A Comparison of Case‐Control and Family‐Based Association Methods: The Example of Sickle‐Cell and Malaria

Ackerman, Hans; Usen, Stanley; Jallow, Muminatou; Sisay-Joof, Fatou; Pinder, Margaret; Kwiatkowski, Dominic P.

doi:10.1111/j.1529-8817.2005.00180.x

Cited by 76 publications

(55 citation statements)

References 12 publications

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“…HbS carriers are strongly protected against severe malaria (2,4,8,67). This clearly supports that there is a significant impact of malaria in selecting HbS as a protective allele, despite the deleterious effect of HbS at the homozygous state.…”

Section: Erythrocyte Polymorphisms and Severe Malariasupporting

confidence: 62%

Host susceptibility to malaria in human and mice: compatible approaches to identify potential resistant genes

Hernandez-Valladares¹,

Rihet

Iraqi

2014

Physiological Genomics

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Hernandez-Valladares M, Rihet P, Iraqi FA. Host susceptibility to malaria in human and mice: compatible approaches to identify potential resistant genes. Physiol Genomics 46: 1-16, 2014. First published October 29, 2013 doi:10.1152/physiolgenomics.00044.2013.-There is growing evidence for human genetic factors controlling the outcome of malaria infection, while molecular basis of this genetic control is still poorly understood. Case-control and family-based studies have been carried out to identify genes underlying host susceptibility to malarial infection. Parasitemia and mild malaria have been genetically linked to human chromosomes 5q31-q33 and 6p21.3, and several immune genes located within those regions have been associated with malaria-related phenotypes. Association and linkage studies of resistance to malaria are not easy to carry out in human populations, because of the difficulty in surveying a significant number of families. Murine models have proven to be an excellent genetic tool for studying host response to malaria; their use allowed mapping 14 resistance loci, eight of them controlling parasitic levels and six controlling cerebral malaria. Once quantitative trait loci or genes have been identified, the human ortholog may then be identified. Comparative mapping studies showed that a couple of human and mouse might share similar genetically controlled mechanisms of resistance. In this way, char8, which controls parasitemia, was mapped on chromosome 11; char8 corresponds to human chromosome 5q31-q33 and contains immune genes, such as Il3, Il4, Il5, Il12b, Il13, Irf1, and Csf2. Nevertheless, part of the genetic factors controlling malaria traits might differ in both hosts because of specific hostpathogen interactions. Finally, novel genetic tools including animal models were recently developed and will offer new opportunities for identifying genetic factors underlying host phenotypic response to malaria, which will help in better therapeutic strategies including vaccine and drug development. malaria; genetic resistance; human; mouse model; QT mapping PLASMODIUM FALCIPARUM MALARIA remains a major cause of morbidity and mortality in many developing countries. According to the World Health Organization (WHO), the number of cases in 2012 reached 219 million [95% confidence interval (CI) 154 -289 million], among which Ͼ660,000 (95% CI 490,000 -836,000) were fatal (62, 181a). Drug-resistant parasite strains are spreading rapidly across the world, and, despite substantial efforts and encouraging results from recent trials, a fully protective malaria vaccine remains a distant prospect (154). Vaccine development faces major difficulties partly due to the genetic control of immunity to the parasite (155,156,163,176) and/or to the parasitic antigenic variation (146).The outcome of human malaria infection is thought to depend on both parasite and host genetic factors. P. falciparum genotypes have been associated with differences in disease outcome (41) and may be subject to selective pressure (34,55). The influ...

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Section: Erythrocyte Polymorphisms and Severe Malariasupporting

confidence: 62%

Host susceptibility to malaria in human and mice: compatible approaches to identify potential resistant genes

Hernandez-Valladares¹,

Rihet

Iraqi

2014

Physiological Genomics

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“…Further in this study, OR ¼ 0.082 and RR ¼ 0.093, indicating very great protection (often calculated as 1-OR or 1-RR) from severe malaria for AS genotypes. Ackerman et al (2005) compared this 'case-control' method with a family-based method in more recent samples from Gambia and found similar OR values of 0.10 and 0.11.…”

Section: Sickle Cell S or B S Or Hbsmentioning

confidence: 99%

Population genetics of malaria resistance in humans

2011

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“…Many factors may contribute to a failure of replication in association studies of complex genetic disorders, 35,36 including study design, sample size, recruiting strategies, power issues, and sources of true variability among populations. Consequently, our study illustrating the association of ASD to Tag SNPs in the DLX1/DLX2 genes in two cohorts of MPX families, as well as SPX families, recruited using different strategies and different subject sources across North America, supports the DLX1/DLX2 genes as contributing factors to ASD etiology.…”

Section: Discussionmentioning

confidence: 99%

The DLX1and DLX2 genes and susceptibility to autism spectrum disorders

Novosedlik

Wang

et al. 2008

Eur J Hum Genet

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An imbalance between excitation and inhibition in the cerebral cortex has been suggested as a possible etiology of autism. The DLX genes encode homeodomain-containing transcription factors controlling the generation of GABAergic cortical interneurons. The DLX1 and DLX2 genes lie head-to-head in 2q32, a region associated with autism susceptibility. We investigated 6 Tag SNPs within the DLX1/2 genes in two cohorts of multiplex (MPX) and one of simplex (SPX) families for association with autism. Family-based association tests showed strong association with five of the SNPs. The common alleles of rs743605 and rs4519482 were significantly associated with autism (Po0.012) in the first sample of 138 MPX families, with the latter remaining significant after correction for multiple testing (P cor ¼ 0.0046). Findings in a second sample of 169 MPX families not only confirmed the association at rs4519482 (P ¼ 0.034) but also showed strong allelic association of the common alleles at rs788172, rs788173 and rs813720 (P cor ¼ 0.0003 -0.04). In the combined MPX families, the common alleles were all significantly associated with autism (P cor ¼ 0.0005-0.016). The GGGTG haplotype was over transmitted in the two MPX cohorts and the combined samples [P cor o0.05: P cor ¼ 0.00007 for the combined MPX families, Odds Ratio: 1.75 (95% CI: 1.33 -2.30)]. Further testing in 306 SPX families replicated the association at rs4519482 (P ¼ 0.033) and the over transmission of the haplotype GGGTG (P ¼ 0.012) although P-values were not significant after correction for multiple testing. The findings support the presence of two functional polymorphisms, one in or near each of the DLX genes that increase susceptibility to, or cause, autism in MPX families where there is a greater genetic component for these conditions.

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A Comparison of Case‐Control and Family‐Based Association Methods: The Example of Sickle‐Cell and Malaria

Cited by 76 publications

References 12 publications

Host susceptibility to malaria in human and mice: compatible approaches to identify potential resistant genes

Host susceptibility to malaria in human and mice: compatible approaches to identify potential resistant genes

Population genetics of malaria resistance in humans

The DLX1and DLX2 genes and susceptibility to autism spectrum disorders

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