Polymorphisms of TNF -enhancer and gene for FcγRIIa correlate with the severity of falciparum malaria in the ethnically diverse Indian population

• Published in: Malaria Journal
• Main Authors: Joshi Hema, Bhatt RM, Ramteke Bheshaj K, Mishra Saroj K, Pati Sudhanshu S, Mohanty Sanjib, Sharma Surya K, Mallick Prashant K, Patibandla Phani K, Sharma Shweta, Mishra Shrawan K, Sinha Swapnil, Dash Aditya P, Ahuja Ramesh C, Awasthi Shally, Venkatesh Vimala, Habib Saman
• Format: Article in Journal/Newspaper
• Language: English
• Published: BMC 2008
• Subjects: Arctic medicine. Tropical medicine; RC955-962; Infectious and parasitic diseases; RC109-216; Arctic; Indian
• Online Access: https://doi.org/10.1186/1475-2875-7-13; https://doaj.org/article/f29377d93f8542688f24e3603c071f70

Abstract Background Susceptibility/resistance to Plasmodium falciparum malaria has been correlated with polymorphisms in more than 30 human genes with most association analyses having been carried out on patients from Africa and south-east Asia. The aim of this study was to examine the possible contribution of genetic variants in the TNF and FCGR2A genes in determining severity/resistance to P. falciparum malaria in Indian subjects. Methods Allelic frequency distribution in populations across India was first determined by typing genetic variants of the TNF enhancer and the FCGR2A G/A SNP in 1871 individuals from 55 populations. Genotyping was carried out by DNA sequencing, single base extension (SNaPshot), and DNA mass array (Sequenom). Plasma TNF was determined by ELISA. Comparison of datasets was carried out by Kruskal-Wallis and Mann-Whitney tests. Haplotypes and LD plots were generated by PHASE and Haploview, respectively. Odds ratio (OR) for risk assessment was calculated using EpiInfo™ version 3.4. Results A novel single nucleotide polymorphism (SNP) at position -76 was identified in the TNF enhancer along with other reported variants. Five TNF enhancer SNPs and the FCGR2A R131H (G/A) SNP were analyzed for association with severity of P. falciparum malaria in a malaria-endemic and a non-endemic region of India in a case-control study with ethnically-matched controls enrolled from both regions. TNF -1031C and -863A alleles as well as homozygotes for the TNF enhancer haplotype CACGG (-1031T>C, -863C>A, -857C>T, -308G>A, -238G>A) correlated with enhanced plasma TNF levels in both patients and controls. Significantly higher TNF levels were observed in patients with severe malaria. Minor alleles of -1031 and -863 SNPs were associated with increased susceptibility to severe malaria. The high-affinity IgG2 binding FcγRIIa AA (131H) genotype was significantly associated with protection from disease manifestation, with stronger association observed in the malaria non-endemic region. These results ...