Genetic variants of TNFα, IL10, IL1β, CTLA4 and TGFβ1 modulate the indices of alcohol-induced liver injury in East Indian population

Alcohol induced liver disease or alcoholic liver disease (ALD), a complex trait, encompasses a gamut of pathophysiological alterations in the liver due to continuous exposure to a toxic amount of alcohol (more than 80g per day). Of all chronic heavy drinkers, only 15-20% develops hepatitis or cirrhosis concomitantly or in succession. Several studies revealed that inter-individual as well as inter-ethnic genetic variation is one of the major factors that predispose to ALD. The role of genetic factors in ALD has long been sought for in ethnically distinct population groups. ALD is fast emerging as an important cause of chronic liver disease in India; even in populations such as "Bengalis" who were "culturally immune" earlier. While the genetic involvement in the pathogenesis of ALD is being sought for in different races, the complex pathophysiology of ALD as well as the knowledge of population level diversity of the relevant alcohol metabolizing and inflammatory pathways mandates the need for well designed studies of genetic factors in ethnically distinct population groups. An array of cytokines plays a critical role as mediators of injury, inflammation, fibrosis and cirrhosis in ALD. We, therefore, studied the association of polymorphisms in five relevant cytokine genes with "clinically significant" ALD in an ethnic "Bengali" population in Eastern India. Compared with "alcoholic" controls without liver disease (n=110), TNFα -238AA genotype, IL1β -511CC genotype, TGFβ1 -509CC genotype and IL10 -592AA genotype were significantly overrepresented in ALD patients (n=181; OR=2.4 and 95% CI 1.2-5.5, P(genotype)=0.042, P(allelic)=0.008; OR=2.7 and 95% CI 1.2-5.9, P(genotype)=0.018, P(allelic)=0.023; OR=4.7 and 95% CI 1.7-13.1, P(genotype)=0.003, P(allelic)=0.014; and OR=2.2 and 95% CI 1.1-4.8, P(genotype)=0.04, P(allelic)=0.039 respectively). Moreover a cumulative genetic risk analysis revealed a significant trend for developing ALD with an increase in the number of risk alleles on IL10 and TGFβ1 loci among alcoholics. The risk genotype of IL1β and TGFβ1 also influences the total bilirubin, albumin and alanine aminotransferase levels among alcoholic "Bengalis". The present study is the first case-control study from Eastern India that comprehensively identified polymorphic markers in TNFα, IL10, IL1β and TGFβ1 genes to be associated with ALD in the Bengali population, accentuating the significance of genetic factors in clinical expressions of ALD.     

No Impact of Vitamin D on the CYP3A Biomarker 4β-Hydroxycholesterol in Patients with Abnormal Glucose Regulation

Purpose

To investigate the effect of vitamin D3 on hepatic Cytochrome P450 enzyme (CYP) 3A4 in patients with abnormal glucose regulation using the endogenous marker 4β-hydroxycholesterol (4β-OHC):cholesterol ratio.

Methods

The present study took advantage of a trial primarily aiming to investigate the effect of vitamin D3 on beta cell function and insulin sensitivity in patients with abnormal glucose regulation. 44 subjects were randomized to receive vitamin D3, 30000 IU given orally once weekly or placebo for 8 weeks. The two sample t-test was used to test the means of the intra-individual differences of 4β-OHC:cholesterol ratio between the two groups.

Results

Mean (SD) 4β-OHC in the whole group of patients before and after the intervention was 26 (11) ng/ml and 26 (12). Mean (SD) 4β-OHC:cholesterol ratio in the whole group of patients before and after the intervention was 0.12 (0.046) and 0.13 (0.047). In the Vitamin D group mean (SD) serum 25-OH-vitamin D3 increased from 46 (16) to 85nM (13) during the corresponding time period. To investigate the impact of vitamin D3 on hepatic CYP3A4 we calculated the mean intra-individual differences in 4β-OHC:cholesterol ratio (delta 4β-OHC:cholesterol ratio) before versus after the intervention in the two treatment groups. The difference (95% CI) between delta 4β-OHC:cholesterol ratio in the control group and intervention group was -0.0010 (-0.0093, 0.0072), a difference being not statistically significant (p = 0.80).

Conclusions

We provide further evidence that vitamin D3 may not substantially affect hepatic CYP3A4. This does not exclude the possibility of an impact of intestinal first-pass metabolism of orally administered drugs which should be investigated.

Trial Registration

ClinicalTrials.gov NCT01497132     

Genetic Polymorphism of Interferon-γ, Interferon-γ Receptor, and Interferon Regulatory Factor-1 Genes in Patients with Hepatitis B Virus Infection

The natural history of hepatitis B virus (HBV) infection is probably related to host immune factors. Interferon-γ (IFN-γ) plays significant roles in immune defense. This study was undertaken to investigate the association between HBV infection and single nucleotide polymorphisms (SNPs) of IFN-γ, IFN-γ receptor (IFNGR)-1 and 2, and interferon regulatory factor (IRF)-1 genes. Between March 2002 and December 2002, 614 Korean patients were enrolled in two different groups: an HBV clearance group (n = 201), who were hepatitis B surface antigen (HBsAg) negative with antibodies to HBsAg and hepatitis B core antigen, and an HBV persistence group (n = 413), who were repeatedly HBsAg positive. We assessed polymorphisms in the IFN-γ gene at position +874, in the IFNGR-1 gene at positions −56 and +95, in the IFNGR-2 gene at the second position of codon 64 (Gln64Arg), and in the IRF-1 gene promoter (−410, −388), and the genotype distributions of the HBV clearance and persistence groups were compared. On the basis of unconditional logistic regression analysis with adjustment for age and sex, no statistically significant association with susceptibility to persistent HBV infection was observed with the IFN-γ, IFNGR-1 and 2, and IRF-1 gene polymorphisms under the codominant, dominant, and recessive models.     

IL1β, IL6 and IL8 gene polymorphisms involvement in recurrent corneal erosion in patients with hereditary stromal corneal dystrophies

TGFBI gene mutations cause corneal stromal dystrophies of autosomal dominant inheritance. The most frequent complication of stromal dystrophies is recurrent corneal erosion with varying degree of accompanying inflammation. IL-1, IL-6 and IL-8 are main cytokines involved in corneal erosion healing. This study aimed to investigate the association between IL1B gene ?511C/T, IL6 gene ?174G/C and IL8 gene ?781C/T polymorphisms and risk of recurrent erosion development in patients with hereditary corneal stromal dystrophies. A trend to decrease of IL1B gene ?511TT genotype frequency in group with erosion (3.7%) comparing to control (6.7%) was observed. IL6 gene ?174C allele carriers frequency in control group (65.9%) was significantly (P < 0.05) lower comparing to patients with erosion (80.5%). Frequency of IL8 ?781TT genotype was significantly (P < 0.05) lower in the group with erosion (10.7%) comparing to patients without erosion (30.8%) and control (25%). IL6 gene ?174C allele may be considered as genetic marker of corneal erosion risk in patients with hereditary stromal corneal dystrophies, whereas IL8 ?781TT genotype is associated with negative recurrent erosion prognosis in such patients.     

Genetic association of IDE,POU2F1, PON1, IL1α and IL1β with type 2 diabetes in Pakistani population

A number of genes are known to be involved in glucose homeostasis. Mutations and polymorphisms in candidate genes may effect insulin production, action or resistance. This study was designed to report the association of genetic polymorphism with the type 2 diabetes (T2D) in Pakistani population. A total of 458 subjects (case n = 288, control n = 170) participated in the study. Nine single nucleotide polymorphisms were investigated in genes IDE (rs6583813 C>T, rs7910977 C>T), POU2F1 (rs3767434 A>T, rs10918682 A>T, rs2146727 A>G), WFS1 (rs734312 A>G), PON1 (rs854560 T>A), IL1α (rs1800587 C>T) and IL1β (rs1143634 C>T). Genotyping was performed by DNA sequencing after nested polymerase chain reaction of targeted regions. Results indicated that rs7910977 in IDE showed significant association with the development of T2D [P = 0.012, OR 1.677 (95 % CI 1.112–2.438)]. The rs10918682 in POU2F1 was associated with T2D [P < 0.001, OR 3.606 (95 % CI 2.165–6.005)]. The rs854560 in PON1was associated with incidences of T2D and increased the risk of cardiovascular complications [P = 0.031, OR 0.663 (95 % CI 0.455–0.965)] in diabetics. The rs734312 from WFS1 gene was associated with diabetes at genotype level (P < 0.01). Haplotype analysis of rs1800587–rs1143634 depicted CC haplotype increased the susceptibility to diabetes (P < 0.05). Haplotype GAA from rs2146727–10918682–rs3767434 was protective against diabetes (P < 0.01) and GGA exhibited the association with T2D (P < 0.01). Haplotype CT from rs6583813–rs7910977 was protective against diabetes (P = 0.02). Our study provided evidence to IDE, PON1, WFS1, POU2F1, IL1α and IL1β associated with T2D in Pakistanis.     

Influence of thrombophlebitis on TGF-β1 and its signaling pathway in the vein wall

Extensive extracellular matrix remodeling of the vein wall is involved in varicose veins pathogenesis. This process is controlled by numerous factors, including peptide growth factors. The aim of the study was to evaluate influence of thrombophlebitis on TGF-β1 and its signaling pathway in the vein wall. TGF-β1 mRNAlevels, growth factor content and its expression were evaluated by RT-PCR, ELISA, and western blot methods, respectively, in the walls of normal veins, varicose veins and varicose veins complicated by thrombophlebitis. Western blot analysis was used to assess TGF-β receptor type II (TGF-β RII) and p-Smad2/3 protein expression in the investigated material. Unchanged mRNA levels of TGF-β1, decreased TGF-β1 content, as well as decreased expression of latent and active forms of TGF-β1 were found in varicose veins. Increased expression of TGF-β RII and p-Smad2/3 were found in varicose veins. Thrombophlebitis led to increased protein expression of the TGF-β1 active form and p-Smad2/3 in the vein wall compared to varicose veins. TGF-β1 may play a role in the disease pathogenesis because of increased expression and activation of its receptor in the wall of varicose veins. Thrombophlebitis accelerates activation of TGF-β1 and activity of its receptor in the varicose vein wall.     

Influence of the photoperiod on TGF-β1 and p15 expression in hamster Leydig cells

Adult hamsters exposed to short photoperiods show a marked atrophy of their internal reproductive organs, including a reduction in size, though not number of Leydig cells. Transforming growth factor-β1 (TGF-β1) is involved in the regulation of growth and proliferation of different cell types. The aim of the present study was to examine the influence of photoperiod on the protein and gene expression of TGF-β1 and its receptors as well as gene expression of p15. The effect of TGF-β1 on the expression of p15 in purified Leydig cells from regressed and non-regressed hamster testes was also tested. Protein and gene expression of TGF-β1 was detected in both regressed and non-regressed testes. In contrast to the activin receptor-like kinase 1 (ALK-1), the TGF-β1, the activin receptor-like kinase 5 (ALK-5) and the co-receptor endoglin all showed a greater basal expression in regressed than non-regressed hamster testes. Melatonin induced the TGF-β1 mRNA expression in purified Leydig cells from non-regressed testes. The p15 mRNA level was greater in regressed than non-regressed testes. A high dose of TGF-β1 during a short incubation period increased the p15 mRNA level in Leydig cells from non-regressed testes. ALK-5 and mitogen-activated protein kinase (MAPK) p38 might have played a role in this process. In regressed hamster testes, the p15 mRNA level increased due to a low dose of TGF-β1 after short incubation periods and to a high dose after longer incubation periods; in both instances, ALK-5, ERK 1/2 and p38 were involved. Collectively, these results suggest that the alterations in p15 expression, mediated by MAPK, are involved in the shift between the active and inactive states in hamster Leydig cells.     

The effects of early life Pb exposure on the expression of IL1-β, TNF-α and Aβ in cerebral cortex of mouse pups

ObjectiveTo investigate the effects of maternal lead (Pb) exposure on the learning and memory ability and expression of interleukin1-β (IL1-β), tumor necrosis factor (TNF-α) and beta amyloid protein (Aβ) in cerebral cortex of mice offspring.MethodsPb exposure initiated from beginning of gestation to weaning. Pb acetate administered in drinking solutions was dissolved in distilled deionized water at the concentrations of 0.1%, 0.5% and 1% groups, respectively. On the PND21, the learning and memory ability were tested by water maze test and the Pb levels were also determined by graphite furnace atomic absorption spectrometry. The expression of IL1-β, TNF-α and Aβ in cerebral cortex was measured by immunohistochemistry and western blotting.ResultsThe Pb levels in blood and cerebral cortex of all exposure groups were significantly higher than that of the control group (P < 0.05). In water maze test, the performances of 0.5% and 1% groups were worse than that of the control group (P < 0.05). The expression of IL1-β, TNF-α and Aβ was increased in Pb exposed groups than that of the control group (P < 0.05).ConclusionsThe high expression of IL1-β, TNF-α and Aβ in the cerebral cortex of pups may contribute to the impairment of learning and memory associated with maternal Pb exposure.     

Influence of TGF-β1 on the expression of BSP,DSP, TGF-β1 receptor I and Smad proteins during reparative dentinogenesis

Reparative dentin has a wide variety of manifestations ranging from a regular, tubular form to an irregular, atubular form. However, the characteristics of reparative dentin have not been clarified. This study hypothesized that the level of bone sialoprotein (BSP) expression will increase if the newly formed reparative dentin is bone-like but the dentin sialophosphoprotein (DSPP) level will decrease. In order to test this hypothesis, the expression of BSP and DSP was examined by immunohistochemistry and the expression of BSP was measured by in situ hybridization in an animal model. The pulps of 12 maxillary right first molars from twelve male rats were exposed and capped with MTA. In addition, in order to understand the role of transforming growth factor-beta 1 (TGF-β1) during reparative dentinogenesis, the expression of BSP and DSPP mRNA was analyzed by RT-PCR in a human dental pulp cell culture, and the transforming growth factor-beta 1 receptors (TβRI) and Smad 2/3 were examined by immunofluorescence in an animal model. DSP was expressed in the normal odontoblasts and odontoblast-like cells of the reparative dentin. Interestingly, BSP was strongly expressed in the odontoblast-like cells of reparative dentin. The level of the TβRI and Smad 2/3 proteins was higher in the reparative dentin than in the normal dentin. TGF-β1 up-regulated BSP in the human pulp cell cultures. This suggests that reparative dentin has both dentinogenic and osteogenic characteristics that are mediated by TGF-β1.     

A Systematically Combined Genotype and Functional Combination Analysis of CYP2E1, CYP2D6, CYP2C9, CYP2C19 in Different Geographic Areas of Mainland China – A Basis for Personalized Therapy

The cytochrome P450 is the major enzyme involved in drug metabolism. Single CYP genotypes and metabolic phenotypes have been widely studied, but no combination analysis has been conducted in the context of specific populations and geographical areas. This study is the first to systematically analyze the combined genotypes and functional combinations of 400 samples of major CYP genes—CYP2E1, CYP2D6, CYP2C9, and CYP2C19 in four geographical areas of mainland China. 167 different genotype combinations were identified, of which 25 had a greater than 1% frequency in the Chinese Han population. In addition, phenotypes of the four genes for each sample were in line with the predictions of previous studies of the four geographical areas. On the basis of the genotype classification, we were able to produce a systemic functional combinations analysis for the population. 25 of the combinations detected had at least two non-wild phenotypes and four showed a frequency above 1%. A bioinformatics analysis of the relationship between particular drugs and multi-genes was conducted. This is the first systematic study to analyze genotype combinations and functional combinations across whole Chinese population and could make a significant contribution in the field of personalized medicine and therapy.     

Effect of vitamin A deficiency on thymosin-β4 and CD4 concentrations

Vitamins are evaluated for their role in immunity. Recently, vitamin A received a particular attention as a critical micronutrient for regulating immune system. Therefore, the present study aimed to search for new about vitamin A. Forty-eight Egyptian adults aged from 18 to 42?years old from both sexes were subjected to clinical examination and nutrition questionnaire and were screened for vitamin A by using ELISA method. Forty subjects were selected and subdivided into two groups. Group 1 with vitamin A at level >200?µg/dl consists of 10 healthy subjects. Group 2 with vitamin A deficiency at level <50?µg/dl consists of 30 subjects. Tβ4 and CD4 levels were also determined by a commercial ELISA kit. Results showed a significant decrease in serum levels of Tβ4 and CD4 in group 2 than group 1 at P < .003 and P < .019 respectively. Both of Tβ4 and CD4 had positive correlation with vitamin A level at P < .000 and P < .003 respectively as well as with each other at p < .000. We concluded that vitamin A deficiency may be influence the levels of Tβ4 and CD4.     

Regio and stereospecific synthesis of 11β-substituted 19-norsteroids: Influence of 11β-substitution on progesterone receptor affinity — (1)

The convenient synthesis of a series of lie-substituted 17-ethynyl-17β-hydroxy-4, 9-estradien-3-ones and their corresponding estradiols is reported. Relative affinities for the progestin and estrogen receptors showed very specific interactions between the progesterone receptor and the unsaturated substituents in the 11β-position of the steroid.     

Influence of manganese exposure on cognitive function,plasma APP and Aβ levels in older men

BackgroundElevated manganese (Mn) exposure impairs cognition in adults and children, but the association between Mn and cognitive function in elderly people is unclear. Previous studies have linked Mn neurotoxicity in AD to Aβ-dependent mechanisms. However, the association between Mn and plasma APP and Aβ in the general elderly population remains unknown. This study aimed to investigate the association between Mn exposure and cognitive function, plasma APP and plasma Aβ in older adults.MethodsCognitive abilities in 375 men aged 60 and older in Guangxi, China were assessed using the Mini-Mental State Examination (MMSE) and cognitive impairment were identified using education-stratified cut-off points of MMSE scores. Urinary Mn levels and plasma APP, and Aβ levels were measured using ICP-MS and ELISA, respectively.ResultsA total of 109 (29.07 %) older men were identified as having cognitive impairment. The median urinary Mn level was 0.22 μg/g creatinine. Urinary Mn levels were negatively correlated with MMSE scores (β = −1.35, 95 % CI: −2.65 to −0.06; p = 0.041). In addition, higher concentrations of urinary manganese were associated with a greater risk of cognitive impairment (OR = 2.03, 95 % CI: 1.14–3.59; comparing the highest and lowest manganese; p = 0.025). Moreover, plasma APP levels were inversely associated with urinary Mn levels (r = −0.123, p = 0.020), and positively associated with MMSE scores (r = 0.158, p = 0.002). Surprisingly, no correlations were observed between plasma Aβ42, Aβ40, Aβ40/Aβ42, or Aβ42/Aβ40 and urinary Mn levels and MMSE scores.ConclusionThese results suggested that Mn exposure is negatively associated with older men’s cognition and plasma APP levels, but not plasma Aβ levels.     

Impact of Three Oral Antidiabetic Drugs on Markers of β-Cell Function in Patients with Type 2 Diabetes: A Meta-Analysis

Background

The effect of metformin, pioglitazone and sitagliptin on β-cell function in the treatment of type 2 diabetes is controversial. Therefore, we performed a systematic review and meta-analysis to obtain a better understanding in the β-cell effects of metformin, pioglitazone and sitagliptin.

Methods

We searched Pubmed and the Cochrane Center Register of Controlled Trials to identify relevant studies. Trials investigating effects of sitagliptin, metformin or pioglitazone on β-cell function were identified. The primary outcomes were homeostasis model assessment of β-cells (HOMA-β) and proinsulin/insulin ratio (PI/IR). Secondary outcome was hemoglobin A1c level. We used version 2 of the Comprehensive Meta Analysis software for all statistical analyses.

Results

Metformin monotherapy was more effective than sitagliptin in improving HOMA-β (18.01% (95% CI 11.09% to 24.94%) vs. 11.29% (95% CI 9.21% to 13.37%), P = 0.040) and more effective (−0.137 (95% CI −0.082 to −0.192)) than both sitagliptin (−0.064 (95% CI −0.036 to −0.092), P = 0.019) and pioglitazone (−0.068 (95% CI −0.044 to −0.093), P = 0.015) in decreasing PI/IR. Metformin and sitagliptin combined (40.23% (95%CI 32.30% to 48.16%)) were more effective than sitagliptin and pioglitazone (11.82% (95% CI 6.61% to 17.04%), P = 0.000) and pioglitazone and metformin(9.81% (95% CI 1.67% to 17.95%), P = 0.022) in improving HOMA-β and decreasing PI/IR (−0.177 (95% CI −0.118 to −0.237); −0.080 (95% CI −0.045 to −0.114), P = 0.007; −0.038 (95% CI, −0.005 to 0.071), P = 0.023).

Limitations

The included RCTs were of short duration (12–54 weeks). We could not determine long term effects on β-cells.

Conclusions

Metformin improves β-cell function more effectively than pioglitazone or sitagliptin in type 2 diabetes patients. Metformin and sitagliptin improved HOMA-β and PI/IR more than other combinations.     

Self-Assembly of Aβ40, Aβ42 and Aβ43 Peptides in Aqueous Mixtures of Fluorinated Alcohols

Fluorinated alcohols such as hexafluoroisopropanol (HFIP) and trifluoroethanol (TFE) have the ability to promote α-helix and β-hairpin structure in proteins and peptides. HFIP has been used extensively to dissolve various amyloidogenic proteins and peptides including Aβ, in order to ensure their monomeric status. In this paper, we have investigated the self-assembly of Aβ40, Aβ42, and Aβ43 in aqueous mixtures of fluorinated alcohols from freshly dissolved stock solutions in HFIP. We have observed that formation of fibrillar and non-fibrillar structures are dependent on the solvent composition. Peptides form fibrils with ease when reconstituted in deionized water from freshly dissolved HFIP stocks. In aqueous mixtures of fluorinated alcohols, either predominant fibrillar structures or clustered aggregates were observed. Aqueous mixtures of 20% HFIP are more favourable for Aβ fibril formation as compared to 20% TFE. When Aβ40, Aβ42, and Aβ43 stocks in HFIP are diluted in 50% aqueous mixtures in phosphate buffer or deionized water followed by slow evaporation of HFIP, Aβ peptides form fibrils in phosphate buffer and deionized water. The clustered structures could be off-pathway aggregates. Aβ40, Aβ42, and Aβ43 showed significant α-helical content in freshly dissolved HFIP stocks. The α-helical conformational intermediate in Aβ40, Aβ42, and Aβ43 could favour the formation of both fibrillar and non-fibrillar aggregates depending on solvent conditions and rate of α-helical to β-sheet transition.     

β-Diversity and Species Accumulation in Antarctic Coastal Benthos: Influence of Habitat,Distance and Productivity on Ecological Connectivity

High Antarctic coastal marine environments are comparatively pristine with strong environmental gradients, which make them important places to investigate biodiversity relationships. Defining how different environmental features contribute to shifts in β-diversity is especially important as these shifts reflect both spatio-temporal variations in species richness and the degree of ecological separation between local and regional species pools. We used complementary techniques (species accumulation models, multivariate variance partitioning and generalized linear models) to assess how the roles of productivity, bio-physical habitat heterogeneity and connectivity change with spatial scales from metres to 100''s of km. Our results demonstrated that the relative importance of specific processes influencing species accumulation and β–diversity changed with increasing spatial scale, and that patterns were never driven by only one factor. Bio-physical habitat heterogeneity had a strong influence on β-diversity at scales <290 km, while the effects of productivity were low and significant only at scales >40 km. Our analysis supports the emphasis on the analysis of diversity relationships across multiple spatial scales and highlights the unequal connectivity of individual sites to the regional species pool. This has important implications for resilience to habitat loss and community homogenisation, especially for Antarctic benthic communities where rates of recovery from disturbance are slow, there is a high ratio of poor-dispersing and brooding species, and high biogenic habitat heterogeneity and spatio-temporal variability in primary production make the system vulnerable to disturbance. Consequently, large areas need to be included within marine protected areas for effective management and conservation of these special ecosystems in the face of increasing anthropogenic disturbance.     

Effects of the Interactions between Dust Exposure and Genetic Polymorphisms in Nalp3, Caspase-1, and IL-1β on the Risk of Silicosis: A Case-Control Study

Objectives

To evaluate the effects of the interactions between polymorphisms in Nalp3, caspase-1, and interleukin(IL)-1β genes and occupational dust exposure on the risk of silicosis.

Methods

We conducted a population-based case-control study in a large iron mine in China. Between January 2006 and December 2009, we identified 179 patients with silicosis to evaluate as cases and 201 individuals without silicosis to evaluate as controls. We estimated cumulative dust exposure (CDE) for all subjects and we genotyped polymorphisms in Nalp3, caspase-1, and IL-1β genes. We estimated odds ratios(ORs), 95% confidence intervals(95%CIs), and p-values using logistic regression models adjusted for selected confounders.

Results

After adjusting for age, smoking status, and CDE, subjects with the CT genotype of Ex4-849C>T in Nalp3 and the GA genotype of Ex2+37G>A in caspase-1 had increased risks of silicosis (adjusted ORs[95%CIs] = 2.40 [1.12–5.12] and 3.62 [1.63–8.02], respectively). Among subjects younger than 70 years old, those with the CC genotype of IVS8-7652A>C in Nalp3 had a lower risk of silicosis than those with other genotypes (adjusted OR[95%CI] = 0.24[0.06–0.88]). Among subjects aged 70 years and older, those with the CT genotype of Ex4-849C>T in Nalp3 and those with the GA genotype of Ex2+37G>A in caspase-1 had a higher risk of silicosis than those with other genotypes (adjusted ORs [95%CI] = 2.52[1.04–6.12] and 5.19[1.88–14.35], respectively). Among subjects with CDE greater than 120 mg/m³×year and among smokers, those with the GA genotype of Ex2+37G>A in caspase-1 had a higher risk of silicosis than those with other genotypes (adjusted ORs[95%CIs] = 26.37[3.35–207.39] and 3.47[1.40–8.64], respectively).

Conclusions

Genetic polymorphisms in Nalp3 and caspase-1 may be associated with individual susceptibility to silicosis, especially when the polymorphisms interact with age, CDE, or smoking status.