Heritability Analysis of Cytokines as Intermediate Phenotypes of Tuberculosis

Stein, Catherine M.; Guwatudde, David; Nakakeeto, Margaret; Peters, Pierre; Elston, Robert C.; Tiwari, Hemant; Mugerwa, Roy D.; Whalen, Christopher C.

doi:10.1086/375249

Cited by 56 publications

(56 citation statements)

References 38 publications

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“…Our results are in line with published data of TNF-␣ heritabilities with a high degree of genetic determination between 0.6 and 0.8 for TNF-␣ (12,18,19). For IFN-␥ a pedigree study from a community in Uganda with a high prevalence of tuberculosis has reported a heritability of 0.4 (19).…”

Section: Discussionsupporting

confidence: 92%

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A Genetic Basis for IFN-γ Production and T-bet Expression in Humans

Hawranek¹,

Reuss²,

Adams³

et al. 2005

The Journal of Immunology

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Th1 and Th2 cytokines secreted by polarized effector T cells play a pivotal role in the development of autoimmune and allergic diseases. However, the genetic basis of cytokine production by T lymphocytes in humans is poorly understood. In this study, we investigated the genetic contribution to cytokine production and regulation of T cell-specific transcription factors in a prospective twin study. We found a substantial genetic contribution to the production of Th1 cytokines such as IFN-γ and TNF-α with heritabilities of 0.85 (95% confidence intervals, 0.74–0.95) and 0.72 (0.50–0.93), respectively, whereas no genetic influence on production of the Th2 signature cytokine IL-4 was observed. Furthermore, the intrapair variability in IFN-γ production by isolated T cells was lower in monozygotic than in dizygotic twins. In contrast to GATA-3, NFAT, and NF-κB, intrapair variability of T-bet, the master transcription factor of Th1 cells, was very low among monozygotic and high among dizygotic twins, indicative of a strong genetic influence on T-bet (heritability 0.93, 95% confidence interval, 0.84–1.0). Our data provide novel insights into the genetic regulation of human Th cell polarization. These data suggest that signature cytokines and cytokine signaling events of Th1 rather than Th2 cells are genetically determined and implicate that Th2-associated diseases in humans might be due to genetic variations in Th1 cytokine regulation via T-bet. This concept is highlighted by the recent finding that inactivation of the T-bet gene in mice results in development of clinical hallmark features of asthma.

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Section: Discussionsupporting

confidence: 92%

“…Heritability of cytokine production has been investigated in a few pedigree studies, including mostly relatives of diseased subjects (12,18,19). Our results are in line with published data of TNF-␣ heritabilities with a high degree of genetic determination between 0.6 and 0.8 for TNF-␣ (12,18,19).…”

Section: Discussionsupporting

confidence: 89%

A Genetic Basis for IFN-γ Production and T-bet Expression in Humans

Hawranek¹,

Reuss²,

Adams³

et al. 2005

The Journal of Immunology

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“…The reasons for ineligibility were as follows: death of one or both twins at or shortly after birth (92), residence outside study area (101) and BCG vaccine given by hospital staff before enrolment (22). Of the 345 eligible pairs, 297 (86%) were enrolled.…”

Section: Resultsmentioning

confidence: 99%

“…Of the 345 eligible pairs, 297 (86%) were enrolled. Reasons for nonenrolment were refusal (22) and no traceable address (26). All twin pairs lived together for the duration of the study.…”

Section: Resultsmentioning

confidence: 99%

“…However, with the exception of HLA, none have been shown definitively to have a role in the regulation of variation in polygenic immune responses at the population level. 20,21 Although studies in adults indicate a potential role for the genetic regulation of immune responses, 22 the genetic contribution to the regulation of immune responses in early human life has never been quantified. Since the immune system in early life is in a state of maturation, the relative contribution of host genes is likely to differ significantly from that observed in adults.…”

Section: Introductionmentioning

confidence: 99%

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Genetic regulation of immune responses to vaccines in early life

et al. 2004

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Infant immunization is the most cost-effective strategy to prevent infectious diseases in childhood, but is limited by immaturity of the immune system. To define strategies to improve vaccine immunogenicity in early life, the role of genetic and environmental factors in the control of vaccine responses in infant twins was studied. Immune responses to BCG, polio, hepatitis B, diphtheria, pertussis and tetanus vaccines were measured at 5 months of age in 207 Gambian twin pairs recruited at birth. Intrapair correlations for monozygous and dizygous pairs were compared to estimate the environmental and genetic components of variation in responses. High heritability was observed for antibody (Ab) responses to hepatitis B (77%), oral polio (60%), tetanus (44%) and diphtheria (49%) vaccines. Significant heritability was also observed for interferon-g and interleukin-13 responses to tetanus, pertussis and some BCG vaccine antigens (39-65%). Non-HLA genes played a dominant role in responses to Ab-inducing vaccines, whereas responses to BCG were predominantly controlled by genes within the HLA class II locus. Genetic factors, particularly non-HLA genes, significantly modulate immune responses to infant vaccination. The identification of the specific genes involved will provide new targets for the development of vaccines and adjuvants for young infants that work independently of HLA.

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