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Ni B.,State Key Laboratory of Reproductive Medicine | Ni B.,Collaborative Innovation Center For Cancer Personalized Medicine | Lin Y.,State Key Laboratory of Reproductive Medicine | Lin Y.,Collaborative Innovation Center For Cancer Personalized Medicine | And 47 more authors.
Human Molecular Genetics | Year: 2015

Genome-wide association studies (GWAS) have identified several common loci contributing to non-obstructive azoospermia (NOA). However, a substantial fraction of NOA heritability remains undefined, especially those low-frequency [defined here as having a minor allele frequency (MAF) between 0.5 and 5%] and rare (MAF below 0.5%) variants. Here, we performed a 3-stage exome-wide association study in Han Chinese men to evaluate the role of low-frequency or rare germline variants in NOA development. The discovery stage included 962 NOA cases and 1348 healthy male controls genotyped by exome chips and was followed by a 2-stage replication with an additional 2168 cases and 5248 controls. We identified three low-frequency variants located at 6p22.2 (rs2298090 in HIST1H1E encoding p.Lys152Arg: OR = 0.30, P = 2.40 × 10-16) and 6p21.33 (rs200847762 in FKBPL encoding p.Pro137Leu: OR = 0.11, P = 3.77 × 10-16; rs11754464 in MSH5: OR = 1.78, P = 3.71 × 10-7) associated with NOA risk after Bonferroni correction. In summary, we report an instance of newly identified signals for NOA risk in genes previously undetected through GWAS on 6p22.2-6p21.33 in a Chinese population and highlight the role of low-frequency variants with a large effect in the process of spermatogenesis. © The Author 2015. Published by Oxford University Press. All rights reserved.

PubMed | Shanghai JiaoTong University, Collaborative Innovation Center For Cancer Personalized Medicine, Nanjing Medical University, Eastern Hepatobiliary Surgery Hospital and and 5 more.
Type: Journal Article | Journal: Human molecular genetics | Year: 2016

Several genome-wide association studies (GWAS) have demonstrated the association between genetic variants in the major histocompatibility complex (MHC) region and chronic hepatitis B (CHB) virus infection, but it is still unknown about the disease-causing loci and potential mechanisms owing to the complicated linkage disequilibrium for this region. To systematically characterize the MHC variations in relation to the CHB infection, we fine mapped the MHC region on our existing GWAS data with SNP2HLA taken the Pan-Asian panel as reference and finally identified four independent associations. The HLA-DP1 amino acid positions 84-87, which drove the effect of reported single nucleotide polymorphisms rs9277535 and rs3077, showed the most significant association (OR = 0.65, P = 2.03 10(-8)). The Leu-15 of HLA-C, conferring the effect of rs3130542, increased the risk of CHB infection independently (OR = 1.61, P = 3.42 10(-7)). The HLA-DR1*13, in perfect LD with glutamic at site 71, and rs400488, an expression quantitative trait locus for HLA-J, were newly identified to be associated with CHB infection independently (OR = 1.84, P = 3.84 10(-9); OR = 0.28, P = 6.27 10(-7), respectively). HLA-DP1 positions 84-87 and HLA-DR1 position 71 implicated the P1 and P4 in the antigen-binding groove, whereas HLA-C position 15 affected the signal peptide. These four independent loci together can explain 6% of the phenotypic variance for CHB infection, accounting for 72.94% of that explained by known genetic variations. We fine mapped the MHC region and identified four loci that independently drove the chronic HBV infection. The results provided a deeper understanding of the GWAS signals and identified additional susceptibility loci which were missed in previous association studies.

Ge Z.,Nanjing Southeast University | Ge Z.,Nanjing Medical University | Ge Z.,Pennsylvania State University | Li M.,Nanjing Medical University | And 9 more authors.
Oncology Letters | Year: 2016

Genetic mutations on signaling pathways are found in patients with T-cell acute lymphoblastic leukemia (T-ALL) and act as markers of high-risk leukemia. Mutations in dynamin 2 (DNM2) have been reported in T-ALL, particularly in early T-cell precursor-ALL. In the present study, DNM2 mutations were screened by sequencing DNM2 exons obtained by polymerase chain reaction amplification and gel purification in adult T-ALL patients. A total of 4 novel DNM2 mutations were identified in adult T-ALL patients, with a mutation rate of 9.5%, and the DNM2 mutations were found to co-exist with NOTCH1 and PHD finger protein 6, and were also associated with high-risk leukemia. A high rate of silent mutation was also found in the patients, but no significant association was found between the silent mutations and patients’ clinical features. The present findings suggested the DNM2 mutations may be involved in the oncogenesis of T-ALL. © 2016, Spandidos Publications. All rights reserved.

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