Mengyuan Kan

The draft genome of the large yellow croaker reveals well-developed innate immunity

The large yellow croaker, Larimichthys crocea, is one of the most economically important marine fish species endemic to China. Its wild stocks have severely suffered from overfishing, and the aquacultured species are vulnerable to various marine pathogens. Here we report the creation of a draft genome of a wild large yellow croaker using a whole-genome sequencing strategy. We estimate the genome size to be 728 Mb with 19,362 protein-coding genes. Phylogenetic analysis shows that the stickleback is most closely related to the large yellow croaker. Rapidly evolving genes under positive selection are significantly enriched in pathways related to innate immunity. We also confirm the existence of several genes and identify the expansion of gene families that are important for innate immunity. Our results may reflect a well-developed innate immune system in the large yellow croaker, which could aid in the development of wild resource preservation and mariculture strategies.

Association of Leukocyte Telomere Length with Type 2 Diabetes in Mainland Chinese Populations

CONTEXT Telomeres are structures at the ends of eukaryotic chromosomes. They help maintain genomic stability. High oxidative stress can lead to accelerated telomere shortening, which causes premature cell senescence. This is implicated in the development of type 2 diabetes (T2D). For this reason, we hypothesize that telomere shortening can characterize T2D. METHODS We investigated the association between leukocyte telomere length (LTL) and T2D in a retrospective case-control study with a sample of 4016 Chinese Han subjects (1936 unrelated T2D cases and 2080 controls). Logistic regression analysis was performed to evaluate the association between LTL and T2D, adjusted for age and gender. Multivariate linear regression analysis was used to test for any association of LTL with a number of clinical, demographic, and diabetes-associated variables. RESULTS Telomere repeat length (T)/copy number of a single-copy gene (S) ratios (T/S) of LTL were found to be significantly shorter in T2D cases [1.00 T/S, 95% confidence interval (CI) = 0.99-1.02] compared with controls (1.08 T/S, 95% CI = 1.06-1.09) over a wide age range (odds ratio of diabetes for a 1-U decrease in ln-transformed TL = 1.52; 95% CI = 1.23-1.88; P = 0.0001). CONCLUSION Our research demonstrates association between shorter LTL and T2D in a population from mainland China. Our study suggests that shorter LTL might be associated with T2D in a manner independent of smoking and drinking habits or the time of T2D onset time.

Common variants near TERC are associated with leukocyte telomere length in the Chinese Han population

A recent genome-wide association study has identified an association between leukocyte telomere length (LTL) and a locus at 3q26 that includes TERC. In order to evaluate the effects of the SNPs rs12696304 and rs16847897 near TERC in the population of mainland China, we conducted an association study of LTL focusing on these two candidate SNPs in a sample of 4016 Chinese Han individuals. Multiple linear regression analyses were performed to evaluate the association of LTL with each SNP adjusted for age, gender and diabetes status. In the study, we confirmed the association of SNP rs12696304 and rs16847897 near TERC with LTL in the Chinese Han population (P∼4.5 × 10−3 and 9.5 × 10−5, respectively). Each copy of the major allele of rs12696304 and rs16847897 was associated with a shorter mean telomere length of 0.024 and 0.031 T/S respectively, which is equivalent to about 3 and 4 years of average age-related telomere attrition. Our short report confirmed the effects of SNPs near TERC on LTL in the Chinese Han population for the first time.

Association of Genetic Loci with Blood Lipids in the Chinese Population

Background Recent genome-wide association (GWA) studies have identified a number of novel genetic determinants of blood lipid concentrations in Europeans. However, it is still unclear whether these loci identified in the Caucasian GWA studies also exert the same effect on lipid concentrations in the Chinese population. Methods and Results We conducted a replication study assessing associations between SNPs at 15 loci and blood lipid and lipoprotein concentrations in two Chinese cohorts, comprising 2533 and 2105 individuals respectively. SNPs in APO(A1/C3/A4/A5), TIMD4-HAVCR1, DOCK7, TRIB1, ABCA1, and TOMM40-APOE showed strong associations with at least one lipids trait, and rs174546 in FADS1/2/3 showed modest association with triglyceride in the Chinese population. Conclusions We successfully replicated 7 loci associated plasma lipid concentrations in the Chinese population. Our study confirmed the implication of APO(A1/C3/A4/A5), TOMM40-APOE, ABCA1, DOCK7, TIMD4-HAVCR1, TRIB1 and FADS1/2 in plasma lipid and lipoprotein concentrations in Chinese population.

Hypermethylated Epidermal growth factor receptor (EGFR) promoter is associated with gastric cancer

Epidermal growth factor receptor (EGFR) is a member of the receptor tyrosine kinases ErbB family and it is found to be overexpressed in gastric cancer. However, the mechanism of the regulation of the EGFR expression is still unknown. We used the Sequenom EpiTYPER assay to detect the methylation status of the EGFR promoter in normal and tumour tissues of 30 patients with gastric cancer. We also carried out quantitative real time PCR (qPCR) to detect the expression level of EGFR in our 30 patients. Notably, increased methylation level at EGFR promoter was found in tumour tissues than the corresponding adjacent noncancerous. In both Region I DMR and Region II DMR detected in our study, tumor tissues were significantly hypermethylated (P = 2.7743E−10 and 2.1703E−05, respectively). Region I_⊿CpG_2 was also found to be associated with the presence of distant metastasis (P = 0.0323). Furthermore, the results showed a strongly significant association between the relative EGFR expression and the EGFR methylation changes in both Region I and Region II (P = 0.0004 and 0.0001, respectively). Our findings help to indicate the hypermethylation at EGFR promoter in gastric cancer and it could be a potential epigenetic biomarker for gastric cancer status and progression.

Genetic variants in IFIH1 play opposite roles in the pathogenesis of psoriasis and chronic periodontitis

The IFIH1 gene is a key factor connecting environmental and genetic factors in the pathogenesis of immune‐related diseases. We aimed to investigate whether it has effects on psoriasis, chronic periodontitis and skin test‐positive penicillin allergy and to confirm whether these diseases have shared molecular mechanisms originating from shared genetics. Two common variants in IFIH1 were genotyped in 561 patients with psoriasis, 421 patients with chronic periodontitis, 175 patients with skin test‐positive penicillin allergy and 1100 shared controls. Then, case–control study was used to analyse the association between IFIH1 and the three diseases. The allele distributions of rs1990760 and rs3747517 in the Chinese population are much different from the European population. The A allele of rs1990760 (OR = 1.30, P = 5.4 × 10−3) and A‐G (rs1990760/rs3747517) haplotype (OR = 1.31, P = 3.8 × 10−3) were highly associated with the risk of psoriasis. However, the A allele of rs1990760 (OR = 0.73, P = 7.8 × 10−3) and A‐G haplotype (OR = 0.71, P = 4.5 × 10−3) were identified as protective factors for chronic periodontitis. IFIH1 affects several immune‐related diseases, including psoriasis and chronic periodontitis, and provides a molecular link between genetic susceptibility, viral infections and immune‐related diseases. Moreover, we also confirm the hypothesis that shared molecular mechanisms from common genetic variants contribute to a spectrum of immune‐related diseases.

No evidence of association between variant rs2075650 in lipid metabolism-related locus APOE/TOMM40 and advanced age-related macular degeneration in Han Chinese population.

Age-related macular degeneration (AMD) is a late-onset, neurodegenerative disease. Genes related to lipid metabolism are important in AMD pathogenesis. Recently, a variant rs2075650 located in lipid metabolism-related locus APOE/TOMM40 was identified to be associated with advanced AMD and early AMD, respectively, in two genome-wide association studies with European ancestry, while no association study between rs2075650 and overall advanced AMD in Chinese population has been conducted before. We evaluated the potential effect of this variant on advanced AMD in a Han Chinese cohort with 204 advanced AMD patients and 1536 healthy controls. The results suggested that rs2075650 was neither associated with advanced AMD in allele level (P = 0.348) nor in genotype level (P = 0.890 under additive model with age and sex adjusted). In conclusion, our study did not confirm the impact of rs2075650 on advanced AMD risk, indicating that rs2075650 is unlikely a superior marker for APOE/TOMM40 susceptible region with advanced AMD in Han Chinese population.

Common variant rs10033900 near the complement factor I gene is associated with age-related macular degeneration risk in Han Chinese population.

Age-related macular degeneration (AMD) is a late-onset, neurodegenerative disease that causes visual impairment and blindness in the elderly population.1 Multiple genetic loci have been identified as contributing to AMD, including complement pathway-related genes (CFH,2, 3, 4 C2-CFB,5 C3,6, 7 CFI8), lipoprotein metabolism-related genes (APOE,9, 10, 11 LIPC,12 TIMP313) and additional loci such as VEGFA14 and ARMS2/HTRA1.15, 16 Fagerness et al8 initially reported the complement factor I (CFI) gene region associated with AMD in a Caucasian cohort (1228 cases and 825 controls), with the rs10033900 variant located in a downstream region near the CFI gene showing the most significant signal (P=6.46 × 10−8). This association signal was also confirmed by meta-analysis in a genome-wide association study (2594 cases and 4134 controls) with follow-up replication (5640 cases and 52174 controls) in the largest sample of individuals with European ancestry (P=4.1 × 10−10).14 In addition, the C allele of rs10033900 has been commonly identified as a protective allele against AMD in genetic studies.8, 14, 17, 18 However, there remains debate as to whether rs10033900 contributes to AMD susceptibility, due to contradicting evidence published in this journal.18, 19, 20 For example, Ennis et al20 confirmed the association between the CFI region and AMD susceptibility in a UK cohort, although rs10033900 showed no association with AMD. Kondo et al18 demonstrated the association of rs10033900 with the C allele in a Japanese cohort, showing the same association direction as the results of Fagerness et al.8 In contrast, Cipriani et al19 observed no association between rs10033900 and AMD in a study of two independent cohorts from England and Scotland. To investigate the reported association of rs10033900 in the Han Chinese population, we studied this locus in our cohort of 288 unrelated AMD patients and 384 healthy controls.

DNA methylation profiling in the thalamus and hippocampus of postnatal malnourished mice, including effects related to long-term potentiation

BackgroundDNA methylation has been viewed as the most highly characterized epigenetic mark for genome regulation and development. Postnatal brains appear to exhibit stimulus-induced methylation changes because of factors such as environment, lifestyle, and diet (nutrition). The purpose of this study was to examine how extensively the brain DNA methylome is regulated by nutrition in early life.ResultsBy quantifying the total amount of 5-methylcytosine (5mC) in the thalamus and the hippocampus of postnatal malnourished mice and normal mice, we found the two regions showed differences in global DNA methylation status. The methylation level in the thalamus was much higher than that in the hippocampus. Then, we used a next-generation sequencing (NGS)-based method (MSCC) to detect the whole genome methylation of the two regions in malnourished mice and normal mice. Notably, we found that in the thalamus, 500 discriminable variations existed and that approximately 60% were related to neuronal development or psychiatric diseases. Pathway analyses of the corresponding genes highlighted changes for 9 genes related to long-term potentiation (5.3-fold enrichment, P = 0.033).ConclusionsOur findings may help to indicate the genome-wide DNA methylation status of different brain regions and the effects of malnutrition on brain DNA methylation. The results also indicate that postnatal malnutrition may increase the risk of psychiatric disorders.

Association study of newly identified age-related macular degeneration susceptible loci SOD2, MBP, and C8orf42 in Han Chinese population

A recent genome-wide association study has reported three newly identified susceptible loci (rs2842992 near the gene SOD2, rs1789110 near the gene MBP and rs722782 near the gene C8orf42) to be associated with the geographic atrophy subtype of age-related macular degeneration in European-descent population. We investigated the correlation between these variants and advanced age-related macular degeneration for the first time in a Han Chinese cohort; however, no evidence supports these previously identified loci contribute to advanced age-related macular degeneration susceptibility in Chinese population.