Polymorphisms in host genes encoding NOSII, C-reactive protein, and adhesion molecules thrombospondin and E-selectin are risk factors for Plasmodium falciparum malaria in India

Abstract

Cytoadherence of Plasmodium falciparum-infected red blood cells (RBCs) in host microvasculature and complex regulation of the immune response are important contributors to the clinical outcome of disease. We tested the association of 23 single nucleotide polymorphisms (SNPs) and a microsatellite repeat in adhesion molecule genes THBS1 and ESEL, and immune regulatory molecule genes NOSII, CRP, and MBL2 with falciparum malaria in populations residing in a malaria-endemic and a non-endemic region of India. The THBS1 haplotype CCCCA (rs1478604, rs7170682, rs2664141, rs12912082, rs3743125) was a risk factor in the endemic region (relative risk = 3.78) and an ESEL SNP (rs5368, His468Tyr) associated with cerebral malaria (CM) [CM vs. non-cerebral malaria (NCM), odds ratio (OR) = 2.23, p = 0.03]. In the non-endemic region, an ESEL 3'UTR SNP (rs5359) associated with enhanced risk of disease (OR = 3.62, p = 1 × 10(-4)) and the CT genotype of the CRP promoter SNP (C/T/A) strongly associated with protection (severe vs. control, OR = 0.29, p = 6 × 10(-5)). Long repeat alleles of the NOSII promoter microsatellite (CCTTT)n exhibited strong association with protection and the NOSII ATG haplotype (rs3729508, rs2297520, rs9282801) was strongly protective against severe malaria in both regions (endemic, severe vs. control, OR = 0.05, p = 0.0001; non-endemic, severe vs. control, OR = 0.3, p = 1 × 10(-5)). Our results suggest differential contribution of variants of the investigated genes in determining the outcome of malaria in Indian populations.

Frequency spectrum of rare and clinically relevant markers in multiethnic Indian populations (ClinIndb): A resource for genomic medicine in India

“…The utility of an India-specific baseline variability has been demonstrated during pre-next-generation sequencing (NGS) days-in infectious diseases (e.g., malaria, HIV), pharmacogenomics studies, disease associations, and identification of at-risk populations for various neurological, cutaneous, and high-altitude adaptation-related disorders (Aggarwal et al, 2010(Aggarwal et al, , 2015Bhattacharjee et al, 2008;Biswas et al, 2007Biswas et al, , 2010Chaki et al, 2011;Giri et al, 2014;Grover et al, 2010;Gupta et al, 2007;P. Jha et al, 2012;Kanchan et al, 2015;Kumar et al, 2009;Sinha, Arya, Agarwal, & Habib, 2009;Sinha et al, 2008;Talwar et al, 2017).…”

“…In addition, mitochondrial and Y chromosome haplogroup‐based studies have also helped in the characterization of the gene pool of diverse Indian populations (Bamshad et al, 2001; Borkar, Ahmad, Khan, & Agrawal, 2011; Kivisild et al, 2003; Majumder et al, 1999; Thanseem et al, 2006). The utility of an India‐specific baseline variability has been demonstrated during pre‐next‐generation sequencing (NGS) days—in infectious diseases (e.g., malaria, HIV), pharmacogenomics studies, disease associations, and identification of at‐risk populations for various neurological, cutaneous, and high‐altitude adaptation‐related disorders (Aggarwal et al, 2010, 2015; Bhattacharjee et al, 2008; Biswas et al, 2007, 2010; Chaki et al, 2011; Giri et al, 2014; Grover et al, 2010; Gupta et al, 2007; P. Jha et al, 2012; Kanchan et al, 2015; Kumar et al, 2009; Sinha, Arya, Agarwal, & Habib, 2009; Sinha et al, 2008; Talwar et al, 2017).…”

Genetic and epigenetic changes in host ABCB1 influences malaria susceptibility to Plasmodium falciparum

“…In order to identify the risk of individual developing malaria and to predict the outcome, we analysed multiple alterations in ABCB1 and related its impact on the disease. Genetic variants, their functional relevance to Pf as well as to other infectious diseases [51] can provide important information on the aetiology of the disease. Previously described protective alleles against malaria relate to genes that are involved with the host immune response such as cytokines, endothelial receptor, complement regulatory gene, HLA gene and RBC structure [50–54].…”

“…They observed that these resistance genes even though present at high frequency among all 3 ethnic groups, show interethnic heterogeneities towards the susceptibility to malaria [62]. Similarly, some of the SNPs show a high correlation to malaria whereas, the same SNP shows no association when the study is carried out either in other population, geographical area, endemic/non-endemic regions, ethnic groups or tissue samples [51, 57, 63]. There are SNPs reported which even show the inverse correlation with respect to sex and age [64].…”

Genomics of rare genetic diseases—experiences from India

“…The findings of the IGV consortium have led to the identification of specific markers and better understanding of genotype-phenotype correlations in Indian sub-populations. The phenotypically distinct outcomes of sub-population specific genotypes could be shown in susceptibility or resistance towards Plasmodium falciparum [23–27], risk of contracting glaucoma [28], homocysteine levels [29], and risk of developing high-altitude pulmonary edema [30, 31], among other examples. Further, case-control studies in ethnically matched groups as defined by IGV consortium allowed identification of Indian-specific susceptibility markers in genes causing Parkinson’s disease, Wilson disease, and albinism [32–35].…”