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Analyses of genome wide association data, cytokines, and gene expression in African-Americans with benign ethnic neutropenia.

ABSTRACT: Background: Benign ethnic neutropenia (BEN) is a hematologic condition associated with people of African ancestry and specific Middle Eastern ethnic groups. Prior genetic association studies in large population showed that rs2814778 in Duffy Antigen Receptor for Chemokines (DARC) gene, specifically DARC null red cell phenotype, was associated with BEN. However, the mechanism of this red cell phenotype leading to low white cell count remained elusive.

Methods: We conducted an extreme phenotype design genome-wide association study (GWAS), analyzed ~16 million single nucleotide polymorphisms (SNP) in 1,178 African-Americans individuals from the Reasons for Geographic and Racial Differences in Stroke (REGARDS) study and replicated from 819 African-American participants in the Atherosclerosis Risk in Communities (ARIC) study. Conditional analyses on rs2814778 were performed to identify additional association signals on chromosome 1q22. In a separate cohort of healthy individuals with and without BEN, whole genome gene expression from peripheral blood neutrophils were analyzed for DARC.

Results: We confirmed that rs2814778 in DARC was associated with BEN (p = 4.09×10-53). Conditioning on rs2814778 abolished other significant chromosome 1 associations. Inflammatory cytokines (IL-2, 6, and 10) in participants in the Howard University Family Study (HUFS) and Multi-Ethnic Study in Atherosclerosis (MESA) showed similar levels in individuals homozygous for the rs2814778 allele compared to others, indicating cytokine sink hypothesis played a minor role in leukocyte homeostasis. Gene expression in neutrophils of individuals with and without BEN was also similar except for low DARC expression in BEN, suggesting normal function. BEN neutrophils had slightly activated profiles in leukocyte migration and hematopoietic stem cell mobilization pathways (expression fold change <2).

Conclusions: These results in humans support the notion of DARC null erythroid progenitors preferentially differentiating to myeloid cells, leading to activated DARC null neutrophils egressing from circulation to the spleen, and causing relative neutropenia. Collectively, these human data sufficiently explained the mechanism DARC null red cell phenotype causing BEN and further provided a biologic basis that BEN is clinically benign.

SUBMITTER: Charles BA

PROVIDER: S-EPMC5875757 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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Analyses of genome wide association data, cytokines, and gene expression in African-Americans with benign ethnic neutropenia.

Charles Bashira A BA Hsieh Matthew M MM Adeyemo Adebowale A AA Shriner Daniel D Ramos Edward E Chin Kyung K Srivastava Kshitij K Zakai Neil A NA Cushman Mary M McClure Leslie A LA Howard Virginia V Flegel Willy A WA Rotimi Charles N CN Rodgers Griffin P GP

PloS one 20180329 3

<h4>Background</h4>Benign ethnic neutropenia (BEN) is a hematologic condition associated with people of African ancestry and specific Middle Eastern ethnic groups. Prior genetic association studies in large population showed that rs2814778 in Duffy Antigen Receptor for Chemokines (DARC) gene, specifically DARC null red cell phenotype, was associated with BEN. However, the mechanism of this red cell phenotype leading to low white cell count remained elusive.<h4>Methods</h4>We conducted an extreme ...[more]

PMID: 29596498

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Project description:Genome-wide association studies of obesity have typically assumed fixed genetic effects across ethnicities, rarely attempting to thoroughly compare and contrast findings across various ethnic groups. Therefore, our study aimed to identify novel genetic associations with body mass index (BMI), a common measure of obesity, and explore their cross-ethnic generalizability in a multiethnic population. To that end, we conducted ?ethnic-specific genome-wide association analyses among 1235 Hispanic, 706 Asian, 1549 African American, and 2395 European American subjects from the Multi-ethnic Study of Atherosclerosis (MESA). We compared findings ?across ethnicities and investigated single-nucleotide polymorphisms (SNPs) with suggestive BMI-association p-values among 3379 Hispanic and 6871 African American subjects from the Women's Health Initiative (WHI).We identified a genome-wide significant association in MESA Hispanics-rs12253976 in KLF6 (beta?=?5.792 kg/m(2) per-allele, 95 % confidence interval (CI): 3.885, 7.698; p?=?3.43?×?10(-9))-and suggestive SNPs with p?<?5?×?10(-6) in MESA Hispanics, European Americans and African Americans that display ethnic-specific effects on BMI. Of these suggestive SNPs, Hispanic SNP rs12255372 and African American SNP rs6435678 had the most evidence of replication in WHI. rs12255372 (in TCF7L2) was associated with lower BMI in both MESA (beta?=?-1.111 kg/m(2), 95 % CI: -1.578, -0.645; p?=?3.33?×?10(-6)) and WHI Hispanics (beta?=?-0.304 kg/m(2), 95 % CI: -0.613, 0.006; p?=?0.054). This TCF7L2 intronic region contains several SNPs (rs7901695, rs4506565, rs4132670, and rs12243326) with low p-values (p < 10(-3)) in MESA and betas of similar magnitude and direction in MESA and WHI, but only rs12243326 is in strong linkage disequilibrium with rs12255372 in our Hispanic populations, suggesting independent signals in this region. rs6435678 (in ERBB4) was associated with greater BMI in both MESA (beta?=?1.104 kg/m(2), 95 % CI: 0.643, 1.564; p?=?2.85?×?10(-6)) and WHI African Americans (beta?=?0.219 kg/m(2), 95 % CI: -0.021, 0.460; p?=?0.074).Two BMI-association signals are present in the TCF7L2 intronic region of Hispanics, one of which is tagged by rs12255372. ERBB4 rs6435678 is a novel BMI-association signal in African Americans. Overall, our data suggest that ethnic-specific associations are involved in the genetic determination of BMI. Ethnic-specificity has potential implications for the development of gene-based therapies for obesity.

Project description:Benign ethnic neutropenia (BEN) is defined as a neutrophil count of <1.5×109 cells/L in healthy individuals and is more common in populations of certain ethnicities, e.g. African or Middle Eastern ethnicity. Neutrophil values are commonly included in eligibility criteria for research participation, but little is known about the relationship between BEN, HIV acquisition, and the occurrence of adverse events during clinical trials. We investigated these relationships using data from an HIV vaccine efficacy trial of healthy adults from 5 South African sites. We analysed data from the double-blind, placebo-controlled, randomized trial HVTN 503, and its follow-on study HVTN 503-S to assess the prevalence of BEN, its association with HIV infection, and adverse event reporting. These data were then compared with a time- and age-matched, non-pregnant cohort from the National Health and Nutrition Examination Survey (NHANES) conducted between 2007-2008 in the United States (US). The 739 South African participants had a median age of 22.0 years (interquartile range = 20-26) and 56% (n = 412) were male. Amongst the US cohort of 845 participants, the median age was 26 (IQR: 21-30) and the majority (54%, 457/745) were also male. BEN was present at enrolment in 7.0% (n = 52) of South African participants (6% in the placebo group versus 8% in the vaccine group); 81% (n = 42) of those with BEN were male. Pretoria North had the highest prevalence of BEN (11.6%, 5/43), while Cape Town had the lowest (0.7%, 1/152). Participants with BEN had a lower median neutrophil count (1.3 vs. 3.2x109 cells/L; p<0.001) and BMI (20.8 vs. 22.3 kg/m2; p<0.001) when compared to those without BEN. A greater proportion of Black South Africans had neutrophil counts <1.5×109 cells/L compared to US non-Hispanic Whites from the NHANES cohort (7% [52/739] vs. 0.6% [3/540]; p<0.001). BEN did not increase the odds for HIV infection (adjusted odds ratio [aOR]: 1.364, 95% confidence interval [95% CI]: 0.625-2.976; p = 0.4351). However, female gender (aOR: 1.947, 95% CI: 1.265-2.996; p = 0.0025) and cannabis use (aOR: 2.192, 95% CI: 1.126-4.266; p = 0.0209) increased the odds of HIV acquisition. The incidence rates of adverse events were similar between participants in the placebo group with BEN, and those without: 12.1 (95% CI: 7.3-20.1) vs. 16.5 (95% CI: 14.6-18.7; p = 0.06) events per 100 person-years (py) were noted in the infections and infestations system organ class, respectively. The vaccine group had an event incidence rate of 19.7 (95% CI: 13.3-29.2) vs. 14.8 (95% CI: 13.0-16.8; p = 0.07) events per 100py in the group with, and without BEN, respectively. BEN is more prevalent in Black South Africans compared to US Non-Hispanic Whites. Our data do not support excluding populations from HIV vaccine trials because of BEN. BEN was not associated with increased risk for HIV infection or Adverse events on a vaccine trial. Predictors of HIV infection risk were females and cannabis use, underlying the continued importance of prevention programmes in focusing on these populations.

Dataset Information

Analyses of genome wide association data, cytokines, and gene expression in African-Americans with benign ethnic neutropenia.

Publications

Analyses of genome wide association data, cytokines, and gene expression in African-Americans with benign ethnic neutropenia.

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