Genetic and Functional Evidence Implicating DLL1 as the Gene That Influences Susceptibility to Visceral Leishmaniasis at Chromosome 6q27

Fakiola, Michaela; Miller, E.N.; Fadl, Manal A.; Mohamed, Hiba S.; Jamieson, Sarra E.; Francis, Richard W.; Cordell, Heather J.; Peacock, Christopher; Raju, Manikandan Vani; Khalil, E. A. G.; Elhassan, Ahmed M.; Musa, Ahmed; Sílveira, Fernando Tobias; Shaw, Jeffrey Jon; Sundar, Shyam; Jerônimo, Selma M. B.; Ibrahim, Muntaser E.; Blackwell, Jenefer M.

doi:10.1093/infdis/jir284

Cited by 15 publications

(15 citation statements)

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“…Clinical VL, in particular, has been associated with high Th2 cytokine responses (Sundar et al, 1997), while Th1-generated interferon-γ is higher in children infected with L. infantum chagasi that do not progress to clinical VL than those who do (Carvalho et al, 1992). The potential for Delta-1 driven Th1 differentiation to alter the course of infection has already been demonstrated for L. major infection in BALB/c mice (Maekawa et al, 2003), making genetic regulation of DLL1 expression a highly plausible explanation for the genetic associations and regulation of splenic expression we previously reported for this 6q27 gene (Fakiola et al, 2011). …”

Section: Introductionmentioning

confidence: 58%

“…Understanding parasite, host and environmental factors that determine asymptomatic infection versus lethal clinical disease is important in disease control. Host genetic factors are known to contribute to disease susceptibility (reviewed (Blackwell et al, 2009)), and in a recent report (Fakiola et al, 2011) we provided genetic and functional evidence to support DLL1, encoding the Delta-like 1 ligand for Notch 3, as the etiological susceptibility gene at the chromosomal region 6q27 previously linked to susceptibility to VL in both Sudan and Brazil (Jamieson et al, 2007; Miller et al, 2007). …”

Section: Introductionmentioning

confidence: 79%

“…The genetic studies undertaken in Sudan and Brazil were limited in terms of sample size and power (Fakiola et al, 2011), making it desirable to determine whether fine mapping of the Chromosome 6q27 region using a well-powered sample would replicate these earlier findings. To achieve this, and to determine the geographical extent of the influence of polymorphism at DLL1 on genetic susceptibility to VL, we turned to the largest global focus of VL in India.…”

Section: Introductionmentioning

confidence: 99%

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Genetic and functional evaluation of the role of DLL1 in susceptibility to visceral leishmaniasis in India

Mehrotra¹,

Fakiola²,

Mishra³

et al. 2012

Infection, Genetics and Evolution

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Chromosome 6q26–27 is linked to susceptibility to visceral leishmaniasis (VL) in Brazil and Sudan. DLL1 encoding the Delta-like 1 ligand for Notch 3 was implicated as the etiological gene. DLL1 belongs to the family of Notch ligands known to selectively drive antigen-specific CD4 T helper 1 cell responses, which are important in protective immune response in leishmaniasis. Here we provide further genetic and functional evidence that supports a role for DLL1 in a well-powered population-based study centred in the largest global focus of VL in India. Twenty-one single nucleotide polymorphisms (SNPs) at PHF10/C6orf70/DLL1/FAM120B/PSMB1/TBP were genotyped in 941 cases and 992 controls. Logistic regression analysis under an additive model showed association between VL and variants at DLL1 and FAM120B, with top associations (rs9460106, OR=1.17, 95%CI 1.01–1.35, P=0.033; rs2103816, OR=1.16, 95%CI 1.01–1.34, P=0.039) robust to analysis using caste as a covariate to take account of population substructure. Haplotype analysis taking population substructure into account identified a common 2-SNP risk haplotype (frequency 0.43; P=0.028) at FAM120B, while the most significant protective haplotype (frequency 0.18; P=0.007) was a 5-SNP haplotype across the interval 5’ of both DLL1 (negative strand) and FAM120B (positive strand) and extending to intron 4 of DLL1. Quantitative RT/PCR was used to compare expression of 6q27 genes in paired pre- and post-treatment splenic aspirates from VL patients (N=19). DLL1 was the only gene to show differential expression that was higher (P<0.0001) in pre- compared to post-treatment samples, suggesting that regulation of gene expression was important in disease pathogenesis. This well-powered genetic and functional study in an Indian population provides evidence supporting DLL1 as the etiological gene contributing to susceptibility to VL at Chromosome 6q27, confirming the potential for polymorphism at DLL1 to act as a genetic risk factor across the epidemiological divides of geography and parasite species.

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Section: Introductionmentioning

confidence: 58%

Section: Introductionmentioning

confidence: 79%

Section: Introductionmentioning

confidence: 99%

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Genetic and functional evaluation of the role of DLL1 in susceptibility to visceral leishmaniasis in India

Mehrotra¹,

Fakiola²,

Mishra³

et al. 2012

Infection, Genetics and Evolution

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“…35 47–53 Antibodies might facilitate the uptake of Leishmania antigen by DC and thereby promote the Th1 response,54 but otherwise are more frequently associated with disease progression 55 56. Dermotropic species and strains of Leishmania parasites (eg, L infantum , L major , L tropica , L aethiopica , L Viannia guyanensis , L Viannia braziliensis , L mexicana, L amazonensis ) cause local skin lesions, whereas systemic disease either results from viscerotropic Leishmania species or strains (eg, L donovani , L infantum ) or from a disturbed cellular immune response 3 11 13 57 58…”

Section: Infection Cycle Pathogenesis and Immunologymentioning

confidence: 99%

Leishmaniasis in rheumatology, haematology and oncology: epidemiological, immunological and clinical aspects and caveats: Figure 1

Bogdan

2012

Ann Rheum Dis

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Leishmaniasis is an intracellular protozoan infection that can lead to cutaneous, mucocutaneous, visceral or systemic manifestations depending on the parasite species and virulence and on the host immune response. It is endemic in countries of Europe (Mediterranean basin), Asia, Africa, Central and South America, but autochthonous cases begin to emerge outside classical disease areas. CD4+ T helper cells, interferon γ, dendritic cells and macrophages are the key components of antileishmanial defence. Leishmaniasis is an important differential diagnosis in patients with chronic lesions of the skin or mucous membranes or with fever, hepatosplenomegaly, lymphadenopathy, pancytopenia, histocytosis, haemophagocytic syndrome or glomerulonephritis. Organ transplant recipients and patients with autoimmune syndromes are at particular risk of developing visceral leishmaniasis following immunosuppressive therapy (eg, with steroids, methotrexate, ciclosporin or tumour necrosis factor-neutralising biological agents). Diagnosis and adequate treatment of leishmaniasis requires the combined use of culture, microscopic and nucleic acid amplication methods and species identification by sequencing and other molecular techniques. Standard regimens for the treatment of visceral leishmaniasis are intravenous liposomal amphotericin B (3 mg/kg body weight for 10 days) or oral miltefosine (150 mg/day for 28 days).

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“…33,35,36 Spatiotemporal and genetic analyses showed clustering of cases in "hot spots" and increased risk of infection and disease in household members of VL cases, underscoring the need for active search of subclinical infections in areas highly endemic for VL. [37][38][39] In a VL endemic focus of Brazil, > 70% of persons were considered to have asymptomatic infections, and around 12% either showed some symptoms of VL or progressed toward overt disease. 35 Asymptomatic infections also could be an important risk factor for recipients of blood and organs from donors inhabiting endemic areas.…”

Section: Discussionmentioning

confidence: 99%

A Novel Molecular Test to Diagnose Canine Visceral Leishmaniasis at the Point of Care

Castellanos-González¹,

Saldarriaga²,

Tartaglino³

et al. 2015

The American Society of Tropical Medicine and Hygiene

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Abstract. Dogs are the principal reservoir hosts of zoonotic visceral leishmaniasis (VL) but current serological methods are not sensitive enough to detect all subclinically infected animals, which is crucial to VL control programs. Polymerase chain reaction (PCR) methods have greater sensitivity but require expensive equipment and trained personnel, impairing its implementation in endemic areas. We developed a diagnostic test that uses isothermal recombinase polymerase amplification (RPA) to detect Leishmania infantum. This method was coupled with lateral flow (LF) reading with the naked eye to be adapted as a point-of-care test. The L. infantum RPA-LF had an analytical sensitivity similar to real time-PCR, detecting DNA of 0.1 parasites spiked in dog blood, which was equivalent to 40 parasites/mL. There was no cross amplification with dog or human DNA or with Leishmania braziliensis, Leishmania amazonensis, or Trypanosoma cruzi. The test also amplified Leishmania donovani strains (N = 7). In a group of clinically normal dogs (N = 30), RPA-LF detected more subclinical infections than rK39 strip test, a standard serological method (50% versus 13.3% positivity, respectively; P = 0.005). Also, RPA-LF detected L. infantum in noninvasive mucosal samples of dogs with a sensitivity comparable to blood samples. This novel molecular test may have a positive impact in leishmaniasis control programs.

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Genetic and Functional Evidence Implicating DLL1 as the Gene That Influences Susceptibility to Visceral Leishmaniasis at Chromosome 6q27

Abstract: DLL1, which encodes Delta-like 1, the ligand for Notch3, is strongly implicated as the chromosome 6q27 VL susceptibility gene.

Cited by 15 publications

References 50 publications

Genetic and functional evaluation of the role of DLL1 in susceptibility to visceral leishmaniasis in India

Genetic and functional evaluation of the role of DLL1 in susceptibility to visceral leishmaniasis in India

Leishmaniasis in rheumatology, haematology and oncology: epidemiological, immunological and clinical aspects and caveats: Figure 1

A Novel Molecular Test to Diagnose Canine Visceral Leishmaniasis at the Point of Care

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