Neutropenia in 6 ethnic groups from the Caribbean and the U.S.

Grann, Victor R.; Bowman, Natalie M.; Joseph, Cecil K.; Wei, Ying; Horwitz, Marshall S.; Jacobson, Judith S.; Santella, Regina P.; Hershman, Dawn L.

doi:10.1002/cncr.23614

Cited by 30 publications

(26 citation statements)

References 21 publications

(35 reference statements)

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“…The Duffy Antigen Receptor for Chemokine ( DARC ) gene, is at least partly responsible for the lower neutrophil counts observed in individuals of African ancestry 6–8 and is associated with resistance to malaria 7 . Several recent genome-wide association studies (GWAS) 9–11 confirmed association of neutrophil counts in people of African descent with single nucleotide polymorphisms in linkage disequilibrium with DARC on chromosome 1q and also identified a locus on chromosome 17q among individuals of European descent, in addition to other genetic regions.…”

Section: Heritability Of Neutrophil Countsmentioning

confidence: 99%

ELANE Mutations in Cyclic and Severe Congenital Neutropenia

Horwitz

Corey

Grimes

et al. 2013

Hematology/Oncology Clinics of North America

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107

103

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There are two main forms of hereditary neutropenia: cyclic and severe congenital neutropenia (SCN). Cyclic neutropenia is an autosomal dominant disorder in which neutrophil counts fluctuate between nearly normal levels and close to zero with 21-day periodicity. In contrast, SCN, also known as Kostmann syndrome, consists of chronic and profound neutropenia, with a characteristic promyelocytic maturation arrest in the bone marrow. Unlike cyclic neutropenia, SCN displays frequent acquisition of somatic mutations in the gene, CSF3R, encoding the Granulocyte Colony-Stimulating Factor Receptor (G-CSFR), and a strong predisposition to developing myelodysplasia (MDS) and/or acute myeloid leukemia (AML). Cyclic neutropenia is caused by heterozygous mutations in the gene, ELANE (formerly known as ELA2), encoding the neutrophil granule serine protease, neutrophil elastase. SCN is genetically heterogeneous, but it is most frequently associated with ELANE mutations. While some of the different missense mutations in ELANE exhibit phenotype-genotype correlation, the same mutations are sometimes found in patients with either form of inherited neutropenia. The mutations lead to production of a mutant polypeptide, but no common biochemical abnormality, including effects on proteolysis, has been identified. Two non-mutually exclusive theories have been advanced to explain how the mutations might produce neutropenia. The mislocalization hypothesis states that mutations within neutrophil elastase or involving other proteins responsible for its intracellular trafficking cause neutrophil elastase to accumulate in inappropriate subcellular compartments. The misfolding hypothesis proposes that mutations prevent the protein from properly folding, thereby inducing the stress response pathway within the endoplasmic reticulum (ER). We discuss how the mutations themselves provide clues into pathogenesis, describe supporting and contradictory observations for both theories, and highlight outstanding questions relating to pathophysiology of neutropenia.

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Section: Heritability Of Neutrophil Countsmentioning

confidence: 99%

ELANE Mutations in Cyclic and Severe Congenital Neutropenia

Horwitz

Corey

Grimes

et al. 2013

Hematology/Oncology Clinics of North America

Self Cite

107

103

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“…There are striking inter-racial differences in white blood cell (WBC) counts, a cellular biomarker. Compared to persons of European ancestry, individuals of African descent have lower WBC counts, attributable mainly to reduced neutrophil counts [125–128]. This hematological condition is referred to as “ethnic leukopenia or neutropenia” [125–129].…”

Section: Mendelian Randomization and Hiv-associated Outcomes: Case Stmentioning

confidence: 99%

Mendelian randomization: potential use of genetics to enable causal inferences regarding HIV-associated biomarkers and outcomes

Castiblanco

Walter³

et al. 2010

Current Opinion in HIV and AIDS

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Purpose of review It is unknown whether biomarkers simply correlate with or are causal for HIV-associated outcomes. Mendelian randomization (MR), is a genetic epidemiologic approach used to disentangle causation from association. Here, we discuss the potential use of MR for differentiating whether biomarkers are correlating with or causal for HIV-associated outcomes. Recent findings MR refers to the random allocation of alleles at the time of gamete formation. In observational epidemiology, this refers to the use of genetic variants to estimate a causal effect between a modifiable risk factor and an outcome of interest. A formal MR study using a genetic marker as a proxy for the biomarker has not been conducted in the HIV field. However, in the post-genomic era this approach is being used increasingly. Examples are evidence for the causal role of body mass index on blood pressure and non-causal role of CRP in coronary heart disease. We discuss the conceptual framework, uses and limitations of MR in the context of HIV infection as well as specific biomarkers (IL-6, CRP) and genetic determinants (e.g., in CCR5, chemokine, and DARC genes) that associate with HIV-related outcomes. Summary Making the distinction between correlation and causality has particular relevance when a biomarker (e.g. IL-6) is potentially modifiable, in which case a biomarker-guided targeted treatment strategy may be feasible. Although the tenets of MR rest on strong assumptions, and conducting an MR study in HIV infection presents many challenges, it may offer the potential to identify causal biomarkers for HIV-associated outcomes.

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“…This possibility is of particular interest because persons of African ancestry, on average, have significantly lower WBC counts, secondary to lower neutrophil cell counts, than persons of European descent. [14][15][16][17] In otherwise healthy persons, low WBC counts in persons of African ancestry are thought to be both genetically determined and benign, as they have not been associated with an increased incidence of bacterial infection. 14 This has resulted in the designation of this condition as "benign ethnic leukopenia or neutropenia."…”

Section: Introductionmentioning

confidence: 99%

“…14 This has resulted in the designation of this condition as "benign ethnic leukopenia or neutropenia." 14,16,17 In light of the preceding discussion, we considered whether differences in WBC counts also result in racial differences in HIV disease outcome. Such an analysis could be confounded by social factors (eg, access to health care, socioeconomic status).…”

Section: Introductionmentioning

confidence: 99%

The Duffy-null state is associated with a survival advantage in leukopenic HIV-infected persons of African ancestry

Kulkarni

Marconi

et al. 2009

Blood

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Persons of African ancestry, on average, have lower white blood cell (WBC) counts than those of European descent (ethnic leukopenia), but whether this impacts negatively on HIV-1 disease course remains unknown. Here, in a large natural history cohort of HIV-infected subjects, we show that, although leukopenia (< 4000 WBC/mm 3 during infection) was associated with an accelerated HIV disease course, this effect was more prominent in leukopenic subjects of European than African ancestry. The Africanspecific ؊46C/C genotype of Duffy Antigen Receptor for Chemokines (DARC) confers the malaria-resisting, Duffy-null phenotype, and we found that the recently described association of this genotype with ethnic leukopenia extends to HIV-infected African Americans (AAs). The association of Duffy-null status with HIV disease course differed according to WBC but not CD4 ؉ T-cell counts, such that leukopenic but not nonleukopenic HIV ؉ AAs with DARC ؊46C/C had a survival advantage compared with all Duffypositive subjects. This survival advantage became increasingly pronounced in those with progressively lower WBC counts. These data highlight that the interaction between DARC genotype and the cellular milieu defined by WBC counts may influence HIV disease course, and this may provide a partial explanation of why ethnic leukopenia remains benign in HIVinfected AAs, despite immunodeficiency.

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Neutropenia in 6 ethnic groups from the Caribbean and the U.S.

Cited by 30 publications

References 21 publications

ELANE Mutations in Cyclic and Severe Congenital Neutropenia

ELANE Mutations in Cyclic and Severe Congenital Neutropenia

Mendelian randomization: potential use of genetics to enable causal inferences regarding HIV-associated biomarkers and outcomes

The Duffy-null state is associated with a survival advantage in leukopenic HIV-infected persons of African ancestry

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