Western Chinese Han Population Research Articles

Gene polymorphisms of an interleukin-23 receptor associated with susceptibility to rheumatoid arthritis in the Western Chinese Han population.

Rheumatoid arthritis (RA) is a chronic inflammatory disease which is closely related to genetic background. Single-nucleotide polymorphisms (SNPs) have been found to play an important role in the development of RA. This study intends to investigate the links between gene polymorphisms in the interleukin-23 receptor (IL23R) and interleukin 17A (IL17A) and susceptibility to RA in the Western Chinese Han population. Four SNPs (rs6693831 T>C, rs1884444 G>T, and rs7517847 T>G in IL23R gene, and rs2275913 G>A in IL17A gene) were genotyped in 246 RA patients and 362 healthy controls by high resolution melting analysis. The comparative analyses among genotype distributions, clinical indicators, and IL-17A and IL-23R levels in RA patients were also performed. The study revealed that the SNP rs6693831 and rs1884444 of IL23R had a significant association with RA susceptibility. The frequencies of rs6693831 genotype CC and allele C were significantly higher in the RA group and associated with higher RA risk compared with genotype TT and allele T (OR=7.797, 95% confidence interval [CI]=4.072-14.932 and OR=5.984, 95%CI=3.190-11.224, respectively). The TT genotype of rs1884444 appeared to decrease the RA risk compared with the GG genotype (OR=.251, 95%CI=.118-.536). The genotype CC and allele C of rs6693831 and the genotype GG and allele G of rs1884444 may be risk factors for RA. IL23R gene polymorphisms may be involved in the risk of RA susceptibility in the Western Chinese Han population.

Genome-wide association study of tuberculosis in the western Chinese Han and Tibetan population.

Tuberculosis (TB) remains a serious global public health threat. Accumulated evidence has demonstrated that human susceptibility to TB has a strong genetic basis. And different susceptibility single nucleotide polymorphisms (SNP) have been reported in different studies. To gain greater insight into the host susceptibility to TB, we perform a two-stage genome-wide association study to identify the susceptible loci of TB. In the discovery stage, 3116 (1532TB patients and 1584 healthy controls) and 439 (211TB patients and 228 healthy controls) individuals were genome-wide genotyped from a western Chinese Han and Tibetan population, respectively. Based on the additive genetic model, we discovered 14 and three independent loci that had potential associations with TB susceptibility in the Chinese Han and Tibetan populations, respectively (p<1×10-5). Furthermore, we conducted an imputation-based meta-analysis on another two East Asia cohorts to replicate our findings. We identified one independent locus harbored by the human leukocyte antigen (HLA) class II genes that was genome-wide significantly associated with TB (lead SNP rs111875628 with a p-value of 2.20×10-9). Our findings suggest a novel mechanism of the interaction with the HLA class II genes and reinforce the importance of the HLA class II alleles in response to TB.

Association of soluble epoxide hydrolase 2 gene with the risk of non-syndromic cleft lip with or without cleft palate in western Han Chinese population.

This study aimed to explore the associations between soluble epoxide hydrolase 2 gene (EPHX2) variants and non-syndromic cleft lip with or without cleft palate (NSCL/P) in Chinese Han population. We recruited 159 NSCL/P cases from Chinese Han population and carried out targeted resequencing using the whole genome sequencing data of 542 healthy Chinese individuals from Novegene internal database as controls. We classified EPHX2 variants as common or rare according to their minor allele frequency and performed an association analysis for common variations and a burden analysis for rare variations. The lowest P-value in NSCL/P was observed at rs57699806 (P=0.000 13, OR=2.849 and 95% CI: 1.691-4.800), followed by rs4732723 (P=0.006 50, OR=0.662 and 95%CI: 0.491-0.892), rs7829267 (P=0.009 20, OR=1.496 and 95%CI: 1.117-2.005), rs721619 (P=0.011 00, OR=1.474 and 95%CI: 1.098-1.980), and rs7816586 (P=0.040 00, OR=1.310 and 95%CI: 1.015-1.691). The odds ratios suggested the C allele at rs4732723 as a protective factor for NSCL/P and the reference alleles at other single nucleotide polymorphisms (SNPs) as the risk factors for NSCL/P. Burden analysis showed no statistical significance (P>0.05). Through targeted resequencing, this study identified five SNPs named rs57699806, rs4732723, rs7829267, rs721619, and rs7816586 around the region of EPHX2 gene associated with NSCL/P in Chinese Han population. Four SNPs of rs57699806, rs4732723, rs7829267, and rs7816586 were first identified.

Target sequencing reveals the association between variants in VAX1 and NSCL/P in Chinese population.

A significant genetic association between rs7078160 in VAX1 and NSCL/P has been established through genome-wide association studies (GWAS), and we previously replicated the association in the Chinese population. The critical issue in the post-GWAS era is to identify functional variations that have a real impact on disease in the susceptible regions highlighted by GWAS. This study aimed to elucidate functional variants in VAX1 fully. Firstly, target sequencing was performed on 159NSCL/P patients, followed by association analysis to discover disease-associated single-nucleotide polymorphisms (SNPs); we then replicated the findings using a larger sample (1626 cases, 2255 controls) and investigated how candidate SNPs affect disease occurrence using extensive annotation databases. Additionally, we compared the genetic profiles of NSCL/P subtypes. In this study, 6 SNPs in VAX1 were identified to be associated with NSCL/P in the Western Han Chinese population. Five of them were predicted to influence transcriptional factor-biding ability and were expression quantitative trait loci (eQTLs) of nearby genes in multiple tissues. The previously reported association between rs7078160 and NSCL/P was successfully replicated. Moreover, our findings firstly revealed that 5 SNPs in VAX1 are associated with NSCL/P in the Western Han Chinese population. Original Reports.

Prospective study of ALDH1A1 gene polymorphisms associated with antituberculosis drug-induced liver injury in western Chinese Han population.

Antituberculosis drug-induced liver injury (ATDILI) has received increasing attention globally, which may limit the effectiveness of antituberculosis (anti-TB) treatment. Many host genetic determinants of ATDILI have been identified recently. As little knowledge is currently available about the association between aldehyde dehydrogenase 1 family member A1 (ALDH1A1) polymorphisms and ATDILI, the association between their variants and the susceptibility to ATDILI was investigated. A total of 747 patients with TB treated by first-line anti-TB drugs were prospectively enrolled at West China Hospital. Genomic DNA was extracted from the peripheral blood sample of each patient and seven single-nucleotide polymorphisms (SNPs) of ALDH1A1 gene were screened and genotyped with a custom-designed 2×48-plex SNP Scan TM kit. The patients were followed up monthly to monitor the development of ATDILI. The C allele and the CA genotype of rs7852860 were significantly associated with an elevated risk for ATDILI (p = .006 and 0.005, respectively), which was consistent with the results in the dominant and additive models. No allele, genotype, or genetic model of the other six SNPs (rs3764435, rs348471, rs63319, rs610529, rs7027604, rs8187876) were found to be associated with susceptibility to ATDILI. The findings first demonstrate that rs7852860 variants in ALDH1A1 gene is associated with susceptibility to ATDILI in the Chinese Han population. Validation studies with larger sample sizes and other ethnic groups are needed to confirm the findings.

Collagen type XVIII alpha 1 chain (COL18A1) variants affect the risk of anti-tuberculosis drug-induced hepatotoxicity: A prospective study.

BackgroundThe role of collagen type XVIII alpha 1 chain (COL18A1) in anti‐tuberculosis drug‐induced hepatotoxicity (ATDH) has not been reported. This study aimed to explore the association between of COL18A1 variants and ATDH susceptibility.MethodsA total of 746 patients were enrolled in our study from December 2016 to April 2018, and all subjects in the study signed an informed consent form. The custom‐by‐design 2x48‐Plex SNPscanTM kit was used to genotype all selected 11 SNPs. Categorical variables were compared by chi‐square (χ2) or Fisher's exact test, while continuous variables were compared by Mann‐Whitney's U test. Plink was utilized to analyze allelic and genotypic frequencies, and genetic models. Multivariate logistic regression analyses were used to adjust potential factors. The odds ratios (ORs) with corresponding 95% confidence intervals (CIs) were also calculated.ResultsAmong patients with successfully genotyping, there were 114 cases and 612 controls. The mutant A allele of rs12483377 conferred the decreased risk of ATDH (OR = 0.13, 95%CI: 0.02–0.98, P = 0.020), and this significance still existed after adjusting age and gender (P = 0.024). The mutant homozygote AA genotype of rs12483377 was associated with decreased total protein levels (P = 0.018).ConclusionOur study first revealed that the A allele of COL18A1 rs12483377 was associated with the decreased risk of ATDH in the Western Chinese Han population, providing new perspective for the molecular prediction, precise diagnosis, and individual treatment of ATDH.

SFTPC genetic polymorphisms are associated with tuberculosis susceptibility and clinical phenotype in a Western Chinese Han population.

Tuberculosis (TB) is one of the most common infectious diseases globally. The surfactant protein C (SFTPC), which is involved in innate immunity and surfactant function in the lung, may contribute toward the progression of TB. The aim of the present study was to preliminarily investigate the possible association of single nucleotide polymorphisms (SNPs) in the SFTPC gene with TB susceptibility and clinical phenotypes in a Western Chinese Han population. The improved multiplex ligation detection reaction method was used to genotype 6 SNPs in SFTPC, in 900 patients with TB and 1,534 healthy control subjects. It was found that the A allele for rs1124 and the C allele for rs8192313 were associated with increased susceptibility to TB, P=0.024 and P=0.045, respectively. However, these two P-values were not significant following Bonferroni correction. In all samples, the haplotype [CGA], representing three SFTPC variants, was revealed to increase the risk of TB (P=0.001 and P=0.005, following Bonferroni correction). Furthermore, patients with the AA genotype for rs1124 and with the CC genotype for rs8192313 were associated with higher levels of C-reactive protein (P=0.001 and P=0.005, respectively). The results of the present study indicated that the SFTPC SNPs may increase the susceptibility to TB and the immune response of the host to Mycobacterium tuberculosis and may potentially be novel biomarkers for the pathogenesis of TB.

Mutation at Paired box gene 9 is associated with non-syndromic cleft lip only from Western Han Chinese population

ObjectivesThis study aimed to initially screen more susceptible variations at PAX9 gene in non-syndromic cleft palate only cases and then test their associations in independent non-syndromic orofacial cleft subtypes from Western Han Chinese population. DesignInitially exons at PAX9 gene were screened for variations among 180 non-syndromic cleft palate only patients by the Sanger sequencing method, and the genotype data from 1000 Genomes Project Database was taken as control to perform Chi-square test. Subsequently, we performed association analysis among 2202 non-syndromic orofacial cleft patients (938 non-syndromic cleft palate only cases, 456 non-syndromic cleft lip only cases and 808 non-syndromic cleft lip and palate cases) and 1823 normal controls to replicate the role of two significant single nucleotide polymorphisms. ResultsTwo intronic single nucleotide polymorphism rs12885612 (P = 0.047, OR = 0.671 and 95−0.996) and rs12881248 (P = 0.047, OR = 1.006 and 95 %CI: 0.443−0.995) were associated non-syndromic cleft palate only in the initial screen phase. Surprisingly, in replication analysis rs12885612 (P = 0.048, OR = 1.25, 95 %CI: 1.0–1.56) and rs12881248 (P = 0.037, OR = 1.26, 95 %CI: 1.01−1.57) exhibited significant association signal in non-syndromic cleft lip only group, but not in non-syndromic cleft palate only group. ConclusionIn summary, this study firstly revealed that rs12885612 and rs12881248 at PAX9 gene associated with non-syndromic cleft lip only from Western Han Chinese population, which indicated that PAX9 is a promising susceptible gene for non-syndromic cleft lip only in Western Han Chinese population.

No Significant Effects of IL-6 and IL-13 Gene Variants on Tuberculosis Susceptibility in the Chinese Population.

Tuberculosis (TB) is an intricate infectious disease that causes a large number of deaths in the population. Interleukin (IL)-6 and IL-13 play functional roles in host resistance to Mycobacterium tuberculosis infection. Our aim in this study was to explore the association of IL-6 and IL-13 polymorphisms with TB susceptibility in the Western Chinese Han population. The case and control groups comprised 900 TB patients and 1534 healthy controls, respectively, and four single-nucleotide polymorphisms (SNPs) were genotyped in IL-6 and five SNPs in IL-13 through the improved multiplex ligation detection reaction method. We found no genetic variants in the IL-6 or IL-13 genes that were related to TB susceptibility in the analysis of alleles, genotypes, genetic models, and TB clinical subtypes, except for a trend toward low pulmonary tuberculosis and extrapulmonary tuberculosis susceptibility for the SNPs rs1295686 and rs20541. Our study did not find a link between IL-6 and IL-13 polymorphisms and TB susceptibility in the Western Chinese Han population. Therefore, our present data revealed the challenge of applying IL-6 and IL-13 SNPs as genetic markers for TB and that increased sample sizes and additional races are needed for further studies.

Association of IL27 and STAT3 genetic polymorphism on the susceptibility of tuberculosis in Western Chinese Han population

ObjectiveHost immune response have a pivotal role in the course of Mycobacterium tuberculosis (Mtb) infection. IL27 plays both pro-inflammatory and anti-inflammatory activities in infectious diseases via STAT1/STAT3 mechanism. To investigate the association of single nucleotide polymorphisms (SNPs) of IL27 and STAT3 on the susceptibility of tuberculosis, we conducted a large size of case-control study in western Chinese Han population. MethodsA total of seven SNPs were genotyped using multiplex ligation detection reaction method in 900 patients with tuberculosis and 1534 healthy controls. ResultsVariants of three SNPs (rs181206, rs17855750, rs26528) within IL27 gene, the genotype and allele frequencies of rs17855750 were significantly different (p = .013, p = .004, respectively) between the TB patients and healthy controls. Subjects carrying C allele for rs17855750 showed a decreased tuberculosis risk (OR = 0.75, 95% CI = 0.62–0.91, p = .004). Genetic model analysis revealed that dominant modal was associated with lower TB risk (OR = 0.74, 95% CI = 0.60–0.92, p = .042). Haplotype of ACG (representing rs181206, rs17855750 and rs26528) showed a reduced risk to TB (OR = 0.79, 95% CI = 0.65–0.96, p = .017). There were no significant differences between TB cases and healthy controls in the variants of four SNPs (rs1053005, rs2293152, rs744166, rs4796793) within STAT3 gene. ConclusionsThe polymorphisms of IL27, rs17855750, but not rs181206 and rs26528, plays a protective role on the susceptibility to TB.

Absence of significant association between UGT2B4 genetic variants and the susceptibility to anti-tuberculosis drug-induced liver injury in a Western Chinese population.

Combination regimens of six-month duration may increase the incidence of anti-tuberculosis drug-induced liver injury (ATLI), which is clinically characterized by mild cholestasis and hepatocanalicular lesions. UGT2B4 is a predominant UDP-glucuronosyltransferase enzyme in the human liver that plays an important role in the detoxification of bile acids, which yields water-soluble inactive compounds that can easily be excreted in the bile or urine. This study aimed to investigate the potential association between UGT2B4 variants and the susceptibility to ATLI. Genomic DNA was extracted from whole blood sample of each patient, and all SNPs were genotyped using an improved multiplex ligation detection reaction method. Clinical symptoms and laboratory results were recorded regularly. Five genetic variants at UGT2B4(rs1131878, rs1966151, rs28361541, rs4557343 and rs79407331) were identified in a prospective study of 118 ATLI cases and 628 non-ATLI controls. All participants were treated by first-line anti-TB drugs in Western China Hospital. The potential association between SNPs, ATLI risk and clinical phenotypes were determined based on the distribution of allelic frequencies and different genetic models. Statistical comparisons of cases and controls after correction for multiple testing did not yield any significant association between genetic variants at UGT2B4 and risk of ATLI via the analyses of single locus and subgroup differences. This is the first study aimed to investigate the association of UGT2B4 polymorphisms with ATLI risk. Our results revealed that UGT2B4 genetic variants are unlikely to confer susceptibility to ATLI in the Western Chinese Han population.

Significance of LncRNA CASC8 genetic polymorphisms on the tuberculosis susceptibility in Chinese population.

BackgroundTuberculosis remains an important disease threatening the security of public health, and no effective targets have been found for the immunological diagnosis or therapy of tuberculosis. The aim of this study was to explore the associations between lncRNA CASC8 genetic polymorphism and tuberculosis risk.MethodA total of 900 tuberculosis patients and 1534 healthy individuals in the Western Chinese Han population were recruited for our study. Candidate SNPs of CASC8 were initially filtered by importing the 1000 genomes database into Haploview, and subsequently genotyped using modified multiplex ligation detection reactions.ResultsThe lncRNA CASC8 genetic variant rs7836840 was associated with an increased tuberculosis risk with a P‐value of .034, but .134 after Bonferroni correction. Using subtype analysis, the C allele in rs7836840 showed a significant association with tuberculosis susceptibility (OR = 1.196, 95% CI = 1.05‐1.362, P = .02739 after Bonferroni correction). Patients carrying genotype AG and GG of rs7825118 and rs9297758 exhibited lower Hb concentrations (P = .006) and neutrophil counts (P = .015), respectively, while genotype AG and AA in rs6981424 demonstrated higher levels of ALT (P = .005) and AST (P = .033) in a dominant model, which were consistent with a tendency toward increased TB risk.ConclusionsThis study was the first to explore the association between lncRNA CASC8 polymorphisms and TB infection risk and clinical manifestations. Our results provide evidence that CASC8 may act as a biomarker for the progression of clinical tuberculosis.

Association of POR and PPARα polymorphisms with risk of anti-tuberculosis drug-induced liver injury in Western Chinese Han population

ObjectivesAnti-tuberculosis drug-induced liver injury (ATDILI) is a common and sometimes severe adverse drug reaction (ADR). This study was conducted to investigate the relationship between polymorphisms of two genes, cytochrome P450 oxidoreductase (POR) and peroxisome proliferator-activated receptor α (PPARα), and the risk of ATDILI in Western Chinese Han population. MethodsA total of 118 tuberculosis (TB) patients with ATDILI and 628 TB patients without ATDILI during anti-TB treatment were recruited from West China Hospital of Sichuan University. DNA was extracted from peripheral blood, and genotypes of the selected 12 single nucleotide polymorphisms (SNPs) (3 SNPs in the POR gene and 9 SNPs in the PPARα gene) were determined. Three genetic models (additive, dominant, and recessive), as well as a haplotype, were used to test the genetic risk of ATDILI. Extended subgroup analysis was conducted according to age, sex and different causality assessments. ResultsThe mutant allele, genotype and genetic model of rs3898649 in the POR gene were found to be associated with increased risk of ATDILI, especially in the younger (<50 years old), female and pulmonary tuberculosis subgroup. The other two SNPs rs28737229 and rs4728533 in the POR gene showed only a potential association with susceptibility to ATDILI after Bonferroni correction (P < .05 but PBonferroni > .05). The other 9 SNPs loci (rs135549, rs9626730, rs4253712, rs4823613, rs4253730, rs6007662, rs4253728, rs2024929 and rs135561) in the PPARα gene showed no significant differences between ATDILI and non-ATDILI in either allele frequencies or genotype (all P >.05). ConclusionsThe results demonstrated the strong correlation between POR gene SNP rs3898649 and ATDILI susceptibility, suggesting the importance of POR rs3898649 in the pathogenesis and development of ATDILI. Therefore, our results indicated that POR rs3898649 might be a valuable biomarker potentially involved in ATDILI.

A Novel Genetic Variation in NCF2, the Core Component of NADPH Oxidase, Contributes to the Susceptibility of Tuberculosis in Western Chinese Han Population.

Mycobacterium tuberculosis (Mtb) is the causative agent of the disease tuberculosis (TB). Macrophages eliminate the Mtb, delivering it to the degradative, phagolysosomal compartment for degradation, in which reactive oxygen species generated by nicotinamide adenine dinucleotide phosphate oxidase (NADPHO) plays an important role. In our study, we aimed at investigating the association of polymorphisms in neutrophil cytosolic factor 2 (NCF2) gene, the core component of NADPHO, with susceptibility of TB in the Western Chinese Han population. We conducted a case-control study of 900 cases and 1534 controls and genotyped four single-nucleotide polymorphisms within the NCF2 gene. We found that the rs10911362 variants were associated with a decreased TB risk in this population (odds ratio [ORG] = 0.83 [0.72-0.95], ORadd = 0.83 [0.72-0.95], ORdom = 0.78 [0.66-0.93], p < 0.05). rs10911362 might fall in a transcriptional factor binding site associated with ZNF410 and may be the expression quantitative trait loci (eQTL) for the SMG7 gene according to the Ensembl data. Our study demonstrated for the first time that the G allele of NCF2 rs10911362 provided a protective role against TB risk in the Western Chinese Han population.

The genetic variants in calcium signaling related genes influence anti-tuberculosis drug induced liver injury: A prospective study.

Although many genetic variants related to anti-tuberculosis drug induced liver injury (ATDILI) have been identified, the prediction and personalized treatment of ATDILI have failed to achieve, indicating there remains an area for further exploration. This study aimed to explore the influence of single nucleotide polymorphisms (SNPs) in Bradykinin receptor B2 (BDKRB2), Teneurin transmembrane protein 2 (TENM2), transforming growth factor beta 2 (TGFB2), and solute carrier family 2 member 13 (SLC2A13) on the risk of ATDILI.The subjects comprised 746 Chinese tuberculosis (TB) patients. Custom-by-design 2x48-Plex SNPscanTM kit was employed to genotype 28 selected SNPs. The associations of SNPs with ATDILI risk and clinical phenotypes were analyzed according to the distributions of allelic and genotypic frequencies and different genetic models. The odds ratio (OR) with corresponding 95% confidence interval (CI) was calculated.Among subjects with successfully genotyped, 107 participants suffered from ATDILI during follow-up. In BDKRB2, patients with rs79280755 G allele or rs117806152 C allele were more vulnerable to ATDILI (PBonferronicorrection = .002 and .03, respectively). Rs79280755 increased the risk of ATDILI significantly whether in additive (OR = 3.218, 95% CI: 1.686–6.139, PBonferroni correction = .003) or dominant model (PBonferroni correction = .003), as well as rs117806152 (Additive model: PBonferroni correction = .05; dominant model: PBonferroni correction = .03). For TENM2, rs80003210 G allele contributed to the decreased risk of ATDILI (PBonferroni correction = .02), while rs2617972 A allele conferred susceptibility to ATDILI (PBonferroni correction = .01). Regarding rs2617972, significant findings were also observed in both additive (OR = 3.203, 95% CI: 1.487–6.896, PBonferroni correction = .02) and dominant model (PBonferroni correction = .02). Moreover, rs79280755 and rs117806152 in BDKRB2 significantly affected some laboratory indicators. However, no meaningful SNPs were observed in TGFB2 and SLC2A13.Our study revealed that both BDKRB2 and TENM2 genetic polymorphisms were interrogated in relation to ATDILI susceptibility and some laboratory indicators in the Western Chinese Han population, shedding a new light on exploring novel biomarkers and targets for ATDILI.

Association of ABCC Gene Polymorphism With Susceptibility to Antituberculosis Drug-Induced Hepatotoxicity in Western Han Patients With Tuberculosis.

Six-month combination regimens could lead to serious hepatotoxicity, which may limit the clinical use of antituberculosis drugs. ABCC transporters are critical to the influx and efflux of compounds into and out of cells. The aim of this study was to explore whether the genetic variants in ABCC genes were related to the development of antituberculosis drug-induced hepatotoxicity. Here, we screened and genotyped 39 single-nucleotide polymorphisms of 13 ABCC genes in 746 eligible patients treated by first-line antituberculosis drugs in Western China Hospital. Genomic DNA was extracted from a peripheral blood sample of each patient, and clinical symptoms and laboratory results were recorded regularly. We found that the incidence rate of hepatotoxicity was 15.8% in the western Chinese Han population. As a result, the ABCC2 rs3740065 genotype, sex, and the baseline level of alanine aminotransferase are independent risk factors of antituberculosis drug-induced hepatotoxicity, with P values of .008, .014, and <.001, respectively. Our findings revealed a fraction of the underlying mechanism of hepatotoxicity, and larger validation studies on different populations are warranted to confirm these findings.

Association of LEPR polymorphisms with predisposition and inflammatory response in anti-tuberculosis drug-induced liver injury: A pilot prospective investigation in Western Chinese Han population

ObjectivesPrevious studies have proposed leptin/leptin receptor (LEPR) pathway has a potential role in the oxidative stress induction as well as in immune and inflammatory responses; however, the effects of leptin/LEPR signaling on anti-tuberculosis drug-induced liver injury (ATLI) remain unexplored. Here, we aimed to investigate the potential relationships between LEPR polymorphisms and ATLI risk and clinical characteristics. MethodsIn total, this prospective study included 745 tuberculosis subjects with isoniazid and rifampin co-administration from West China. Six candidate single nucleotide polymorphisms (SNPs) in LEPR gene were genotyped by using a custom-by-design 48-Plex SNPscan kit. All subjects were monitored for six months to assess the occurrence of ATLI. Genetic association analysis at both the single-SNP and haplotype levels was performed. Significant SNPs were further explored in relation to clinical features and inflammatory response of ATLI cases. ResultsATLI was identified in 118 of 745 subjects with a prevalence rate of 15.84%. Significant differences were observed in the allele and genotype distribution of LEPR rs2025804 in ATLI cases compared to non-ATLI controls (allele: OR = 1.64, 95% CI = 1.15–2.32, adjusted-p = .036; dominant model: OR = 1.73, 95% CI = 1.14–2.61, adjusted-p = 0.054; additive model: OR = 1.64, 95% CI = 1.15–2.34, adjusted-p = 0.036). Haplotype AA comprising of rs2025804 and rs2104564 was associated with a 1.58-fold increased predisposition to ATLI with p = 0.013. Furthermore, among ATLI patients, individuals carrying minor allele-containing genotypes in rs10889551, rs2025804 and rs2104564 loci had higher levels of C-reactive protein as compared to those homozygous major allele carriers, at p of 0.002, 0.057 and 0.012, respectively. ConclusionOurs is the first study which shows that LEPR polymorphisms may increase the risk for ATLI and may influence the inflammatory response in ATLI patients among Western Chinese Han tuberculosis patients.

RIPK2 polymorphisms and susceptibility to tuberculosis in a Western Chinese Han population

ObjectiveHost genetic factors play an important role in susceptibility to Mycobacterium tuberculosis (MTB) infection and tuberculosis (TB). Receptor interacting-serine/threonine-protein kinase 2 (RIPK2) is a critical adapter protein for signal propagation of NOD2, dysregulation of which leads to defects in bacterial detection. To investigate the role of RIPK2 on the susceptibility of tuberculosis, we conducted a large sample size case-control study in a Western Chinese Han population. MethodsFive single-nucleotide polymorphisms (SNPs) within or near to RIPK2 were genotyped in 1359 TB cases and 1534 controls using the improved multiplex ligation detection reaction method in a case-control study. ResultsOf the five variants, rs39509 was observed to be associated with TB risk in the allelic effects (P = 0.015), additive (P = 0.020) and recessive model (P = 0.005) after Bonferroni correction. Rs39509 might fall in putative functional regions and might be eQTL for the RIPK2 and long non-coding RNA RP11-37B2.1 according to the Genotype-Tissue Expression (GTEx) Project. ConclusionsOur findings firstly exhibit that the G allele of rs39509 in nearGene-3 region of RIPK2 might serve as a hazard for TB in this Western Chinese Han population. Further validation studies on a variety of ethnic populations and function experiments are needed to confirm the roles of the variants identified.

Family-based study of association between MAFB gene polymorphisms and NSCL/P among Western Han Chinese population.

Non-syndromic cleft lip with or without cleft palate (NSCL/P) are the most common human congenital birth defects with a complex etiology. MAFB has been reported as a candidate gene involved in the pathogenesis of NSCL/P from genome-wide association study (GWAS) findings, and no replication studies have been performed in Western Han Chinese. The aim of this study was to investigate the associations of MAFB among NSCL/P trios in Western Han Chinese. We selected 6 single nucleotide polymorphisms (SNPs) (rs6072081, rs6065259, rs17820943, rs13041247, rs11698025 and rs6102085) near MAFB based on previous GWAS findings and recruited 298 case-parents trios with NSCL/P from Western Han Chinese population, while genotypes were done by SNPscan technology. Strong evidence of an association was found at rs17820943 (p = 0.0023; odds ratio - ORtranmission = 0.7 and 95% confidence interval [CI]: 0.55-0.88) and rs13041247 (p = 0.0023; ORtranmission = 0.7 and 95% CI: 0.55-0.88) among NSCL/P; genotypic transmission-disequilibrium test (TDT) analysis further confirmed this. C/C homozygote at rs17820943 (z = 3.44 and p = 0.00058) and T/T homozygote at rs13041247 (z = 3.14 and p = 0.0017) was over-transmitted among NSCL/P, which indicated they could increase the risk of having an affected baby. Sliding window haplotype analysis showed that haplotypes consisting of C allele at rs17820943 and T allele at rs13041247 were still over-transmitted among NSCL/P (lowest p = 0.0021). This study further confirmed that the targeted SNPs at MAFB were associated with NSCL/P trios from Western Han Chinese population, which provides more scientific evidence for the future research and genetic counseling.

Influence of Genetic Polymorphism Towards Pulmonary Tuberculosis Susceptibility.

Tuberculosis (TB) is still remains the major threat for human health worldwide. Several case-control, candidate-gene, family studies and genome-wide association studies (GWAS) suggested the association of host genetic factors to TB susceptibility or resistance in various ethnic populations. Moreover, these factors modulate the host immune responses to tuberculosis. Studies have reported genetic markers to predict TB development in human leukocyte antigen (HLA) and non-HLA genes like killer immunoglobulin-like receptor (KIR), toll-like receptors (TLRs), cytokine/chemokines and their receptors, vitamin D receptor (VDR) and SLC11A1 etc. Highly polymorphic HLA loci may influence antigen presentation specificities by modifying peptide binding motifs. The recent meta-analysis studies revealed the association of several HLA alleles in particular class II HLA-DRB1 with TB susceptibility and valuable marker for disease development especially in Asian populations. Case-control studies have found the association of HLA-DR2 in some populations, but not in other populations, this could be due to an ethnic specific association of gene variants. Recently, GWAS conducted in case-control and family based studies in Russia, Chinese Han, Morocco, Uganda and Tanzania revealed the association of genes such as ASAP1, Alkylglycerol monooxygenase (AGMO), Forkhead BoxP1 (FOXP1), C-terminal domain phosphatase 1 (UBLCP1) and intergenic SNP rs932347C/T with TB. Whereas, SNP rs10956514A/G were not associated with TB in western Chinese Han and Tibetan population. In this review, we summarize the recent findings of genetic variants with susceptibility/resistance to TB.