF208 and RTEL1 , were also identified as determinants of LTL. Discussion: This is the first study of telomere length in African Americans using a sequencing approach. We are unable to confirm the European-based GWAS variants but identify several associations mapping to genes of importance in telomere biology. Our results provide evidence that the set of SNPs to be included in calculation of a telomeric genetic CAD risk score may be different in populations of European and African ancestry.

scholarly journals The genetic diversity of multiple sclerosis risk among Hispanic and African American populations living in the United States

2019 ◽  
Vol 26 (11) ◽  
pp. 1329-1339 ◽  
Author(s):  
AH Beecham ◽  
L Amezcua ◽  
A Chinea ◽  
CP Manrique ◽  
C Rubi ◽  
...  
Keyword(s):  
United States ◽  
Multiple Sclerosis ◽  
African American ◽  
African Americans ◽  
Genetic Risk ◽  
Statistical Power ◽  
Genetic Risk Score ◽  
The United States ◽  
European Ancestry ◽  
Risk Scores

Background: Substantial progress has been made toward unraveling the genetic architecture of multiple sclerosis (MS) within populations of European ancestry, but few genetic studies have focused on Hispanic and African American populations within the United States. Objective: We sought to test the relevance of common European MS risk variants outside of the major histocompatibility complex ( n = 200) within these populations. Methods: Genotype data were available on 2652 Hispanics (1298 with MS, 1354 controls) and 2435 African Americans (1298 with MS, 1137 controls). We conducted single variant, pathway, and cumulative genetic risk score analyses. Results: We found less replication than statistical power suggested, particularly among African Americans. This could be due to limited correlation between the tested and causal variants within the sample or alternatively could indicate allelic and locus heterogeneity. Differences were observed between pathways enriched among the replicating versus all 200 variants. Although these differences should be examined in larger samples, a potential role exists for gene–environment or gene–gene interactions which alter phenotype differentially across racial and ethnic groups. Cumulative genetic risk scores were associated with MS within each study sample but showed limited diagnostic capability. Conclusion: These findings provide a framework for fine-mapping efforts in multi-ethnic populations of MS.

scholarly journals Genome-wide admixture mapping of eGFR and CKD identify European and African ancestry-of-origin loci in U.S. Hispanics/Latinos

2021 ◽  
Author(s):  
Andrea R.V.R. Horimoto ◽  
Jianwen Cai ◽  
James P. Lash ◽  
Martha L. Daviglus ◽  
Nora Franceschini ◽  
...  
Keyword(s):  
African Americans ◽  
Complex Traits ◽  
African Ancestry ◽  
Genetic Ancestry ◽  
European Ancestry ◽  
Health Study ◽  
Admixture Mapping ◽  
Chromosome 14 ◽  
Genome Wide ◽  
Increased Risk

Background Admixture mapping is a powerful approach for gene mapping of complex traits that leverages the diverse genetic ancestry in populations with recent admixture such as U.S. Hispanics/Latinos (HL), who have increased risk of chronic kidney disease (CKD). Methods Genome-wide admixture mapping was performed for CKD and estimated glomerular filtration rate (eGFR) in a sample of 12601 participants from the Hispanic Community Health Study/Study of Latinos, with validation in a sample of 8191 African Americans from the Women's Health Initiative (WHI). Results Three novel ancestry-of-origin loci were identified on chromosomes 2, 14 and 15 for CKD and eGFR. The chromosome 2 locus (2p16.3) consisted of two European ancestry regions encompassing the FSHR and NRXN1 genes, with European ancestry at this locus associated with increased risk for CKD. The chromosome 14 locus (14q32.2) located within the DLK1-DIO3 imprinted domain was driven by European ancestry, and was associated with lower eGFR. The chromosome 15 locus (15q13.3-14) included intronic variants of RYR3 and was within an African-specific genomic region that was associated with higher eGFR. These findings were compared to the conventional genome-wide association study that failed to identify significant associations in these regions. We validated the chromosome 14 and 15 loci for eGFR in the WHI African Americans. Conclusions This study provides evidence of shared ancestry-specific genomic regions influencing eGFR in HL and African Americans, and illustrates the potential for leveraging genetic ancestry in recently admixed populations for novel discovery of kidney trait loci.

Abstract 050: Fine-mapping and Bioinformatics Characterization of QT Interval Loci in African Americans: The Population Architecture Using Genomics and Epidemiology (PAGE) Study

Circulation ◽  
2012 ◽  
Vol 125 (suppl_10) ◽  
Author(s):  
Christy L Avery ◽  
Praveen Sethupathy ◽  
Steven Buyske ◽  
Q. C He ◽  
Dan Y Lin ◽  
...  
Keyword(s):  
African American ◽  
African Americans ◽  
Fine Mapping ◽  
Qt Interval ◽  
Functional Characterization ◽  
Regulatory Elements ◽  
European Ancestry ◽  
Functional Evaluation ◽  
Human Cardiomyocytes

The QT interval (QT) is a heritable trait and its prolongation is an established risk factor for ventricular tachyarrhythmia and sudden cardiac death. Most genetic studies of QT have examined populations of European ancestry, although the increased genetic diversity in populations of African descent provides opportunity for fine-mapping, which can help narrow association signals and identify candidates for functional characterization. We examined whether eleven previously identified QT loci comprising 6,681 variants on the Illumina Metabochip array were associated with QT in 7,516 African American participants from the Atherosclerosis Risk in Communities study and Women’s Health Initiative clinical trial. Among associated loci, we used conditional analyses and queried bioinformatics databases to identify and functionally categorize signals. We identified nine of the eleven QT loci in African American populations ( P <0.0045 under an additive genetic model adjusting for ancestry and demographic characteristics: NOS1AP, ATP1B1, SCN5A, SLC35F1, KCNH2, KCNQ1, LITAF, NDRG4, and RFFL ). We also identified two independent secondary signals in NOS1AP and ATP1B1 ( P < 7.4x10 −6 ). Conditional analyses adjusting for published loci in European populations demonstrated that eight of these eleven SNPs (nine primary; two secondary) were independent of previously reported SNPs. We then performed the first bioinformatics-based functional characterization of QT loci using the eleven primary and secondary variants and SNPs in strong LD (r 2 > 0.5) among these African American participants. Only the SCN5A locus included a non-synonymous coding variant (rs1805124, H558R, r 2 = 0.7 with primary SNP rs9871385, P = 4.7x10 −4 ). The remaining ten loci harbored variants located exclusively within non-coding regions. Specifically, three contained SNPs within candidate long-range regulatory elements in human cardiomyocytes, five were in or near annotated promoter regions, and the remaining two were in un-annotated, but highly conserved non-coding elements. Several of the QT risk alleles at these SNPs significantly alter the predicted binding affinity for transcription factors, such as TBX5 and AhR, which have been previously implicated in cardiac formation and function. In summary, the findings provide compelling evidence that the same genes influence variation in QT across global populations and that additional, independent signals exist in African Americans. Moreover, of those SNPs identified as strong candidates for functional evaluation, the majority implicate gene regulatory dysfunction in QT prolongation.

Depressive symptoms in a treated multiple sclerosis cohort

2003 ◽  
Vol 9 (6) ◽  
pp. 616-620 ◽  
Author(s):  
Scott B Patten ◽  
Shanika Fridhandler ◽  
Cynthia A Beck ◽  
Luanne M Metz
Keyword(s):  
Multiple Sclerosis ◽  
Depressive Symptoms ◽  
Interferon Beta ◽  
Rating Scale ◽  
Epidemiological Studies ◽  
Treatment Groups ◽  
Increased Risk ◽  
The University ◽  
Depression Ratings

Background: Recent side effect data from clinical trials of interferon beta in multiple sclerosis (MS) have failed to confirm that these medications are associated with an increased risk of depression. However, these studies have used highly selected samples and the results may not be generalizable to real world settings. Methods: C linical data on subjects from southern A lberta who have applied for, or are receiving, public reimbursement for MS treatment are maintained in a database at the University of C algary Multiple Sclerosis C linic. Depression ratings obtained using the C enter for Epidemiological Studies Depression Rating Scale (C ES-D) are included in this database. In the current analysis, these longitudinal data were used to determine whether depressive symptoms were associated with disease-modifying treatments. Results: A t baseline, ratings were available for 163 subjects. Those choosing interferon beta resembled those choosing glatiramer acetate in most respects. During follow-up, no differences were observed in the prevalence or incidence of depression and C ES-D scores were not found to differ between the treatment groups. Conclusions: The failure to identify higher rates of depression both in previous intervention studies and in the current observational study provides confirmation that these drugs are not substantially associated with the occurrence of depression.

scholarly journals The Effect of Biracial Status and Color on Crystallized Intelligence in the U.S.-Born African–European American Population

Psych ◽  
2019 ◽  
Vol 1 (1) ◽  
pp. 44-54
Author(s):  
John Fuerst ◽  
Richard Lynn ◽  
Emil Kirkegaard
Keyword(s):  
African Americans ◽  
Cognitive Ability ◽  
African Ancestry ◽  
Significant Negative Correlation ◽  
European Ancestry ◽  
European American ◽  
Crystallized Intelligence ◽  
Black And White ◽  
Nationally Representative ◽  
Sub Saharan

The relationship between biracial status, color, and crystallized intelligence was examined in a nationally representative sample of adult Black and White Americans. First, it was found that self-identifying biracial individuals, who were found to be intermediate in color and in self-reported ancestry, had intermediate levels of crystallized intelligence relative to self-identifying White (mostly European ancestry) and Black (mostly sub-Saharan African ancestry) Americans. The results were transformed to an IQ scale: White (M = 100.00, N = 7569), primarily White–biracial (M = 96.07, N = 43, primarily Black–biracial (M = 94.14 N = 50), and Black (M = 89.81, N = 1381). Next, among self-identifying African Americans, a statistically significant negative correlation of r = −0.102 (N = 637) was found between interviewer-rated darker facial color and vocabulary scores. After correction for the reliability of the measures, this correlation increased to r = −0.21. Corrections for the validity of color as an index of African ancestry would raise this correlation to around r = −0.48. This association among self-identifying African Americans was not accounted for by confounding factors, such as region of residence and interviewer race, or by parental socioeconomic status and individual educational attainment. In the multivariate models, the standardized betas for color and crystallized intelligence among African Americans ranged from β = −0.112 to β = −0.142. Based on the coefficients from the multivariate analysis, it was further found that cognitive ability was a significant mediator in the context of color and education, while education was not in the context of color and cognitive ability. It is concluded that these results further substantiate the statistical relation between intelligence and biogeographic ancestry in African and European American populations.

ABCA7, a Genetic Risk Factor Associated with Alzheimer’s Disease Risk in African Americans

2022 ◽  
pp. 1-15
Author(s):  
Kaitlyn E. Stepler ◽  
Taneisha R. Gillyard ◽  
Calla B. Reed ◽  
Tyra M. Avery ◽  
Jamaine S. Davis ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
African American ◽  
Amyloid Beta ◽  
Disease Risk ◽  
African Ancestry ◽  
European Ancestry ◽  
Black Adults ◽  
American Black ◽  
The Impact

African American/Black adults are twice as likely to have Alzheimer’s disease (AD) compared to non-Hispanic White adults. Genetics partially contributes to this disparity in AD risk, among other factors, as there are several genetic variants associated with AD that are more prevalent in individuals of African or European ancestry. The phospholipid-transporting ATPase ABCA7 (ABCA7) gene has stronger associations with AD risk in individuals with African ancestry than in individuals with European ancestry. In fact, ABCA7 has been shown to have a stronger effect size than the apolipoprotein E (APOE) ɛ4 allele in African American/Black adults. ABCA7 is a transmembrane protein involved in lipid homeostasis and phagocytosis. ABCA7 dysfunction is associated with increased amyloid-beta production, reduced amyloid-beta clearance, impaired microglial response to inflammation, and endoplasmic reticulum stress. This review explores the impact of ABCA7 mutations that increase AD risk in African American/Black adults on ABCA7 structure and function and their contributions to AD pathogenesis. The combination of biochemical/biophysical and ‘omics-based studies of these variants needed to elucidate their downstream impact and molecular contributions to AD pathogenesis is highlighted.

Abstract 15312: Racial Disparities in Trends in Mortality From Cardiac Arrests in the United States

Circulation ◽  
2020 ◽  
Vol 142 (Suppl_3) ◽  
Author(s):  
Anas M Al Zubaidi ◽  
Graham Bevan ◽  
Mariam Rana ◽  
Abdul Rahman Al Armashi ◽  
Mustafa Alqaysi ◽  
...  
Keyword(s):  
United States ◽  
Cardiac Arrest ◽  
African American ◽  
African Americans ◽  
Cause Of Death ◽  
Census Data ◽  
International Classification Of Diseases ◽  
The United States ◽  
Population Based ◽  
Increased Risk

Background: African Americans are at increased risk of fatal cardiac arrests, but population-based studies exploring contemporary epidemiology are not available. We sought to identify the trend in race-specific mortality from cardiac arrest in the United States. Methods: Using the multiple cause of death database, we identified all patients (Caucasians or African Americans) who died of cardiac arrest (International Classification of Diseases, 10th revision code I46.x listed as underlying cause of death) between 1999 and 2018. Age-adjusted mortality rates were standardized to the 2000 US census data, and stratified by age group (<35 years, 35-64 years, and ≥ 65 years). Results: A total of 311,065 cardiac arrest deaths were identified, with an overall age-adjusted mortality of 53.6 per million (Caucasian: 49.1 per million, African American: 90.6 per million). Overall, age-adjusted mortality decreased from 80.1 per million persons (1999) to 44.3 per million persons (2012), followed by 8.8% increase to 48.2 (2018). Between 2012 and 2018, African Americans had higher rates of increase (10.9%) compared with Caucasians (6.9%). Largest disparities in relative changes between 2012 and 2018 occurred in patients younger than 35 years (African American: 35%, Caucasians -11%), and patients ≥ 65 years (African Americans: 8%, Caucasians 4%), figure. Conclusions: Although the mortality due to cardiac arrest has declined in the US between 1999 and 2012, a recent increase has been noted between 2012 and 2018, particularly among younger African Americans. Studies should focus on identifying causes of disparities and identifying methods to reduce the racial gap.

scholarly journals Cardiovascular Outcomes in African Americans with Sickle Cell Trait and Chronic Kidney Disease

2019 ◽  
Vol 49 (2) ◽  
pp. 93-102 ◽  
Author(s):  
Kabir O. Olaniran ◽  
Nwamaka D. Eneanya ◽  
Andrew S. Allegretti ◽  
Sophia H. Zhao ◽  
Maureen M. Achebe ◽  
...  
Keyword(s):  
Chronic Kidney Disease ◽  
African American ◽  
Cardiovascular Risk ◽  
African Americans ◽  
Kidney Disease ◽  
Sickle Cell ◽  
Sickle Cell Trait ◽  
Increased Risk ◽  
The Mean

Background: Sickle cell trait (SCT) is common among African Americans and has been historically considered to be benign. Recently, SCT has been associated with an increased risk for chronic kidney disease (CKD) and cardiovascular disease in the general population. Our understanding of SCT has been extrapolated largely from data of patients with sickle cell disease (SCD). Notably, in SCD, the outcomes differ by sex. The effect of SCT on cardiovascular risk in the African American CKD population is unknown, and the interaction between SCT and sex on cardiovascular risk has not been investigated. Methods: We performed a 2-center retrospective cohort study of all African American patients with SCT using international classification of disease diagnosis codes and CKD (using the 2012 Kidney Disease Improving Global Outcomes criteria) with at least 1 year of follow-up between January 2005 and December 2017. A reference group of ­African American CKD patients without SCT was used as a comparator during the same period. SCT patients and the reference patients were matched at baseline for age, sex, comorbidities, and proteinuria. Primary outcomes were incident coronary artery disease (CAD), incident stroke, and all-cause mortality. Analysis of effect modification between sex and SCT on primary outcomes was performed. Results: We identified 621 African American CKD patients, 217 SCT patients, and 404 reference patients. The mean age was 56 ± 13 years and 66% were female. The mean estimated glomerular filtration rate was 69 ± 30 mL/min. The mean follow-up time was 8 ± 4 years. There were no significant differences in the primary outcomes comparing SCT patients to matched controls. The interaction term between SCT and sex, however, was significant in the CAD model (p < 0.01). Stratification by sex showed no increased risk in females but a significantly increased risk for CAD in male SCT patients (hazard ratio [HR] 2.14; 95% CI 1.18–3.86), which persisted after multivariable analysis (HR 2.13; 95% CI 1.17–3.86). Conclusion: SCT is associated with an increased risk for CAD in African American males with CKD. The excess risk in males with SCT appears to follow the same pattern as risk in males with SCD. Larger studies are needed to confirm these findings.

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