Protective effects of the sickle cell gene against malaria morbidity and mortality

Aidoo, Michael; Terlouw, Dianne J.; Kolczak, Margarette S.; McElroy, Peter D.; Kuile, Feiko O. ter; Kariuki, Simon; Nahlen, Bernard L.; Lal, Altaf A.; Udhayakumar, Venkatachalam

doi:10.1016/s0140-6736(02)08273-9

Cited by 568 publications

(432 citation statements)

References 4 publications

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“…Frequencies of the heterozygous state for the sickle cell gene (HbAS) range from 2% to 38% in sub-Saharan Africa where HbS allele frequencies frequently exceed 25% [14,16,40]. Sickle-cell trait is the best described host-specific factor shown to confer strong protection against P. falciparum in numerous studies over the course of the last 50 years [41,42,43,44].…”

Section: Discussionmentioning

confidence: 99%

Analysis of malaria associated genetic traits in Cabo Verde, a melting pot of European and sub Saharan settlers

Alves¹,

Machado²,

Silva³

et al. 2010

Blood Cells, Molecules, and Diseases

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Section: Discussionmentioning

confidence: 99%

Analysis of malaria associated genetic traits in Cabo Verde, a melting pot of European and sub Saharan settlers

Alves¹,

Machado²,

Silva³

et al. 2010

Blood Cells, Molecules, and Diseases

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“…Convincing demonstrations of overdominance have been provided for a small number of human genes including glucose-6-phosphate dehydrogenase, 53 hemoglobin-b, 54 the cystic fibrosis transmembrane conductance regulator, 55 a member of the interleukin-1 family (IL1F5) 48 and the Kidd blood group antigen gene; 23 in all these cases, the responsible selective pressure is thought to be accounted for by an infectious agent. 56 Our data indicate that balancing selection maintaining two major lineages at the MEFV ex5ÀUTR region is likely due to overdominance in Caucasians and AS; indeed, a number of heterozygotes higher than expected is observed in these populations and in the case of EAs the deviation we observed for MEFV is the most extreme in the set of NIEHS genes (Figure 3).…”

Section: Discussionmentioning

confidence: 99%

“…56 Our data indicate that balancing selection maintaining two major lineages at the MEFV ex5ÀUTR region is likely due to overdominance in Caucasians and AS; indeed, a number of heterozygotes higher than expected is observed in these populations and in the case of EAs the deviation we observed for MEFV is the most extreme in the set of NIEHS genes (Figure 3). Overdominance might stem from different effects; in the case of G6PD and HBB mutations, for example, heterozygotes are partially protected from malaria; 53,54 alternatively, heterozygotes might experience increased immune response flexibility by modulating allele-specific gene expression in different cell types 57 and in response to diverse stimuli/cytokines. 58 This effect possibly applies to the promoter regions of DEFB1, 51 CCR5 47 and FUT2 23 and might be more likely to apply when balanced polymorphisms are maintained in regulatory (rather than coding) regions, as is the case of MEFV.…”

Section: Discussionmentioning

confidence: 99%

A population genetics study of the Familial Mediterranean Fever gene: evidence of balancing selection under an overdominance regime

et al. 2009

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Familial Mediterranean Fever (FMF) is a recessively inherited systemic autoinflammatory disease caused by mutations in the MEFV gene. The frequency of different disease alleles is extremely high in multiple populations from the Mediterranean region, suggesting heterozygote advantage. Here, we characterize the sequence variation and haplotype structure of the MEFV 3 0 gene region (from exon 5 to the 3 0 UTR) in seven human populations. In non-African populations, we observed high levels of nucleotide variation, an excess of intermediate-frequency alleles, reduced population differentiation and a genealogy with two common haplotypes separated by deep branches. These features are suggestive of balancing selection having acted on this region to maintain one or more selected alleles. In line with this finding, an excess of heterozygotes was observed in Europeans and Asians, suggesting an overdominance regime. Our data, together with the earlier demonstration that the MEFV exon 10 has been subjected to episodic positive selection over primate evolution, provide evidence for an adaptive role of nucleotide variation in this gene region. Our data suggest that further studies aimed at clarifying the role of MEFV variants might benefit from the integration of molecular evolutionary and functional analyses.

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“…Compared to both wild type (HbA) and mutant (HbS) homozygotes, heterozygotes (HbAS) are protected from the high mortality associated with severe infection [3,4]. Over several generations this can lead to high population frequencies of the HbS allele.…”

Section: Introductionmentioning

confidence: 99%

Predicted declines in sickle allele frequency in Jamaica using empirical data

Hanchard¹,

Hambleton²,

Harding³

et al. 2006

Am. J. Hematol.

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The high frequency of the sickle allele in some parts of Africa is understood to be a consequence of high malarial endemicity. One corollary of this is that the sickle allele frequency should be declining in populations of African ancestry that are no longer exposed to malaria. We have previously shown that there has been no change in sickle allele frequency in malaria-free Jamaica between two large-scale neonatal screening exercises conducted in 1973-1981 and 1995-2003. To evaluate the determinants of, and derive expected values for, sickle allele frequency in Jamaica, local empirical data were used to estimate the parameters of deterministic models of allele frequency decline. We found that although model predictions were broadly consistent with observed values in the 1973-1981 cohort, the predicted change in allele frequency between the two cohorts was larger than the observed, nonsignificant, reduction. Close agreement between predicted and observed values was only achieved by simulating a recent, marked increase in HbSS fitness. Thus, the \unexpected" persistence of the sickle allele in Jamaica may reflect the fact that the actual fitness among SS individuals is higher than that previously realized. If true, our models suggest that without substantial changes in current screening and counseling practice, there will be little \natural" reduction in sickle allele frequency for several hundred years. Better estimates of relative fitness will be helpful in refining these predictions and may aid in assigning health care priorities in Jamaica and the African Diaspora. Am. J. Hematol. 81:817-823, 2006. V V C 2006 Wiley-Liss, Inc.

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Protective effects of the sickle cell gene against malaria morbidity and mortality

Cited by 568 publications

References 4 publications

Analysis of malaria associated genetic traits in Cabo Verde, a melting pot of European and sub Saharan settlers

Analysis of malaria associated genetic traits in Cabo Verde, a melting pot of European and sub Saharan settlers

A population genetics study of the Familial Mediterranean Fever gene: evidence of balancing selection under an overdominance regime

Predicted declines in sickle allele frequency in Jamaica using empirical data

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