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 between TL1A gene polymorphisms and systemic lupus erythematosus in a Chinese Han population

Our previous studies showed elevated tumor necrosis factor-like ligand 1 aberrance (TL1A) expression in systemic lupus erythematosus (SLE). However, TL1A polymorphisms with SLE susceptibility remain to be elucidated. In addition, we made meta-analysis to evaluate the relationship of TL1A polymorphisms and autoimmune diseases owing to inconsistent results. The present research was carried out by 404 SLE, 150 primary Sjogren's syndrome (pSS) patients, and 574 healthy individuals. Three TL1A polymorphisms (rs3810936, rs6478109, rs7848647) were genotyped using TaqMan genotyping assay. Then, the meta-analysis was performed by collecting the present case-control study and previously published research. Results showed that genotypes of rs3810936, rs7848647 were different between SLE patients and healthy controls, whereas no significant association was observed in the three polymorphisms and pSS patients. Genotypes distribution of rs6478109, rs7848647 were strongly related to lupus nephritis within SLE (p = 0.004, p = 0.011), respectively. Moreover, combined meta-analysis consisted of ten comparative research involving 4,305 patients and 5,600 controls. An association between autoimmune diseases and rs6478109 polymorphism was found. Our findings indicate that gene polymorphisms (rs3810936, rs7848647) of TL1A might correlate with lupus.     

Association between gout and polymorphisms in GCKR in male Han Chinese

Several genome-wide association studies (GWASs) have reported associations between single nucleotide polymorphisms (SNPs) and uric acid concentrations or gout in a number of different ethnic populations. To clarify the global relevance of the previously identified SNPs in the development of the qualitative trait gout, in the present study, the associations between two SNPs in the glucokinase (hexokinase 4) regulator (GCKR) gene and gout were assessed in a male Chinese Han population. The study population comprised 476 male gout patients and 465 male controls. Multiple PCR was performed using time-of-flight mass spectrometry (MALDI-TOF MS) to identify genotypes. Two SNPs, rs780093 and rs780094, located in intronic regions of the GCKR gene were found to be significantly associated with the development of gout. Thus, the association between the two GCKR SNPs and gout was replicated in the male Han Chinese population investigated in the present study. Furthermore, GCKR was identified as a novel candidate gene associated with gout.     

Association study of ACE polymorphisms and systemic lupus erythematosus in Northern Chinese Han population

Systemic lupus erythematosus (SLE) is an autoimmune disease, with multiple genetic and environmental factors involving in its etiology. Angiotensin converting enzyme (ACE) gene was reported to have important roles in the development and progression of SLE. In this study, a case-control study was carried out to investigate the effects of seven SNPs and I/D in ACE gene in the development of SLE in Northern China. Seven SNPs including A5466C, T3892C, A240T, C1237T, G2215A, A2350G and C3409T were genotyped by PCR-RFLP method, and I/D was examined by agarose gel electrophoresis followed PCR directly. 314 SLE patients were compared to 320 normal controls in the study. Data were analyzed by SPSS 13.0 and HaploView software. The frequency distribution of SNP A2350G and Alu I/D and five haplotypes (AAAACCCI, AGAACCTD, AAAATCTI, TAAATTTI and TAAATCTI) were demonstrated to be different between case and control groups significantly. Whereas other SNPs and haplotypes had no differences in two cohorts. The results revealed that variations of ACE gene had association with SLE, which indicated ACE gene may play an important role in pathogenesis of SLE in Northern Chinese Han population.     

Association study of promoter polymorphisms in the CETP gene with longevity in the Han Chinese population

The cholesteryl ester transfer protein (CETP), which is involved in the regulation of reverse cholesterol transport and metabolism of high-density lipoprotein cholesterol, has been proposed as a candidate gene for human longevity. SNPs in the promoter region of the CETP gene is likely important in regulation of the expression of the CETP gene. To explore the potential effects of the promoter polymorphisms in the CETP gene on longevity, we investigated the promoter polymorphisms in a sample of long-lived (≥90 years old) Han Chinese collected from Southwestern China (N = 380). By resequencing 934 bp of the promoter region, genotypes of four SNPs (?573A/G, ?629A/C, ?971A/G, ?1046T/C) were examined in this sample. However, no association could be confirmed between longevity and these SNPs or haplotypes inferred from them. A novel rare variant ?573A/G was found and was found in heterozygote state only in five persons in the Longevity group. But it was not statistically significant (p = 0.075). We also examined this novel polymorphism ?573A/G in another Han Chinese sample from Yunnan province, and it was not associated with longevity. The results from both samples suggest that there is likely no association of the CETP gene promoter polymorphisms with longevity, at least among Han Chinese.     

Identification of Drosophila genes modulating Janus kinase/signal transducer and activator of transcription signal transduction

The JAK/STAT pathway was first identified in mammals as a signaling mechanism central to hematopoiesis and has since been shown to exert a wide range of pleiotropic effects on multiple developmental processes. Its inappropriate activation is also implicated in the development of numerous human malignancies, especially those derived from hematopoietic lineages. The JAK/STAT signaling cascade has been conserved through evolution and although the pathway identified in Drosophila has been closely examined, the full complement of genes required to correctly transduce signaling in vivo remains to be identified. We have used a dosage-sensitive dominant eye overgrowth phenotype caused by ectopic activation of the JAK/STAT pathway to screen 2267 independent, newly generated mutagenic P-element insertions. After multiple rounds of retesting, 23 interacting loci that represent genes not previously known to interact with JAK/STAT signaling have been identified. Analysis of these genes has identified three signal transduction pathways, seven potential components of the pathway itself, and six putative downstream pathway target genes. The use of forward genetics to identify loci and reverse genetic approaches to characterize them has allowed us to assemble a collection of genes whose products represent novel components and regulators of this important signal transduction cascade.     

Association study of TLR-9 polymorphisms and systemic lupus erythematosus in Northern Chinese Han population

Background

Systemic lupus erythematosus (SLE) is an autoimmune disease, with multiple genetic and environmental factors involving in its etiology. The toll-like receptor 9 (TLR9) gene has been reported to have important roles in the development and progression of SLE. We performed a case–control study to investigate the effects of 4 SNPs in the TLR9 gene in the development of SLE in Northern Chinese population.

Methods

Four SNPs including rs187084, rs5743836, rs352139 and rs352140 were genotyped using the SNaPshot® method. A group of 430 SLE patients were compared to 424 normal controls. Data were analyzed by SPSS 17.0 and HaploView v 4.1 software.

Results

The frequency distributions of SNP rs351240 and haplotype H2 (TGCT) and H3 (CATT) were found to differ significantly between patient and control groups (p < 0.05), while other SNPs and haplotypes showed no significant difference between the two cohorts (p > 0.05).

Conclusion

The results revealed that variations in the TLR9 gene are associated with SLE, indicating that TLR9 may play an important role in the pathogenesis of SLE in the northern Chinese Han population.     

Association of PTEN polymorphisms with susceptibility to hepatocellular carcinoma in a Han Chinese population

The phosphate and tension homolog (PTEN) is a tumor suppressor gene that controls a variety of biological processes including cell proliferation, migration, and death. The association of PTEN polymorphisms with risk for many cancers has been reported, but hepatocellular carcinoma (HCC) has not yet been studied. The present study is the first attempt to assess the association of PTEN polymorphisms with HCC susceptibility. We genotyped one insertion/deletion polymorphism (rs34421660) by polymerase chain reaction (PCR) method and three tag single-nucleotide polymorphisms (rs10490920, rs532678, and rs701848) by polymerase chain reaction-restriction fragment length polymorphism in 134 HCC patients and 215 healthy controls. We found that the four polymorphisms were not associated with HCC, at both the allele and genotype levels. However, after reconstructing PTEN haplotypes according to genotyping data and linkage disequilibrium status of four polymorphisms, we found that the T-C-C-del haplotype was associated with decreased HCC risk (odds ratio?=?0.19, 95% confidence interval?=?0.06-0.56) and the T-T-T-ins haplotype was associated with increased HCC risk (odds ratio?=?1.63, 95% confidence interval?=?1.14-2.33). Thus, our results prove that PTEN haplotypes may be associated with HCC susceptibility in a Chinese Han population.