Daizhan Zhou

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

CONTEXTnTelomeres 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.nnnMETHODSnWe 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.nnnRESULTSnTelomere 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).nnnCONCLUSIONnOur 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.

Amyloid-β-Related Genes SORL1 and ACE are Genetically Associated With Risk for Late-onset Alzheimer Disease in the Chinese Population

Late-onset Alzheimer Disease (LOAD) is a common neurodegenerative disease, and one of its major pathologic characteristics is senile plaques. Proteins encoded by SORL1 and ACE have been shown to be related to the processing, trafficking, and degradation of Amyloid-&bgr;, the principal component of senile plaques. In this paper, we investigated whether SORL1 and ACE are associated with LOAD. We recruited 144 LOAD patients and 476 controls from Shanghai, China and conducted a case–control study on 9 single-nucleotide polymorphisms (SNPs): 6 in SORL1 (rs2070045, rs661057, rs668387, rs689021, rs3824968, rs2282649) and 3 in ACE (rs1800764, rs4343, rs1799752). Despite the small case sample size (144), we observed that rs1800764, rs4343, rs1799752 in ACE, and rs2070045, rs3824968, rs2282649 in SORL1 showed significantly different allele frequencies between patients and controls (P=4.57×10−2, 5.24×10−3, 1.95×10−4, 1.77×10−4, 6.44×10−3, and 3.11×10−3, respectively). Moreover, haplotypes on ACE and on SORL1 were significantly associated with LOAD (all P-value<0.009 in ACE and all P-value <0.003 in SORL1). In ACE, we found the most significant protective haplotype encompasses SNPs rs2070045, rs3824968, and rs2282649 (C-G-D: OR=0.20, P=8.96×10−14). In SORL1, we detected a “complementary” haplotype (G-A-T: OR=1.54, P=2.67×10−3; T-T-C: OR=0.63, P=2.36×10−3) composed of SNPs rs2070045, rs3824968, and rs2282649. In addition, we carried out meta-analysis with 3 other Asian populations on 3 SNPs in SORL1 (rs2070045, rs3824968, and rs2282649). Results supported our initial finding that these 3 SNPs were associated with LOAD. Our data suggested that SORL1 and ACE might play a role in LOAD susceptibility among Han Chinese.

Positive association between the brain-derived neurotrophic factor (BDNF) gene and bipolar disorder in the Han Chinese population.

Brain‐derived neurotrophic factor (BDNF) is the most widely distributed neurotrophin in the central nervous system (CNS), and services many biological functions such as neural survival, differentiation, and plasticity. Previous studies have suggested that the Val66Met (also known as rs6265 or G196A) variant of BDNF is associated with bipolar disorder (BPD), but the results have been inconclusive. We therefore genotyped the Val66Met polymorphism in a Han Chinese population sample (498 cases and 501 control subjects). We found that the BDNF genotype is associated with BPD in this population (χ2u2009=u20099.4666, dfu2009=u20092, Pu2009=u20090.00884). Furthermore, our data suggested that the Met allele rather than the Val allele increased the risk for BPD in our Han population (ORu2009=u20091.44; 95% CIu2009=u20091.070–1.950; Pu2009=u20090.016). Further studies are necessary to elucidate the involvement of the BDNF gene in the pathophysiology of BPD.

Effects of genetic variants on lipid parameters and dyslipidemia in a Chinese population

A number of recent genome-wide association (GWA) studies have identified several novel genetic determinants of plasma lipid and lipoprotein concentrations in European populations. However, it is still unclear whether these loci identified in Caucasian GWA studies also exert the same effect on lipid and lipoprotein concentrations in a Chinese population. We genotyped 10 single-nucleotide polymorphisms (SNPs) in nine loci in a Chinese Han population sample (n = 4,192) and assessed the associations of these SNPs with metabolic traits, using linear regression adjusted for age, gender, diabetes status, and body mass index. Three variants (rs12654264, P ∼ 1.7 × 10−6; rs3764261, P ∼ 7.1 × 10−7; and rs4420638, P ∼ 1.1 × 10−3) showed strong evidence for association with total cholesterol; four variants (rs780094, P ∼ 1.8 × 10−11; rs17145738, P ∼ 5.0 × 10−7; rs326, P ∼ 2.3 × 10−6; and rs439401, P ∼ 2.2 × 10−5) showed strong evidence for association with triglycerides, four variants (rs17145738, P ∼ 1.9 × 10−4; rs326, P ∼ 9.7 × 10−4; rs1800588, P ∼ 1.5 × 10−7; and rs3764261, P ∼ 4.3 × 10−14) showed strong evidence for association with HDL-cholesterol (HDL-C), two variants (rs12654264, P ∼ 2.3 × 10−5; and rs4420638, P ∼ 3.6 × 10−4) showed strong evidence for association with LDL-C, and four variants (rs326, P ∼ 2.8 × 10−3; rs1800588, P ∼ 6.1 × 10−4; rs3764261, P ∼ 2.0 × 10−3; and rs4420638, P ∼ 9.4 × 10−5) showed strong evidence for association with total cholesterol-HDL-C-related ratio. These SNPs generated strong combined effects on lipid traits and dyslipidemia. Our findings indicate that the variants that associated with metabolic traits in Europeans may also play a role in a Chinese Han population.

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.

The ENPP1 K121Q polymorphism is not associated with type 2 diabetes or obesity in the Chinese Han population.

Type 2 diabetes (T2D) mellitus is a metabolic disorder characterized by chronic hyperglycemia and insulin resistance. It has been a worldwide public health problem, which is increasing rapidly, especially in developing countries such as China. The ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1) gene, also known as plasma cell membrane glycoprotein 1, has been reported by genetic association studies as being associated with T2D and obesity in various populations, such as Caucasian and African American. However, there are also some controversial results in Asian populations. Our study tried to examine the associations between ENPP1 and T2D and obesity. Rs1044498 (K121Q) and rs7754561 were genotyped in 1912 patients and 2041 control subjects through TaqMan technology on the ABI7900 system. They showed no statistical association with T2D, obesity or any metabolic quantitative traits. Our meta-analysis result was consistent with it. Our study did not replicate the positive association found previously and suggested that K121Q of ENPP1 might not have a major role in the susceptibility to T2D or obesity in the Chinese Han population.

C677T methylenetetrahydrofolate reductase gene polymorphisms in bipolar disorder: an association study in the Chinese population and a meta-analysis of genetic association studies.

The methylenetetrahydrofolate reductase (MTHFR) gene variant C677T is suspected to be a risk factor for psychiatric disorders, but it remains uncertain whether the MTHFR C677T variant is associated with bipolar disorders. To investigate possible association, unrelated controls (n=461) with no history of psychiatric disorders and patients (n=501) diagnosed with bipolar disorder were recruited in this study. In addition, six association studies published up to June 2008 were included in a subsequent meta-analysis. No significant difference was found in either allele frequencies or genotype distribution between patients and controls in our association study in the Chinese population. Similarly, the meta-analysis result showed no significant association between MTHFR C677T and bipolar disorder. In conclusion, the MTHFR C677T variant is unlikely to play a major role in the susceptibility to bipolar disorder, although MTHFR plays an important role in the one-carbon metabolism and DNA methylation.

Association of the CHRNA3 Locus with Lung Cancer Risk and Prognosis in Chinese Han Population

Introduction: Recent genome-wide association studies in Caucasians revealed association with lung cancer risk of single nucleotide polymorphisms (SNPs) in the locus containing two nicotine acetylcholine receptor CHRNA genes. However, the reported risk SNPs are extremely rare in Asians. This study sought to identify other variants on CHRNA3 associated with lung cancer susceptibility and to explore whether SNPs of CHRNA3 are of prognostic factors in patients with non-small cell lung cancer (NSCLC) in Chinese Han population. Methods: A case-control study of 529 cases and 567 controls was performed to study the association of three SNPs (rs3743076, rs3743078, and rs3743073) in CHRNA3 with lung cancer risk in Chinese Han population using logistic regression models. The relationship between CHRNA3 polymorphisms with overall survival among 122 patients with advanced stage (stage IIIb and IV) NSCLC were evaluated using Cox multiple model based on the International Association for the Study of Lung Cancer recommended tumor, node, metastasis new staging. Results: Patients with genotypes TG or GG for the novel SNP rs3743073 in CHRNA3 gene, compared with those with TT, showed an increased risk of lung cancer (adjusted odds ratio = 1.91; 95% confidence interval, 1.38–2.63; p = 9.67 × 10−5) and worst survival (adjusted hazard ratio = 2.35; 95% confidence interval, 1.05–5.26; p = 0.04) in patients with advanced stage NSCLC based on International Association for the Study of Lung Cancer recommended tumor, node, metastasis new staging. Conclusions: These results suggest that the rs3743073 polymorphism in CHRNA3 is predictive for lung cancer risk and prognostic in advanced stage NSCLC in Chinese Han population.

Exome sequencing identifies a de novo mutation in HDAC8 associated with Cornelia de Lange syndrome

Cornelia de Lange syndrome (CdLS) is a clinically and genetically heterogeneous developmental disorder. The clinical features of CdLS include growth retardation, intellectual disability, limb defects, typical facial dysmorphism and other systemic involvement. Here, we present the clinical and genetic characterization of a sporadic CdLS trio. The proband is a 7-year-old girl with typical CdLS, and both parents are apparently healthy. Whole-exome sequencing of the patient and of both her unaffected parents revealed a previously unobserved de novo mutation in exon 6 of the HDAC8 gene (chrX: 71684483, c.586 A>T; p.M196K). Thus, we have further founded that the p.M196K mutation in HDAC8 is a relevant causal mutation for CdLS.