Replication study of genetic loci influencing age at menopause in Southern Chinese women

Session - Ovarian AgeingThis journal issue contain Abstracts: 10th EMAS Congress 2015INTRODUCTION: Age at menopause is a highly heritable trait. Previous genome-wide meta-analysis in European and Northern Chinese identified 26 loci underlying age at menopause. OBJECTIVES: To validate these 26 genetic loci in Southern Chinese women. AIMS: To study genetic factors which may influence age at menopause in Southern Chinese. METHODS: This study was performed on 653 women who participated in the Hong Kong Osteoporosis Study, whose age at menopause was available. These women consented to have blood taken and archived for genotyping. DNA was extracted from the buffy coat, and genotyping was performed using Sequenom iPLEX. Age at menopause ...postprin

Coriolus versicolor Yun-Zhi could delay deterioration of patients with advanced non-small cell lung cancer

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Genome-wide association study of hepatocellular carcinoma in Southern Chinese patients with chronic hepatitis B virus infection

One of the most relevant risk factors for hepatocellular carcinoma (HCC) development is chronic hepatitis B virus (HBV) infection, but only a fraction of chronic HBV carriers develop HCC, indicating that complex interactions among viral, environmental and genetic factors lead to HCC in HBV-infected patients. So far, host genetic factors have incompletely been characterized. Therefore, we performed a genome-wide association (GWA) study in a Southern Chinese cohort consisting of 95 HBV-infected HCC patients (cases) and 97 HBV-infected patients without HCC (controls) using the Illumina Human610-Quad BeadChips. The top single nucleotide polymorphisms (SNPs) were then validated in an independent cohort of 500 cases and 728 controls. 4 SNPs (rs12682266, rs7821974, rs2275959, rs1573266) at chromosome 8p12 showed consistent association in both the GWA and replication phases (OR combined = 1.31-1.39; p combined = 2.71×10 -5-5.19×10 -4; PAR combined = 26-31%). We found a 2.3-kb expressed sequence tag (EST) in the region using in-silico data mining and verified the existence of the full-length EST experimentally. The expression level of the EST was significantly reduced in human HCC tumors in comparison to the corresponding non-tumorous liver tissues (P<0.001). Results from sequence analysis and in-vitro protein translation study suggest that the transcript might function as a long non-coding RNA. In summary, our study suggests that variations at chromosome 8p12 may promote HCC in patients with HBV. Further functional studies of this region may help understand HBV-associated hepatocarcinogenesis. © 2011 Chan et al.published_or_final_versio

Identification of QTL genes for BMD variation using both linkage and gene-based association approaches

Low bone mineral density (BMD) is a risk factor for osteoporotic fracture with a high heritability. Previous large scale linkage study in Northern Chinese has identified four significant quantitative trait loci (QTL) for BMD variation on chromosome 2q24, 5q21, 7p21 and 13q21. We performed a replication study of these four QTL in 1,459 Southern Chinese from 306 pedigrees. Successful replication was observed on chromosome 5q21 for femoral neck BMD with a LOD score of 1.38 (nominal p value = 0.006). We have previously identified this locus in a genome scan meta-analysis of BMD variation in a white population. Subsequent QTL-wide gene-based association analysis in 800 subjects with extreme BMD identified CAST and ERAP1 as novel BMD candidate genes (empirical p value of 0.032 and 0.014, respectively). The associations were independently replicated in a Northern European population (empirical p value of 0.01 and 0.004 for CAST and ERAP1, respectively). These findings provide further evidence that 5q21 is a BMD QTL, and CAST and ERAP1 may be associated with femoral neck BMD variation

Gene network analysis of candidate loci for human anorectal malformations

Posters: Complex Traits and Polygenic Disorders: abstract no. 1027TAnorectal malformations (ARMs) are birth defects that require surgery and carry significant chronic morbidity. Our genome-wide copy number variation (CNV) study had provided a wealth of candidate loci. To find out whether these candidate loci are related to important developmental pathways, we have ...postprin

Functional role of ICAM-3 polymorphism in genetic susceptibility to SARS infection.

Key Messages 1. Severe acute respiratory syndrome (SARS) patients who are homozygous for intercellular adhesion molecule-3 (ICAM-3) Gly143 showed significant association with higher lactate dehydrogenase levels and lower total white blood cell counts on admission. 2. In vitro functional studies demonstrated low level binding of ICAM-3 to DC-SIGN and a wide variation in T-cell response of the wild-type ICAM-3 genotype.published_or_final_versio

Association of a single nucleotide polymorphism in the CD209 (DC-SIGN) promoter with SARS severity.

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Genome-wide Haplotype Association Mapping in mice identifies a genetic variant in CER1 associated with bone mineral density and fracture in southern Chinese women

INTRODUCTION: Osteoporosis is characterized by a decrease in bone mass, deterioration of bone tissue, impaired bone strength and increased fracture risk. It is a medically, socially, and economically important disease, especially among the aging population. Bone Mass Density (BMD) is a quantitative index of osteoporosis. Acquisition of bone mineral is a complex process involving genetics and environmental factors. METHODS: A genome-wide Haplotype Association Mapping (HAM) approach was performed by using inbred mice strains which had been genotyped and phenotyped in the Mouse Phenome Project. In HAM, a dense SNPs map was first partitioned into blocks of three SNPs with an average length of 1Mb. Modified F-statistics were calculated for the whole genome to test if blocks exist where the haplotypes can partition inbred strains into high and low BMD groups. In this study, the candidate gene Cerberus 1 (Cer1) suggested from HAM analysis was eventually tested by a human case-control cohort of 1,083 subjects. RESULTS AND CONCLUSION: In this study, we used a HAM approach to identify a haplotype block within Cer1 that partitions inbred mice strains into high and low BMD groups. A cohort of 1083 high and low BMD human subjects were studied and a non-synonymous SNP (rs3747532) in human CER1 was identified to be associated with increased risk of both low BMD in premenopausal women (OR 2.2; 95% confidence interval: 1.0 - 4.6; p < 0.05) and increased risk of vertebral fractures (OR 1.82, p=0.025) in the post-menopausal cohort. We also showed that Cer1 is expressed in mouse bone and growth plate by RT-PCR, immunohistochemistry and in situ hybridization, consistent with polymorphisms potentially influencing bone mineral density. Our successful identification of an association with CER1 in humans together with our mouse study suggests that CER1 may play a role in the development of bone or its metabolism.postprintThe 59th Annual Meeting of The American Society of Human Genetics (ASHG), Honolulu, HI., 20-24 October 2009

Risk assessment for the spread of Serratia marcescens within dental-unit waterline systems using Vermamoeba vermiformis

Vermamoeba vermiformis is associated with the biofilm ecology of dental-unit waterlines (DUWLs). This study investigated whether V. vermiformis is able to act as a vector for potentially pathogenic bacteria and so aid their dispersal within DUWL systems. Clinical dental water was initially examined for Legionella species by inoculating it onto Legionella selective-medium plates. The molecular identity/profile of the glassy colonies obtained indicated none of these isolates were Legionella species. During this work bacterial colonies were identified as a non-pigmented Serratia marcescens. As the water was from a clinical DUWL which had been treated with Alpron™ this prompted the question as to whether S. marcescens had developed resistance to the biocide. Exposure to Alpron™ indicated that this dental biocide was effective, under laboratory conditions, against S. marcescens at up to 1x108 colony forming units/millilitre (cfu/ml). V. vermiformis was cultured for eight weeks on cells of S. marcescens and Escherichia coli. Subsequent electron microscopy showed that V. vermiformis grew equally well on S. marcescens and E. coli (p = 0.0001). Failure to detect the presence of S. marcescens within the encysted amoebae suggests that V. vermiformis is unlikely to act as a vector supporting the growth of this newly isolated, nosocomial bacterium

Genome-wide copy number variation study in anorectal malformations

Anorectal malformations (ARMs, congenital obstruction of the anal opening) are among the most common birth defects requiring surgical treatment (2-5/10 000 live-births) and carry significant chronic morbidity. ARMs present either as isolated or as part of the phenotypic spectrum of some chromosomal abnormalities or monogenic syndromes. The etiology is unknown. To assess the genetic contribution to ARMs, we investigated single-nucleotide polymorphisms and copy number variations (CNVs) at genome-wide scale. A total of 363 Han Chinese sporadic ARM patients and 4006 Han Chinese controls were included. Overall, we detected a 1.3-fold significant excess of rare CNVs in patients. Stratification of patients by presence/absence of other congenital anomalies showed that while syndromic ARM patients carried significantly longer rare duplications than controls (P = 0.049), non-syndromic patients were enriched with both rare deletions and duplications when compared with controls (P = 0.00031). Twelve chromosomal aberrations and 114 rare CNVs were observed in patients but not in 868 controls nor 11 943 healthy individuals from the Database of Genomic Variants. Importantly, these aberrations were observed in isolated ARM patients. Gene-based analysis revealed 79 genes interfered by CNVs in patients only. In particular, we identified a de novo DKK4 duplication. DKK4 is a member of the WNT signaling pathway which is involved in the development of the anorectal region. In mice, Wnt disruption results in ARMs. Our data suggest a role for rare CNVs not only in syndromic but also in isolated ARM patients and provide a list of plausible candidate genes for the disorder.postprin