Patterns of nucleotide and haplotype diversity at ICAM-1 across global human populations with varying levels of malaria exposure

Abstract

Malaria is one of the strongest selective pressures in recent human evolution. African populations have been and continue to be at risk for malarial infections. However, few studies have re-sequenced malaria susceptibility loci across geographically and genetically diverse groups in Africa. We examined nucleotide diversity at Intercellular adhesion molecule-1 (ICAM-1), a malaria susceptibility candidate locus, in a number of human populations with a specific focus on diverse African ethnic groups. We used tests of neutrality to assess whether natural selection has impacted this locus and tested whether SNP variation at ICAM-1 is correlated with malaria endemicity. We observe differing patterns of nucleotide and haplotype variation in global populations and higher levels of diversity in Africa. Although we do not observe a deviation from neutrality based on the allele frequency distribution, we do observe several alleles at ICAM-1, including the ICAM-1Kilifi allele, that are correlated with malaria endemicity. We show that the ICAM-1Kilifi allele, which is common in Africa and Asia, exists on distinct haplotype backgrounds and is likely to have arisen more recently in Asia. Our results suggest that correlation analyses of allele frequencies and malaria endemicity may be useful for identifying candidate functional variants that play a role in malaria resistance and susceptibility.

Prevalence and changes of anemia among young children and women in 47 low- and middle-income countries, 2000-2018

“…The countries with a high prevalence of anemia (more than 60%) in this study were mainly from the African and South-East Asia/Western Pacific regions, which might be due to endemic schistosomiasis in the African region [18] and the Asian-Pacific region [19] , [20] , [21] . Besides, sickle cell disease is a common health problem for children living in Saharan Africa [ 22 , 23 ] and Asian, amplified by those with malaria susceptibility candidate locus [24] or migration [22] . Therefore, schistosomiasis and sickle cell disease might be the core mission of anemia mitigation in these two regions.…”

Genetic Variation and Adaptation in Africa: Implications for Human Evolution and Disease

“…A large number of genetic variants that are associated with malaria-protective phenotypes have been identified and many of them cause serious disease (Ko et al 2012;Gomez et al 2013a). For example, variants associated with hemoglobinopathies, a and b thalassemias, and the structural hemoglobin variants S, C, and E, are classic examples of deleterious genetic variants that nevertheless confer protection from malaria (Weatherall 2001;Gomez et al 2013b). Early studies of thalassemias (Haldane 1949;Flint et al 1986) noted that these diseases have a geographic distribution that coincides with P. falciparum endemicity.…”

Genetic variants of TLR4, including the novel variant, rs5030719, and related genes are associated with susceptibility to clinical malaria in African children

“…Interestingly, the ICAM1 SNPs, rs5490, rs5491, and rs5498, have been published as being associated with malaria [ 33 , 34 , 36 – 40 , 43 ], a finding which was later scrutinized in a larger meta-analysis, which could not corroborate the earlier findings [ 44 ]. Further examination of the risk alleles of the ICAM1 SNPs in association with clinical malaria phenotypes (Additional file 4 : Table S4), suggests that maternal mutations in rs5490 (A>C) and rs5491 (A>T) increased the risks of malarial anaemia odds ratios of 3.027 and 2.043, respectively).…”