Dingding Zhang

Exome sequencing identifies ZNF644 mutations in high myopia

Myopia is the most common ocular disorder worldwide, and high myopia in particular is one of the leading causes of blindness. Genetic factors play a critical role in the development of myopia, especially high myopia. Recently, the exome sequencing approach has been successfully used for the disease gene identification of Mendelian disorders. Here we show a successful application of exome sequencing to identify a gene for an autosomal dominant disorder, and we have identified a gene potentially responsible for high myopia in a monogenic form. We captured exomes of two affected individuals from a Han Chinese family with high myopia and performed sequencing analysis by a second-generation sequencer with a mean coverage of 30× and sufficient depth to call variants at ∼97% of each targeted exome. The shared genetic variants of these two affected individuals in the family being studied were filtered against the 1000 Genomes Project and the dbSNP131 database. A mutation A672G in zinc finger protein 644 isoform 1 (ZNF644) was identified as being related to the phenotype of this family. After we performed sequencing analysis of the exons in the ZNF644 gene in 300 sporadic cases of high myopia, we identified an additional five mutations (I587V, R680G, C699Y, 3′UTR+12 C>G, and 3′UTR+592 G>A) in 11 different patients. All these mutations were absent in 600 normal controls. The ZNF644 gene was expressed in human retinal and retinal pigment epithelium (RPE). Given that ZNF644 is predicted to be a transcription factor that may regulate genes involved in eye development, mutation may cause the axial elongation of eyeball found in high myopia patients. Our results suggest that ZNF644 might be a causal gene for high myopia in a monogenic form.

A genome-wide meta-analysis identifies two novel loci associated with high myopia in the Han Chinese population

High myopia, highly prevalent in the Chinese population, is a leading cause of visual impairment worldwide. Genetic factors play a critical role in the development of this visual disorder. Genome-wide association studies in recent years have revealed several chromosomal regions that contribute to its progression. To identify additional genetic variants for high myopia susceptibility, we used a genome-wide meta-analysis to examine the associations between the disease and 286 031 single-nucleotide polymorphisms (SNPs) in a combined cohort of 665 cases and 960 controls. The most significant SNPs (n = 61) were genotyped in a replication cohort (850 cases and 1197 controls), and 14 SNPs were further tested through genotyping in two additional validation cohorts (combined 1278 cases and 2486 controls). As a result of this analysis, four SNPs reached genome-wide significance (P < 2.0 × 10(-7)). The most significantly associated SNP, rs2730260 [overall P = 8.95 × 10(-14); odds ratio (95% CI) =1.33 (1.23-1.44)], is located in the VIPR2 gene, which is located in the MYP4 locus. The other three SNPs (rs7839488, rs4395927 and rs4455882) in the same linkage disequilibrium block are located in the SNTB1 gene, with -P values ranging from 1.13 × 10(-8) to 2.13 × 10(-11). The VIPR2 and SNTB1 genes are expressed in the retina and the retinal pigment epithelium and have been previously reported to have potential functions for the pathogenesis of myopia. Our results suggest that variants of the VIPR2 and SNTB1 genes increase susceptibility to high myopia in Han Chinese.

Mutation spectrum of CYP1B1 in Chinese patients with primary open-angle glaucoma

Purpose The CYP1B1 gene has been shown to be related to primary open-angle glaucoma (POAG). This study aimed to identify the mutation profile of CYP1B1 in Chinese individuals with POAG. Methods The study included 416 unrelated cases diagnosed as POAG by standard ophthalmological examinations, and 657 unrelated healthy controls in a Chinese population. Genomic DNA was collected from peripheral blood of all the participants. The coding sequence of CYP1B1 was amplified by PCR from genomic DNA, followed by direct DNA sequencing. Results Among 416 patients with POAG, 13 missense mutations, including nine reported mutations and four novel mutations (p.P93S, p.R259C, p.A295T, p.L475P), were detected in 25 patients. All these mutations were found as heterozygotes and the reported mutations have been previously found in primary congenital glaucoma and/or POAG patients. Three of them (p.L107V, p.E229K, p.V320L) were also found in healthy controls. In addition, six previously reported single nucleotide polymorphisms (p.R48G, p.A119S, p.V243V, p.V432L, p.D449D, p.N453S) were also observed in POAG patients and controls, and they showed no obvious frequency difference between patients and controls. Conclusions This study provides a mutation spectrum of CYP1B1 resulting in POAG development in a Chinese population, which may demonstrate an involvement of the gene in a proportion of subjects with POAG and help to improve our understanding of the pathogenesis of CYP1B1-associated POAG.

Association study of polymorphisms in FOXO3, AKT1 and IGF-2R genes with human longevity in a Han Chinese population

FOXO3, AKT1 and IGF-2R are critical members of the insulin/IGF-1 signaling pathway. Previous studies showed that polymorphisms (SNPs) in FOXO3, AKT1 and IGF-2R were associated with human longevity in Caucasian population. However, the association of these SNPs in different ethnic groups is often inconsistent. Here, we investigated the association of genetic variants in three genes with human longevity in Han Chinese population. Twelve SNPs from FOXO3, AKT1 and IGF-2R were selected and genotyped in 1202 long-lived individuals (nonagenarians and centenarians) and younger individuals. Rs9486902 of FOXO3 was found to be associated with human longevity in both genders combined in this study (allelic P = 0.002, corrected P = 0.024). The other eleven SNPs were not significantly associated with human longevity in Han Chinese population. The haplotypes TTCTT, CCTTC and CTCCT of FOXO3 as well as GGTCGG and GGTCAG of AKT1 were shown to have a significant difference between case and control (P =0.006, 2.78×10−5, 4.68×10−6, 0.003,0.005, respectively). The estimated prevalence of diabetes and prediabetes in long-lived individuals was significantly lower than in common adult populations (P = 0.001, 2.3×10−26). Therefore, the search for longevity-associated genes provides the identification of new potential targets beneficial for the treatment of diabetes.

Association between hOGG1 polymorphism rs1052133 and gastric cancer

Purpose To conduct a comprehensive evaluation of the association of the human8-oxoguanine glycosylase 1 (hOGG1) gene polymorphism rs1052133 with gastric cancer (GC) through a systematic review and meta-analysis of genetic association study. Results A total of 15 articles from published papers were included in our analysis. The meta-analyses for hOGG1 rs1052133, composed of 4024GC patients and 6022controls, showed low heterogeneity for the included populations in all the genetic models, except for the Caucasian population under allelic genetic model, the Asian population under addictive model and Caucasian population under dominant model. The analyses of all the genetic models in overall pooled populations did not identify any significant association between GC and hOGG1 rs1052133 (Allelic model: C vs. G, p = 0.746; Addictive model: CC vs. GG, p = 0.888; Recessive model: CC +GC vs. GG, p = 0.628; Dominant model: CC vs. GG+GC, p = 0.147), even though stratified analyses were conducted in different ethnicities under each genetic model. Materials and Methods All case-control association studies on hOGG1 and GC reported up to December 15, 2016 in PubMed, Embase, Web of Science, and the Chinese Biomedical Database were retrieved. Odds ratios (ORs) and 95% confidence intervals (95% CIs) were calculated for single-nucleotide polymorphism (SNP) using fixed- and random- effects models according to between-study heterogeneity. Publication bias analyses were conducted using Begg test. Conclusions This meta-analysis showed there was no association between hOGG1 rs1052133 and GC. Given the limited sample size, further investigations including more ethnic groups are required to validate the association.

New insight into power-law behavior of fragment size distributions in the C60 multifragmentation regime

Previous experimental work has shown that a phase transition in C60 multifragmentation induced by nanosecond laser occurs at almost constant temperature covering a wide range of laser fluency. Here the relative yields of ionic fragments (IFs) C(n)(+) (n = 1-20) resulting from the multifragmentation are measured within the phase transition region. By excluding two small IFs and magic IFs due to their abnormal behavior, the data for residual IFs are used to estimate the size distributions of primary intermediate-mass IFs in the multifragmentation regime. The distributions are found to obey power laws n(-τ). Furthermore, the exponent τ values have sensitive dependence on lower laser fluency and converge to a constant of about 2.4 ± 0.2 for larger fluencies. These observations are in good agreement with an explanation based on the Fisher droplet model, offering the tantalizing possibility of a liquid-to-gas phase transition in C60 systems.

Possible evidence for a liquid-gas phase transition in C60 systems

We demonstrate that C60 fragmentation may be associated with a liquid-to-gas phase transition by analyzing the fragment size distributions in the C60 multifragmentation regime. The results will provide useful information to understand the formation mechanism of primary C60 in interstellar environments.

Analysis of ionic fragment size distribution in collision of nanosecond laser with the C60 molecule

At the critical point of fragmentation phase transition occurring in C60 system, we found that the yield distribution of ionic fragments Cn+ (n=3-16) originating from the multi-fragmentation pattern can be approximated fairly well by a power-law attenuation form of n−λ. Under the framework of Fisher model, the experimental result implies that the ionization-degree distribution of fragments obeys a power law enhancement form as the size n.