Aditya K. Panda

Vitamin D levels in Indian systemic lupus erythematosus patients: association with disease activity index and interferon alpha

IntroductionLow levels of vitamin D have been associated with several autoimmune disorders including multiple sclerosis, rheumatoid arthritis, type 1 diabetes and systemic lupus erythematosus (SLE). The major source of vitamin D is sunlight but exposure of SLE patients to UV rays has been shown to exacerbate disease pathology. Studies in various populations have shown an association between low vitamin D levels and higher SLE disease activity.MethodsWe enrolled 129 patients who fulfilled American College of Rheumatology criteria in the study. There were 79 treatment-naïve cases and 50 patients who were under treatment for underlying SLE. There were 100 healthy subjects from similar geographical areas included as controls. Plasma 25-OH vitamin D3 and interferon (IFN)-α levels were quantified by enzyme-linked immunosorbent assay (ELISA). The gene expression level of IFN-α was determined by quantitative real-time reverse transcriptase polymerase chain reaction (RT-PCR).ResultsPlasma 25-OH vitamin D3 significantly correlated in an inverse manner with systemic lupus erythematosus disease activity index (SLEDAI) scores (P <0.0001, r = -0.42), anti-dsDNA (P <0.0001, r = -0.39), plasma IFN-α (P <0.0001, r = -0.43) and levels of IFN-α gene expression (P = 0.0009, r = -0.45). Further, plasma levels of IFN-α positively correlated with gene expression of IFN-α (P <0.0001, r = 0.84). Treatment-naïve SLE patients displayed significantly higher plasma levels of IFN-α compared to patients under treatment (P <0.001) and controls (P <0.001).ConclusionsThese results suggest an important role of vitamin D in regulating disease activity in SLE patients and the need to supplement vitamin D in their treatment.

Mannose binding lectin: a biomarker of systemic lupus erythematosus disease activity

IntroductionA role for mannose binding lectin (MBL) in autoimmune diseases has been demonstrated earlier and elevated level of MBL has been shown in systemic lupus erythematosus (SLE) patients. In the current study, we investigated MBL as a potential biomarker for disease activity in SLE.MethodsIn a case control study SLE patients (93 females) and 67 age, sex, ethnicity matched healthy controls were enrolled. Plasma MBL levels were quantified by enzyme linked immunosorbent assay (ELISA). Clinical, serological and other markers of disease activity (C3, C4 and anti-dsDNA) were measured by standard laboratory procedures.ResultsPlasma MBL levels were significantly high in SLE patients compared to healthy controls (P < 0.0001). MBL levels were variable in different clinical categories of SLE. Lower levels were associated with musculoskeletal and cutaneous manifestations (P = 0.002), while higher and intermediate MBL levels were significantly associated with nephritis in combination with other systemic manifestations (P = 0.01 and P = 0.04 respectively). Plasma MBL correlated with systemic lupus erythematosus disease activity index (SLEDAI) (P = 0.0003, r = 0.36), anti-dsDNA (P < 0.0001, r = 0.54), proteinuria (P < 0.0001, r = 0.42) and negatively correlated with C3 (P = 0.007, r = -0.27) and C4 (P = 0.01, r = -0.29).ConclusionsPlasma MBL is a promising marker in the assessment of SLE disease activity.

A Serotonin Transporter Gene (SLC6A4) Polymorphism Is Associated with Reduced Risk of Irritable Bowel Syndrome in American and Asian Population: A Meta-Analysis

Aim Association studies of serotonin transporter gene SLC6A4 I/S polymorphism and irritable bowel syndrome (IBS) have shown inconsistent and contradictory results among different populations. In the present study, meta-analysis was performed to evaluate the association between SLC6A4 I/S polymorphism and IBS susceptibility. Methodology Systemic assessment was performed for the published studies based on the association of SLC6A4 I/S polymorphism and IBS risk from PubMed (Medline), EMBASE search. A meta-analysis was done to appraise the said association. Pooled odds ratios (ORs) and 95% confidence intervals (CIs) were calculated for allele contrast, homozygous, heterozygous, dominant and recessive genetic model. Results A total of twelve studies comprising 2068 IBS cases and 2076 controls were included in this meta-analysis. Overall, no significant results were obtained for S allele carrier (S vs. I: p=0.488; OR=1.073, 95% CI=0.879 to 1.311) Co-dominant (SS vs. II; p=0.587; OR=1.112, 95% CI=0.758 to 1.631), (IS vs. II; p=0.361; OR=0.878, 95% CI=0.665 to 1.160). Similarly, dominant (SS+IS vs. II: p=0.853; OR=0.974, 95% CI=0.736 to 1.288) and recessive (SS vs. II+IS: p=0.267; OR=1.172, 95% CI=0.886 to 1.522) genetic models did not demonstrate risk. In the subgroup population based analysis, reduced risks were found in American (IS vs. II: p=0.009; OR=0.685, 95% CI=0.516 to 0.908) and Asian (SS+IS vs. II; p=0.001; OR=0.116, 95% CI=0.068 to 0.197) population. However, no risk was observed in European population. Conclusions This investigation clearly demonstrates that SLC6A4 (Ins/Del) polymorphism is associated with reduced risk of IBS in American and Asian population. However, future well-designed studies with stratified case control and biological characterization will be needed to validate this finding.

Low producer MBL genotypes are associated with susceptibility to systemic lupus erythematosus in Odisha, India

Variants of MBL gene have been associated with autoimmune disorders. The aim of this study was to explore whether common polymorphisms in MBL gene are associated with susceptibility to systemic lupus erythematosus (SLE) and its clinical manifestations in a cohort from eastern India. A total of 108 female SLE patients and 105 age, sex, and ethnically matched healthy controls were enrolled in the study. MBL2 codon and promoter polymorphisms were genotyped by AS-PCR and dARMS PCR, respectively. Plasma level of MBL was quantified by ELISA. Higher frequency of BB genotype and minor allele (B) was observed in patients of SLE compared to healthy controls (BB genotype: P = 0.0002; OR = 5.75, 95% CI = 2.09-15.76, B allele: P < 0.0001; OR = 2.78, 95% CI = 1.66-4.64). MBL codon 54, H-550L, Y-221X polymorphisms and combined MBL genotypes contributed to plasma MBL levels. Prevalence of MBL low producer genotype (LXA/LYB, LYB/LYB and LXB/LXB) was significantly higher in SLE patients compared to healthy control. (P = 0.005; OR = 3.09, 95% CI = 1.38-6.91). On analysis of clinical manifestations, MBL low producer genotype was significantly associated with autoimmune haemolytic anaemia (P = 0.006; OR = 13.06). Results of the present study indicate MBL2 variants as possible risk factors for development of SLE and clinical manifestation in eastern India.

TLR-9 promoter polymorphisms (T-1237C and T-1486C) are not associated with systemic lupus erythematosus: A case control study and meta-analysis

Toll like receptors (TLRs) are essential molecules implicated in both innate and adaptive immune response. Polymorphisms in TLR gene have been associated with various infectious diseases and autoimmune disorders. Role of TLR9 has been elegantly demonstrated in both human systemic lupus erythematosus (SLE) and mice model of lupus. In the present study we investigated association of TLR-9 promoter polymorphisms (T-1237C and T-1486C) with susceptibility/resistance to SLE in an Eastern Indian state which is endemic to parasitic diseases. 210 Female SLE patients who fulfilled the American College of Rheumatology criteria were enrolled along with matched healthy controls from Odisha, India. TLR-9 polymorphisms (T-1237C and T-1486C) were typed by polymerase chain reaction followed by restriction fragment length polymorphism. For meta-analysis, relevant literatures were searched from PubMed database and comprehensive meta-analysis V2 software was employed for analysis. Allele and genotype frequency of TLR-9 promoter polymorphisms (T-1237C and T-1486C) were comparable among SLE patients and controls. Further, meta-analysis of earlier reports and present study did not reveal a significant association of TLR-9 (T-1237C and T-1486C) polymorphisms with SLE. Data from the present study suggest that TLR-9 promoter polymorphisms are not associated with susceptibility to SLE in an area endemic to parasitic diseases.

Human Lymphatic Filariasis: Genetic Polymorphism of Endothelin-1 and Tumor Necrosis Factor Receptor II Correlates With Development of Chronic Disease

BACKGROUND Hydrocele and elephantiasis are 2 clinically very diverse and often mutually exclusive chronic manifestations of human bancroftian filariasis. Plasma levels of endothelin-1 (ET-1), a major angiogenic factor, and tumor necrosis factor receptors (TNFRs) that regulate host inflammation have been associated with development of chronic filariasis, although their genetic basis are not known. METHODS We studied polymorphisms of ET-1 (Ala288Ser) and TNFR-II (Met196Arg) genes by means of the polymerase chain reaction confronting 2 pairs primers method and restriction fragment length polymorphism, respectively. Plasma ET-1 level was measured by enzyme-linked immunosorbent assay. RESULTS Met196Arg genotype frequency of TNFR-II polymorphism was significantly greater in hydrocele patients, compared with elephantiasis patients (OR, 4.34 [95% CI, 2.04-9.20]). Conversely, a significantly high prevalence of the Ala288Ser mutation of ET-1 was observed in elephantiasis patients, compared with hydrocele cases (OR, 2.15 [95% CI, 1.13-4.10]). Decreased plasma ET-1 levels associated significantly with Ala288Ser mutation in the study population. A combined analysis indicated a 23-fold higher risk for developing elephantiasis in individuals with TNFR-II (Met196Met) and ET-1 mutants (Ala288Ser + Ser288Ser). CONCLUSIONS ET-1 (Ala288Ser) and TNFR-II (Met196Arg) polymorphisms are associated with development of one or the other form of chronic disease in bancroftian filariasis.

Complement Receptor 1 Variants Confer Protection from Severe Malaria in Odisha, India

Background In Plasmodium falciparum infection, complement receptor-1 (CR1) on erythrocyte’s surface and ABO blood group play important roles in formation of rosettes which are presumed to be contributory in the pathogenesis of severe malaria. Although several studies have attempted to determine the association of CR1 polymorphisms with severe malaria, observations remain inconsistent. Therefore, a case control study and meta-analysis was performed to address this issue. Methods Common CR1 polymorphisms (intron 27 and exon 22) and blood group were typed in 353 cases of severe malaria (SM) [97 cerebral malaria (CM), 129 multi-organ dysfunction (MOD), 127 non-cerebral severe malaria (NCSM)], 141 un-complicated malaria and 100 healthy controls from an endemic region of Odisha, India. Relevant publications for meta-analysis were searched from the database. Results The homozygous polymorphisms of CR1 intron 27 and exon 22 (TT and GG) and alleles (T and G) that are associated with low expression of CR1 on red blood cells, conferred significant protection against CM, MOD and malaria deaths. Combined analysis showed significant association of blood group B/intron 27-AA/exon 22-AA with susceptibility to SM (CM and MOD). Meta-analysis revealed that the CR1 exon 22 low expression polymorphism is significantly associated with protection against severe malaria. Conclusions The results of the present study demonstrate that common CR1 variants significantly protect against severe malaria in an endemic area.

CD14 −159 C>T Gene Polymorphism with Increased Risk of Tuberculosis: Evidence from a Meta-Analysis

Cluster of differentiation 14 (CD14) gene is an important component of the human innate immune system and its role in tuberculosis (TB) has been sparsely documented. The enhanced plasma CD14 levels in TB patients as compared to healthy controls are associated with CD14 gene promoter (C-159T) polymorphism. In the past few years, the relationship between CD14 −159 C>T (rs2569190) polymorphism and risk of TB has been reported in various ethnic populations; however, those studies have yielded contradictory results. In this study systemic assessment was done for the published studies based on the association between CD14 −159 C>T polymorphism and TB risk retrieved from PubMed (Medline) and EMBASE search. A total number of 1389 TB cases and 1421 controls were included in this study and meta-analysis was performed to elucidate the association between CD14 −159 C>T polymorphism and its susceptibility towards TB. Pooled odds ratios (ORs) and 95% confidence intervals (95% CIs) were calculated for allele contrast, homozygous comparison, heterozygous comparison, dominant and recessive genetic model. It was found that T allele carrier was significantly associated with increased TB risk (T vs. C: p-value = 0.023; OR = 1.305, 95% CI = 1.038 to 1.640). Similarly, homozygous mutant TT genotype also revealed 1.6 fold increased risk of TB (TT vs. CC; p-value = 0.040; OR = 1.652, 95% CI = 1.023 to 2.667). Additionally, dominant genetic model demonstrated increased risk of developing TB (TT vs. CC+CT: p-value = 0.006; OR = 1.585, 95% CI = 1.142 to 2.201). The study demonstrates that CD14 gene (−159 C>T) polymorphism contributes increased susceptibility for TB. Moreover, this meta-analysis also suggests for future larger studies with stratified case control population and biological characterization for validation studies.

Bacteraemia in adult patients presenting with malaria in India

Severe falciparum malaria is a major health problem in Odisha, India, contributing to high mortality. Multi organ dysfunction is a predominant manifestation of severe disease in Odisha, unlike in Africa, where cerebral malaria and anaemia are common. There are several studies implicating bacteraemia with severe malaria in African children while there are no reports in adults in India. This study has addressed this issue by enrolling 67 P. falciparum infected adult patients categorized into severe and uncomplicated malaria. Blood culture failed to confirm bacteraemia in any sample with the exception of one case of uncomplicated malaria. Study is inconclusive with regard to use of antibiotics in adult patients.

A Genetic Association Study of CCL5 -28 C>G (rs2280788) Polymorphism with Risk of Tuberculosis: A Meta-Analysis

Aim The CC chemokine ligand 5 (CCL5), plays a key role in the inflammatory response by recruiting mononuclear cells during tuberculosis (TB) infection. Association studies of CCL5 -28 C>G (rs2280788) polymorphism and TB risk have shown inconsistent and contradictory results among different ethnic populations. The aim of this meta-analysis is to investigate the association between CCL5 -28 C>G polymorphism and TB susceptibility. Methodology We performed quantitative synthesis for published studies based upon association between CCL5 -28 C>G polymorphism and TB risk from PubMed (Medline), EMBASE web databases. The meta-analysis was performed and pooled odds ratios (ORs) and 95% confidence intervals (95% CIs) were calculated for all genetic models. Results A total of six studies including 1324 TB cases and 1407 controls were involved in this meta-analysis. Variant allele (G vs. C: p = 0.257; OR = 1.809, 95% CI = 0.649 to 5.043), heterozygous (CG vs. CC: p = 0.443; OR = 1.440, 95% CI = 0.567 to 3.658) and homozygous (GG vs. CC: p = 0.160; OR = 5.140, 95% CI = 0.524 to 50.404) carriers did not show increased risk compare with those individual with the CC genotype. Similarly, no associations were found in the dominant (GG+CG vs. CC: p = 0.295; OR = 1.802, 95% CI = 0.599 to 5.412) and recessive (GG vs. CC+CG: p = 0.188; OR = 3.533, 95% CI = 0.541 to 23.085) models. Conclusions Overall findings of this meta-analysis suggest that genetic polymorphism -28 C>G in CCL5 is not associated with increased TB risk. However, future larger studies with group of populations will be needed to analyze the relationship between the CCL5 -28 C>G polymorphism and risk of TB.