Association of programmed death‐1 gene polymorphisms with the risk of basal cell carcinoma

Environmental and genetic factors play a fundamental role in the pathogenesis of basal cell carcinoma (BCC) defined as the most common cancer of skin. Programmed death‐1 (PD‐1), encoded by programmed cell death‐1 (PDCD1) gene, serves as an inhibitory molecule in the suppression of immune responses and a risk factor in the development of different cancers. In this study, we investigated the role of two single nucleotide polymorphisms (SNPs) within PDCD1 gene, and haplotypes defined by these SNPs, in the development of BCC in an Iranian population. Whole blood samples were obtained from 210 BCC and 320 healthy subjects. Genomic DNA was extracted from whole blood samples, polymerase chain reaction‐restriction fragment length polymorphism (PCR‐RFLP) was used to genotype determinations of PD1.3 (rs11568821) and PD1.5 (rs2227981) SNPs, and 4 haplotypes were constructed by PDCD1 SNPs. The frequency of G allele of PD1.3 was significantly higher in BCC patients than healthy subjects (p < 0.02), while these significant differences were not observed in the frequencies of PD1.5 alleles between BCC and healthy subjects. Moreover, we found that there were no statistically significant differences in PD1.3 and PD1.5 genotypes between BCC and control groups. Of all estimated haplotypes for PDCD1, only AC haplotype was associated with BCC (OR = 0.22, 95% CI = 0.06–0.79, p < 0.01). These findings suggest that PD1.3G allele and AC haplotype of PDCD1 contribute to BCC in the Iranian population. However, further studies in different populations with larger sample size are required to confirm this study.     

Association of single nucleotide polymorphisms in TPM1 rs11071720, rs3803499, rs12148828, and rs1972041 with the risk of nonsyndromic cleft lip with or without cleft palate in a sample of the Iranian population,a preliminary report

Several lines of evidence support an association between tropomyosin 1 (TPM1) and the risk of nonsyndromic cleft lip with or without cleft palate (NSCL/P). The present study aimed to investigate the association between TPM1 polymorphisms and the risk of NSCL/P in an Iranian population. This case‐control was done on 105 NSCL/P patients and 110 unrelated healthy controls. TPM1 rs11071720, rs3803499, rs12148828, and rs1972041 polymorphisms were genotyped by the polymerase chain reaction‐restriction fragment length polymorphism method. The finding showed that rs11071720 polymorphism significantly increased the risk of NSCL/P in homozygous codominant (odds ratio [OR] = 2.54, 95% confidence interval [CI] = 1.14–5.69, p = 0.023, TT vs. CC), recessive (OR = 2.33, 95% CI = 1.06–5.18, p = 0.021, TT vs. CT + CC), and allele (OR = 1.53, 95% CI = 1.02–2.30, p = 0.030, T vs. C). The rs12148828 polymorphism was associated with protection against NSCL/P in codominant (OR = 0.27, 95% CI = 0.15–0.48, p < 0.001, TC vs. TT) and allele (OR = 0.38, 95% CI = 0.22–0.64, p < 0.001, C vs. T). Regarding rs3803499, the findings proposed that this polymorphism significantly increased the risk of NSCL/P in codominant (OR = 3.86, 95% CI = 1.19–12.56, p = 0.025, CC vs. TT) and recessive (OR = 3.74, 95% CI = 1.09–14.15, p = 0.018, CC vs. CT + TT). No significant association was practical between rs1972041 polymorphism and NSCL/P. In conclusion, the findings proposed that TPM1 polymorphisms may contribute to the etiology of NSCL/P in a sample of the Iranian population.     

Genetic polymorphism of human leucocyte antigen and susceptibility to multidrug‐resistant and rifampicin‐resistant tuberculosis in Han Chinese from Hubei Province

We determined the high‐resolution allele and haplotype frequencies at the human leucocyte antigen (HLA)A, B and DRB1 loci in the Han population of Hubei province, the TB endemic area of Central China, with pulmonary tuberculosis (PTB), and established the relationship between HLA‐A, B and DRB1 alleles as well as haplotypes and susceptibility to multidrug‐resistant and rifampicin‐resistant tuberculosis (MDR/RR‐TB). Blood samples were drawn from 174 patients with MDR/RR‐TB and 838 patients with drug‐susceptible PTB in ethnic Han population from Hubei province (central China). Four‐digit allele genotyping of HLA‐ A, B and DRB1 loci was performed using polymerase chain reaction with sequence‐specific oligonucleotide probes (PCR‐ SSOP). The allele and haplotype frequencies of HLA‐A, B and DRB1 were determined and compared between patients with MDR/RR‐TB and patients with drug‐susceptible PTB. Statistical analysis of the generated data indicated no departure from expectation of Hardy–Weinberg equilibrium (HWE) at all loci of the control group. Multivariate analysis identified allele DRB1*08:01 (p < .0001; OR = 174.5, 95% CI 15.3–1987.2) as independent predictor of MDR/RR‐TB, except for old age (p < .0001; OR = 10. 9, 95% CI 7.6–15.8), previous treatment history (p < .0001; OR = 11.0, 95% CI 7.2–16.7) and poor compliance to treatment (p < .0001; OR = 12.9, 95% CI 8.4–20.0). While in the subgroup of new TB cases, DRB1*08:01 (p < .0001; OR = 80.3, 95% CI 7.0–917.1) and older age (p < .0001; OR = 3.9, 95% CI 2.4–6.4) were independent susceptibility factors for primary MDR/RR‐TB. Our results suggest that a combination of clinical and host genetic information about tuberculosis patients may contribute to prediction and early detection of MDR/RR‐TB.     

IL‐1A rs1800587, IL‐1B rs1143634 and IL‐1R1 rs2234650 polymorphisms in Iranian patients with systemic sclerosis

Systemic Sclerosis (SSc) is a systemic autoimmune disorder, with ambiguous pathogenesis. Genetic and environmental factors were proved to be correlated with SSc aetiology. Single nucleotide polymorphisms (SNPs) in cytokine genes can alter the structure and function of the cytokines and consequently may increase the susceptibility to a specific disease. In this study, we investigated SNPs of the IL‐1 gene cluster in Iranian SSc patients. We obtained blood samples from 170 SSc patients and 213 healthy individuals. Cytokine genotyping results were obtained by polymerase chain reaction with sequence‐specific primers (PCR‐SSP). IL‐1A rs1800587, IL‐1B rs1143634 and IL‐1R1 rs2234650 were evaluated for SNP study. The frequency of the IL‐1B rs1143634 CT genotype was significantly lower in SSc patients compared to the controls (OR = 0.584; 95% CI = 0.385–0.886; P‐value = 0.023), so we propose that CT genotype of this allele might be protective. According to our haplotype analysis, CCC haplotype frequency is higher in the control group compared to SSc patients (OR = 1.575; 95% CI = 1.176–2.111; P‐value = 0.008) and in contrast, CTC haplotype frequency is lower in the control group compared to SSc patients (OR = 0.152; 95% CI = 0.047–0.484; P‐value = 0.002), so they might decrease and increase the susceptibility of having SSc, respectively. In addition, we reported two significant diplotypes frequency differences among SSc patients and healthy individuals. It is highly important that there is not much resemblance between the IL‐1 gene cluster polymorphism in different populations, so we can indicate that SNPs may play critical roles when they are combined with other genetic and environmental factors.     

Association of interleukin 22 gene polymorphisms and serum IL‐22 level with risk of systemic lupus erythematosus in a Chinese population

The aim of this study was to investigate the association between the single‐nucleotide polymorphisms (SNPs) of the interleukin 22 (IL‐22) gene and systemic lupus erythematosus (SLE) in a Chinese population. Three IL‐22 SNPs (rs2227485, rs2227513 and rs2227491) were genotyped using SNaPshot SNP genotyping assays and identified by sequencing in 314 SLE patients and 411 healthy controls. The IL‐22 level of serum was assessed by enzyme‐linked immunosorbent assay (ELISA) kits. Data were analysed by spss version 17.0 software. We found that rs2227513 was associated with an increased risk of SLE [AG versus AA: adjusted odds ratio (aOR) = 2·24, 95% confidence interval (CI) = 1·22–4·12, P = 0·010; G versus· A: adjusted OR = 2·18, 95% CI = 1·20‐3·97, P = 0·011]. Further analysis in patients with SLE showed that the AG genotype and G allele were associated with an increased risk of renal disorder in SLE (G versus A: aOR = 3·09, 95% CI = 1·30–7·33, P = 0·011; AG versus· AA: aOR = 3·25, 95% CI = 1·35–7·85, P = 0·009). In addition, the concentration of IL‐22 was significantly lower in the rs2227513 AG genotype compared with AA genotype (P = 0·028). These results suggest that rs2227513 polymorphism might contribute to SLE susceptibility, probably by decreasing the expression of IL‐22.     

Association of IL‐1β +3954 C/T and IL‐10‐1082 G/A Cytokine Gene Polymorphisms with Susceptibility to Tuberculosis

Tuberculosis (TB) constitutes the major cause of death due to infectious diseases. Cytokines play a major role in defence against Mycobacterium tuberculosis infection. Polymorphisms in the genes encoding various cytokines have been associated with tuberculosis susceptibility. Household contacts (HHC) are at increased risk of developing the disease. In this study, we examined the association of IL‐1β and IL‐10 cytokine gene polymorphisms with risk of developing tuberculosis in TB patients, their HHC and healthy controls (HC) using JavaStat and SPSS. Multifactor dimensionality reduction (MDR) analyses were performed to explore the potential gene–gene interactions. The genotype and allele frequencies of IL‐1β +3954C/T polymorphism did not vary significantly between TB patients and HC. GG (P < 0.005, OR = 0.219 and 95% CI = 0.059–0.735) and GA (P < 0.0001, OR = 2.938 and 95% CI = 1.526–5.696) genotypes of IL‐10‐1082 G/A polymorphism were found to be significantly associated with patients versus HC. HHC with CC (P < 0.03, OR = 1.833 and 95% CI = 1.1–3.35) genotype in IL‐1β and GA (P < 0.0001, OR = 4.612 and 95% CI = 2.225–9.702) genotype in IL‐10 were at increased risk of developing tuberculosis. MDR tests revealed high‐risk genotypes in IL‐1β and IL‐10 based on the association model. Our results demonstrate that the polymorphisms of IL‐1β and IL‐10 genes may be valuable markers to predict the risk for the development of TB in household contacts.     

Associative role of HLA‐DRB1 SNP genotypes as risk factors for susceptibility and severity of rheumatoid arthritis: A North‐east Indian population‐based study

Rheumatoid arthritis (RA) is a complex, multifactorial, systemic autoimmune disease. Reports are suggestive of the role of HLA especially HLA‐DRB1 alterations in RA pathogenesis. Existing data involving different geographical populations on the role of alterations in specific locus of HLA‐DRB1 in RA susceptibility and severity are equivocal, with no data available from ethnically distinct North‐east Indian population, where RA cases are alarmingly increasing. This study aimed to evaluate the association of HLA‐DRB1 gene SNPs (rs13192471, rs660895 and rs6457617) with susceptibility and severity of RA in an ethnically distinct North‐east Indian population. Whole blood was collected from clinically characterized RA cases (satisfying the American College of Rheumatology 1987 criteria) (n = 123) and community‐based age and sex‐matched healthy controls (n = 156) with informed consent. The HLA‐DRB1 SNP analysis was performed for all the RA and control cases using ARMS‐PCR using case and control genomic DNA as template. Statistical analysis was performed by SPSSv13.0 software. The HLA‐DRB1 rs660895 showed both wild (AA) and heterozygote (AG) genotype but the heterozygote allele was found to be associated with reduced risk of RA compared to controls [OR = 0.531, p = .024]. The difference in distribution of rs6457617 polymorphism between RA and control cases was comparable [OR = 0.525, p = .079]. Significantly higher distribution of variant rs13192471 genotype was observed in RA cases (69.92%) compared to controls (46.75%) (p < .001) and was associated with increased risk of susceptibility to RA [OR = 2.576, p < .001] compared to controls, as well as progression to severity in RA cases [OR = 2.404, p = .048]. Combinatorially also, the presence of rs13192471 variant genotype was associated with increased risk of RA susceptibility [OR = 8.267, p = .026] and RA severity [OR = 3.647, p = .280]. Alterations in HLA‐DRB1 are associated with RA susceptibility. HLA‐DRB1 rs13192471 SNP plays a critical role in RA susceptibility and severity in North‐east Indian cases and has prognostic significance in RA.     

Interleukin 10 gene promoter polymorphisms (rs1800896, rs1800871 and rs1800872) and haplotypes are associated with the activity of systemic lupus erythematosus and IL10 levels in an Iranian population

Systemic lupus erythematosus (SLE) is a chronic autoimmune disease with unknown aetiology. According to the role of interleukin 10 (IL10) in SLE pathogenesis, the genetic alterations in its promoter region could be associated with elevated IL10 levels and exacerbated disease. Here, we investigated the association of genotype and haplotype frequencies of three IL10 gene promoter polymorphisms with susceptibility to SLE, IL10 plasma levels and disease activity of patients in an Iranian population. A total of 116 SLE patients and 131 healthy subjects were enrolled. The PCR‐RFLP technique was used to detect IL10 promoter genotypes at the positions of ?1082 (G/A), ?819 (C/T) and ?592 (C/A) in association with IL10 plasma levels and SLEDAI scores. The GG genotype of ?1082 polymorphism was associated with the increased risk of SLE [OR = 2.65, 95% CI (1.21–5.82), p‐value = 0.046]. The CC genotype in ?819 region was associated with SLE susceptibility [OR = 3.38, 95% CI (1.26–9.07), p‐value = 0.034] and C allele was introduced as risk allele [OR = 1.86, 95% CI (1.15–3.01), p‐value = 0.009] in this region. IL10 plasma levels were overexpressed in CC genotype carriers of ?592 SNP and decreased in AA genotype carriers of ?1082. IL10 was also increased in SLE patients with CGT (?592/?1082/?819) haplotype. The SLEDAI score was higher among CC genotype carriers at the position of ?592 and TT genotype carriers at the region of ?819. SLEDAI was also elevated among patients with CGC (?592/?1082/?819) and CAC (p = 0.011) haplotypes. The present study suggests that the IL10 –819(C/T), ?1082(G/A) and ?592(C/A) polymorphisms and the haplotypes are associated with SLE susceptibility, increased disease activity and elevated IL10 levels. While this is the first time to report such an association in an Iranian population, further studies are needed to confirm these findings.     

Analysis of PTPN22, ZFAT and MYO9B polymorphisms in Turner Syndrome and risk of autoimmune disease

Turner syndrome (TS) is one of the most common sexual chromosome abnormalities and is clearly associated with an increased risk of autoimmune diseases, particularly thyroid disease and coeliac disease (CD). Single‐nucleotide polymorphism analyses have been shown to provide correlative evidence that specific genes are associated with autoimmune disease. Our aim was to study the functional polymorphic variants of PTPN22 and ZFAT in relation to thyroid disease and those of MYO9B in relation to CD. A cross‐sectional comparative analysis was performed on Mexican mestizo patients with TS and age‐matched healthy females. Our data showed that PTPN22 C1858T (considered a risk variant) is not associated with TS (X² = 3.50, p = .61, and OR = 0.33 [95% CI = 0.10–1.10]). Also, ZFAT was not associated with TS (X² = 1.2, p = .28, and OR = 1.22 [95% CI = 0.84–1.79]). However, for the first time, rs2305767 MYO9B was revealed to have a strong association with TS (X² = 58.6, p = .0001, and OR = 10.44 [95% C = 5.51–19.80]), supporting a high level of predisposition to CD among TS patients. This report addresses additional data regarding the polymorphic variants associated with autoimmune disease, one of the most common complications in TS.     

Association of PDCD1 polymorphisms with childhood-onset systemic lupus erythematosus

A regulatory single nucleotide polymorphism (SNP) PD1.3G/A located on programmed cell death 1 (PDCD1) gene, was shown to be involved in susceptibility to systemic lupus erythematosus (SLE) in Swedish, European American, and Mexican cases. However, association to childhood-onset SLE has not been analyzed. The aim of this study was to investigate the association of PDCD1 polymorphisms and haplotypes with susceptibility to childhood-onset SLE in Mexican population. Three PDCD1 SNPs, PD1.3G/A, PD1.5C/T, PD1.6G/A, were analyzed in 250 childhood-onset SLE Mexican patients and 355 healthy controls in a case-control association study. Polymorphisms were genotyped by TaqMan technology. Stratification analysis was performed on the SLE cohort to investigate the SNP association with renal disorder. In addition, haplotypes were constructed with these three SNPs. The PD1.3A allele was significantly associated to childhood-onset SLE (P=0.0019, odds ratio (OR) 2.73, 95% confidence interval (95% CI) 1.35-5.56). The other PDCD1 SNPs did not show association. A total of 155 patients (62%) had nephritis, and no association was observed with PDCD1 SNPs. The ACG haplotype (PD1.3A, PD1.5C, PD1.6G) included almost all PD1.3A alleles, and it was more frequent in SLE patients (5.5%) than in controls (2.1%) (P=0.003; OR 2.73, 95% CI 1.37-5.46). The haplotype structure in Mexican controls was significantly different from those reported in Spanish and Swedish. Our results support association of the PD1.3A SNP to susceptibility of childhood-onset SLE in Mexican population and does not show association to lupus nephritis in this age group.     

TNFSF4 polymorphisms are associated with systemic lupus erythematosus in the Malaysian population

Tumour necrosis factor superfamily 4 (TNFSF4) gene has been reported to be associated with systemic lupus erythematosus (SLE) susceptibility due to its encoding for OX40L protein that can increase autoantibody production and cause imbalance of T‐cell proliferation. The purpose of this study was to investigate the association of TNFSF4 rs2205960, rs1234315, rs8446748 and rs704840 with SLE in the Malaysian population. A total of 476 patients with SLE and 509 healthy controls were recruited. Real‐time polymerase chain reaction (PCR) was applied to genotype the selected single nucleotide polymorphisms (SNPs). Allelic and genotypic frequencies of each SNP were calculated for each ethnic group, and association test was performed using logistic regression. The overall association of each SNP in Malaysian patients with SLE was determined with meta‐analysis. The frequency of minor T allele of TNFSF4 rs2205960 was significant in Chinese and Indian patients with SLE, with P values of 0.05 (OR = 1.27, 95% CI: 1.00–1.61) and 0.004 (OR = 3.16, 95% CI: 1.41–7.05), respectively. Significant association of minor G allele of rs704840 with SLE was also observed in Chinese (P = 0.03, OR = 1.26, 95% CI: 1.02–1.56). However, after Bonferroni correction, only T allele of rs2205960 remained significantly associated with Indian cohort. Overall, minor G allele of rs704840 showed significant association with SLE in the Malaysian population with P values of 0.05 (OR = 1.20, 95% CI: 1.00–1.43). We suggested TNFSF4 rs704840 could be the potential SLE risk factors in the Malaysian population.     

Association Between TNF‐α Promoter −308 A/G Polymorphism and Systemic Lupus Erythematosus Susceptibility: A Case–Control Study and Meta‐Analysis

The tumour necrosis factor‐α (TNF‐α) promoter −308 A/G polymorphism plays an important role in the aetiology of systemic lupus erythematosus (SLE). Several studies have estimated the association between TNF‐α −308 A/G and SLE risk. However, results were inconsistent. A case–control study was carried out to explore the association between TNF‐α −308 A/G and the SLE risk in a Chinese Han population. Meta‐analysis combining present with previous studies was conducted to further explore the association. Our case–control study included 556 patients with SLE along with 570 matched healthy controls. TNF‐α −308 A allele was significantly increased in patients with SLE compared with controls (OR = 2.184, 95% CI: 1.718–2.778, P < 0.001). Genotypes AA and AG were associated with the susceptibility to SLE as compared with the GG genotype, as well as the dominant model (AA+AG versus GG), respectively. The meta‐analysis included 41 comparative studies involving 4799 patients and 6635 controls. An association between SLE and allele A was found in the overall populations (OR = 1.70, 95% CI: 1.46–1.98, P < 0.001). In addition, we discussed the correlation between this polymorphism and lupus nephritis (LN) risk, showing that allele A was significantly related to LN in the overall populations (OR = 1.80, 95% CI: 1.21–2.68, P = 0.004). The results from our case–control study and the meta‐analysis indicate that the TNF‐α −308 A allele is significantly associated with an increased risk of SLE/LN.     

Polymorphisms in IL‐1A are associated with endometrial cancer susceptibility among Chinese Han population: A case–control study

Endometrial cancer (EC) is one of the most common malignant tumours of the female genital tract, and it has become a serious malignant disease of the female genital tract in China. Existing researches have revealed the association between polymorphisms of IL‐1A and several gynaecological diseases. In this research, we analysed the association between IL‐1A gene polymorphisms and endometrial cancer susceptibility in Chinese female population. A total of 81 patients and 198 healthy people were selected. Odds ratio (OR) and 95% confidence intervals (CIs) were calculated using unconditional logistic regression. Genetic models and analyses showed that IL‐1A rs3783550 TT and rs3783546 CC increased the risk of endometrial cancer under the recessive model, respectively (rs3783550: OR = 2.80, 95%CI: 1.32–5.92, p = .008; rs3783546: OR = 2.79, 95%CI: 1.32–5.89, p = .008). In the recessive model, we also found that both IL‐1A rs1609682 and IL‐1A rs3783521 increased the risk of endometrial cancer, respectively (rs1609682: OR = 2.79, 95%CI: 1.32–5.89, p = .0081; rs3783521: OR = 2.80, 95%CI: 1.32–5.92, p = .008). Haplotype analysis was performed that did not reveal any significant results. In summary, IL‐1A rs3783550, rs3783546, rs1609682 and rs3783521 polymorphisms may be associated with an increased risk of endometrial cancer in Chinese female populations.     

Associations between interleukin 1 polymorphisms and susceptibility to systemic lupus erythematosus: A meta-analysis

Objective

This study determined whether interleukin 1 (IL1) polymorphisms are associated with susceptibility to systemic lupus erythematosus (SLE).

Methods

A meta-analysis was conducted on the associations between the IL1A, IL1B, and IL1 receptor antagonist (IL1RN) polymorphisms and SLE.

Results

A total of 15 studies involving 1956 SLE cases and 2347 controls were included in the meta-analysis. The meta-analysis showed an association between SLE and the IL1A −889 T allele in the overall population and Europeans (OR = 0.858, 95% CI = 0.737–0.986, p = 0.032; OR = 0.827, 95% CI = 0.687–0.994, p = 0.043). Meta-analysis of the IL1RN polymorphism revealed an association with SLE in all study subjects (OR for IL1RN^∗2 = 1.539, 95% CI = 1.266–1.871, p = 1.5 × 10⁻²) and in Europeans and Asians (OR = 1.483, 95% CI = 1.187–1.852, p = 0.001; OR = 1.787, 95% CI = 1.167–2.736, p = 0.008). No associations were found between SLE and the IL1B −511 C/T, 3953 C/T, and IL1A +4845 G/T polymorphisms.

Conclusions

This meta-analysis suggests IL1A −889 C/T polymorphism is associated with susceptibility to SLE in Europeans, and that the IL1RN^∗2 allele is associated with susceptibility to SLE in Europeans and Asians.     

Association between two single nucleotide polymorphisms of PDCD6 gene and increased endometriosis risk

Programmed cell death 6 (PDCD6), a calcium binding protein of the penta EF-hand protein family, and its receptors are involved in regulation of apoptosis pathways. To evaluate the relationship between genetic polymorphisms of PDCD6 gene and endometriosis (ED) risk, we investigated the association of two single nucleotide polymorphisms (SNPs) of PDCD6 gene (rs4957014 and rs3756712) in 220 endometriosis patients and 386 unrelated healthy controls. The genotypes of these two SNPs were determined by using polymerase chain reaction (PCR)–restriction fragment length polymorphism (RFLP) and DNA sequencing methods. Significantly increased endometriosis risk was observed to be associated with G allele of rs4957014 locus (OR = 1.31, 95% CI = 1.03–1.69). We have also observed increased ED risk was statistically associated with rs4957014 polymorphism in a dominant model (OR = 1.52, 95% CI = 1.09–2.13). Although no association has been found between ED risk and the allele frequencies of rs3756712 locus (a marginal P = 0.066, OR = 1.27, 95% CI = 0.98–1.65), but in a dominant model, increased endometriosis risk was significantly associated with rs3756712 polymorphism (OR = 1.54, 95% CI = 1.11–2.17). In conclusion, the current study indicates that PDCD6 gene may be a new susceptibility gene to endometriosis.     

Association of hepatocellular carcinoma risk with polymorphisms in tumour necrosis factor alpha gene in a Chinese Han population

Hepatocellular carcinoma (HCC) is the third leading cause of cancer‐related death worldwide. Studies have shown that the tumour necrosis factor alpha (TNF‐α) plays an important role in the development of HCC; however, the association between genetic variations of TNF‐α and HCC is not yet fully understood. To evaluate the correlation of TNF‐α polymorphisms with HCC, we randomly selected 327 HCC patients and 432 healthy controls, all these subjects reported Han nationality. Genotyping of four TNF‐α SNPs (rs1799724, rs1800629, rs1799964 and rs1800610) was performed using the matrix‐assisted laser desorption ionization‐time of flight mass spectrometry (MALDI‐TOF‐MS) method. Distributions of rs1799964 genotypes and rs1800610 alleles were found to be significantly different between cases and controls (p = .011, p = .001). The recessive model of rs1799964 significantly increased HCC risk (p = .0015), while the dominant and over‐dominant models of rs1800610 significantly reduced HCC risk (p = .0096, p = .014). Haplotype analysis of the four TNF‐α SNPs revealed that the TGTA haplotype was associated with a reduced HCC risk (p = .0033, OR = 0.53), while the TGTG haplotype was associated with an increased HCC risk (p = .0032, OR = 9.69). These findings indicated that specific TNF‐α polymorphisms may be associated with the susceptibility to HCC.     

TNFRSF1A polymorphisms and their role in multiple sclerosis susceptibility and severity in the Slovak population

Tumour necrosis factor (TNF)‐mediated signalling plays a key role in inflammatory and neurodegenerative processes leading to the development of multiple sclerosis (MS). Recent studies have highlighted the role of tumour necrosis factor receptor superfamily member 1A (TNFRSF1A) gene encoding the type 1 TNF receptor in the genetic predisposition to MS. This study aimed to validate the association of TNFRSF1A rs1800693 and rs4149584 polymorphisms with susceptibility to MS in the Slovak population and analyse their influence on age at disease onset, severity, and disability progression. Polymerase chain reaction–restriction fragment length polymorphism method was used to genotype both TNFRSF1A polymorphisms in 541 MS patients and 724 healthy controls. Logistic regression analysis revealed a significantly increased risk of developing MS for the carriers of rs1800693 C allele (TC + CC vs. TT: pcorr = 0.005; OR = 1.61; 95% CI = 1.23–2.12), irrespective of sex and carriage of the major MS risk allele HLA‐DRB1*15:01. On the other hand, no association could be found between rs4149584 and MS risk (GA + AA vs. GG: pcorr = 1.00; OR = 1.25; 95% CI = 0.71–2.21). Moreover, neither polymorphism was significantly associated with age at disease onset, MS Severity Score (MSSS) or MS Progression Index (PI) in any of the inheritance models. In conclusion, our results provide support for a sex‐ and HLA‐DRB1*15:01‐independent association of TNFRSF1A rs1800693 SNP with MS susceptibility, but not with age at disease onset, severity or rate of disability accumulation.     

Insomnia as a mediating therapeutic target for depressive symptoms: A sub‐analysis of participant data from two large randomized controlled trials of a digital sleep intervention

Insomnia predicts the onset of depression, commonly co‐presents with depression and often persists following depression remission. However, these conditions can be challenging to treat concurrently using depression‐specific therapies. Cognitive behavioural therapy for insomnia may be an appropriate treatment to improve both insomnia and depressive symptoms. We examined the effects of a fully‐automated digital cognitive behavioural therapy intervention for insomnia (Sleepio) on insomnia and depressive symptoms, and the mediating role of sleep improvement on depressive symptoms in participants from two randomized controlled trials of digital cognitive behavioural therapy for insomnia. We also explored potential moderators of intervention effects. All participants met criteria for probable insomnia disorder and had clinically significant depressive symptomatology (PHQ‐9 ≥ 10; n = 3,352). Individuals allocated to treatment in both trials were provided access to digital cognitive behavioural therapy. Digital cognitive behavioural therapy significantly improved insomnia (p < .001; g = 0.76) and depressive symptoms (p < .001; g = 0.48) at post‐intervention (weeks 8–10), and increased the odds (OR = 2.9; 95% CI = 2.34, 3.65) of clinically significant improvement in depressive symptoms (PHQ‐9 < 10). Improvements in insomnia symptoms at mid‐intervention mediated 87% of the effects on depressive symptoms at post‐intervention. No variables moderated effectiveness outcomes, suggesting generalizability of these findings. Our results suggest that effects of digital cognitive behavioural therapy for insomnia extend to depressive symptoms in those with clinically significant depressive symptomatology. Insomnia may, therefore, be an important therapeutic target to assist management of depressive symptoms.     

Single‐nucleotide polymorphisms of IRF8 gene are associated with systemic lupus erythematosus in Chinese Han population

Interferon regulatory factor 8 (IRF8) has been shown to have diverse roles in the regulation of the immune system. Two recent studies had revealed the association between the single‐nucleotide polymorphisms (SNPs; rs11644034 and rs2280381) of IRF8 and systemic lupus erythematosus (SLE) in a multiethnic population. The purpose of this study was to evaluate whether the association could be replicated in a Chinese Han population. Genotypes were determined by a multiplex polymerase chain reaction–ligase detection reaction (PCR–LDR) in 358 patients and 357 geographically matched healthy controls. Significant differences in genotype frequency were found between SLE and control individuals (rs11644034: AA vs. GG, P = 0.014, odds ratio (OR) = 0.980, 95% confidence internal (CI): 0.964–0.996; rs2280381: CC vs. TT, P = 0.005, OR = 0.150, 95% CI: 0.033–0.676). Conditional logistic regression analysis showed that the association of rs2280381 remained significant (P adjusted = 0.028) after adjustment for rs11644034, but not vice versa (P adjusted = 0.361).When stratifying patients with SLE according to clinical subtypes, SNP rs2280381 was found to be associated with low complement in patients with SLE. However, SNP rs11644034 was not found to be associated with SLE clinical subgroups. Analysis of the haplotypes revealed that haplotype G‐T and G‐C were also significantly associated with SLE (P = 0.002 and P = 0.012, respectively). Our study indicated that the IRF8 gene polymorphisms might be associated with susceptibility to SLE and with disease‐related clinical manifestations in Chinese Han population.