Polymorphisms of TNF-enhancer and gene for FcγRIIa correlate with the severity of falciparum malaria in the ethnically diverse Indian population
- Swapnil Sinha1,
- Shrawan K Mishra1,
- Shweta Sharma1,
- Phani K Patibandla2,
- Prashant K Mallick3,
- Surya K Sharma4,
- Sanjib Mohanty5,
- Sudhanshu S Pati6,
- Saroj K Mishra5,
- Bheshaj K Ramteke7,
- RM Bhatt8,
- Hema Joshi3,
- Aditya P Dash3,
- Ramesh C Ahuja9,
- Shally Awasthi10,
- Indian Genome Variation Consortium11,
- Vimala Venkatesh2 and
- Saman Habib1Email author
© Sinha et al; licensee BioMed Central Ltd. 2008
Received: 19 October 2007
Accepted: 14 January 2008
Published: 14 January 2008
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.
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.
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 represent the first genetic analysis of the two immune regulatory molecules in the context of P. falciparum severity/resistance in the Indian population.
Association of specific TNF and FCGR2A SNPs with cytokine levels and disease severity/resistance was indicated in patients from areas with differential disease endemicity. The data emphasizes the need for addressing the contribution of human genetic factors in malaria in the context of disease epidemiology and population genetic substructure within India.
The association of severity of malaria with several human genetic factors is well documented  and the disease has been the selective pressure behind several erythrocytic defects such as sickle cell disease, G6PD deficiency and thalassaemia [2, 3]. Malaria susceptibility/resistance has been correlated with polymorphisms in more than 30 other genes, some of which have exhibited differential association in distinct populations of the world . Plasmodium falciparum blood infection levels and fever episodes have been linked to chr 5q31–33  and chr10 . While most human gene polymorphism-disease association studies for malaria susceptibility have been carried out on populations from Africa and south-east Asia, there is limited information on malaria-associated gene polymorphisms in Indian populations [6–8].
Single nucleotide polymorphisms (SNPs) in the 5' regulatory region of TNF and coding region of FCGR2A have been associated with P. falciparum malaria [12–17]. Tumour Necrosis Factor (TNF) is involved in multiple inflammatory and immune responses and plays an important role in the pathogenesis of many infectious diseases including P. falciparum malaria . The transcription of TNF is complex and tightly regulated [19, 20]. SNPs in the 5' regulatory region of the gene have been shown to correlate with many infectious and inflammatory diseases [21, 22] with conflicting reports regarding their functional significance. SNPs at positions -1031, -857, -376 (rs1800750, G>A), -308 and -238 in the proximal enhancer of the TNF gene exhibit differential associations to malaria and TNF production in different populations [12–14, 23–25] suggesting that individual TNF responses may be genetically determined.
The human IgG receptor FcγRIIa (CD32) is an important link between the cellular and humoral arms of the immune system. It is a low affinity receptor for immunoglobulin subtypes IgG1–4 and also binds C-reactive protein (CRP) with high affinity. A polymorphism in exon 4 of FCGR2A (R131H, G/A) alters its function in vitro; the product of the G allele (131R) has preferential affinity for IgG1 and IgG3 while the A allele (131H) product binds efficiently to IgG2 while retaining its affinity for IgG1 and IgG3 . The high-affinity IgG2 binding 131H allele has been correlated with susceptibility to severe P. falciparum malaria in Africa, particularly in children in Kenya and Gambia [15, 16], but failed to show significant independent association with severity of malaria in Thai adults . A recent report  has implicated the 131H allele in protection from severe malaria in Sudan.
Screening of the enhancer region of the TNF gene for genetic variants in the ethnically diverse Indian population and correlation of two SNPs (-1031 and -863) with circulating plasma TNF levels in healthy individuals and P. falciparum malaria patients is reported here. Correlation of TNF levels and 5' regulatory region SNPs with severity of disease was investigated in a case-control study with patients and controls drawn from a P. falciparum endemic and a non-endemic region of the country. The FcγRIIa R131H polymorphism was also evaluated for correlation with susceptibility to severe malaria in these regions.
Study subjects and sample collection
Analysis of allele frequency distribution of the selected TNF (RefSeq NT_007592.14) and FCGR2A (RefSeq NM_021642) SNPs was carried out in the existing Indian Genome Variation Consortium (IGVC) samples. This validation panel consisted of 1,871 samples drawn from 55 ethnically and linguistically diverse endogamous populations across India .
For the case-control study for an endemic (Antagarh, Chhattisgarh and Sundargarh, Orissa) and a non-endemic (Lucknow and surrounding areas of Uttar Pradesh) region (Figure 1a), approval was obtained from ethical committees of all participating institutions. Informed consent was obtained from each volunteer/guardian prior to collection. Blood samples (2 to 5 ml) were drawn from patients above five years of age diagnosed with P. falciparum malaria. Diagnosis was carried out by rapid diagnostic test kits (Optimal/Paracheck) followed by confirmation by examination of thick and thin film blood smears. Categorization of severe and non-severe cases was performed according to WHO guidelines . Non-severe malaria patients were blood smear-positive, had fever and lacked symptoms that characterized severe malaria. Severe malaria cases were categorized as cerebral and non-cerebral. Cerebral malaria was characterized by impaired consciousness (coma) with fever. Any one of the following symptoms together with a positive blood smear indicated severe (non-cerebral malaria): severe anaemia, acidotic breathing, pulmonary oedema, hypoglycaemia, increased serum creatinine levels. A total of 121 patients (68 and 53 patients from the endemic and non-endemic region, respectively) and 100 healthy control individuals (42 and 58 uninfected individuals from the endemic and non-endemic region, respectively) were included in the study. Plasma TNF levels in the context of disease severity were analyzed for 175 patients (101 and 74 patients from the endemic and non-endemic region, respectively) and 186 control individuals (98 and 88 individuals from the endemic and non-endemic region, respectively). Control samples were taken from ethnically-matched, unrelated individuals from the endemic region and non-endemic region. Plasma was separated at the time of collection and stored in liquid nitrogen. G6PD level and HbA/S status of each individual was determined.
Genomic DNA extraction and genotyping
Genomic DNA was extracted from peripheral blood leucocytes using salting-out procedure . For validation of reported SNPs and discovery of novel SNPs, a 511 bp region of the TNF enhancer (-1 to -511) was sequenced in a discovery panel comprising 43 samples from different populations of India . Genotyping of all TNF and FCGR2A SNPs in the IGVC validation panel was done by Sequenom mass spectroscopy. For patient and control samples, genotyping of -1031, -863 and -857 TNF SNPs was done by direct sequencing of a 292 bp PCR product covering nt -782 to -1073. Typing of other TNF SNPs (-308, -238, -76) and FCGR2A G/A (R131H) SNP was done by SNaPShot method (Applied Biosystems). All DNA sequencing and genotyping was performed on 3130xl automated DNA sequencer (Applied Biosystems). Approximately 10% genotypings carried out by SNaPshot were quality checked by DNA sequencing.
ELISA for TNF
A sandwich ELISA was performed to measure plasma TNF levels using capture monoclonal anti-human TNF antibody (Pierce) and a paired biotinylated anti-human TNF antibody (Pierce). The minimum detection limit of the assay was 2 pg/ml.
The chi-square test was performed to evaluate whether the allele frequencies of the populations are in Hardy-Weinberg equilibrium. Comparison of TNF levels among genotypes of the -1031 and -863 SNPs was carried out by non-parametric Kruskal-Wallis test . Pairwise comparison of means for TNF levels was carried out by Mann-Whitney test. Haplotypes for TNF SNPs were generated by PHASE. Linkage disequilibrium (LD) plot for TNF SNPs was generated using Haploview. Odds ratio (OR) for risk assessment was determined using EpiInfo™ version 3.4 software with the P-value calculated by Fisher Exact or Mantel-Haenszel test.
TNF regulatory region and FCGR2A SNP frequencies vary across Indian populations
TNF enhancer and FCGR2A SNP frequencies in IGVdb populations from the P. falciparum endemic and non-endemic regions included in this study.
Minor allele frequency
Homozygotes of TNF -1031C and -863A alleles are associated with elevated circulating TNF levels
The five TNF regulatory region SNPs described above as well as the -857 SNP previously correlated with cerebral malaria  were typed in patients and controls. As the -857, -308, -238 and -76 SNPs had relatively low frequency, only the -1031 and -863 SNPs were analyzed further.
Correlation of TNF levels with genotypes of the -1031 and -863 SNPs in controls and patients. Comparison of means was carried out by Kruskal-Wallis test.
TNF levels as mean ± S.D. (pg/ml)
Controls (n = 100)
Patients (n = 111)
18.2 ± 22.17 (n = 58)
P = 0.0178
27.9 ± 29.14 (n = 58)
P = 0.0089
21.3 ± 23.2 (n = 36)
40.9 ± 64.9 (n = 47)
56.56 ± 35.1 (n = 6)a
126.6 ± 80.82 (n = 6)b
19.01 ± 22.9 (n = 61)
P = 0.0481
25.6 ± 29.3 (n = 62)
P = 0.0231
17.79 ± 17.9 (n = 30)
47.5 ± 66.8 (n = 44)
52.27 ± 35.1 (n = 9)c
124.7 ± 90.2 (n = 5)d
High TNF levels correlate with severe P. falciparum malaria
Elevated TNF levels in malaria patients have been correlated with severe disease manifestation in other world populations [34, 35] although significant differences between plasma TNF levels were not observed between uncomplicated, severe anemia, and cerebral malaria patients in a recent report on Malian children  suggesting the possibility of population-specific differences. An earlier study from India  reported higher TNF level in patients with multiple organ dysfunction and those who died. Our results indicated significantly higher TNF levels in patients with severe P. falciparum malaria when compared with controls (P < 0.0001) or with patients with non-severe malaria (P = 0.0009) (Figure 3c). The difference in TNF levels between non-severe patients and controls was not significant (P = 0.25). Significant differences were not seen between non-cerebral severe and cerebral malaria patients (P = 0.102) suggesting correlation with severe disease manifestation including cerebral malaria.
Correlation of TNF and FCGR2A SNPs with susceptibility to severe P. falciparum malaria
Genotype distribution of TNF regulatory region SNPs in controls and patients.
Control (n = 100)
Non-severe (n = 57)
Severe (n = 54)
The role of TNF during P. falciparum malaria infection has been described as both protective and pathogenic [37, 38]. At low levels, TNF is believed to augment parasite killing by macrophage activation and subsequent release of cytokines, whereas high TNF level has been associated with severe manifestations like acute respiratory distress and cerebral malaria. A recent study on lethal malaria in mice has implicated high levels of TNF in impairment of dendritic cell function thus contributing to immunosuppression associated with malaria . Individual variation in TNF production mainly by macrophages and NK cells is likely to influence severe disease manifestation. Although the effect of TNF enhancer SNPs on transcription levels of the cytokine remains controversial [40, 41], several studies have implicated their role in determining TNF levels in individuals and consequently influencing their response to a gamut of autoimmune and infectious diseases including P. falciparum malaria [42, 43]. While association of the -863A substitution with reduced TNF levels was described in the Swedish population , a study from Japan  reported association of the -1031, -863 and -857 polymorphisms with increased reporter gene expression and increased concanavalin A-stimulated TNF production from peripheral blood mononuclear cells. Additionally, the ubiquitous transcription factor OCT-1 has been reported to exhibit allele-specific binding to the variant allele -863A or -857T . In our study as well, higher circulating TNF levels in both controls and patients were associated with the -1031C and -863A polymorphisms. The two SNPs were in LD and the CACGG haplotype (-1031C, -863A, -857C, -308G, -238G) was strongly associated with higher plasma TNF levels. This haplotype had the highest estimated frequency in controls (0.115) after the major haplotype TCCGG (0.58). As the -1031 and -863 polymorphisms are present in high frequency in India and the CAGGT haplotype (-1031C, -863A, -308G, -238G, -76T) is also the predominant haplotype after the major haplotype TCGGT in most of the 55 IGVdb populations analyzed by us, the two SNPs may play a significant role in modulating the immune response and influencing the outcome of several infectious diseases.
Our results indicated association of the -1031 and -863 TNF SNPs with increased risk of severe malaria. A recent study on Thailand/Myanmar border populations reported association of the TNF -1031C, -863C, -857C allele with severe malaria . This allele was not in significant LD with HLA-DRB1 and HLA-B alleles indicating that association with susceptibility to cerebral malaria was not because of LD with the HLA alleles. To our knowledge, our study is the first report of independent association of the -863 polymorphism with increased risk of severe disease.
In contrast to previous reports [15, 16, 27], our data implicates the low-IgG2 binding 131R allele in susceptibility to P. falciparum malaria with the high-affinity IgG2 binding 131H/H genotype being associated with protection from disease. Our results are in agreement with a recent study on subjects from Sudan that demonstrated that the 131R/R genotype and the 131R allele were significantly associated with the odds of severe malarial disease . The 131H/H genotype was associated with a reduced risk of both non-severe and severe malaria in our study, indicating a role for the polymorphism in protection from clinical manifestation of disease. The FcγRIIa 131H receptor binds IgG3 more efficiently than 131R and is the only high-affinity receptor for IgG2 [47, 48]. Cytophilic antibodies are thought to be critical in protective immunity and several studies have shown an association between increased levels of IgG1 and IgG3 subclasses and protection from malarial infection or disease [49–51]. High levels of IgG2 antibodies to MSP-2 and RESA have been associated with resistance to P. falciparum malaria in Burkina Faso . IgG2 antibodies may be cytophilic in individuals carrying the 131H allele as these bind Fcγ receptor with greater affinity. Nasr et al.  showed that IgG3 antibodies specific to crude malarial antigen were more associated with reduced risk of clinical malaria in 131H/H individuals than in 131R/R individuals; weak but statistically significant association between low levels of anti-malarial IgG2 antibodies specific to a recombinant antigen in 131H allele carriers and reduced risk of severe malaria was also found. Our results also suggest a role for the 131H/H genotype in protection against clinical malaria. This may be mediated by enhanced phagocytosis of P. falciparum-infected erythrocytes by cells expressing the 131H receptor  or by FcγRIIa and FcγRIII-dependent parasite neutralizing activity of monocytes during antibody-dependent cell-mediated inhibition of parasite growth .
A difference in the degree of association of the FcγRIIa 131R allele with severe malaria observed in the two regions included in our study may be a reflection of the nature of immune response against malaria in areas characterized by low and seasonal transmission or endemic areas with high transmission rates. Although a more detailed analysis of this is warranted, it may be relevant that association of high IgG2 levels with protection from severe P. falciparum malaria observed in the Burkina Faso study  as well as the association of the low IgG2 binding 131R allele with disease severity in a Sudanese population  were both carried out from areas characterized by seasonal P. falciparum malaria transmission. As evident from the map of P. falciparum incidence in India (Figure 1d) and the distribution of the FcγRIIa AA genotype (Figure 1c), higher frequency of the protective 131H/H genotype was observed in 'high risk' and endemic areas of east and north-east India. This is suggestive of possible selection of the protective A allele in populations exposed to P. falciparum malaria in these regions.
In light of the increasing incidence of P. falciparum malaria and its concentration in specific regions of India, we initiated a case-control study to understand the role of genetic variants of specific immune regulatory molecules in malaria severity/resistance in an endemic and non-endemic region of the country. Differences in frequencies of TNF enhancer and FCGR2A SNPs were observed in populations from the two regions. Association of specific TNF and FCGR2A SNPs with cytokine levels and disease severity/resistance was indicated in patients. The TNF enhancer haplotype carrying the -1031 and -863 SNPs is the predominant haplotype after the major haplotype in most Indian populations and correlated with enhanced TNF levels. In addition, the FcγRIIa 131R low affinity IgG2-binding allele was associated with susceptibility to disease with the 131H/H genotype being protective against P. falciparum malaria. Differences in FcγRIIa allelic association profiles were observed in regions with differential P. falciparum prevalence and transmission. The data underlines the need for addressing the contribution of human genetic factors in malaria in the context of disease epidemiology and population genetic substructure within India.
tumour necrosis factor
Fc gamma receptor IIa
single nucleotide polymorphism
minor allele frequency
enzyme-linked immunosorbent assay.
We are grateful to all donors and their families. We thank Dr. Debasis Das for help with gradient maps, Dr. Prashant, Dr. Prerna, Dr. G.N. Jha and Subir Biswas for help with sample collection and the UP State Department for Malaria and Vector Borne Diseases for support. This work was supported by grants to SH from the Council of Scientific and Industrial Research (CSIR) (CMM0016) and to SH and VV from the Department of Biotechnology, Government of India (BT/PR6065/MED/14/738/2005). This is CDRI communication number 7319.
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