ACE deletion allele is associated with susceptibility to SARS-CoV-2 infection and mortality rate: An epidemiological study in the Asian population.

BACKGROUND: Severe acute respiratory syndrome corona virus-2 (SARS-CoV-2) is believed to have emerged from Wuhan, China, and spreads over 215 countries worldwide. The spike protein of SARS-CoV-2 binds to angiotensin-converting enzyme-2 (ACE-2) receptors and enter the host cells. Several reports have been highlighted the importance of ACE-2 on the pathogenesis of COVID-19. In the present study, we hypothesize that a functional insertion/deletion polymorphism in the ACE gene could be associated with SARS-CoV-2 infection and mortality. MATERIALS AND METHODS: PubMed and Google scholar search engines were used to obtained data on the prevalence of ACE I/D polymorphism in different countries of the Asia continent. Data on COVID-19 infection rate (per million), mortality/million, and percentage of recovery were acquired form worldometer website. The Spearman rank correlation test performed to investigate the correlation of allele 'D' with SARS-CoV-2 infection, mortality rate, and recovery percentage. RESULTS: Epidemiological investigation revealed a significant positive correlation of D allele of ACE polymorphism with SARS-CoV-2 infection (r = 0.502, p = 0.008, n = 26) and mortality rate (r = 0.620, p = 0.002, n = 22) in Asian population. However, no significant role of ACE I/D polymorphism was observed with recovery rate of patients from SARS-CoV-2 infection (r = -0.208, p = 0.352, n = 22). CONCLUSIONS: Allele D of ACE insertion/deletion polymorphism is associated with the rate of infection and mortality in the Asian population.

Association of MBL-2 gene polymorphisms with systemic lupus erythematosus: an updated meta-analysis and trial sequential analysis.

OBJECTIVES: Mannose-binding lectin (MBL), an essential innate immune molecule, enhances the opsonization process and activates the complement system. Genetic variations at the promoter and coding region of the MBL-2 gene have been associated with susceptibility to systemic lupus erythematosus (SLE); however, reports remained inconsistent. The present study performs a meta-analysis of published peer-reviewed articles to draw a definitive conclusion. MATERIALS AND METHODS: Published peer-reviewed articles on the association of MBL-2 gene polymorphisms and SLE were screened on various databases such as PubMed (Medline), ScienceDirect, and Google Scholar. A total of 23 eligible articles were included in the present study, comprising 3074 SLE patients and 3985 controls. Genotype and/or allele data for MBL-2 polymorphisms (A > B, A > C, A > D, A > O, Y > X and H > L) were extracted and analyzed by Comprehensive Meta-Analysis software (CMA V3.1). RESULTS: The overall analysis revealed a significant association of MBL-2 (A > O) polymorphism with a predisposition to SLE in allele contrast (p = 0.000; OR = 1.261), homozygous (p = 0.005; OR = 1.482), heterozygous (p = 0.004; OR = 1.247), dominant (p = 0.000; OR = 1.303) and recessive (p = 0.025; OR = 1.356) genetic comparison model. Similar results were also observed in the comparison of allele and the dominant genetic model of MBL-2 (A > B) polymorphism in overall (allele: p = 0.000, OR = 1.46, dominant: p = 0.001, OR = 1.31) and in the Asian cohorts (allele: p = 0.007, OR = 1.43, dominant: p = 0.008, OR = 1.32). Interestingly, MBL-2 (Y-221X) polymorphism exhibited protection against the development of SLE in heterozygous (p = 0.005, OR = 0.619) and dominant genetic comparison (p = 0.01, OR = 0.672) models. CONCLUSIONS: MBL-2 variants (A > O and A > B) are associated with predisposition to SLE. Conversely, promoter polymorphism (Y-221X) offers protection against SLE development.

Link between MnSOD Ala16Val (rs4880) polymorphism and asthma risk is insignificant from sequential meta-analysis.

The mitochondrial manganese superoxide dismutase (MnSOD) enzyme protects lungs against oxidative stress by neutralizing the free radical superoxide produced in the respiratory function. This has relevance to asthma. Therefore, it is of interest to describe the potential effect of MnSOD Ala16Val genetic polymorphism to asthma risk. Known data in this context is inconclusive in nature. The possible link between MnSOD Ala16Val polymorphism and asthma is explored using sequence meta-analysis. Data from the pooled analysis of MnSOD Ala16Val polymorphism using five genetic models i.e., allelic (Val vs. Ala: p=0.846; OR=1.033, 95% CI=0.742 to 1.440) is discussed. Homozygous (Val Val vs. Ala Ala: p=0.517; OR=1.307, 95% CI=0.582 to 2.932) and heterozygous (Val Ala vs. Ala Ala: p=0.307; OR=1.138, 95% CI=0.888 to 1.459) data using the described models are documented. Data from the dominant model (Val Val + Val Ala vs. Ala Ala: p=0.301; OR=1.289, 95% CI=0.797 to 2.085) and the recessive model (Val Val vs. Val Ala + Ala Ala: p=0.761; OR=0.924, 95% CI=0.555 to 1.538) analyses for several ethnic subgroups in this context is reported.

TNF-α promoter polymorphisms (G-238A and G-308A) are associated with susceptibility to Systemic Lupus Erythematosus (SLE) and P. falciparum malaria: a study in malaria endemic area.

Tumor necrosis factor-α (TNF-α) is a proinflammatory cytokine associated with autoimmune and infectious diseases. Importance of TNF-α in P. falciparum malaria and systemic lupus erythematosus (SLE) have been demonstrated. However, association of functional promoter variants with SLE and malaria is lacking in malaria endemic population. A total of 204 female SLE patients and 224 age and sex matched healthy controls were enrolled in the study. Three hundred fourteen P. falciparum infected patients with different clinical phenotypes were included. TNF-α polymorphisms (G-238A & G-308A) were genotyped by PCR-RFLP. Plasma levels of TNF-α was quantified by ELISA. Heterozygous mutants and minor alleles of TNF-α (G-238A and G-308A) polymorphisms were significantly higher in SLE patients compared to healthy controls and associated with development of lupus nephritis. In addition, both promoter variants were associated with severe P. falciparum malaria. SLE patients demonstrated higher levels of plasma TNF-α compared to healthy controls. TNF-α (G-238A and G-308A) variants were associated with higher plasma TNF-α. In conclusion, TNF-α (G-238A & G-308A) variants are associated with higher plasma TNF-α levels in SLE patients residing in malaria endemic areas and could be a contributing factor in the development of SLE and susceptibility to severe P. falciparum malaria.

Pharmacogenetic association between NAT2 gene polymorphisms and isoniazid induced hepatotoxicity: trial sequence meta-analysis as evidence.

Hepatotoxicity is a severe problem generally faced by tuberculosis (TB) patients. It is a well-known adverse reaction due to anti-TB drugs in TB patients undergoing long-term treatment. The studies published previously have explored the connection of N-acetyltransferase 2 (NAT2) gene polymorphisms with isoniazid-induced hepatotoxicity, but the results obtained were inconsistent and inconclusive. A comprehensive trial sequence meta-analysis was conducted employing 12 studies comprising 3613 controls and 933 confirmed TB cases using the databases namely, EMBASE, PubMed (Medline) and Google Scholar till December 2017. A significant association was observed with individuals carrying variant allele at position 481C>T (T vs. C: P = 0.001; OR = 1.278, 95% CI = 1.1100-1.484), at position 590G>A (A vs. G: P = 0.002; OR = 1.421, 95% CI = 1.137-1.776) and at position 857G>A (A vs. G: P = 0.0022; OR = 1.411, 95% CI = 1.052-1.894) to higher risk of hepatotoxicity vis-à-vis wild-type allele. Likewise, the other genetic models of NAT2 gene polymorphisms have also shown increased risk of hepatotoxicity. No evidence of publication bias was observed. These results suggest that genetic variants of NAT2 gene have significant role in isoniazid induced hepatotoxicity. Thus, NAT2 genotyping has the potential to improve the understanding of the drug-enzyme metabolic capacity and help in early predisposition of isoniazid-induced hepatotoxicity.

Association between vitamin D receptor polymorphisms and systemic lupus erythematosus in an Indian cohort.

AIM: Systemic lupus erythematosus (SLE) is an autoimmune disorder with various clinical manifestations. Susceptibility to development of SLE has been linked to several factors, such as genetic, environmental and hormonal. Vitamin D appears to have a regulatory role on disease manifestation and activity. Vitamin D exerts its effect through vitamin D receptors (VDR). Several studies have demonstrated an association between VDR polymorphisms and susceptibility to SLE in different populations, although the results are still inconclusive. In the present study, we investigated the association of VDR polymorphisms with SLE in a cohort of patients from Odisha, India. METHODS: Female SLE patients (n = 331) who fulfilled the revised American College of Rheumatology classification criteria were enrolled along with 282 healthy controls from similar geographical areas. VDR polymorphisms (BsmI, ApaI, TaqI and FokI) were typed by polymerase chain reaction followed by restriction fragment length polymorphism. Plasma level of 25-OH vitamin D was quantified by enzyme-linked immunosorbent assay. RESULTS: Prevalence of FokI (Ff) and TaqI (Tt) heterozygotes were significantly higher in SLE patients compared to healthy controls (Ff: P < 0.0001, odds ratio [OR] = 2.80, 95%CI = 1.99-3.95; Tt: P < 0.0001, OR = 2.07, 95%CI = 1.49-2.89). Furthermore, the minor alleles of FokI (f) and TaqI (t) polymorphisms were also more frequent in SLE patients than healthy controls (f: P < 0.0001, OR = 1.96, 95%CI = 1.52-2.52; t: P = 0.0002, OR = 1.60, 95%CI = 1.25-2.09). CONCLUSIONS: FokI and TaqI variants are significantly associated with SLE in an eastern Indian cohort. The cause-effect relationship can be assessed from the combined analyses of VDR polymorphism, plasma vitamin D levels and clinical manifestations.

A Meta-analysis of MBL2 Polymorphisms and Tuberculosis Risk.

MBL2 gene encodes mannose-binding lectin, is a member of innate immune system. Earlier studies revealed that MBL2 gene variants, rs1800451, rs1800450, rs5030737, rs7096206, rs11003125 and rs7095891 are associated with impaired serum level and susceptibility to TB, but their results are inconsistent. A meta-analysis was performed by including 22 studies (7095 TB-patients and 7662 controls) and data were analyzed with respect to associations between alleles, genotypes and minor allele carriers to evaluate the potential association between MBL2 polymorphisms and TB risk. Statistically significant results were found only for the homozygous variant genotype (CC vs. AA: p = 0.045; OR = 0.834, 95% CI = 0.699 to 0.996) of rs1800451 and showed reduced risk of TB in overall population. However, other genetic models of rs1800450, rs5030737, rs7096206, rs11003125, rs7095891 and combined rs1800450, rs1800451, rs5030737 polymorphisms of MBL2 gene did not reveal any association with TB risk. Stratified analysis by ethnicity showed decreased risk of TB in African population for rs1800450 and rs1800451. Whereas, no association was observed between other MBL2 polymorphisms and TB risk in all the evaluated ethnic populations. In conclusion, MBL2 rs1800450 and rs1800451 polymorphisms play a protective role in TB infection and reinforce their critical significance as a potential genetic marker for TB resistance.

Heterozygous mutants of TIRAP (S180L) polymorphism protect adult patients with Plasmodium falciparum infection against severe disease and mortality.

Toll-interleukin-1 receptor domain containing adapter protein (TIRAP) plays a crucial role in TLR2 and TLR4 signaling pathways. Glycosylphospatidylinositol (GPI), considered a toxin molecule of Plasmodium falciparum, interacts with TLR2 and 4 to induce an immune inflammatory response. A single nucleotide polymorphism at coding region of TIRAP (S180L) has been reported to influence TLRs signaling. In the present study, we investigated the association of TIRAP (S180L) polymorphism with susceptibility/resistance to severe P. falciparum malaria in a cohort of adult patients from India. TIRAP S180L polymorphism was typed in 347 cases of severe malaria (SM), 232 uncomplicated malaria and 150 healthy controls. Plasma levels of TNF-α was quantified by ELISA. Heterozygous mutation (S/L) conferred significant protection against MOD (multi organ dysfunction), NCSM (non-cerebral severe malaria) as well as mortality. Interestingly, homozygous mutants (L/L) had 16 fold higher susceptibility to death. TIRAP mutants (S/L and L/L) were associated with significantly higher plasma TNF-α levels compared to wild type (S/S). The results of the present study demonstrate that TIRAP S180L heterozygous mutation may protect patients against severe malaria and mortality.