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Homozygosity and risk of childhood death due to invasive bacterial disease.

Lyons EJ, Amos W, Berkley JA, Mwangi I, Shafi M, Williams TN, Newton CR, Peshu N, Marsh K, Scott JA, Hill AV - BMC Med. Genet. (2009)

Bottom Line: At five markers homozygosity was strongly associated with mortality (odds ratio range 4.7 - 12.2) with evidence of interactions between some markers.Balanced polymorphisms appear to be more widespread in humans than previously appreciated and play a critical role in modulating susceptibility to infectious disease.The effect sizes we report, coupled with the stochasticity of exposure to pathogens suggests that infection and mortality are far from random due to a strong genetic basis.

View Article: PubMed Central - HTML - PubMed

Affiliation: The Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford OX3 7BN, UK. e.lyons@imperial.ac.uk

ABSTRACT

Background: Genetic heterozygosity is increasingly being shown to be a key predictor of fitness in natural populations, both through inbreeding depression, inbred individuals having low heterozygosity, and also through chance linkage between a marker and a gene under balancing selection. One important component of fitness that is often highlighted is resistance to parasites and other pathogens. However, the significance of equivalent loci in human populations remains unclear. Consequently, we performed a case-control study of fatal invasive bacterial disease in Kenyan children using a genome-wide screen with microsatellite markers.

Methods: 148 cases, comprising children aged <13 years who died of invasive bacterial disease, (variously, bacteraemia, bacterial meningitis or neonatal sepsis) and 137 age-matched, healthy children were sampled in a prospective study conducted at Kilifi District Hospital, Kenya. Samples were genotyped for 134 microsatellite markers using the ABI LD20 marker set and analysed for an association between homozygosity and mortality.

Results: At five markers homozygosity was strongly associated with mortality (odds ratio range 4.7 - 12.2) with evidence of interactions between some markers. Mortality was associated with different non-overlapping marker groups in Gram positive and Gram negative bacterial disease. Homozygosity at susceptibility markers was common (prevalence 19-49%) and, with the large effect sizes, this suggests that bacterial disease mortality may be strongly genetically determined.

Conclusion: Balanced polymorphisms appear to be more widespread in humans than previously appreciated and play a critical role in modulating susceptibility to infectious disease. The effect sizes we report, coupled with the stochasticity of exposure to pathogens suggests that infection and mortality are far from random due to a strong genetic basis.

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Analysis of variance of standardized observed homozygosity values for cases and controls. SOH is the Standardised Observed Homozygosity for an individual genotyped for i loci, calculated as:  where Nhom is the number of homozygote genotypes in the individual concerned and Hoi is the observed frequency of homozygotes at one of the i loci scored in this individual. ***indicates a highly significant test where P < 1 × 10-5. The IBI + malaria group includes individuals who had invasive bacterial disease but also malaria parasitaemia so that the contribution of the latter to mortality could not be determined with certainty. Sample sizes for the disease classes are as follows: control = 183, bacteraemia = 71, meningitis = 18, neonatal sepsis = 26 and IBI + malaria parasitaemia = 34. IBI: invasive bacterial infection. Error bars are ± 1 standard error.
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Figure 1: Analysis of variance of standardized observed homozygosity values for cases and controls. SOH is the Standardised Observed Homozygosity for an individual genotyped for i loci, calculated as: where Nhom is the number of homozygote genotypes in the individual concerned and Hoi is the observed frequency of homozygotes at one of the i loci scored in this individual. ***indicates a highly significant test where P < 1 × 10-5. The IBI + malaria group includes individuals who had invasive bacterial disease but also malaria parasitaemia so that the contribution of the latter to mortality could not be determined with certainty. Sample sizes for the disease classes are as follows: control = 183, bacteraemia = 71, meningitis = 18, neonatal sepsis = 26 and IBI + malaria parasitaemia = 34. IBI: invasive bacterial infection. Error bars are ± 1 standard error.

Mentions: We first asked whether SOH varied significantly among disease categories by conducting a one-way ANOVA. Raw SOH values exhibit a slightly skewed distribution, but this is removed by a simple log transformation (Shapiro-Wilk normality test, W = 0.9941, p = 0.322). Following transformation, SOH revealed highly significant variation among disease classes (F [5,281] = 6.75, P = 5.89 × 10-6) (Figure 1). However, when the control class was excluded, the ANOVA was no longer significant (F [4,144] = 0.785, P = 0.54), indicating that the main effect is driven by a difference in heterozygosity between cases and controls rather than between disease classes. The direction of the deviation is toward greater homozygosity in cases compared with the controls.


Homozygosity and risk of childhood death due to invasive bacterial disease.

Lyons EJ, Amos W, Berkley JA, Mwangi I, Shafi M, Williams TN, Newton CR, Peshu N, Marsh K, Scott JA, Hill AV - BMC Med. Genet. (2009)

Analysis of variance of standardized observed homozygosity values for cases and controls. SOH is the Standardised Observed Homozygosity for an individual genotyped for i loci, calculated as:  where Nhom is the number of homozygote genotypes in the individual concerned and Hoi is the observed frequency of homozygotes at one of the i loci scored in this individual. ***indicates a highly significant test where P < 1 × 10-5. The IBI + malaria group includes individuals who had invasive bacterial disease but also malaria parasitaemia so that the contribution of the latter to mortality could not be determined with certainty. Sample sizes for the disease classes are as follows: control = 183, bacteraemia = 71, meningitis = 18, neonatal sepsis = 26 and IBI + malaria parasitaemia = 34. IBI: invasive bacterial infection. Error bars are ± 1 standard error.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2714084&req=5

Figure 1: Analysis of variance of standardized observed homozygosity values for cases and controls. SOH is the Standardised Observed Homozygosity for an individual genotyped for i loci, calculated as: where Nhom is the number of homozygote genotypes in the individual concerned and Hoi is the observed frequency of homozygotes at one of the i loci scored in this individual. ***indicates a highly significant test where P < 1 × 10-5. The IBI + malaria group includes individuals who had invasive bacterial disease but also malaria parasitaemia so that the contribution of the latter to mortality could not be determined with certainty. Sample sizes for the disease classes are as follows: control = 183, bacteraemia = 71, meningitis = 18, neonatal sepsis = 26 and IBI + malaria parasitaemia = 34. IBI: invasive bacterial infection. Error bars are ± 1 standard error.
Mentions: We first asked whether SOH varied significantly among disease categories by conducting a one-way ANOVA. Raw SOH values exhibit a slightly skewed distribution, but this is removed by a simple log transformation (Shapiro-Wilk normality test, W = 0.9941, p = 0.322). Following transformation, SOH revealed highly significant variation among disease classes (F [5,281] = 6.75, P = 5.89 × 10-6) (Figure 1). However, when the control class was excluded, the ANOVA was no longer significant (F [4,144] = 0.785, P = 0.54), indicating that the main effect is driven by a difference in heterozygosity between cases and controls rather than between disease classes. The direction of the deviation is toward greater homozygosity in cases compared with the controls.

Bottom Line: At five markers homozygosity was strongly associated with mortality (odds ratio range 4.7 - 12.2) with evidence of interactions between some markers.Balanced polymorphisms appear to be more widespread in humans than previously appreciated and play a critical role in modulating susceptibility to infectious disease.The effect sizes we report, coupled with the stochasticity of exposure to pathogens suggests that infection and mortality are far from random due to a strong genetic basis.

View Article: PubMed Central - HTML - PubMed

Affiliation: The Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford OX3 7BN, UK. e.lyons@imperial.ac.uk

ABSTRACT

Background: Genetic heterozygosity is increasingly being shown to be a key predictor of fitness in natural populations, both through inbreeding depression, inbred individuals having low heterozygosity, and also through chance linkage between a marker and a gene under balancing selection. One important component of fitness that is often highlighted is resistance to parasites and other pathogens. However, the significance of equivalent loci in human populations remains unclear. Consequently, we performed a case-control study of fatal invasive bacterial disease in Kenyan children using a genome-wide screen with microsatellite markers.

Methods: 148 cases, comprising children aged <13 years who died of invasive bacterial disease, (variously, bacteraemia, bacterial meningitis or neonatal sepsis) and 137 age-matched, healthy children were sampled in a prospective study conducted at Kilifi District Hospital, Kenya. Samples were genotyped for 134 microsatellite markers using the ABI LD20 marker set and analysed for an association between homozygosity and mortality.

Results: At five markers homozygosity was strongly associated with mortality (odds ratio range 4.7 - 12.2) with evidence of interactions between some markers. Mortality was associated with different non-overlapping marker groups in Gram positive and Gram negative bacterial disease. Homozygosity at susceptibility markers was common (prevalence 19-49%) and, with the large effect sizes, this suggests that bacterial disease mortality may be strongly genetically determined.

Conclusion: Balanced polymorphisms appear to be more widespread in humans than previously appreciated and play a critical role in modulating susceptibility to infectious disease. The effect sizes we report, coupled with the stochasticity of exposure to pathogens suggests that infection and mortality are far from random due to a strong genetic basis.

Show MeSH
Related in: MedlinePlus