Han Chinese Subjects Research Articles

SORCS1 and APOE polymorphisms interact to confer risk for late-onset Alzheimer's disease in a Northern Han Chinese population

Sortilin-related VPS domain containing receptor 1 (SORCS1), is located on chromosome 10q23.3, a chromosomal region of interest in Alzheimer's disease (AD) defined by many genome-wide and chromosome10-specific studies. Recently, three intronic variants (rs12571141, rs17277986 and rs6584777) within SORCS1 were reported to be associated with AD in Caucasian. In order to assess the involvement of the SORCS1 polymorphisms in the progression of late-onset AD (LOAD), we conducted an independent replication study in 1198 unrelated Northern Han Chinese subjects comprising 598 LOAD patients and 600 healthy controls matched for gender and age. The results revealed no significant differences in the distributions of genotype or allele between LOAD and control groups in the total sample. However, when these data were stratified by the Apolipoprotein E (APOE) ε4 status, we observed significant differences in the genotypes and allele frequencies (rs12571141: P=0.001, rs17277986: P=0.005, rs6584777: P=0.023) in APOE ε4 allele carriers. Moreover, the association was further demonstrated in logistic regression analysis (rs12571141: P=0.002, OR=0.424; rs17277986: P=0.004, OR=0.447; rs6584777: P=0.019, OR=0.523) and haplotype analysis (GCC: P=0.002, ATT: P=0.002, ACC: P=0.025) in this subset. Our data suggested that SORCS1 was in interaction with APOE in the development of LOAD in a Northern Han Chinese population.

Association of Sterol Regulatory Element-Binding Transcription Factor Gene Polymorphisms with Ischaemic Stroke

To explore the association between polymorphisms of the sterol regulatory element-binding transcription factor (SREBF) gene and ischaemic stroke. The SREBF1c 54G>C and SREBPF2 1784G>C genotypes were assessed using restriction fragment length polymorphism analysis in 446 Han Chinese ischaemic stroke patients and 355 Han Chinese control subjects without cerebrovascular disease. The frequencies of the SREBF2 1784G>C CC genotype and the C allele were significantly higher in the ischaemic stroke group than in controls. Patients with ischaemic stroke who had the SREBF2 1784G>C CC genotype had significantly lower high-density lipoprotein (HDL) levels, compared with ischaemic stroke patients and control subjects with the GC or GG genotypes. Multivariate logistic regression analysis revealed a significant positive association between SREBF2 1784G>C and ischaemic stroke; an inverse association was observed between HDL level and risk of ischaemic stroke. The CC genotype of the SREBF2 1784G>C polymorphism was associated with an increased risk of ischaemic stroke, possibly through decreasing the HDL level, which was inversely associated with the risk of ischaemic stroke.

Joint Effects of Genetic Variants in Multiple Loci on the Risk of Coronary Artery Disease in Chinese Han Subjects

The aim of the present study was to explore risk variants for coronary artery disease (CAD) and to evaluate their joint effects (quantified by genetic risk score; GRS) on the discrimination of CAD in a Chinese Han sample. An association analysis of 91 single nucleotide polymorphisms (SNPs) with CAD risk was undertaken in 1,007 CAD patients and 889 healthy controls. Two GRSs, counted GRS (cGRS) and weighted GRS (wGRS), were calculated using the significant SNPs, and their discriminant power for CAD was assessed using receiver-operating characteristic (ROC) curve analysis. Eight SNPs (rs11206510, rs10118757, rs2383206, rs501120, rs2075292, rs174547, rs173539, and rs255052) were nominally significantly associated with CAD (P<0.05), and 5 of them were newly reported. The GRSs derived from the 8 SNPs improved the discrimination of CAD compared to that using 4 conventional risk factors (P=0.002 for cGRS and P=0.009 for wGRS). After 10-fold cross-validation 100 times, the average areas under the curve were 0.668 (95% confidence interval [CI]: 0.667-0.669), 0.686 (95% CI: 0.685-0.687) and 0.690 (95% CI: 0.689-0.691) for models with conventional risk factors only, conventional risk factors plus cGRS, and conventional risk factors plus wGRS, respectively. A multigenic GRS, generated by combining multiple gene variants, can improve discrimination of CAD, thereby confirming the joint effects of these gene variants on CAD in this Chinese Han population.

Genetic variants and haplotypes of the UGT1A9, 1A7 and 1A1 genes in Chinese Han

In this report, we describe combined polymorphisms of the UGT1A9, UGT1A7 and UGT1A1 genes in 100 unrelated, healthy Chinese Han subjects. The functional regions of these genes were sequenced and comprehensively analyzed for genetic polymorphisms. Thirty variants were detected, including five novel forms. Tentative functional predictions indicated that a Cys → Arg substitution at position 277 in the UGT1A7 gene could alter the protein conformation and that 12460T > G in the 3′UTR might influence protein translation through specifically expressed miRNAs. UGT1A9*1b was a major functional variant in the subjects examined whereas the *1f allele had a frequency of only 0.5%. A special functional haplotype (GAGAAC) was identified for UGT1A9, 1A7 and 1A1. These findings provide fundamental genetic information that may serve as a basis for larger studies designed to assess the metabolic phenotypes associated with UGT1A polymorphisms. They also provide important data for the implementation of personalized medicine in Chinese Han.

Are bone mineral density loci associated with hip osteoporotic fractures? A validation study on previously reported genome-wide association loci in a Chinese population

Osteoporosis is a heritable disease characterized mainly by low bone mineral density (BMD) and/or osteoporotic fractures (OF). Most genome-wide association studies on osteoporosis have focused on BMD, whereas little effort has been expended to identify genetic variants directly linked to OF. To determine whether BMD-loci are also associated with OF risk, we performed a validation study to examine 23 BMD-loci reported by recent genome-wide association studies for association with hip OF risk. Our sample consisted of 700 elderly Chinese Han subjects, 350 with hip OF and 350 healthy matched controls. We identified four BMD-loci that were significantly associated with hip OF in this Chinese population, including 7q21 (FLJ42280, P = 1.17 × 10(-4) for rs4729260; P = 0.008 for rs7781370), 6p21 (MHC, P = 0.004 for rs3130340), 13q14 (TNFSF11, P = 0.012 for rs9533090; P = 0.018 for rs9594759; P = 0.020 for rs9594738; P = 0.044 for rs9594751), and 18q21 (TNFRSF11A, P = 0.015 for rs884205). The SNP rs4729260 at 7q21 remained significantly associated, even after conservative Bonferroni's correction. Our results further highlight the importance of these loci in the pathogenesis of osteoporosis, and demonstrate that it is feasible and useful to use OF as the direct phenotype to conduct genetic studies, to enhance our understanding of the genetic architecture of osteoporosis.

RELN gene polymorphisms and susceptibility to autism in Chinese Han population

Single nucleotide polymorphisms (SNPs) in the Reelin gene (RELN) are likely candidates to confer risk for autism. The objective of the present study is to investigate the association of RELN gene SNPs with autism. A total of 367 Chinese Han subjects were recruited, including 186 autism patients and 181 unrelated healthy controls. Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) and DNA sequencing methods were used to detect RELN gene polymorphisms. The association between SNPs and autism was analyzed in this study. The g.333509A>C in intron12 and g.504742G>A in exon60 were detected in the RELN gene and a significant association was found between the g.504742G>A polymorphism and autism. Allele and genotype frequencies for the g.504742G>A polymorphism in autistic patients were significantly different for healthy subjects. There was no significantly difference in g.333509A>C polymorphism and autism in the studied populations. Our findings indicated that g.333509A>C was not significantly associated with autism. The g.504742G>A polymorphic variant in the RELN gene might affect subjects susceptibility toward autism in Chinese Han population.

Association of myostatin gene polymorphisms with obesity in Chinese north Han human subjects

ContextMyostatin (MSTN) is a member of the TGF-β superfamily of signal transduction proteins, which plays an important role in muscular growth and lipid metabolism. ObjectiveTo study the association of myostatin gene polymorphisms with obesity in Chinese north Han human subjects. Design297 healthy and 606 over-weight/obesity Chinese north Han subjects were selected as healthy control group and overweight/obesity group, respectively. The methods of DNA Sequencing, Restriction Fragment Length Polymorphism (RFLP) and TaqMan® probe were used to screen myostatin gene SNPs and clarify genotype in every individual. ResultsTotal 11 SNPs in MSTN gene were identified by DNA sequencing and three SNPs including rs35781413 (G/A), rs3791783 (A/G) and rs3791782 (A/G) were selected for further study in total 903 samples. The results showed that the frequency of AA genotype of rs3791783 A/G SNP was significantly higher (56.4% vs. 50.8%) and the frequency GG genotype was significantly lower (3.2% vs. 6.7%) in overweight/obese patients than in normal weight subjects. A logistic regression analysis under a recessive inheritance model (AA+AG vs.GG) demonstrated that the Odd ratio for AA+AG vs.GG were 1.985 (95% CI 1.078–3.643; P=0.029). Among three genotypes of rs3791783, the subjects with AA genotype have much more higher body weight, BMI, waist circumference, TC, TG and LDL-C than those with GG genotype. ConclusionsOur data firstly suggest that genetic variant rs3791783 A/G in myostatin gene are associated with obesity. The A allele carriers in rs3791783 SNP have an increased susceptibility to obesity compared with the G allele carriers. Participants with AA genotype in rs3791783 SNP site will have higher risk suffered from overweight or obesity than those with GG genotype.

GWAS-linked GAK locus in Parkinson’s disease in Han Chinese and meta-analysis

Genome-wide association studies of Parkinson's disease (PD) have recently identified a new susceptibility locus GAK (PARK17) (rs1564282 variant) in subjects of European ancestry. Its role in other races is still unclear. The potential differences of the clinical characteristics between carriers and non-carriers have not been examined in detail. Using a case-control methodology, we analyzed the GAK rs1564282 variant in an ethnic Han Chinese population and conducted a meta-analysis combining our result and available published data. A total of 1,574 ethnic Han Chinese study subjects comprising 812 sporadic PD patients and 762 control individuals were included. The minor allele frequency was significantly different at SNP rs1564282 between the cases and the controls (OR = 1.59, 95% CI = 1.09, 1.69, P = 0.007) in the overall PD population. Subjects with CT + TT genotypes have an increased risk (OR = 1.34, 95% CI = 1.05, 1.72, P = 0.017) compared to those with CC genotype. A meta-analysis revealed that the frequency of carrier's genotypes was significantly higher in PD than in control subjects (OR = 1.31, 95% CI = 1.19, 1.44, P < 0.00001). The gender, age of onset, Hoehn-Yahr stage and UPDRS scores and clinical features were similar between carriers and non-carriers. In conclusion, we demonstrated that the rs1564282 variant in GAK (PARK17) increases the risk of PD in Han Chinese patients from mainland China and the meta-analysis with European populations revealed a similar finding. However, carriers cannot be distinguished from non-carriers based on their clinical features or motor severity. Functional studies of GAK to unravel its role in the pathophysiologic pathway of PD will be useful.

Phenotypic and mutation spectrums of Thai patients with isovaleric acidemia

Isovaleric acidemia (IVA) is an autosomal recessive disorder caused by deficiency of isovaleryl-CoA dehydrogenase (IVD). Clinical features include vomiting, lethargy, metabolic acidosis, and "sweaty feet" odor. The pathognomonic metabolite, isovalerylglycine, is detected on urine organic acid analysis. Clinical diagnosis of IVA can be confirmed on mutation analysis of the IVD gene. The cases of five unrelated Thai patients with IVA, identified on urine organic acid analysis, are described. Mutation analysis of the IVD gene was performed using polymerase chain reaction sequencing of the entire coding regions. Four out of the five IVA patients had an acute neonatal form. The hematologic abnormalities were common and thus could be presenting symptoms in the absence of metabolic acidosis. As for the neurological outcome, only one patient had normal intelligence. Mutation analysis of the IVD gene identified the mutations c.457-3_2CA>GG, c.1199A>G (p.Y371C), c.281C>G (p.A65G), c.358G>A (p.G91R), and c.827T>C (p.L247P). The poor outcome in most patients might be explained by the delayed diagnosis and initial unavailability of the metabolic formulas and medications in Thailand. The c.457-3_2CA>GG mutation was identified in all of the present patients. This suggests that it is the most common mutation in the Thai population. Therefore, it could be a founder mutation in Thai subjects. One of the present Thai IVA patients also had the p.Y371C mutation, which is common in Han Chinese subjects. In addition, two novel mutations, p.A65G and p.L247P, were identified. The present study provides additional knowledge on the genotype-phenotype of IVA, suggesting that IVD mutations in Asian populations are distinct from these in Western populations.

Three-Dimensional Reconstruction of Maxillae Using Spiral Computed Tomography and Its Application in Postoperative Adult Patients With Unilateral Complete Cleft Lip and Palate

To establish a method to analyze malformed maxillae of postoperative adult patients with unilateral complete cleft lip and palate in 3 dimensions. A total of 35 landmarks were defined and used to reconstruct 3-dimensional maxillary images of healthy Chinese Han subjects and 30 postoperative Chinese Han adult patients (17 men and 13 women, with mean age of 19.07 years) with unilateral complete cleft lip and palate. This was done using spiral computed tomography, and their corresponding parameters were analyzed using SimPlant software, version 11.04, and compared by t test using SAS software, version 6.12. Of the 7 centered landmarks, A and ANS in the patients were obviously deviated to the nonoperative side (P < .01) and the symmetrical landmark pairs INM'-INM, SNM'-SNM and SPr'-SPr, but not MA'-MA, SoF'-SoF, and LPAC-LPA in the infraorbital region and piriform aperture peritreme in healthy subjects were shifted toward the coordinate sagittal plane S. The data also showed that the maxillae in the patients' operative side were hypoplastic, especially in the posteroanterior direction compared with the nonoperative side and healthy subjects. The proposed method can precisely measure the distances of the maxillary landmarks to 3-dimensional coordinates and has application potential in evaluating maxillary deformity in patients with postoperative unilateral complete cleft lip and palate.

Differences in genotype and allele frequency distributions of polymorphic drug metabolizing enzymes CYP2C19 and CYP2D6 in mainland Chinese Mongolian, Hui and Han populations

Cytochrome P450 2C19 (CYP2C19) and CYP2D6 are important xenobiotic metabolic enzymes and both show considerable genetic variability between Orientals and Caucasians. There are known marked heterogeneity in susceptibility to various cancers and hypertension among Chinese Mongolian, Hui and Han ethnic groups, but the molecular mechanisms are unknown. Our objective was to investigate the patterns of distribution of CYP2C19 and CYP2D6 polymorphisms among healthy Chinese subjects to determine whether any observed inter-ethnic variability might be worth further investigation as possible contributors to the known differences in disease prevalence. Blood samples were collected from 454 unrelated Chinese healthy subjects (214 Han, 111 Hui, 129 Mongolian) for genotyping analysis. The single nucleotide polymorphisms (SNPs) CYP2C19*2 (681G>A in exon 5), CYP2C19*3 (636G>A in exon 4) and CYP2D6*10 (188C>T in exon 1) were determined by the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. Significantly higher frequencies of the CYP2C19 poor metabolic genotypes were observed in Chinese Han (18·7%), Chinese Hui (25·0%) and Chinese Mongolian (10·9%) subjects than has been reported for Caucasians (1·7-3·0%, P < 0·01). The prevalent defective allele CYP2C19*2 occurred more frequently in both Chinese Hui (32·4%) and Han (29·7%) than in Chinese Mongolian (18·2%, P < 0·01) subjects. The CYP2C19*2 and CYP2C19*3 defective alleles were significantly more frequent in Chinese Han and Chinese Hui ethnic groups than have been reported for Caucasians (11·1-16·3% and 0-0·2%, P < 0·01). CYP2D6*1/*10 heterozygotes and CYP2D6*10/*10 homozygotes were observed more frequently in Chinese Han (43·1% and 27·2%), Hui (40·6% and 30·7%) and Mongolian subjects (31·3% and 9·6%, both P < 0·01) than have been reported for Caucasians (5·5% and 0·3%, P < 0·01). In Chinese Mongolians, the CYP2D6*10 allele occurred at a frequency (25·2%, P < 0·01) intermediate between those reported for Caucasians and the other two Chinese ethnic populations. This is first report of interethnic differences in frequencies of functional CYP2C19 and CYP2D6 genes among Chinese Mongolian, Hui and Han populations. These differences may be important in explaining reported inter-ethnic differences in disease prevalence and response to drugs.

Genetic association between ADAM10 gene polymorphism and Alzheimer's disease in a Northern Han Chinese population

The ADAM10 gene encodes a member of a disintegrin and metalloprotease family, which, after overexpression in Alzheimer's disease (AD), prevents amyloid pathology and improves long-term potentiation and memory. A common polymorphism (rs2305421) within ADAM10 has been recently associated with the risk of developing AD in Europeans. In order to assess the involvement of the ADAM10 polymorphism in the risk of developing late-onset AD (LOAD), we analyzed the genotype and allele distributions of the ADAM10 (rs2305421) polymorphism in 788 Northern Han Chinese subjects. The results revealed no significant differences in the distributions of allele or genotype between LOAD and control groups. However, when these data were stratified by the Apolipoprotein E (ApoE) ε4 status, in the subjects with ApoE ε4, there were significant differences in the allele (P=0.037) and genotype (P=0.035). Moreover, logistic regression analysis revealed that the rs2305421 polymorphism presented strong associations with LOAD in the recessive model (OR=0.611, 95% CI=0.408–0.931, P=0.023). This study suggests that the rs2305421 polymorphism in ADAM10 gene could modify the risk for LOAD in a Northern Han Chinese population.

Genetic variants in MMP9 and TCF2 contribute to susceptibility to lung cancer

The Wnt signaling pathway is crucial for pulmonary development and differentiation; dysregulation of the Wnt signaling pathway may impair lung function. Indeed, single nucleotide polymorphisms (SNPs) of Wnt pathway-related genes have been suggested as risk factors for certain types of cancers. In this study, we aimed to evaluate the influence of SNPs in Wnt-related genes (TCF2, MMP9) on susceptibility to lung cancer. Polymorphisms of TCF2 rs4430796, MMP9 rs2250889, and MMP9 rs17576 were studied in Han Chinese subjects, including 135 patients with lung cancer and 176 controls, using the Sequenom MassARRAY platform. The association of genotypes with susceptibility to lung cancer was analyzed using odds ratio (OR), with 95% confidence interval (95% CI) and χ(2). The three SNPs (rs4430796, rs2250889, and rs17576) were found to be significantly associated with an increased risk of lung cancer. The AA genotype and AG+AA genotype of rs4430796 showed a significantly increased susceptibility to lung cancer compared with the GG genotype (adjusted OR=6.03, 95% CI: 1.30-28.09, P=0.022; 5.55, 95% CI: 1.20-25.58, P=0.028). Compared with the rs17576 GG genotype, the AG and AG+AA genotypes were also associated with a significant risk (adjusted OR=2.65, 95% CI: 1.60-4.37, P≤0.001; 2.57, 95% CI: 1.59-4.19, P≤0.001) whereas the rs2250889 CG and CG+GG genotypes had 2.97-fold (95% CI: 1.81-4.85; P≤0.001) and 2.80-fold increased associations with lung cancer (95% CI: 1.73-4.54; P≤0.001), respectively, compared with the rs2250889 CC genotype. Furthermore, the association of rs4430796 with lung cancer became insignificant (P>0.05) after adjusting for gender and rs2250889. The three SNPs may play a role in the predisposition of members of the Han Chinese population to lung cancer.

Copy Number Variation in CNP267 Region May Be Associated with Hip Bone Size

Osteoporotic hip fracture (HF) is a serious global public health problem associated with high morbidity and mortality. Hip bone size (BS) has been identified as one of key measurable risk factors for HF, independent of bone mineral density (BMD). Hip BS is highly genetically determined, but genetic factors underlying BS variation are still poorly defined. Here, we performed an initial genome-wide copy number variation (CNV) association analysis for hip BS in 1,627 Chinese Han subjects using Affymetrix GeneChip Human Mapping SNP 6.0 Array and a follow-up replicate study in 2,286 unrelated US Caucasians sample. We found that a copy number polymorphism (CNP267) located at chromosome 2q12.2 was significantly associated with hip BS in both initial Chinese and replicate Caucasian samples with p values of 4.73E-03 and 5.66E-03, respectively. An important candidate gene, four and a half LIM domains 2 (FHL2), was detected at the downstream of CNP267, which plays important roles in bone metabolism by binding to several bone formation regulator, such as insulin-like growth factor-binding protein 5 (IGFBP-5) and androgen receptor (AR). Our findings suggest that CNP267 region may be associated with hip BS which might influence the FHL2 gene downstream.

Association analyses of MAOA in Chinese Han subjects with attention‐deficit/hyperactivity disorder: Family‐based association test, case–control study, and quantitative traits of impulsivity

Monoamine oxidase A (MAOA) plays a critical role in the metabolism of monoamine neurotransmitters including serotonin (5-HT), norepinephrine (NE), and dopamine (DA). Genetic studies have found an association between MAOA and attention-deficit/hyperactivity disorder (ADHD), especially impulsivity. However, there has been inconsistency among studies which may be due to the complexity and heterogeneity of ADHD, including its sexual dimorphism and the presence of several subtypes. We conducted transmission disequilibrium tests (TDTs) in 1,253 trios and found no association between five single nucleotide polymorphisms (SNPs) of MAOA with ADHD in general or in the predominantly inattentive (ADHD-I) or combined types (ADHD-C), but with the predominantly hyperactive/impulsivity type (ADHD-HI). The association with MAOA was restricted to males, especially males with ADHD-HI. Logistic regression analyses of data from 1,824 cases and 957 controls did not indicate any association. We used analysis of covariance to analyze the association between MAOA genotype with the "inhibit" factor of the Behavior Rating Inventory of Executive Function (BRIEF) in 640 probands and performance on the Stroop test in 810 probands. Probands homozygous for risk alleles found in the TDT test had higher "inhibit" scores on the BRIEF scale which represents more severe impulsivity; this results also was restricted to males. No association was found with Stroop test performance. In conclusion, our results provide some evidence that MAOA may be associated with the ADHD-HI subtype and support the association between MAOA and impulsivity, which may be a potential endophenotype of ADHD. However, the results were strongly influenced by gender.

Pathway-Based Association Analyses Identified TRAIL Pathway for Osteoporotic Fractures

IntroductionHip OF carries the highest morbidity and mortality. Previous studies revealed that individual genes/loci in the Tumor Necrosis Factor (TNF) -Related Apoptosis-Inducing Ligand (TRAIL) pathway were associated with bone metabolism. This study aims to verify the potential association between hip OF and TRAIL pathway.MethodsUsing genome-wide genotype data from Affymetrix 500 K SNP arrays, we performed novel pathway-based association analyses for hip OF in 700 elderly Chinese Han subjects (350 with hip OF and 350 healthy matched controls).ResultsThe TRAIL pathway achieved a significant p value (p = 0.01) for association with hip OF. Among the 38 genes in the TRAIL pathway, seven genes achieved nominally significant association with hip OF (p<0.05); the TNFSF10 (TRAIL) gene obtained the most significant p value (p = 1.70×10−4). SNPs (rs719126, rs6533015, rs9594738, rs1805034, rs11160706) from five genes (CFLAR, NFKB1, TNFSF11, TNFRSF11A, TRAF3) of the pathway had minor alleles that appear to be protective to hip OF. SNPs (rs6445063 and rs4259415) from two genes (TNFSF10 and TNFRSF10B) of the pathway had minor alleles (A) that are associated with an increased risk of hip OF, with the ORs (odds ratios) of 16.51 (95%CI:3.83–71.24) and 1.37 (95%CI:1.08–1.74), respectively.ConclusionsOur study supports the potential role of the TRAIL pathway in the pathogenesis of hip OF in Chinese Han population. Further functional study of this pathway will be pursued to determine the mechanism by which it confers risk to hip OF.

NINJ2 polymorphism is associated with ischemic stroke in Chinese Han population

Recently, a genome-wide association study reported an association between two single nucleotide polymorphisms (SNPs) rs11833579 and rs12425791 near NINJ2 gene and ischemic stroke in Caucasians. Therefore, NINJ2 gene is an important candidate locus in the prevalence of ischemic stroke. We performed a hospital based genetic association study in Chinese Han subjects to investigate the relationship between NINJ2 gene and ischemic stroke. We genotyped 14 tagging single nucleotide polymorphisms (tSNP) in 749 ischemic stroke subjects and 924 control subjects and conducted the association between these tSNPs and ischemic stroke. We detected a tSNP rs10849373 in the first intron of the NINJ2 gene significantly associated with ischemic stroke (both genotype and allelic p=0.0001). The minor A allele increased the risk of ischemic stroke with a per-allele OR of 1.37 for the additive genetic model in univariate analysis (p=0.0001). The significance remained after adjustment for the covariates of age, gender, BMI, cigarette smoking, alcohol drinking, hypertension, and diabetes. Therefore, we report a new genetic variant, rs10849373, located in the first intron of the NINJ2 gene, conferring risk of ischemic stroke in Chinese Han subjects. Further genetic association and functional studies are required to search the causal functional variant in linkage disequilibrium with this polymorphism.

SNP and mRNA expression for glutathione peroxidase 4 in Kashin-Beck disease

Kashin-Beck disease (KBD) is a chronic endemic osteoarthropathy, which mainly occurs in West and Northeast China. Epidemiological studies suggest that Se deficiency is an important environmental factor for the incidence of KBD. Glutathione peroxidase 4 (GPx4) belongs to the glutathione peroxidase family, which is crucial for optimal antioxidant defences. Our purpose is to investigate the putative association between GPx4 polymorphisms and the risk of KBD. Restriction fragment length polymorphism-PCR was used to detect two SNP (rs713041, rs4807542) in 219 cases and 194 controls in Han Chinese subjects, and quantitative analysis for the GPx4 mRNA level was performed by the real-time PCR method. The results revealed that linkage disequilibrium existed in the two SNP. A significant difference was observed in the haplotype A-T (P=0·0066) of GPx4, which was obviously lower in the KBD cases (0·006 v. 0·032%). Correlation analysis based on a single locus showed no association between each SNP and KBD risk. Furthermore, the GPx4 mRNA level was dramatically lower in the blood of KBD patients. Overall, our finding indicated GPx4 polymorphisms and decreased mRNA level may be related to the development of KBD in the Chinese population, suggesting GPx4 as a possible candidate susceptibility gene for KBD.

Selection of 29 highly informative InDel markers for human identification and paternity analysis in Chinese Han population by the SNPlex genotyping system

The interest of forensic researchers in single nucleotide polymorphism (SNP) has been attracted because of its potential advantages, such as low mutation rates, amenable to high-throughput automated platform and the improved application in the analysis of degraded samples. In this paper, 29 highly informative insertion/deletion (InDel, a special kind of SNP) markers were selected from the dbSNP ( http://www.ncbi.nlm.nih.gov/SNP/ ) according to the given criteria. 109 unrelated Chinese Han subjects were genotyped for the 29 InDels with SNPlex genotyping system. The allele frequency data revealed that the combined power of discrimination for the 29 InDel markers was 0.999999999990867 and the combined probability of paternity exclusion (PE) was 0.9930. Sensitivity studies were performed to evaluate the flexibility of the SNPlex genotyping system on the set of 29 InDels. Highly reproducible results could be obtained with 40-100 ng genomic DNA and the proportion of total allele drop-in was significantly increased when the amount of DNA added to PCR was lower than 35 ng. These results suggested that the set of 29 InDels was useful in paternity analysis or human identification in the future.

Characterization and polymorphic analysis of 4.5 kb genomic full-length HLA-C in the Chinese Han population.

This study used long-range polymerase chain reaction to sequence 4.5 or 4.3 kb of genomic DNA covering human leukocyte antigen C (HLA-C) and its flanks in 45 Chinese Han subjects to better characterize variation in the gene in a single population. Sequences of 35 HLA-C alleles were obtained from the population, including major alleles of 13 lineages of HLA-C. Four novel alleles, C*03:04:01:02, C*04:01:01:03, C*08:22, and C*17:01:01:02, were identified, and complete full-length sequences of 18 HLA-C alleles were obtained for the first time. All sequences herein reported also represent extensions through the promoter region and the 3'-untranslated region. Fourteen 5'-nucleotide sequences and 14 3'-nucleotide sequences were detected outside the coding region. In total, 316 single-nucleotide polymorphisms unequally distributed in HLA-C subregions were observed. In addition to exons 2 and 3, nucleotide variability was found to be particularly high in exon 5, which encodes the transmembrane region. The differentiation of the C*07 and C*17 lineages in this region accounts for the high variability. The congruence of phylogeny across most regions of the gene suggests that gene conversion or recombination has not markedly influenced divergence between lineages in the evolution of HLA-C.