SP110 polymorphisms are not associated with pulmonary tuberculosis in a South African population

Susceptibility to tuberculosis (TB) in mice has recently been attributed to the Ipr1 gene. Polymorphisms in the human homologue, SP110, have been investigated in various populations with only one study finding an association with TB susceptibility. We investigated eight SP110 polymorphisms in a South African population, including two novel polymorphisms. No significant association was found with any of the polymorphisms investigated, including two polymorphisms that were previously found to be associated with TB susceptibility in West African populations.     

Resequencing and association analysis of the SP110 gene in adult pulmonary tuberculosis

Recently, the Intracellular pathogen resistance 1 (Ipr1) gene was shown to control susceptibility to Mycobacterium tuberculosis in mice. We examined whether common sequence variants of its human orthologue, the SP110 gene, are associated with susceptibility to tuberculosis in a human population. We resequenced SP110 exons in 96 individuals and identified new polymorphisms. Then, we combined our sequence and HapMap data for 83 distinct polymorphisms and selected tags that capture information for all common variants in the 100 kb region around SP110. We genotyped 29 single nucleotide polymorphisms including seven amino-acid changing variants in 1,912 HIV-negative culture-confirmed adult pulmonary tuberculosis patients and 2,104 adult healthy controls from Russia and found no evidence of association. Our results indicate that common polymorphisms of the SP110 gene have no major effect on susceptibility to tuberculosis in this population. Electronic supplementary material Supplementary material is available in the online version of this article at and is accessible for authorized users.     

Genetic variants in MARCO are associated with the susceptibility to pulmonary tuberculosis in Chinese Han population

Background

Susceptibility to tuberculosis is not only determined by Mycobacterium tuberculosis infection, but also by the genetic component of the host. Macrophage receptor with a collagenous structure (MARCO) is essential components required for toll like receptor-signaling in macrophage response to Mycobacterium tuberculosis, which may contribute to tuberculosis risk.

Principal Findings

To specifically investigated whether single nucleotide polymorphisms (SNPs) in MARCO gene are associated with pulmonary tuberculosis in Chinese Han population. By selecting tagging SNPs in MARCO gene, 17 tag SNPs were identified and genotyped in 923 pulmonary tuberculosis patients and 1033 healthy control subjects using a hospital based case-control association study. Single-point and haplotype analysis revealed an association in intron and exon region of MARCO gene. One SNP (rs17009726) was associated with susceptibility to pulmonary tuberculosis, where the carriers of the G allele had a 1.65 fold (95% CI = 1.32–2.05, p _corrected = 9.27E–5) increased risk of pulmonary tuberculosis. Haplotype analysis revealed that haplotype GC containing G allele of 17009726 and haplotype TGCC (rs17795618T/A, rs1371562G/T, rs6761637T/C, rs2011839C/T) were also associated with susceptibility to pulmonary tuberculosis (p _corrected = 0.0001 and 0.029, respectively).

Conclusions

Our study suggested that genetic variants in MARCO gene were associated with pulmonary tuberculosis susceptibility in Chinese Han population, and the findings emphasize the importance of MARCO mediated immune responses in the pathogenesis of tuberculosis.     

Association of killer cell immunoglobulin-like receptors with pulmonary tuberculosis in Chinese Han

Killer cell immunoglobulin-like receptors (KIRs) are involved in the pathogenesis of a variety of diseases. However, whether KIR polymorphism is associated with susceptibility to pulmonary tuberculosis was unknown. We examined a possible association of KIR polymorphism with susceptibility to pulmonary tuberculosis in Chinese Han. We analyzed 15 KIR genes in 109 pulmonary tuberculosis patients and 110 healthy controls using sequence-specific primer PCR analysis of genomic DNA. We found that the frequencies of KIR2DS1, 2DS3 and 3DS1 were significantly higher in patients than in the control group. In addition, the number of subjects carrying more than two activating KIR genes in the patient group was significantly higher than in the control group. The gene cluster containing KIR3DS1-2DL5-2DS1-2DS5 was also significantly more frequent in the patient group. In conclusion, KIR genes 2DS1, 2DS3 and 3DS1 appear to be associated with resistance to pulmonary tuberculosis in the Chinese Han population. KIR genes apparently have a role in resistance to pulmonary tuberculosis.     

IFNG polymorphisms are associated with tuberculosis in Han Chinese pediatric female population

Host genetic factors play a major role in determining differential susceptibility to human tuberculosis (TB), a re-emerging infectious disease throughout the world. Genetic variations in the IFNG gene coding for interferon gamma (IFN-γ), have been identified in TB patients. To investigate the association of the IFNG polymorphisms with TB susceptibility in Chinese pediatric population. A case–control study of 189 TB patients and 164 controls was performed using single-nucleotide polymorphism (SNP) analysis. Genomic DNA was extracted from leukocytes in peripheral blood. Three SNPs of IFNG, including ?1616C/T (rs2069705), +874A/T (rs2430561), and +3234C/T (rs2069718), were selected for genotyping and analysis. The +874A and +3234C alleles were more frequent among TB patients (P = 0.108 and P = 0.088), especially in females (both P = 0.029), although this difference was not significant since Bonferroni corrected significance threshold was 0.025 (two of three SNPs were found to be in linkage disequilibrium). More pronounced differences for the +874 and +3234 polymorphisms were found under the genotype comparison between TB cases and controls in the total population [P = 0.026 (borderline non-significance) and P = 0.020, respectively], and in the female subgroup (P = 0.020 and P = 0.020). The dominant model of inheritance was shown to be significant for +874A and +3234C alleles (both P = 0.019) in the female subgroup. The +874A and +3234C alleles were more frequently found in extrapulmonary TB patients than in controls (P = 0.039). Haplotype analysis carried out on these three SNPs showed the TTT haplotype to be more frequent in controls than in TB cases, and this difference showed a strong significance (P = 0.005). The +874A and +3234C alleles may be related to TB susceptibility in the female subgroup in the Chinese pediatric population of North China. The higher rate of +874A (known to correlate with lower IFN-γ expression) in the extrapulmonary TB subgroup suggests a sufficient IFN-γ expression to be not only an important factor for the onset of TB disease but also for limiting its dissemination to lungs.     

Relationship between single nucleotide polymorphism of interleukin-18 and susceptibility to pulmonary tuberculosis in the Chinese Han population

Interleukin-18 (IL-18) is a multi-functional cytokine capable of inducing either Th1 or Th2 polarization depending on the immunologic milieu. IL-18 may influence the host response to Mycobacterium tuberculosis (M.tb) infection. To investigate the relationship between single nucleotide polymorphisms of the IL-18 and susceptibility to pulmonary tuberculosis in the Chinese Han population, the IL-18 gene was sequenced to detect polymorphisms and to examine the genotype frequencies in 300 patients and 702 healthy controls. DNA sequencing revealed three IL-18 variants: rs1946518, rs5744247, and rs549908. It also revealed that allele A of rs1946518 confers a 1.47-fold increased risk of developing tuberculosis (TB) (P = 0.0001, OR [95%CI] = 1.47 [1.21-1.78]), and that the C allele of rs5744247 confers a 0.77-fold decreased risk of disease (P = 0.01, R [95%CI] = 0.77 [0.632-0.937]). The genotypes rs1946518, rs5744247 and rs549908 were found to be significantly associated with TB. Estimation of the frequencies of haplotypes revealed a potential risk haplotype AGA (P = 0.01, OR [95%CI] = 1.41 [1.15-1.72]) and a protective haplotype CCA (P = 0.01, OR [95%CI] = 0.70 [0.57-0.85]) for TB. The present findings suggest that polymorphisms in the IL-18 gene may affect susceptibility to TB and increase the risk of developing the disease in the Chinese Han population.     

Association between ACE I/D polymorphism and pulmonary tuberculosis in Chinese population

Tuberculosis (TB) remains a global public health problem worldwide. The objective of the current study is to investigate the possible association of ACE I/D polymorphism with pulmonary TB (PTB) for Chinese in Sichuan province. Three hundred eighty-six PTB patients and 398 healthy controls were genotyped to analyze the I/D polymorphism using PCR method. The results showed that the I/D polymorphism was not associated with susceptibility to PTB for Chinese (D vs. I: OR 1.03, 95 % CI 0.84–1.26, and P = 0.77; DD vs. II+DI: OR 1.09, 95 % CI 0.73–1.63, and P = 0.68; DD+DI vs. II: OR 1.00, 95 % CI 0.74–1.33, and P = 0.98). The I/D polymorphism in the ACE gene may not a risk factor for PTB in Chinese.     

Gender-specific associations between MICA-STR and nasopharyngeal carcinoma in a southern Chinese Han population

Previous studies have identified several HLA-B specificities that are associated with nasopharyngeal carcinoma (NPC) in populations of Chinese descent, in particular HLA-B35, -B38, -B46, and -B58. Perhaps except for HLA-B46, other associations cannot be simply accounted for by the linkage disequilibrium between HLA-A and B loci. The human major histocompatibility complex (MHC) class I chain-related gene A (MICA) maps 46 kb centromeric to HLA-B and is highly polymorphic; it encodes a stress-inducible protein which functions as a ligand for the NKG2D/DAP10 complex to activate natural killer (NK) cells, γδ T cells, and CD8⁺ T cells. We postulated MICA gene as a susceptibility factor for nasopharyngeal carcinoma, an Epstein–Barr virus-associated malignancy. In this study, 218 unrelated patients newly diagnosed with NPC and 196 randomly selected healthy controls from southern China mainland were analyzed for the short tandem repeat polymorphism of exon 5 of MICA gene (MICA-STR) and MICA gene deletion, using fluorescent polymerase chain reaction-gene scanning (PCR/size-sequencing) and polymerase chain reaction-sequence-specific priming (PCR/SSP) technology. MICA*A9 was present at significantly increased frequency in the patient group (P _C=0.0001002, OR=2.528, 95% CI=1.636–3.907), whereas the frequency of MICA*A5.1 was significantly decreased (P _C=0.006, OR=0.594, 95% CI=0.437–0.806). Gender-based stratification revealed a significant increase of MICA*A9 frequency (P _C=0.000072, OR=3.255, 95% CI=1.855–5.709) and a significant decrease of MICA*A5.1 frequency (P _C=0.000737, OR=0.486, 95% CI=0.337–0.702) in male patients with NPC (N=166), compared with male normal controls (N=120). A significant interaction between MICA*A9 and gender was observed (=41.58, P=0.0001). Statistics also revealed heterogeneity of effects among MICA*A5.1/MICA*A9-bearing phenotypes and a dose-dependent effect of MICA*A5.1 and MICA*A9 on NPC risk in male subgroup. This constitutes the first demonstration of a gender-specific association between MICA-STR polymorphism and NPC, which could largely be attributable to the underlying gender-related mechanisms that modulate MICA gene expression. The results provide strong supporting evidence suggesting that MICA*A9 may be a genetic risk factor for NPC in male individuals in this population. The potential interaction between MICA and other non-HLA host factors and environmental exposures remains to be further studied.     

IL-28B genetic variant is associated with the risk of schizophrenia in the Chinese Han population

Schizophrenia is a severe psychiatric disorder. Although its exact cause is unknown, it is widely accepted that environmental factors and genes integrate in the pathogenesis of schizophrenia. 19q13, which contains IL-28B, is a newly identified potential susceptibility locus. IL-28B is a cytokine that functionally has anti-viral activity, but, structurally, is related to the interleukin-10 family. Both virus infection and cytokine changes have been documented in schizophrenia. We selected the single-nucleotide polymorphism rs8099917, which is associated with IL-28B gene expression, to study its relationship to the susceptibility to schizophrenia. A total of 256 Chinese patients with schizophrenia and 329 healthy controls were studied. Both genotype and allele frequencies showed significant differences between patients and normal subjects (p=0.03 and p=0.04, respectively). Our study suggested that the frequency of allele T was a risk factor for the susceptibility of schizophrenia (odds ratio [OR]=1.76, 95% confidence interval [CI]=1.03-3.03). When all subjects were grouped by symptoms, both the genotype and the allele frequency were associated with patients having disorganized speech (genotype: χ(2)=5.75, p=0.02; allele: χ(2)=5.41, p=0.02, OR=3.67, 95% CI=1.14-11.82) and negative symptoms (genotype: χ(2)=5.09, p=0.02; allele: χ(2)=4.80, p=0.03, OR=1.95, 95% CI=1.06-3.56) as well as cognitive symptoms (genotype: χ(2)=5.97, p=0.02; allele: χ(2)=5.53, p=0.02, OR=2.04, 95% CI=1.11-3.74). The results in this study may lead to a better understanding of the etiology of schizophrenia.     

汉族有耳垂人群的指纹研究

汉族人群有耳垂者与无耳垂者之间,其指纹分布是否存在着规律性变化,对在校汉族大学生进行了调查,采用面对面调查方式获取被检者耳垂资料,记录在调查表中,用油墨拓印法获取被检者指纹图样,并置于放大镜下确认,耳垂组与对照组指纹中的弓形纹、箕形纹、和斗型纹三种基本纹理图形,经X2检验均无显著性差异(P＞0.05).控制耳垂的显性基因与决定指纹形成的多基因是如何相互作用的?有待进行更深入的研究     

CRP Gene polymorphism contributes genetic susceptibility to dyslipidemia in Han Chinese population

C-reactive protein (CRP), an inflammatory marker that statistically predicts future cardiovascular risk, has been reported to be associated with plasma lipid level changes. Whether CRP genetic variants affect lipid metabolism is of importance to investigate. A community-based study population including 2,731 adult subjects aged 18–62 years was used to evaluate the association of CRP gene with dyslipidemia and five tagging SNPs (tagSNPs) were genotyped. Multiple logistic regression was applied to further evaluate relationships between the SNPs and lipid metabolism abnormality and general linear model was applied to compare plasma lipid levels between genotypes. Association analyses indicated that recessive model of SNPs rs876537 and rs4285692 had significant association with elevated HDL after adjustment for covariates. Odds ratio (OR) of rs876537 were 0.60 for HDL > 1.54 versus 1.04–1.54 mmol/L (P = 0.011), as well as, ORs were 0.617 for HDL > 1.83 versus ≤1.35 mmol/L (P = 0.002) and 0.724 for HDL = 1.59–1.83 versus ≤1.35 mmol/L (P = 0.028) respectively. OR of rs4285692 was 0.634 for HDL > 1.83 versus ≤1.35 mmol/L (P = 0.027). Further stratification analysis found significant associations of rs10737175 with elevated HDL (>1.54 vs. 1.04–1.54 mmol/L, OR 0.629 and P = 0.027) and elevated TG (≥1.70 vs. <1.70 mmol/L, ORs of additive and dominant models were 0.628, 0.545 and P values were 0.006, 0.003 respectively) in female. rs4285692 was significantly associated with elevated LDL (≥3.37 vs. <3.37 mmol/L), ORs equaled to 1.532, 2.281 for additive model and recessive model and P values were 0.028, 0.024 respectively in male. Furthermore, quantitative trait analysis indicated the variation T to C of rs876537 significantly affect decreased plasma HDL level (P = 0.014). Our findings suggest that CRP genetic polymorphisms independently had positive association with the risk of HDL, LDL and TG elevating and further replication in other large population and biological function research would be warranted.     

The genetic polymorphisms of cathepsin S were associated with metabolic disorders in a Chinese Han population

Cathepsin S (CTSS) played an important role in the etiology of cardiovascular disease and metabolic syndrome. Few studies had been reported on the association between the polymorphisms of CTSS and metabolic disorders in Asian population. Therefore we explored the association between the polymorphisms of CTSS and metabolic disorders in a Chinese Han population. The subjects were a Chinese Han cohort with 1160 participants, and the genotyping was performed with PCR-RFLP. Polymorphism rs16827671 was associated with BMI and serum total cholesterol (P = 0.001; P = 0.02, respectively). Subjects with CT genotype of rs16827671 had a higher risk of hypercholesterolemia (OR = 1.64, 95% CI: 1.15–2.33, P = 0.006) compared with TT genotype. Subjects with AG genotype of rs11576175 had lower risks of hypertriglyceridemia and borderline hypercholesterolemia (OR = 0.52, 95% CI: 0.36–0.73, P = 0.0001; OR = 0.52, 95% CI: 0.35–0.77, P = 0.001, respectively) compared with GG genotype. Compared with the haplotype TG, haplotype TA had a lower risk of hypertriglyceridemia and a higher risk of borderline hypercholesterolemia (OR = 0.62, 95% CI: 0.44–0.88, P = 0.002; OR = 1.59, 95% CI: 1.10–2.31, P = 0.008, respectively), and haplotype CA had a lower risk of hypercholesterolemia (OR = 0.35, 95% CI: 0.18–0.68, P = 0.002). In conclusion, we found that the genetic polymorphisms of CTSS were associated with metabolic disorders in a Chinese Han population, which would enrich the knowledge on genetic mechanisms of the pathogenesis of metabolic disorders.     

A rare variant in COL11A1 is strongly associated with adult height in Chinese Han population

Human height is a highly heritable trait in which multiple genes are involved. Recent genome-wide association studies(GWASs) have identified that COL11A1 is an important susceptibility gene for human height. To determine whether the variants of COL11A1 are associated with adult and children height,we analyzed splicing and coding single-nucleotide variants across COL11A1 through exome-targeted sequencing and two validation stages with a total 20,426 Chinese Han samples. A total of 105 variants were identified by exome-targeted sequencing, of which 30 SNPs were located in coding region. The strongest association signal was chr1_103380393 with P value of 4.8 * 10~(-7). Chr1_103380393 also showed nominal significance in the validation stage(P = 1.21 * 10~(-6)). Combined analysis of 16,738 samples strengthened the original association of chr1_103380393 with adult height(P_(combined)= 3.1 * 10~(-8)), with an increased height of 0.292sd(standard deviation) per G allele(95% CI:0.19-0.40). There was no evidence(P = 0.843) showing that chr1_103380393 altered child height in 3688 child samples. Only the group of 12-15 years showed slight significance with P value of 0.0258.This study firstly shows that genetic variants of COL11A1 contribute to adult height in Chinese Han population but not to children height, which expand our knowledge of the genetic factors underlying height variation and the biological regulation of human height.     

Whole-exome sequencing reveals genetic risks of early-onset sporadic dilated cardiomyopathy in the Chinese Han population

To reveal genetic risks of early-onset sporadic dilated cardiomyopathy (DCM) patients in the Chinese Han population, we enlisted 363 DCM cases and 414 healthy controls. Whole-exome sequencing and phenotypic characterization were conducted. In total, we identified 26 loss-of-function (LOF) candidates and 66 pathogenic variants from 33 genes, most of which were novel. The deleterious variants can account for 25.07% (91/363) of all patients. Furthermore, rare missense variants in 21 genes were found to be significantly associated with DCM in burden tests. Other than rare variants, twelve common SNPs were significantly associated with an increased risk of DCM in allele-based genetic model association analysis. Of note, in the cumulative risk model, high-risk subjects had a 3.113-fold higher risk of developing DCM than low-risk subjects. Also, DCM in the high-risk group had a younger age of onset than that in the low-risk group. In terms of cardiac function, the mean left ventricular ejection fraction of patients with the deleterious variants was lower than those without (27.73%±10.02% vs. 30.61%±10.85%, P=0.026). To conclude, we mapped a comprehensive atlas of genetic risks in Chinese patients with DCM that might lead to new insights into the mechanisms and risk stratification for DCM.

     

Association of the CTLA-4 +49A/G polymorphism with rheumatoid arthritis in Chinese Han population

Cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) is an important molecule in the regulation of T cells, so the CTLA-4 gene has been considered as a strong candidate associated with T cell-mediated autoimmune diseases such as rheumatoid arthritis (RA). CTLA-4 has many variants and polymorphic forms, among which the +49A/G polymorphism, causing a non-synonymous substitution, has been studied most. However, previous studies of the association between the +49A/G polymorphism of the CTLA-4 gene and RA have provided conflicting results. The aim of this study was to determine the potential relationship of the CTLA-4 +49A/G polymorphism and the risk of RA in Chinese Han population. TaqMan assay was used to genotype the +49A/G polymorphism in 1,489 RA patients and 1,200 healthy controls. Furthermore, a meta-analysis of all studies relating this polymorphism in Chinese population to the risk of RA was performed. The genotype and allele frequencies of the CTLA-4 +49A/G in patients with RA differed significantly from those of controls (P = 0.03 and P = 0.007, respectively). The meta-analysis also revealed that the CTLA-4 +49G allele was associated with an increased risk of RA in Chinese population. Our results suggested that the CTLA-4 gene might contribute to the pathogenesis of RA, and the +49A/G polymorphism of this gene was a risk factor associated with increased RA susceptibility in Chinese Han population.     

Identification of genetic associations of ECHS1 gene with milk fatty acid traits in dairy cattle

Our previous genome‐wide association study identified 83 genome‐wide significant SNPs and 20 novel promising candidate genes for milk fatty acids in Chinese Holstein. Among them, the enoyl‐CoA hydratase, short chain 1 (ECHS1) and enoyl‐CoA hydratase and 3‐hydroxyacyl CoA dehydrogenase (EHHADH) genes were located near two SNPs and one SNP respectively, and they play important roles in fatty acid metabolism pathways. We herein validated whether the two genes have genetic effects on milk fatty acid traits in dairy cattle. By re‐sequencing the full‐length coding region, partially adjacent introns and 3000 bp up/downstream flanking sequences, we identified 12 SNPs in ECHS1: two in exons, four in the 3′ flanking region and six in introns. The g.25858322C>T SNP results in an amino acid replacement from leucine to phenylalanine and changes the secondary structure of the ECHS1 protein, and single‐locus association analysis showed that it was significantly associated with three milk fatty acids (P = 0.0002–0.0013). The remaining 11 SNPs were found to be significantly associated with at least one milk fatty acid (P = <0.0001–0.0040). Also, we found that two haplotype blocks, consisting of nine and two SNPs respectively, were significantly associated with eight milk fatty acids (P = <0.0001–0.0125). However, none of polymorphisms was observed in the EHHADH gene. In conclusion, our findings are the first to indicate that the ECHS1 gene has a significant genetic impact on long‐chain unsaturated and medium‐chain saturated fatty acid traits in dairy cattle, although the biological mechanism is still undetermined and requires further in‐depth validation.     

Common ABCB1 polymorphisms associated with susceptibility to infantile spasms in the Chinese Han population

Infantile spasms are a severe epileptic encephalopathy with a variety of etiologies that occur in infancy and early childhood. Subjects with infantile spasms are at a higher risk for evolving into intractable epileptic spasms, tending to be refractory to conventional antiepileptic drugs. Genetic polymorphisms of the P-glycoprotein-encoding gene ABCB1 are suspected to be associated with pharmacoresistance phenotypes in epilepsy patients. Conflicting findings have been reported in different populations; few studies have explored whether this apparent association is affected by other host factors, such as specific epilepsy syndrome. We performed a case-control study to determine whether the risk of infantile spasms is influenced by common ABCB1 polymorphisms in a Han Chinese children's population consisting of 91 patients and 368 healthy individuals. DNA was isolated from whole blood, and three genetic polymorphisms (C1236T, G2677T/A, and C3435T) were assayed by PCR-RFLP. There were significant differences in the distributions of 3435TT [P = 0.001; odds ratio = 2.47; 95% confidence interval (CI) = 1.44-4.27] and 3435CT [P < 0.001; odds ratio = 0.28; 95% CI = 0.15-0.54] genotypes between infantile spasm cases and controls. No significant differences were observed in allelic and haplotypic frequencies of ABCB1 polymorphisms between the two groups. This study demonstrated that variations in the C3435T gene play an important role in the pathogenesis of infantile spasms in the Han Chinese population; 3435TT is associated with increased risk of having this epilepsy syndrome.