Chinese Han Individuals Research Articles

Could routine forensic STR genotyping data leak personal phenotypic information?

The application of forensic genetic markers must comply with privacy rights and legal policies on a premise that the markers do not expose phenotypic information. The most widely-used short tandem repeats (STRs) are generally viewed as ‘junk’ DNA because most STRs are located in non-coding regions and therefore refrain from leaking phenotypic traits. But with a deepening understanding of phenotypes and underlying genetic structure, whether STRs could potentially reflect any phenotypic information may need re-examining. Therefore, we performed the following analyses. First, we analyzed the association between 15 STRs and three facial characteristics (single or double eyelid, with or without epicanthus, unattached or attached earlobe) on 721 unrelated Han Chinese individuals. Then, we collected 27199 individuals’ STRs and geographic data from the literature to investigate the association between STRs and bio-geographic information, and predict geographic information by STRs on additional 1993 unrelated individuals. We found that there was scarcely any association between STRs with studied facial characteristics. Although allele19 in D2S1338 and allele 18 in FGA (P = 0.0032, P = 0.0030, respectively after Bonferroni correction) showed statistical significance, the prediction effectiveness was very low. For the STRs and bio-geographic information, the principal component analysis showed the first three components could explain 87.7% of the variance, but the prediction accuracy only reached 25.2%. We demonstrated that the forensic phenotypes are usually complex traits, it is hardly possible to uncover phenotypic information by testing only dozens of STR loci.

Association of DNA Methylation in Blood Pressure-Related Genes With Ischemic Stroke Risk and Prognosis.

BackgroundA genome-wide association study identified 12 genetic loci influencing blood pressure and implicated a role of DNA methylation. However, the relationship between methylation and ischemic stroke has not yet been clarified. We conducted a large-sample sequencing study to identify blood leukocyte DNA methylations as novel biomarkers for ischemic stroke risk and prognosis based on previously identified genetic loci.MethodsMethylation levels of 17 genes were measured by sequencing in 271 ischemic stroke cases and 323 controls, and the significant associations were validated in another independent sample of 852 cases and 925 controls. The associations between methylation levels and ischemic stroke risk and prognosis were evaluated.ResultsMethylation of AMH, C17orf82, HDAC9, IGFBP3, LRRC10B, PDE3A, PRDM6, SYT7 and TBX2 was significantly associated with ischemic stroke. Compared to participants without any hypomethylated targets, the odds ratio (OR) (95% confidence interval, CI) for those with 9 hypomethylated genes was 1.41 (1.33–1.51) for ischemic stroke. Adding methylation levels of the 9 genes to the basic model of traditional risk factors significantly improved the risk stratification for ischemic stroke. Associations between AMH, HDAC9, IGFBP3, PDE3A and PRDM6 gene methylation and modified Rankin Scale scores were significant after adjustment for covariates. Lower methylation levels of AMH, C17orf82, PRDM6 and TBX2 were significantly associated with increased 3-month mortality. Compared to patients without any hypomethylated targets, the OR (95% CI) for those with 4 hypomethylated targets was 1.12 (1.08–1.15) for 3-month mortality (P = 2.28 × 10−10).ConclusionThe present study identified blood leukocyte DNA methylations as potential factors affecting ischemic stroke risk and prognosis among Han Chinese individuals.

Forensic age prediction and age classification for critical age thresholds via 3.0T magnetic resonance imaging of the knee in the Chinese Han population.

To assess the performance of knee MRI for forensic age prediction and classification for 12-, 14-, 16-, and 18-year thresholds. The ossification stages of distal femoral epiphyses and proximal tibial epiphyses were assessed using an integrated staging system by Schmeling et al. and Kellinghaus et al. for knee 3.0T MRI with T1-weighted turbo spin-echo (T1-TSE) in sagittal orientation among 852 Chinese Han individuals (483 males and 369 females) aged 7-30 years. Regression models for age prediction were constructed and their performances were evaluated based on mean absolute deviation (MAD) values. In addition, the performances of age classification were assessed using receiver operating characteristic (ROC) analyses. The intra- and inter-observer agreement levels were very good (κ > 0.80). The complete fusion of those two types of epiphyses took place before 18.0 years in our study participants. The minimum MAD values were 2.51 years (distal femur) and 2.69 years (proximal tibia) in males, and 2.75 years (distal femur) and 2.87 years (proximal tibia) in females. The specificity values of constructed prediction models were all above 90% for the 12-, 14-, and 16-year thresholds, compared to the 74.8-84.6% for the 18-year threshold. Better performances of age prediction and classification were observed in males by distal femoral epiphyses. Ossification stages via 3.0T MRI of the knee with T1-TSE sequence using an integrated staging system could be a reliable noninvasive method for age prediction or for age classification for 12-, 14-, and 16-year thresholds, especially in males by distal femoral epiphyses. However, assessments based on the full bony fusion of the distal femoral epiphysis and proximal tibial epiphysis seemed not reliable for age classification for the 18-year threshold in the Chinese Han population.

The association between the CASP5 rs7939842 polymorphism and the risk of rheumatoid arthritis in Chinese Han individuals

The association between inflammatory cysteinyl aspartate protease-5 (CASP5) and the susceptibility to rheumatoid arthritis (RA) remains unclear. This study examined whether the CASP5 rs7939842 polymorphism affects RA risk in Chinese Han individuals. This study recruited 805 RA patients and 1095 healthy controls to investigate the association between the CASP5 rs7939842 polymorphism and RA risk. Genotype was examined using the 48-Plex SNPscan™ Kit. Plasma CASP5 levels were determined using enzyme-linked immunosorbent assays, and CASP5 gene expression was detected by quantitative polymerase chain reaction in 40 RA patients and 40 healthy controls. The CASP5 rs7939842 polymorphism G allele is a putative risk factor for RA. After stratified analyses, this polymorphism increased the risk of RA among CRP-, ACPA-, RF-, and ESR-positive individuals, as well as individuals with DAS28 ≥ 3.20 and functional class III + IV. Furthermore, the plasma CASP5 levels and CASP5 mRNA expression were higher in RA patients than in healthy controls. The CASP5 rs7939842 polymorphism appears to be associated with an elevated risk of RA in Chinese Han individuals. Blood CASP5 protein and mRNA levels were significantly higher in RA patients than in healthy controls.

Genetic Epidemiology of Medication Safety and Efficacy Related Variants in the Central Han Chinese Population With Whole Genome Sequencing.

Medication safety and efficacy-related pharmacogenomic research play a critical role in precision medicine. This study comprehensively analyzed the pharmacogenomic profiles of the central Han Chinese population in the context of medication safety and efficacy and compared them with other global populations. The ultimate goal is to improve medical treatment guidelines. We performed whole-genome sequencing in 487 Han Chinese individuals and investigated the allele frequencies of pharmacogenetic variants in 1,731 drug response-related genes. We identified 2,139 (81.18%) previously reported variants in our population with annotations in the PharmGKB database. The allele frequencies of these 2,139 clinical-related variants were similar to those in other East Asian populations but different from those in other global populations. We predicted the functional effects of nonsynonymous variants in the 1,731 pharmacogenes and identified 1,281 novel and 4,442 previously reported deleterious variants. Of the 1,281 novel deleterious variants, five are common variants with an allele frequency >5%, and the rest are rare variants with an allele frequency <5%. Of the 4,442 known deleterious variants, the allele frequencies were found to differ from those in other populations, of which 146 are common variants. In addition, we found many variants in non-coding regions, the functions of which require further investigation. This study compiled a large amount of data on pharmacogenomic variants in the central Han Chinese population. At the same time, it provides insight into the role of pharmacogenomic variants in clinical medication safety and efficacy.

Prevalence of Germline Sequence Variations Among Patients With Pancreatic Cancer in China

A higher incidence of pancreatic cancer has been reported in the Chinese population compared with the White population, but genetic differences are unknown to date. Large-sample germline testing for both familial and sporadic pancreatic cancers has been conducted predominantly in White populations, whereas similar studies in Chinese populations are limited. To assess the prevalence of germline sequence variations in patients with pancreatic diseases in China. This genetic association study was a case series that included genetic data from patients with pancreatic ductal adenocarcinoma (PDAC) or non-PDAC pancreatic diseases seen at The First Affiliated Hospital of Nanjing Medical University in Nanjing, China, between January 2006 and December 2017 (Nanjing cohort). Comparator group data were obtained for a US cohort from Johns Hopkins Hospital (JHH), a population from East Asia from the Exome Aggregation Consortium (ExAC) database, and the larger population from China from the ChinaMAP database. Data were updated and analyzed in July 2021. Next-generation sequencing technology was used to examine the prevalence of deleterious variations in 59 genes of the included Chinese patients with DNA extracted from peripheral blood samples. The Fisher exact test was used to assess differences among the frequencies of germline variations in the study patients vs the comparator groups. A total of 1009 patients with PDAC (627 [62.1%] male; mean [SD] age, 62.8 [10.2] years) and 885 with non-PDAC diseases (477 [53.9%] male; mean [SD] age, 52.0 [15.9] years) from the Nanjing cohort were included for genetic analysis; all were Han Chinese individuals. Pathogenic variations were detected in 63 patients with PDAC (6.2%; 95% CI, 4.7%-7.7%). Variations in BRCA2 (odds ratio [OR], 3.2; 95% CI, 1.4-7.7; P = .008) and PALB2 (OR, 5.2; 95% CI, 1.6-17.0; P = .007) were significantly associated with pancreatic risk in the Nanjing cohort. Pathogenic variants of genes associated with homologous recombination DNA damage repair, including ATM, BRCA1/2, PALB2, BRIP1, FANCA, FANCC, RAD51D, and XRCC2, were found in 34 patients with PDAC (3.4%). No Ashkenazi Jewish-specific BRCA2 variation (p.Ser1982fs) was detected. The odds ratio of a SPINK1 variation in patients with PDAC was 3.2 (95% CI, 1.8-5.7; P < .001) in the Nanjing cohort compared with the ExAC cohort. Variations in the pancreatic secretory enzyme genes CPA1 and CPB1 were not detected in the Nanjing cohort. In this genetic association study, sporadic pancreatic cancer was associated with pathogenic germline variations in a cohort from China. These findings provide insights into the genetic background of pancreatic cancer in the Han Chinese population with PDAC.

Polymorphic mutations in the polb gene promoter and their impact on transcriptional activity.

BackgroundDNA polymerase β is one of the key enzymes involved in DNA damage repair and its proper expression is strictly controlled within different cells. We previously reported that three genetic mutations in the promoter region of the polb gene are prevalent in the Chinese Han population and two types of mutation are associated with thymic hyperplasia. The purpose of this study was to explore whether other mutated sites exist within the promoter region of the polb gene.MethodsGenomic DNAs of 421 healthy Chinese Han individuals were extracted from whole blood samples and used for gene amplification of the promoter region of the polb gene. After gel purification, PCR amplicons were sequenced by the Sanger sequencing method and used for sequence alignment with the Lasergene program. PCR products with novel mutations were then subcloned into luciferase reporter plasmid pGL4.10 and transfected into 293T cells for dual‐luciferase activity analysis.ResultsIn total, 11 mutated sites were detected in the Chinese Han population and eight of these were reported for the first time. Using a dual luciferase reporter system, it was found that one novel mutation −142 C > G could decrease the transcription activity of the polb gene, whereas two novel mutations, −152_−151insC and −218 C > G, could significantly increase the transcription activity of the polb gene.ConclusionsHigh polymorphic sites could be found in the promoter region of polb gene and approximately half of them could influence its transcription activity.

Correlations between mandibular ramus height and occlusal planes in Han Chinese individuals with normal occlusion: A cross-sectional study

Objectives: The objective of the study is to determine the relationships between ramus height and occlusal planes (OPs) in Han Chinese individuals with normal occlusion. Materials and Methods: Two hundred and four participants with normal occlusion were included and their cephalograms were analyzed. The ramus height (Ar-Go), Frankfort horizontal plane-posterior OP (FH-POP), FH-anterior OP (FH-AOP) and FH-OP, anterior and posterior cranial base length, SNA, SNB, ANB, Frankfort-mandibular plane angle, SN-MP, jaw angle, and mandibular body length were measured on the subjects’ cephalograms. Pearson correlation coefficients were calculated among continuous variables. The ramus height was considered as dependent variable and the OPs as independent variables. Age, sex, and other cephalometric parameters were considered as possible confounding factors. Univariate and multivariate analyses were performed to determine whether the relationships were significant. Results: The FH-POP and FH-OP were moderately associated with ramus height, while the FH-AOP showed a weak association (P &lt; 0.001). After adjusting age and sex, FH-POP, FH-AOP, and FH-OP showed significant negative associations with ramus height (β = −0.36, −0.28, and −0.37, respectively, P &lt; 0.001). The OP flattened with the ramus height increased. After adjusting all the confounding factors, FH-POP and FH-OP showed significant negative associations with ramus height. The ramus height increased by 0.19 mm/1° flattening of FHPOP (β = −0.19, P = 0.002). Conclusion: After adjust age, sex, and other possible confounding factors, the FH-POP and FH-OP were associated with the ramus height. The flattening of FH-POP was associated with the increase of ramus height. The results should be treated with caution since it’s a cross-sectional study.

Pharmacometabolomic study of drug response to antihypertensive medications for hypertension marker identification in Han Chinese individuals in Taiwan

Various groups of antihypertensive drugs targeting different pathways have been developed; however, the pharmacometabolic responses to these drugs have rarely been compared to elucidate the common pathway of blood pressure regulation. Here, we performed a comparative multi-dimensional pharmacometabolic study on the four major lines of antihypertensive drugs, namely angiotensin-converting enzyme inhibitors (ACEis), angiotensin receptor blockers (ARBs), calcium channel blockers (CCBs), and diuretics (DIURs), through ultra-performance liquid chromatography coupled to quantum time-of-flight mass spectrometry. Two hundred fifty patients with young-onset hypertension, who were equally divided among five study groups: non-medicated, ACEi, ARB, CCB, and DIUR groups, were recruited. In a metabolome-wide association study conducted through analysis of covariance, 37 molecular features significantly associated with pharmacometabolic responses to antihypertensive drugs were identified. One-third of these features were shared by multiple medications. ACEis, ARBs, and DIURs shared more features than CCB, partially reflecting that ACEis, ARBs, and DIURs affect the renin-angiotensin-aldosterone system. Thirteen molecular features were consistently identified by all four models of the analysis of covariance. A tandem mass spectrometry (or MS/MS) experiment was performed to decipher the chemical structure of these 13 molecular features, including ARB-associated lysophosphatidylcholine (P4135), CCB-associated diacylglycerol(15:0/18:2) (P1175), and DIUR-associated oleamide (P1516). In addition, diacylglycerol(15:0/14:2) (P408) was significantly associated with the pharmacometabolic response to all four antihypertensive drugs. The identified metabolites provide insights into the mechanisms of blood pressure regulation and potential predictive markers of pharmacometabolic responses to antihypertensive drugs.

Association between HLA alleles and sub-phenotype of childhood steroid-sensitive nephrotic syndrome

BackgroundFew studies have addressed the effects of human leukocyte antigen (HLA) alleles on different clinical sub-phenotypes in childhood steroid-sensitive nephrotic syndrome (SSNS), including SSNS without recurrence (SSNSWR) and steroid-dependent nephrotic syndrome/frequently relapse nephrotic syndrome (SDNS/FRNS). In this study, we investigated the relationship between HLA system and children with SSNSWR and SDNS/FRNS and clarified the value of HLA allele detection for precise typing of childhood SSNS.MethodsA total of 241 Chinese Han individuals with SSNS were genotyped using GenCap-WES Capture Kit, and four-digit resolution HLA alleles were imputed from available Genome Wide Association data. The distribution and carrying frequency of HLA alleles in SSNSWR and SDNS/FRNS were investigated. Additionally, logistic regression and mediating effects were used to examine the relationship between risk factors for disease process and HLA system.ResultsCompared with SSNSWR, significantly decreased serum levels of complement 3 (C3) and complement 4 (C4) at onset were detected in SDNS/FRNS (C3, P < 0.001; C4, P = 0.018). The average time to remission after sufficient initial steroid treatment in SDNS/FRNS was significantly longer than that in SSNSWR (P = 0.0001). Low level of C4 was further identified as an independent risk factor for SDNS/FRNS (P = 0.008, odds ratio = 0.174, 95% confidence interval 0.048–0.630). The HLA-A*11:01 allele was independently associated with SSNSWR and SDNS/FRNS (P = 0.0012 and P = 0.0006, respectively). No significant HLA alleles were detected between SSNSWR and SDNS/FRNS. In addition, a mediating effect among HLA-I alleles (HLA-B*15:11, HLA-B*44:03 and HLA-C*07:06), C4 level and SDNS/FRNS was identified.ConclusionsHLA-I alleles provide novel genetic markers for SSNSWR and SDNS/FRNS. HLA-I antigens may be involved in steroid dependent or frequent relapse in children with SSNS as mediators of immunoregulation.

Preliminary Study of Genome-Wide Association Identified Novel Susceptibility Genes for Hemorheological Indexes in a Chinese Population

Background: Genome-wide association studies for various hemorheological characteristics have not been reported. We aimed to identify genetic loci associated with hemorheological indexes in a cohort of healthy Chinese Han individuals. Methods: Genotyping was performed using Applied Biosystems Axiom™ Precision Medicine Diversity Array in 838 individuals, and 6,423,076 single nucleotide polymorphisms were available for genotyping. The relations were examined in an additive genetic model using mixed linear regression and combined with identical by descent matrix. Results: We identified 38 genetic loci (p < 5 × 10⁻⁶) related to hemorheological traits. In which, LOC102724502-OLIG2 rs28371438 was related to the levels of nd30 (p = 8.58 × 10⁻⁰⁷), nd300 (p = 1.89 × 10⁻⁰⁶), erythrocyte rigidity (p = 1.29 × 10⁻⁰⁶), assigned viscosity (p = 6.20 × 10⁻⁰⁸) and whole blood high cut relative (p = 7.30 × 10⁻⁰⁸). The association of STK32B rs4689231 for nd30 (p = 3.85 × 10⁻⁰⁶) and nd300 (p = 2.94 × 10⁻⁰⁶) and GTSCR1-LINC01541 rs11661911 for erythrocyte rigidity (p = 9.93 × 10⁻⁰⁹) and whole blood high cut relative (p = 2.09 × 10⁻⁰⁷) was found. USP25-MIR99AHG rs1297329 was associated with erythrocyte rigidity (p = 1.81 × 10⁻⁰⁶) and erythrocyte deformation (p = 1.14 × 10⁻⁰⁶). Moreover, the association of TMEM232-SLC25A46 rs3985087 and LINC00470-METTL4 rs9966987 for fibrinogen (p = 1.31 × 10⁻⁰⁶ and p = 4.29 × 10⁻⁰⁷) and plasma viscosity (p = 1.01 × 10⁻⁰⁶ and p = 4.59 × 10⁻⁰⁷) was found. Conclusion: These findings may represent biological candidates for hemorheological indexes and contribute to hemorheological study.

Association Between the Polymorphism of Steroid Hormone Metabolism Genes and High-Altitude Pulmonary Edema in the Chinese Han Population.

PurposeSteroid hormone metabolism plays an essential role in high-altitude pulmonary edema (HAPE) progression. This study aimed to investigate the association between polymorphism in seven steroid hormone metabolism genes (STAR, HSD3B1, HSD3B2, CYP17A1, CYP21A2, CYP11B1, and CYP11B2) and HAPE susceptibility among Han Chinese.Patients and MethodsA total of 41 tagSNPs in the seven genes were genotyped using Sequenom MassARRAY SNP assays from 169 HAPE patients (HAPE-p) and 309 matched Han Chinese individuals resistant to HAPE (HAPE-r). The genotypic and allele frequencies, odds ratios (ORs), and 95% confidence intervals (95% CIs) were calculated.ResultsFour SNPs, including the allele C of rs6203 (p = 0.034, OR [95% CI] = 1.344 [1.022−1.767]) in HSD3B1, allele G of rs3740397 (p = 0.044, OR [95% CI] = 1.314 [1.007−1.714]) and allele C of rs10786712 (p = 0.039, OR [95% CI] = 0.751 [0.572−0.986]) in CYP17A1, and allele T of rs6402 (p = 0.006, OR [95% CI] = 0.504 [0.306−0.830]) in CYP11B1, were significantly associated with HAPE. The distribution of the genotypes of these SNPs also significantly differed between the HAPE-p and HAPE-r groups. Moreover, six haplotypes (the linkage disequilibrium block including rs10883783, rs4919686, rs3740397, rs3824755, and rs10786712) of CYP17A1 were also significantly associated with HAPE.ConclusionThe four SNPs located in HSD3B1 (rs6203), CYP17A1 (rs3740397 and rs10786712), and CYP11B1 (rs6402) and the six haplotypes of CYP17A1 are likely to have an effect on HAPE.

Pairwise kinship analysis of 17 pedigrees using massively parallel sequencing

With the tremendous development of massively parallel sequencing (MPS) in the last decade, it has been widely applied in basic science, clinical diagnostics, microbial genomics, as well as forensic genetics. MPS has lots of advantages that may facilitate the kinship analysis. In this study, 243 Chinese Han individuals from 17 families were involved and sequenced using the ForenSeq™ DNA Signature Prep Kit (Verogen, Inc., San Diego, USA), which provided the sequence information of 27 autosomal STRs (A-STRs), 7 X chromosomal STRs (X-STRs), 24 Y chromosomal STRs (Y-STRs) and 94 identity-informative SNPs (iSNPs). A total of 275 pairs of parent-child, 123 pairs of full siblings, 1 pair of twins, 1 pair of half siblings, 158 pairs of grandparent-grandchild, 222 pairs of uncle/aunt-nephew/niece and 121 pairs of first cousins, as well as 701 pairs of unrelated individuals were identified. Using both likelihood ratio (LR) and identical by state (IBS) methods, the kinship analysis was conducted among these relative and non-relative pairs based on the A-STRs and SNPs. As a result, the ForenSeq Signature Kit could solve the analysis of parent-child (t1 = −4, t2 = 4), full siblings (t1 = −2, t2 = 2) and most second-degree kinships (t1 = −1, t2 = 1) using the LR method. When the IBS method was applied, 123 full sibling pairs had a higher average IBS value than other kinship groups in this study. And the IBS method could play a role in the testing of parent-child and full siblings.

Copy Number Variation Analysis of IL22 and LCE3C in Different Subtypes of Psoriasis in a Chinese Han Population.

BackgroundPsoriasis is a chronic, immune-mediated and hyperproliferative skin disease with both genetic and environmental components. Copy number variations (CNV) of IL22 and LCE3C-LCE3B deletion have been confirmed to be predisposed to psoriasis vulgaris (PsV) in several ethnic groups. However, it remains to be clarified whether CNVs of IL22 and LCE3C are associated with different subtypes of psoriasis (psoriatic arthritis, PsA; erythrodermic psoriasis, EP; and generalized pustular psoriasis, GPP).Material/MethodsWe enrolled 897 Han Chinese individuals, including 478 patients and 419 healthy controls, and detected CNVs of IL22 and LCE3C using the comparative CT method by real-time PCR, and Pearson’s χ2 test was used to evaluated the copy number difference among subtypes.ResultsCNVs of IL22 were significantly higher in PsV than in healthy controls (P<0.001). CNV of LCE3C in PsV, PsA, and GPP groups were significantly lower compared to healthy controls. When linked with clinical parameters, mild psoriasis carried less IL22 copy numbers than that in severe psoriasis (P=0.043). Neither IL22 or LCE3C CNVs were associated with age of onset.ConclusionsCNVs of LCE3C and IL22 might differentially contribute to subtypes of psoriasis. These findings suggest complex and diverse genetic variations in and among different clinical subtypes of psoriasis.

The Positivity Rate of IA-2A and ZnT8A in the Chinese Han Population With Type 1 Diabetes Mellitus: Association With rs1143627 and rs1143643 Polymorphisms in the IL1B Gene.

Objective: To investigate the association between susceptibility to type 1 diabetes mellitus (T1DM) and polymorphisms (rs1143627 and rs1143643) in the interleukin 1 beta (IL1B) gene in the Chinese Han population. Methods: The Meso Scale Discovery (MSD) method was used to detect the concentration of IL-1β in 24 T1DM patients and 27 healthy controls. MassARRAY was used to analyze the polymorphisms in the IL1B gene in 510 patients with classic T1DM and 531 healthy controls. The general data of the T1DM patients and healthy controls were compared by the chi-square test and Mann-Whitney U test. The chi-square test and logistic regression were used to analyze the frequency distributions of alleles and genotypes of polymorphisms in the IL1B gene. The Kruskal-Wallis H test and chi-square test were used for the genotype-phenotype analysis of rs1143627 and rs1143643 in the IL1B gene. Results: ① The concentration of IL-1β in T1DM patients was significantly higher than that in healthy controls. ② rs1143627 and rs1143643 in the IL1B gene were significantly correlated with the positivity rates for IA-2A and ZnT8A; genotype GG at rs1143627 and genotype CC at rs1143643 in the case group showed lower positivity rates for IA-2A and ZnT8A. ③ There was no significant difference in the genotypes or allele frequencies at rs1143627 (GG/GA/AA) or rs1143643 (CC/CT/TT) between the case group and control group (p > 0.05). ④ rs1143627 and rs1143643 were not found to be linked to T1DM susceptibility under different genetic models. Conclusion: rs1143627 and rs1143643 in the IL1B gene correlate with the positivity rate of IA-2A and ZnT8A in Chinese Han individuals with T1DM.

Same total normal forms sperm counts of males from Lhasa and Shanghai, China.

Male infertility may be caused by genetic and/or environmental factors that impair spermatogenesis and sperm maturation. High-altitude (HA) hypoxic environments represent one of the most serious challenges faced by humans that reside in these areas. To assess the influence of the plateau environment on semen parameters, 2,798 males, including 1,111 native Tibetans and 1,687 Han Chinese individuals living in the plains (HCILP) who underwent pre-pregnancy checkups, were enrolled in this study. The semen samples of males were evaluated to determine conventional sperm parameters, sperm morphology, and sperm movement. Reproductive endocrine hormones (REHs) were detected in 474 males, including 221 Tibetans and 253 HCILP. Due to recurrent abortions in partners, the DNA fragmentation index (DFI) of 133 native Tibetans and 393 HCILP individuals was further compared. Luteinizing hormone (LH) (4.94 ± 2.12 vs. 3.29 ± 1.43 U/L), prolactin (11.34 ± 3.87 vs. 8.97 ± 3.48nmol/L), E2/T (0.22 ± 0.11 vs 0.11 ± 0.05), median total sperm motility (61.20% vs. 51.56%), and DFI (23.11% vs. 7.22%) were higher in males from plateau areas while median progressive motility (PR) (35.60% vs. 41.12%), total number of PR sperms (51.61 vs. 59.63 mil/ejaculate), percentage of normal form sperms (3.70% vs. 6.00%), curvilinear velocity (36.10 vs. 48.97μm/s), straight-line (rectilinear) velocity (14.70 vs. 31.52μm/s), estradiol (103.82 ± 45.92 vs. 146.01 ± 39.73pmol/L), progesterone (0.29 ± 0.27 vs. 2.22 ± 0.84nmol/L), testosterone (4.90 ± 1.96 vs. 14.36 ± 5.24nmol/L), and testosterone secretion index (ratio of testosterone to LH) (33.45 ± 22.86 vs 145.78 ± 73.41) were lower than those in males from the plains. There was no difference in median total sperm number (157.76 vs. 151.65 mil/mL), sperm concentration (52.40 vs. 51.79 mil/mL), volume (3.10 vs. 3.10mL), total normal form sperms (5.91 vs. 6.58 mil/ejaculate, p50), and follicle-stimulating hormone (FSH) levels (4.13 ± 2.55 U/L vs 3.82 ± 2.35 U/L) between the two groups of males. The REH and sperm parameters of males from HA hypoxic environments were adaptively altered. Although the total number of PR sperm decreased and DFI increased, the Tibetan population that lives at HAs has been found to grown continuously and rapidly. These results supplement prior findings regarding the impact of HA on male reproductive function.

A highly polymorphic panel of 40-plex microhaplotypes for the Chinese Han population and its application in estimating the number of contributors in DNA mixtures

Microhaplotypes (MHs) have great potential in multiple forensic applications and have proven to be promising markers in complex DNA mixture analysis. In this study, we developed a multiplex panel of 40 highly polymorphic MHs for the Chinese Han population, evaluated its forensic values, and explored its application in predicting the number of contributors (NOCs) in DNA mixtures. The panel consisted of 20 newly proposed loci and 20 previously reported loci with lengths spanning less than 120 bp. The average effective number of alleles (Ae) was 3.77, and the cumulative matching probability (CMP) and the cumulative power of exclusion (CPE) reached 1.2E-37 and 1–2.1E-12, respectively, in the Chinese Han population from the 1000 Genomes Project. Further validation on 150 Chinese Han individuals showed that Ae ranged from 2.62 to 4.41 with a mean value of 3.61, and CMP and CPE were 3.61E-36 and 1–1.84E-12, respectively, indicating that this panel was informative for personal identification and paternity testing in the studied population. To estimate NOC in DNA mixtures, we developed a machine learning model based on this panel. As a result, the accuracies in artificial DNA mixtures reached 95.24% for 2- to 4-person mixtures and 83.33% for 2- to 6-person mixtures. Furthermore, the NOC estimation on simulated profiles with allele dropout showed that this panel was still robust under slight dropout. In conclusion, this panel has value for forensic identification and NOC estimation of DNA mixtures.

Influence of the rs6736 Polymorphism on Ischemic Stroke Susceptibility in Han Chinese Individuals via the Disruption of miR-7-1 Binding to the C14orf119 Gene.

This study investigates the association between the C14orf119 gene rs6736 polymorphism and ischemic stroke (IS) susceptibility, and explores the influence of the rs6736 polymorphism on the binding between miR-7-1 and the C14orf119 gene. mRNA expression levels were determined in 45 IS patients and 45 matched controls via real-time quantitative PCR. A total of 774 IS patients and 793 matched controls were recruited from a Han Chinese population for genotyping, performed with the Sequenom MassARRAY iPLEX platform. A dual-luciferase reporter assay was used for the analysis of miRNA-mRNA binding. The results showed that the mRNA expression of C14orf119 differed significantly between IS patients and controls (t = -2.235, P = 0.030). Significant associations were noted between the C14orf119 gene rs6736 polymorphism and IS susceptibility in Han Chinese individuals under the additive model [ORadj (95% CI) = 0.87 (0.76-1.00) Padj = 0.048] and dominant model [ORadj (95% CI) = 0.76 (0.61-0.94), Padj = 0.014], with adjustment for age and sex. Mutations in the rs6736 polymorphism disrupted the binding of miR-7-1 and the C14orf119 gene. The results of this study show that the rs6736 polymorphism in the 3'-untranslated region of the C14orf119 gene not only is associated with IS but also modifies the binding between miR-7-1 and the C14orf119 gene. The C14orf119 gene may participate in the relationship between IS and miR-7-1.

Identification of novel loci influencing refractive error in East Asian populations using an extreme phenotype design

The global “myopia boom” has raised significant international concerns. Despite a higher myopia prevalence in Asia, previous large-scale genome-wide association studies (GWASs) were mostly based on European descendants. Here, we report a GWAS of spherical equivalent (SE) in 1852 Chinese Han individuals with extreme SE from Guangzhou (631 < −6.00D and 574 > 0.00D) and Wenzhou (593 < −6.00D and 54 > −1.75D), followed by a replication study in two independent cohorts with totaling 3538 East Asian individuals. The discovery GWAS and meta-analysis identify three novel loci, which show genome-wide significant associations with SE, including 1q25.2 FAM163A, 10p11.22 NRP1/PRAD3, and 10p11.21 ANKRD30A/MTRNR2L7, together explaining 3.34% of SE variance. 10p11.21 is successfully replicated. The allele frequencies of all three loci show significant differences between major continental groups (P < 0.001). The SE reducing (more myopic) allele of rs10913877 (1q25.2 FAM163A) demonstrates the highest frequency in East Asians and much lower frequencies in Europeans and Africans (EAS = 0.60, EUR = 0.20, and AFR = 0.18). The gene-based analysis additionally identifies three novel genes associated with SE, including EI24, LHX5, and ARPP19. These results provide new insights into myopia pathogenesis and indicate the role of genetic heterogeneity in myopia epidemiology among different ethnicities.

Fine-Scale Genetic Structure and Natural Selection Signatures of Southwestern Hans Inferred From Patterns of Genome-Wide Allele, Haplotype, and Haplogroup Lineages.

The evolutionary and admixture history of Han Chinese have been widely discussed via traditional autosomal and uniparental genetic markers [e.g., short tandem repeats, low-density single nucleotide polymorphisms). However, their fine-scale genetic landscapes (admixture scenarios and natural selection signatures) based on the high-density allele/haplotype sharing patterns have not been deeply characterized. Here, we collected and generated genome-wide data of 50 Han Chinese individuals from four populations in Guizhou Province, one of the most ethnolinguistically diverse regions, and merged it with over 3,000 publicly available modern and ancient Eurasians to describe the genetic origin and population admixture history of Guizhou Hans and their neighbors. PCA and ADMIXTURE results showed that the studied four populations were homogeneous and grouped closely to central East Asians. Genetic homogeneity within Guizhou populations was further confirmed via the observed strong genetic affinity with inland Hmong-Mien people through the observed genetic clade in Fst and outgroup f3/f4-statistics. qpGraph-based phylogenies and f4-based demographic models illuminated that Guizhou Hans were well fitted via the admixture of ancient Yellow River Millet farmers related to Lajia people and southern Yangtze River farmers related to Hanben people. Further ChromoPainter-based chromosome painting profiles and GLOBETROTTER-based admixture signatures confirmed the two best source matches for southwestern Hans, respectively, from northern Shaanxi Hans and southern indigenes with variable mixture proportions in the historical period. Further three-way admixture models revealed larger genetic contributions from coastal southern East Asians into Guizhou Hans compared with the proposed inland ancient source from mainland Southeast Asia. We also identified candidate loci (e.g., MTUS2, NOTCH4, EDAR, ADH1B, and ABCG2) with strong natural selection signatures in Guizhou Hans via iHS, nSL, and ihh, which were associated with the susceptibility of the multiple complex diseases, morphology formation, alcohol and lipid metabolism. Generally, we provided a case and ideal strategy to reconstruct the detailed demographic evolutionary history of Guizhou Hans, which provided new insights into the fine-scale genomic formation of one ethnolinguistically specific targeted population from the comprehensive perspectives of the shared unlinked alleles, linked haplotypes, and paternal and maternal lineages.