Publications by authors named "Klaus Lindpaintner"

64 Publications

Antibody and antigen contact residues define epitope and paratope size and structure.

J Immunol 2013 Aug 24;191(3):1428-35. Epub 2013 Jun 24.

Antibody Discovery Research and Development, SDIX, Inc, Newark, DE 19702, USA.

A total of 111 Ag-Ab x-ray crystal structures of large protein Ag epitopes and paratopes were analyzed to inform the process of eliciting or selecting functional and therapeutic Abs. These analyses illustrate that Ab contact residues (CR) are distributed in three prominent CR regions (CRR) on L and H chains that overlap but do not coincide with Ab CDR. The number of Ag and Ab CRs per structure are overlapping and centered around 18 and 19, respectively. The CR span (CRS), a novel measure introduced in this article, is defined as the minimum contiguous amino acid sequence containing all CRs of an Ag or Ab and represents the size of a complete structural epitope or paratope, inclusive of CR and the minimum set of supporting residues required for proper conformation. The most frequent size of epitope CRS is 50-79 aa, which is similar in size to L (60-69) and H chain (70-79) CRS. The size distribution of epitope CRS analyzed in this study ranges from ~20 to 400 aa, similar to the distribution of independent protein domain sizes reported in the literature. Together, the number of CRs and the size of the CRS demonstrate that, on average, complete structural epitopes and paratopes are equal in size to each other and similar in size to intact protein domains. Thus, independent protein domains inclusive of biologically relevant sites represent the fundamental structural unit bound by, and useful for eliciting or selecting, functional and therapeutic Abs.
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http://dx.doi.org/10.4049/jimmunol.1203198DOI Listing
August 2013

A 7-plex microbead-based immunoassay for serotyping Shiga toxin-producing Escherichia coli.

J Microbiol Methods 2013 Feb 7;92(2):226-30. Epub 2012 Dec 7.

U.S. Food and Drug Administration San Francisco District Laboratory, 1431 Harbor Bay Parkway, Alameda, CA 94502, USA.

Serotyping of Shiga toxin-producing Escherichia coli (STEC) has been contingent upon the availability of antisera. Here we describe a 7-plex microbead-based immunoassay to simultaneously serotype seven STECs (i.e., belonging to serogroups O26, O45, O103, O111, O121, O145, and O157) by the Luminex xMAP® technology. This technology presents many advantages: Its multiplexed format (up to 100 analytes) saves time, reagents, and test sample, and many regulatory agencies currently utilize this platform for other assays. In this study, a total of seventy-nine STEC strains belonging to the 7 different serogroups of interest were tested. These strains had been previously serotyped and their serogroup was confirmed by PCR. Except for one strain belonging to the O111 serogroup, nearly all strains (i.e., 98.7%; 78/79) were correctly identified on the Bio-Plex 100 instrument in less than 4h. This newly developed microbead-based immunoassay could be extended to include other STEC serogroups, virulence factors, and/or bacterial species.
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http://dx.doi.org/10.1016/j.mimet.2012.11.023DOI Listing
February 2013

Detection of the top six non-O157 Shiga toxin-producing Escherichia coli O groups by ELISA.

Foodborne Pathog Dis 2012 Nov;9(11):1044-8

E. coli Reference Center, Department of Veterinary and Biomedical Sciences, Pennsylvania State University, University Park, PA 16802, USA.

There is a growing concern of a public health risk associated with non-O157 Shiga toxin-producing Escherichia coli (STEC) since E. coli serogroups O26, O45, O103, O111, O121, and O145 are frequently implicated in outbreaks of human illness worldwide. Recently, the Food Safety and Inspection Service of the U.S. Department of Agriculture declared these six STEC O groups to be adulterants in beef. We describe here a rapid, sensitive, and highly specific enzyme-linked immunosorbent assay (ELISA) for the detection of these top six non-O157 STEC O groups. The assays were tested against 174 reference E. coli O groups, with 60 clinical isolates belonging to the target O groups and 10 non-E coli strains belonging to the family Enterobacteriaceae. Assays for serogroups O103, O111, and O121 exhibited 100% specificity, while assays for serogroups O26 and O45 had 98.2% specificity, and O145 had 99.1% specificity. ELISA conducted using artificially inoculated ground beef samples displayed 100% accuracy. The sensitivity of the assay was 5×10(5) colony-forming unit (CFU)/mL, with limits of detection in the range of 1-10 CFU/25 g of ground beef sample following enrichment. The findings of the study suggest that the assay described is simple and rapid, and can be employed to detect target STEC O groups in beef and other food samples. In addition, the assay provides a conceptual framework that can be adapted for the development of similar tests for the rapid detection of other serogroups of E. coli.
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http://dx.doi.org/10.1089/fpd.2012.1231DOI Listing
November 2012

SDIX RapidChek Listeria F.A.S.T. environmental test system for the detection of Listeria species on environmental surfaces.

J AOAC Int 2012 May-Jun;95(3):850-9

USA.

The SDIX RapidChek Listeria F.A.S.T. test system was validated against the U.S. Department of Agriculture-Food Safety and Inspection Service (USDA-FSIS) cultural reference method for the detection of Listeria species on stainless steel, plastic, rubber, and painted concrete. The SDIX method uses a proprietary RapidChek Listeria enrichment media for a one-step, 24-40 h enrichment at 30 degrees C, and detects Listeria on an immunochromatographic lateral flow device in 10 min. Different Listeria species were used to spike each of the environmental surfaces. Environmental surfaces were spiked at levels ranging from 50 to 400 CFU/surface (1 in.2 swabs for painted concrete, 4 in.(2) for sponge). A total of 120 spiked samples were tested by the SDIX method at 24 and 40 h and the cultural reference method. Total confirmed positives were 49, 54, and 48 for the SDIX 24 h method, the SDIX 40 h method, and the USDA-FSIS cultural reference method, respectively. Nonspiked samples from all environmental surfaces were reported as negative for Listeria spp. by all methods. The overall Chi square was 0.017 (P = 0.104) and 0.611 (P= 0.566) after a 24 and 40 h enrichment, respectively, indicating that the test method was equivalent in performance to the reference method at both enrichment times. The SDIX method was evaluated for the detection of 50 Listeria and 35 non-Listeria bacterial strains. All 50 Listeria strains were detected by the method (100% sensitivity). Five out of 35 non-Listeria species gave light test signals when grown in nonselective broth culture and tested undiluted. However, when grown in the RapidChek Listeria F.A.S.T. proprietary media, only one bacterial strain (Staphylococcus aureus) was detected, giving a very low test signal (97% specificity). The method was shown to be robust toward several alterations in testing and storage conditions.
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http://dx.doi.org/10.5740/jaoacint.11-480DOI Listing
August 2012

Toward a roadmap in global biobanking for health.

Eur J Hum Genet 2012 Nov 20;20(11):1105-11. Epub 2012 Jun 20.

Department of Genes and Environment, Division of Epidemiology, The Norwegian Institute of Public Health, Oslo, Norway.

Biobanks can have a pivotal role in elucidating disease etiology, translation, and advancing public health. However, meeting these challenges hinges on a critical shift in the way science is conducted and requires biobank harmonization. There is growing recognition that a common strategy is imperative to develop biobanking globally and effectively. To help guide this strategy, we articulate key principles, goals, and priorities underpinning a roadmap for global biobanking to accelerate health science, patient care, and public health. The need to manage and share very large amounts of data has driven innovations on many fronts. Although technological solutions are allowing biobanks to reach new levels of integration, increasingly powerful data-collection tools, analytical techniques, and the results they generate raise new ethical and legal issues and challenges, necessitating a reconsideration of previous policies, practices, and ethical norms. These manifold advances and the investments that support them are also fueling opportunities for biobanks to ultimately become integral parts of health-care systems in many countries. International harmonization to increase interoperability and sustainability are two strategic priorities for biobanking. Tackling these issues requires an environment favorably inclined toward scientific funding and equipped to address socio-ethical challenges. Cooperation and collaboration must extend beyond systems to enable the exchange of data and samples to strategic alliances between many organizations, including governmental bodies, funding agencies, public and private science enterprises, and other stakeholders, including patients. A common vision is required and we articulate the essential basis of such a vision herein.
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http://dx.doi.org/10.1038/ejhg.2012.96DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3477856PMC
November 2012

Genetics research: Clinical standards not practical in the lab.

Nature 2012 Mar 7;483(7388):158. Epub 2012 Mar 7.

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http://dx.doi.org/10.1038/483158cDOI Listing
March 2012

Impact of immunization technology and assay application on antibody performance--a systematic comparative evaluation.

PLoS One 2011 20;6(12):e28718. Epub 2011 Dec 20.

Research and Development, SDIX, Newark, Delaware, United States of America.

Antibodies are quintessential affinity reagents for the investigation and determination of a protein's expression patterns, localization, quantitation, modifications, purification, and functional understanding. Antibodies are typically used in techniques such as Western blot, immunohistochemistry (IHC), and enzyme-linked immunosorbent assays (ELISA), among others. The methods employed to generate antibodies can have a profound impact on their success in any of these applications. We raised antibodies against 10 serum proteins using 3 immunization methods: peptide antigens (3 per protein), DNA prime/protein fragment-boost ("DNA immunization"; 3 per protein), and full length protein. Antibodies thus generated were systematically evaluated using several different assay technologies (ELISA, IHC, and Western blot). Antibodies raised against peptides worked predominantly in applications where the target protein was denatured (57% success in Western blot, 66% success in immunohistochemistry), although 37% of the antibodies thus generated did not work in any of these applications. In contrast, antibodies produced by DNA immunization performed well against both denatured and native targets with a high level of success: 93% success in Western blots, 100% success in immunohistochemistry, and 79% success in ELISA. Importantly, success in one assay method was not predictive of success in another. Immunization with full length protein consistently yielded the best results; however, this method is not typically available for new targets, due to the difficulty of generating full length protein. We conclude that DNA immunization strategies which are not encumbered by the limitations of efficacy (peptides) or requirements for full length proteins can be quite successful, particularly when multiple constructs for each protein are used.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0028718PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3243671PMC
April 2012

RapidChek SELECT Salmonella enteritidis test system for the detection of Salmonella enteritidis in poultry house drag swabs, shell egg pools, and chicken carcass rinsates.

J AOAC Int 2011 Jul-Aug;94(4):1138-53

SDIX, 128 Sandy Dr, Newark, DE 19713, USA.

The RapidChek SELECT Salmonella Enteritidis Test System was validated for the detection of Salmonella Enteritidis (SE) in poultry house drag swabs, shell egg pools, and chicken carcass rinsates. The method utilizes RapidChek SELECT Salmonella (AOAC PTM License No. 080601) proprietary primary and secondary enrichment media. Following enrichment, an immunochromatographic test strip is inserted into the tube containing the secondary enrichment broth, developed for 10 min, and interpreted. Salmonella Enteritidis-inoculated samples (1-5 CFU SE/analytical unit) were tested by the test method as well as the appropriate cultural reference method U.S. Food and Drug Administration-Bacteriological Analytical Manual (drag swabs and egg pools) or U.S. Department of Agriculture-Food Safety and Inspection Service (chicken carcass rinsates). A total of 80 samples were tested by both methods in the study. Fifty-two samples were positive by the RapidChek SELECT Salmonella Enteritidis method and 38 were found positive by the respective reference method. The sensitivity of the method was 100% and the specificity was 100%. The accuracy of the test method was 137%, indicating that the method was more sensitive than the reference method. The RapidChek SELECT Salmonella Enteritidis method was tested with 82 Salmonella Group D1 strains including 63 Salmonella Enteritidis strains as well as 32 non-Salmonella Group D1 strains representing 10 bacteria genera. The test method detected all 82 Group D1 strains (100% sensitivity). None of the non-Salmonella Group D1 or other genera of bacteria were detected, indicating a specificity of 100%. The method was shown to be highly robust and stable under control and accelerated stability conditions.
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October 2011

From genomic databases to translation: a call to action.

J Med Ethics 2011 Aug 26;37(8):515-6. Epub 2011 May 26.

Department of Human Genetics, McGill University, Montreal, Quebec, H3A 1A4, Canada.

The rapid rise of international collaborative science has enabled access to genomic data. In this article, it is argued that to move beyond mapping genomic variation to understanding its role in complex disease aetiology and treatment will require extending data sharing for the purposes of clinical research translation and implementation.
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http://dx.doi.org/10.1136/jme.2011.043042DOI Listing
August 2011

Biomarkers: call on industry to share.

Nature 2011 Feb;470(7333):175

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http://dx.doi.org/10.1038/470175dDOI Listing
February 2011

A1166C genetic variation of the angiotensin II type I receptor gene and susceptibility to coronary heart disease: collaborative of 53 studies with 20,435 cases and 23,674 controls.

Atherosclerosis 2010 Nov 4;213(1):191-9. Epub 2010 Aug 4.

Brigham and Women's Hospital, School of Medicine, Harvard University, Boston, MA 02115, USA.

Objective: Angiotensin II induces vasoconstriction and vascular smooth muscle growth via stimulation of the angiotensin II type I receptor (AGTR1). Some studies have reported an association between a genetic variant (A1166C) in the 3' un-translated region of AGTR1 and increased risk of coronary heart disease (CHD), but other have yielded apparently conflicting results.

Methods: Literature-based meta-analyses were performed on 48 papers including 53 studies published before June 2008 in relation to the A1166C polymorphism (NCBI, dbSNP: rs5186) of the AGTR1, involving a total of 20,435 CHD cases and 23,674 controls. We also explored potential sources of heterogeneity and conducted appropriate stratified analyses.

Results: In a combined analysis, the per-allele odds ratio (OR) for CHD of the A1166C polymorphism was 1.11 (95% confidence interval: 1.03-1.19), but there is an indication of publication bias and heterogeneity among the 53 studies. Sample size and study quality were significant sources of heterogeneity among studies of the A1166C polymorphism with possibly overestimates in studies of smaller sample-size and poor-quality. When the analyses were restricted to 11 larger studies (≥500 cases), and to 8 high-quality studies (quality score: ≥11 points), the summary per-allele odds ratios were 0.992 (95% confidence interval, 0.944-1.042) and 0.990 (95% confidence interval, 0.915-1.072), respectively.

Conclusions: An overall weak association between the A1166C polymorphism and CHD is observed but this is likely to be due to publication bias and heterogeneity between studies. There were no significant associations among the larger sample-size and high-quality studies which are less prone to selective publication and have greater power to detect a true association.
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http://dx.doi.org/10.1016/j.atherosclerosis.2010.07.046DOI Listing
November 2010

The common rs9939609 variant of the fat mass and obesity-associated gene is associated with obesity risk in children and adolescents of Beijing, China.

BMC Med Genet 2010 Jul 5;11:107. Epub 2010 Jul 5.

Department of Epidemiology, Capital Institute of Pediatrics, 2 Ya Bao Road, 100020 Beijing China.

Background: Previous genome-wide association studies for type 2 diabetes susceptibility genes have confirmed that a common variant, rs9939609, in the fat mass and obesity associated (FTO) gene region is associated with body mass index (BMI) in European children and adults. A significant association of the same risk allele has been described in Asian adult populations, but the results are conflicting. In addition, no replication studies have been conducted in children and adolescents of Asian ancestry.

Methods: A population-based survey was carried out among 3503 children and adolescents (6-18 years of age) in Beijing, China, including 1229 obese and 2274 non-obese subjects. We investigated the association of rs9939609 with BMI and the risk of obesity. In addition, we tested the association of rs9939609 with weight, height, waist circumference, waist-to-height ratio, fat mass percentage, birth weight, blood pressure and related metabolic traits.

Results: We found significant associations of rs9939609 variant with weight, BMI, BMI standard deviation score (BMI-SDS), waist circumference, waist-to-height ratio, and fat mass percentage in children and adolescents (p for trend = 3.29 x 10-5, 1.39 x 10-6, 3.76 x 10-6, 2.26 x 10-5, 1.94 x 10-5, and 9.75 x 10-5, respectively). No significant associations were detected with height, birth weight, systolic and diastolic blood pressure and related metabolic traits such as total cholesterol, triglycerides, HDL-cholesterol, LDL-cholesterol and fasting plasma glucose (all p > 0.05). Each additional copy of the rs9939609 A allele was associated with a BMI increase of 0.79 [95% Confidence interval (CI) 0.47 to 1.10] kg/m2, equivalent to 0.25 (95%CI 0.14 to 0.35) BMI-SDS units. This rs9939609 variant is significantly associated with the risk of obesity under an additive model [Odds ratio (OR) = 1.29, 95% CI 1.11 to 1.50] after adjusting for age and gender. Moreover, an interaction between the FTO rs9939609 genotype and physical activity (p < 0.001) was detected on BMI levels, the effect of rs9939609-A allele on BMI being (0.95 +/- 0.10), (0.77 +/- 0.08) and (0.67 +/- 0.05) kg/m2, for subjects who performed low, moderate and severe intensity physical activity.

Conclusion: The FTO rs9939609 variant is strongly associated with BMI and the risk of obesity in a population of children and adolescents in Beijing, China.
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http://dx.doi.org/10.1186/1471-2350-11-107DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2914647PMC
July 2010

Positive association between GRIN2B gene and bipolar disorder in the Chinese Han Population.

Psychiatry Res 2011 Jan 26;185(1-2):290-2. Epub 2010 May 26.

Bio-X Center and affiliated Changning Mental Health Center, Shanghai Jiao Tong, University, PR China.

In the present work we genotyped three single-nucleotide polymorphisms (SNPs) (rs7301328, rs1805247, and rs1805502) of the GRIN2B gene in a set of 480 unrelated bipolar disorder patients and 480 unrelated genetically matched normal controls in Chinese Han population by either allelic-specific multiplex ligation-detection reaction (AMLR) technology or direct sequencing. Rs1805247 and the haplotype consisting of rs1805502 and rs1805247 were significantly associated, suggesting GRIN2B as having a role in the etiology of bipolar disorder.
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http://dx.doi.org/10.1016/j.psychres.2009.11.026DOI Listing
January 2011

Voluntary exploratory data submissions to the US FDA and the EMA: experience and impact.

Nat Rev Drug Discov 2010 06;9(6):435-45

Genomics Group, Office of Clinical Pharmacology, Office of Translational Sciences, Center for Drug Evaluation and Research, US FDA, Building 51, 10903 New Hampshire Avenue, Silver Spring, Maryland 20903-002, USA.

Heterogeneity in the underlying mechanisms of disease processes and inter-patient variability in drug responses are major challenges in drug development. To address these challenges, biomarker strategies based on a range of platforms, such as microarray gene-expression technologies, are increasingly being applied to elucidate these sources of variability and thereby potentially increase drug development success rates. With the aim of enhancing understanding of the regulatory significance of such biomarker data by regulators and sponsors, the US Food and Drug Administration initiated a programme in 2004 to allow sponsors to submit exploratory genomic data voluntarily, without immediate regulatory impact. In this article, a selection of case studies from the first 5 years of this programme - which is now known as the voluntary exploratory data submission programme, and also involves collaboration with the European Medicines Agency - are discussed, and general lessons are highlighted.
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http://dx.doi.org/10.1038/nrd3116DOI Listing
June 2010

Association study between RGS4 and bipolar disorder in the Chinese Han population.

Psychiatr Genet 2010 Jun;20(3):130-2

Bio-X Center and affiliated Changning Mental Health Center, Shanghai Jiao Tong University, Jiulong, Matang District, Wuhu, China.

This abstract concerns a brief association study between RGS4 and bipolar disorder, by an association study of five single nucleotide polymorphisms, rs951436, rs951439, rs2842030, rs2661319, and rs2344671, in 484 patients and 288 controls from the Chinese Han population. In our case-control study, the T allele of the single nucleotide polymorphism rs951436 tended to be protective (P=0.0078), and in addition, a haplotype containing this T allele was also protective for bipolar disorder (P=0.02). Our results provide further evidence to support RGS4 as a potential susceptible gene for bipolar disorder.
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http://dx.doi.org/10.1097/YPG.0b013e32833a2009DOI Listing
June 2010

The Val/Met functional polymorphism in COMT confers susceptibility to bipolar disorder: evidence from an association study and a meta-analysis.

J Neural Transm (Vienna) 2009 Oct 4;116(10):1193-200. Epub 2009 Jul 4.

Bio-X Center, Shanghai Jiao Tong University, PO Box 501, Haoran Building, 1954 Huashan Road, 200030, Shanghai, People's Republic of China.

The COMT gene is considered as one of the prominent candidate genes for susceptibility to BP, and most studies focused a functional polymorphism in the gene: the Val/Met polymorphism (rs4680). However, results from these studies are sometimes contradictory, due to small sample size or heterogeneity. In this study, we first investigate the possible association between the Val/Met polymorphism in COMT and bipolar disorder in the Han population, which has never been done before. Then a systematic meta-analysis was conducted to determine if the low-activity allele (Met) increases the risk of BP in different ethnic groups. A total of 478 BP patients and 469 healthy subjects were recruited in our case/control study. MIX software package was employed to perform the meta-analysis on 19 studies after careful search and selection. We observed statistically-significant differences in allele (p = 0.00060) and genotype (p = 0.00203) frequencies between patients and controls in our samples. The meta-analysis also provided a significant pooled OR for association of the Met allele in rs4680 with BP in the total population (p = 0.0223) and in the Asian population (p = 0.0232). Although a significant pooled OR was also found for the Caucasian population (p = 0.0409) after one of the studies as discussed below was removed, the role for Val/Met polymorphism in BP in Caucasian ethnicity was not yet to be confirmed. In conclusion, the low-activity allele (Met) of rs4680 in COMT gene possibly confers risk for bipolar disorder in the Han population, while it needs further evidence for concluding its association with BP in the Caucasian population.
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http://dx.doi.org/10.1007/s00702-009-0260-7DOI Listing
October 2009

The 1425G/A SNP in PRKCH is associated with ischemic stroke and cerebral hemorrhage in a Chinese population.

Stroke 2009 Sep 11;40(9):2973-6. Epub 2009 Jun 11.

First Affiliated Hospital, Medical College of Shantou University, Shantou, China.

Background And Purpose: PRKCH (the gene encoding protein kinase C eta) has a role in the pathogenesis of ischemic stroke. The 1425G/A SNP in PRKCH (rs2230500) is significantly associated with ischemic stroke in Japanese. The aim of the present study is to investigate the associations in ischemic stroke and other types of stroke in the Chinese population.

Methods: A total of 1209 patients with stroke and 1174 controls were examined using a case-control methodology. The 1425G/A SNP in PRKCH was genotyped by allele-specific real-time PCR assay.

Results: The 1425G/A SNP in PRKCH was significantly associated with both ischemic stroke (odds ratio [OR]=1.31; 95% confidence interval [CI], 1.08 to 1.60; P=0.0058) and cerebral hemorrhage (OR=1.94; 95% CI, 1.21 to 3.10; P=0.0054) under a dominant model. Even after age- and sex-adjustment, the significant associations remained (in ischemic stroke, for AA+AG versus GG, OR=1.37, 95% CI, 1.12 to 1.67, P=0.0019; in cerebral hemorrhage, for AA+AG versus GG, OR=1.96, 95% CI, 1.21 to 3.19, P=0.0064).

Conclusions: The 1425G/A SNP in PRKCH increases the risk of both ischemic stroke and cerebral hemorrhage in the Chinese population.
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http://dx.doi.org/10.1161/STROKEAHA.109.551747DOI Listing
September 2009

Association of two CETP polymorphisms with HDL levels in the Chinese obese population.

Obesity (Silver Spring) 2009 Dec 14;17(12):2196-201. Epub 2009 May 14.

Laboratory of Human Genetics, Beijing Hypertension League Institute, Beijing, China.

The association of two cholesterol ester transfer protein (CETP) polymorphisms, D442G and TAQIB (B1-->B2), with high-density lipoprotein (HDL) levels in 932 Chinese obese individuals (BMI >or= 27) was investigated in comparison with normal controls (BMI
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http://dx.doi.org/10.1038/oby.2009.138DOI Listing
December 2009

Association study on the NAPG gene and bipolar disorder in the Chinese Han population.

Neurosci Lett 2009 Jul 27;457(3):159-62. Epub 2009 Mar 27.

Bio-X Center, Key Laboratory of Developmental Genetics and Neuropsychiatric Diseases, Ministry of Education, Shanghai Jiao Tong University,1954 Hushan Road, Shanghai 200030, PR China.

Background: Bipolar disorder is a mental health problem throughout the world. Chromosome 18p11 has been identified by several studies as a susceptiblilty region for bipolar disorder and NAPG, located on 18p11, has been suggested as being associated with bipolar disorder in European population.

Methods: Our study employed five SNPs (rs2290279, rs495484, rs510110, rs617040 and rs473938) to investigate the role of NAPG in the Chinese Han population based on a sample of 465 controls vs. 499 bipolar patients.

Results: Rs617040 was excluded from further analysis because of deviation from Hardy-Weinberg equilibrium. Rs473938 and rs2290279 showed significant association in both allele and genotype frequencies (rs473938: allele p=0.0028 after 100,000 permutations, genotype p=0.0018; rs2290279: allele p=0.0042 after 100,000 permutations, genotype p=0.0028). Several combinations of haplotype were found to be associated with bipolar disorder. Haplotype T-A-T of rs473938-rs2290279-rs495484 was defined by confidence intervals algorithm and had a p value of 0.0038 after 100,000 permutations.

Conclusions: Our study supports NAPG as a candidate for susceptibility to bipolar disorder.
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http://dx.doi.org/10.1016/j.neulet.2009.03.070DOI Listing
July 2009

TAQIB and I405V polymorphisms of CETP are moderately associated with obesity risk in the Chinese adult population.

Acta Diabetol 2010 Sep 10;47(3):217-24. Epub 2009 Apr 10.

Beijing Hypertension League Institute, China.

Associations between the TAQIB and I405V polymorphisms and obesity risk were studied for a single locus as well as in combination. A total of 934 obese subjects and 924 normal controls were included in the study. TAQIB was associated with high-density lipoprotein (HDL) levels (P < 0.001), while I405V was associated with levels of low-density lipoprotein (P = 0.03) and total cholesterol (P = 0.007). Less common alleles of TAQIB and I405V were associated with decreased obesity risk and further drops in odds ratio (OR) were observed in carriers with rare homozygous alleles on both loci (OR = 0.659, P = 0.02). The TAQIB B2 allele was associated with reductions in both hip circumference (P = 0.034) and triceps skinfold thickness (TST) (P = 0.045), although this effect was completely abolished after controlling for HDL levels. The 405V variant was associated with reductions in hip circumference (P = 0.031), body fat composition (P = 0.039) and TST (P = 0.036); these effects were weakened (P < 0.1) after controlling for HDL levels. In conclusion, less common alleles of TAQIB and I405V appear to be modestly associated with obesity risk in an adult Chinese population. Adjustments for HDL levels completely (TAQIB) or partially (I405V) abolished the observed association.
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http://dx.doi.org/10.1007/s00592-009-0117-4DOI Listing
September 2010

First evidence of association between G72 and bipolar disorder in the Chinese Han population.

Psychiatr Genet 2009 Jun;19(3):151-3

Changing Institute of Mental Health, Institute of Neuropsychiatric Science and Systems Biological Medicine, Xiehe Road 299, Bio-X Center Hospital, Bio-X Center, Shanghai Jiao Tong University, Shanghai, PR China.

The G72/G30 (D-amino-acid oxidase activator) complex was the first gene to be associated with bipolar disorder (BPD) in European populations, but until now no such association has been identified in Asian populations. To investigate possible association in the Chinese Han population, we carried out a study involving 475 BPD patients and 588 healthy controls. The results provide first evidence for the single nucleotide polymorphism rs778293 in G72 as a potential candidate in altering risk for BPD in the Chinese Han population.
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http://dx.doi.org/10.1097/YPG.0b013e32832a50f1DOI Listing
June 2009

The functional variant rs1048990 in PSMA6 is associated with susceptibility to myocardial infarction in a Chinese population.

Atherosclerosis 2009 Sep 12;206(1):199-203. Epub 2009 Feb 12.

The First Affiliated Hospital, Medical College of Shantou University, Shantou, China.

A recent case-control study reported that a functional single nucleotide polymorphism (SNP) in the proteasome subunit alpha type 6 gene (PSMA6) (rs1048990, C/G) was associated with susceptibility to myocardial infarction (MI) in the Japanese population. Replication studies have been performed in European and other Japanese study samples, but the results were not conclusive. The purpose of the present study was to determine whether this locus confers significant susceptibility to MI in a Chinese population. We conducted a case-control association study on a cohort of 1884 MI patients and 2643 unrelated controls from the Chinese population. Genotyping of the rs1048990 SNP was performed by the Allele-specific Real Time PCR method. We found that rs1048990 was significantly associated with MI (adjusted for age and sex, odds ratio 1.22, p=0.000005, allele frequency model; odds ratio 1.44, p=0.0000025; recessive model; odds ratio 1.56, p=0.00000048, additive model). A meta-analysis yielded a combined OR for MI of 1.15 (95% CI: 1.11-1.21) with an allele frequency model, 1.37 (95% CI: 1.23-1.51) with a recessive model and 1.44 (95% CI: 1.29-1.60) with an additive model. There was no relationship between rs1048990 and age, sex or other conventional cardiovascular risk factors. Our results indicate that the PSMA6 variant rs1048990 is a risk factor of myocardial infarction in the Chinese population.
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http://dx.doi.org/10.1016/j.atherosclerosis.2009.02.004DOI Listing
September 2009

Association study on the mitochondrial gene NDUFV2 and bipolar disorder in the Chinese Han population.

J Neural Transm (Vienna) 2009 Mar 5;116(3):357-61. Epub 2009 Feb 5.

Bio-X Center, Shanghai Jiao Tong University, Haoran Building, 1954 Huashan Road, 200030, Shanghai, People's Republic of China.

Bipolar disorder is known to be subject to maternal transmission. Mitochondrial DNA has been suggested as playing a role in the illness. NDUFV2, located on 18p11.31-p11.2, encodes an important subunit of mitochondrial NADH (complex I). Previous studies have reported the association of NDUFV2 with bipolar disorder in the Japanese and Caucasian populations. Whether it is also a susceptible gene in the Chinese population is unknown. To study the role of NDUFV2 in bipolar disorder in the Chinese population, 506 unrelated bipolar patients and 507 unrelated controls of Chinese Han origin were recruited. Six SNPs (rs11661859, rs6506640, rs1156044, rs4148965, rs906807, rs977581) were genotyped using either TaqMan technology or direct sequencing. The haplotype consisting of rs6506640 (-342G > A) and rs906807 (86C > T) was found to be associated with bipolar disorder (global p = 0.012 before corrected, p = 0.030 after 10,000 permutations; individual p (A-T of rs6506640-rs906807) = 0.014 after 100,000 permutations (p = 0.0065 before corrected). The genotype frequency of rs906807 differed between bipolar female patients and female controls (p = 0.012, uncorrected). No other individual associations of SNPs with bipolar were detected. Our study indicated that the regions spanning from the promoter to the exon 2 may contain susceptible polymorphisms which predispose to bipolar disorder.
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http://dx.doi.org/10.1007/s00702-009-0185-1DOI Listing
March 2009

A meta-analysis of candidate gene polymorphisms and ischemic stroke in 6 study populations: association of lymphotoxin-alpha in nonhypertensive patients.

Stroke 2009 Mar 8;40(3):683-95. Epub 2009 Jan 8.

Laboratory of Human Genetics, Beijing Hypertension League Institute, Beijing, China.

Background And Purpose: Ischemic stroke is a multifactorial disease with a strong genetic component. Pathways, including lipid metabolism, systemic chronic inflammation, coagulation, blood pressure regulation, and cellular adhesion, have been implicated in stroke pathophysiology, and candidate gene polymorphisms in these pathways have been proposed as genetic risk factors.

Methods: We genotyped 105 simple deletions and single nucleotide polymorphisms from 64 candidate genes in 3550 patients and 6560 control subjects from 6 case-control association studies conducted in the United States, Europe, and China. Genotyping was performed using the same immobilized probe typing system and meta-analyses were based on summary logistic regressions for each study. The primary analyses were fixed-effects meta-analyses adjusting for age and sex with additive, dominant, and recessive models of inheritance.

Results: Although 7 polymorphisms showed a nominal additive association, none remained statistically significant after adjustment for multiple comparisons. In contrast, after stratification for hypertension, 2 lymphotoxin-alpha polymorphisms, which are in strong linkage disequilibrium, were significantly associated among nonhypertensive individuals: LTA 252A>G (additive model; OR, 1.41 with 95% CI, 1.20 to 1.65; P=0.00002) and LTA 26Thr>Asn (OR, 1.19 with 95% CI, 1.06 to 1.34; P=0.003). LTA 252A>G remained significant after adjustment for multiple testing using either the false discovery rate or by permutation testing. The 2 single nucleotide polymorphisms showed no association in hypertensive subjects (eg, LTA 252A>G, OR, 0.93; 95% CI, 0.84 to 1.03; P=0.17).

Conclusions: These observations may indicate an important role of LTA-mediated inflammatory processes in the pathogenesis of ischemic stroke.
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http://dx.doi.org/10.1161/STROKEAHA.108.524587DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2757095PMC
March 2009

Association of four DNA polymorphisms with acute rejection after kidney transplantation.

Transpl Int 2008 Sep 25;21(9):879-91. Epub 2008 Apr 25.

Department of Nephrology, Hospital de Bellvitge, University of Barcelona, Barcelona, Spain.

Renal transplant outcomes exhibit large inter-individual variability, possibly on account of genetic variation in immune-response mediators and genes influencing the pharmacodynamics/pharmacokinetics of immunosuppressants. We examined 21 polymorphisms from 10 genes in 237 de novo renal transplant recipients participating in an open-label, multicenter study [Cyclosporine Avoidance Eliminates Serious Adverse Renal-toxicity (CAESAR)] investigating renal function and biopsy-proven acute rejection (BPAR) with different cyclosporine A regimens and mycophenolate mofetil. Genes were selected for their immune response and pharmacodynamic/pharmacokinetic relevance and were tested for association with BPAR. Four polymorphisms were significantly associated with BPAR. The ABCB1 2677T allele tripled the odds of developing BPAR (OR: 3.16, 95% CI [1.50-6.67]; P=0.003), as did the presence of at least one IMPDH2 3757C allele (OR: 3.39, 95% CI [1.42-8.09]; P=0.006). BPAR was almost fivefold more likely in patients homozygous for IL-10 -592A (OR: 4.71, 95% CI [1.52-14.55]; P=0.007) and twice as likely in patients with at least one A allele of TNF-alpha G-308A (OR: 2.18, 95% CI [1.08-4.41]; P=0.029). There were no statistically significant interactions between polymorphisms, or the different treatment regimens. Variation in genes of immune response and pharmacodynamic/pharmacokinetic relevance may be important in understanding acute rejection after renal transplant.
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http://dx.doi.org/10.1111/j.1432-2277.2008.00679.xDOI Listing
September 2008

Soluble epoxide hydrolase is a susceptibility factor for heart failure in a rat model of human disease.

Nat Genet 2008 May;40(5):529-37

Max-Delbrück Center for Molecular Medicine, Robert-Rössle-Strasse 10, 13125 Berlin, Germany.

We aimed to identify genetic variants associated with heart failure by using a rat model of the human disease. We performed invasive cardiac hemodynamic measurements in F2 crosses between spontaneously hypertensive heart failure (SHHF) rats and reference strains. We combined linkage analyses with genome-wide expression profiling and identified Ephx2 as a heart failure susceptibility gene in SHHF rats. Specifically, we found that cis variation at Ephx2 segregated with heart failure and with increased transcript expression, protein expression and enzyme activity, leading to a more rapid hydrolysis of cardioprotective epoxyeicosatrienoic acids. To confirm our results, we tested the role of Ephx2 in heart failure using knockout mice. Ephx2 gene ablation protected from pressure overload-induced heart failure and cardiac arrhythmias. We further demonstrated differential regulation of EPHX2 in human heart failure, suggesting a cross-species role for Ephx2 in this complex disease.
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http://dx.doi.org/10.1038/ng.129DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7370537PMC
May 2008

Intercellular adhesion molecule 1 (ICAM1) Lys56Met and Gly241Arg gene variants, plasma-soluble ICAM1 concentrations, and risk of incident cardiovascular events in 23,014 initially healthy white women.

Stroke 2007 Dec 25;38(12):3152-7. Epub 2007 Oct 25.

Donald W. Reynolds Center for Cardiovascular Research, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, 900 Commonwealth Avenue East, Boston, MA 02215, USA.

Background And Purpose: The objective of this study was to examine the association of 2 nonsynonymous intercellular adhesion molecule 1 (ICAM1) gene variants (Lys56Met and Gly241Arg) with baseline plasma soluble ICAM1 concentrations and with risk of total and selected cardiovascular disease (CVD) events in a prospective cohort of 23 014 apparently healthy white American women followed for 10 years. ICAM1 variations have been associated with plasma soluble ICAM1 concentrations and inflammatory conditions, including atherosclerosis. However, to date, no large prospective, genetic-epidemiological data set is available that would allow evaluation of the degree of association of these gene variants with risk of CVD.

Methods: ICAM1 genotypes and baseline plasma soluble ICAM1 concentrations were determined. The primary outcome measure was a composite CVD end point (incident ischemic stroke, myocardial infarction, or death due to ischemic CVD); other measures were incident ischemic stroke, myocardial infarction, and coronary revascularization. During follow-up, 751 total incident CVD events, 187 incident myocardial infarction cases, 203 incident ischemic stroke cases, and 433 coronary revascularization events occurred.

Results: All observed genotype frequencies were in Hardy-Weinberg equilibrium across the whole sample population. We found baseline plasma soluble ICAM1 concentrations to be significantly reduced among carriers of Met56 allele (P<0.0001) and Arg241 allele (P<0.0001) as compared with the respective noncarriers of these variants. However, the polymorphisms tested and the respective haplotypes were neither associated with overall risk nor with risk with risk for selected CVD events regardless of whether analyses were adjusted for traditional CVD risk factors/confounders (all P values >0.10).

Conclusions: In this large prospective study, we found an association of the nonsynonymous gene variants tested with reduced baseline plasma soluble ICAM1 concentrations. However, no evidence was found for an association of the gene variants tested with the overall or selected CVD end points examined, suggesting that these variants may not add useful aids to current risk predictors for early assessment of cardiovascular events.
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http://dx.doi.org/10.1161/STROKEAHA.107.490219DOI Listing
December 2007

C-reactive protein gene variation and type 2 diabetes mellitus: a case-control study.

Atherosclerosis 2008 Apr 27;197(2):931-6. Epub 2007 Sep 27.

Center for Cardiovascular Disease Prevention, Brigham and Women's Hospital and Harvard Medical School, 900 Commonwealth Avenue East, Boston, MA 02215, USA.

Objective: C-reactive protein (CRP) gene variation, in particular an rs2794521 variant was recently associated with type 2 diabetes mellitus (T2DM) in Pima Indians.

Research Design And Methods: The present investigation was conducted to replicate this previous association, and to further examine the potential association of a set of common CRP gene variants with the prevalence of T2DM in a case-control investigation. A total of 629 T2DM cases (476 Whites, and 153 Blacks), and 579 controls (481 Whites, and 98 Blacks) were examined. Seven CRP variants were evaluated: rs3093059, rs2794521, rs3091244, rs1417938, rs1800947, rs1130864, and rs1205.

Results: Using a marker-by-marker logistic regression analysis, adjusting for age, smoking, gender, and body mass index, we found an association of rs3093059 (recessive: OR, 7.01; 95% CI, 1.16-42.22; p=0.03) with T2DM in the white study population, and an association, albeit not statistically significant, of rs2794521 with T2DM in the Black study population. Moreover, further analysis using a haplotype-based analysis showed no evidence for an association of the haplotypes tested with T2DM.

Conclusion: Further studies are needed to examine the possible involvement of C-reactive protein gene variation in the pathogenesis of type 2 diabetes mellitus.
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http://dx.doi.org/10.1016/j.atherosclerosis.2007.08.013DOI Listing
April 2008

Homocysteine, 5,10-methylenetetrahydrofolate reductase 677C>T polymorphism, nutrient intake, and incident cardiovascular disease in 24,968 initially healthy women.

Clin Chem 2007 May 1;53(5):845-51. Epub 2007 Mar 1.

Donald W. Reynolds Center for Cardiovascular Research, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.

Background: Hyperhomocysteinemia has been associated with a higher risk of cardiovascular disease (CVD) in epidemiological studies, but recent trials have failed to show a benefit of lowering homocysteine. To address this apparent paradox, we explored whether interaction between genetic and dietary factors related to homocysteine metabolism contributes to CVD risk.

Methods: We evaluated the associations of homocysteine, methylenetetrahydrofolate reductase (MTHFR) 677C>T genotype, and dietary intake of folate/B-vitamins with subsequent CVD events in 24 968 apparently healthy white American women followed for 10 years. Plasma homocysteine was measured using an enzymatic assay. MTHFR genotype was determined with a multiplex PCR using biotinylated primers.

Results: In unadjusted analyses, homocysteine showed moderately strong linear associations with CVD, with hazard ratios (95% CI) comparing top with bottom quintiles for total CVD of 1.92 (1.55-2.37), myocardial infarction 2.32 (1.52-3.54), and ischemic stroke 2.25 (1.45-3.50), all P(trend) <0.001. These ratios were markedly attenuated after adjusting for traditional risk factors and socioeconomic status to 1.08 (0.86-1.36), P(trend) = 0.12; 1.20 (0.76-1.87), P(trend) = 0.14; and 1.21 (0.75-1.94), P(trend) = 0.50, respectively. Homocysteine was associated with MTHFR genotype (1.4 micromol/L higher homocysteine for TT vs CC, P <0.001) and inversely with intake of folate, vitamin B(2), B(6), and B(12), all P(trend) <0.001. However, there was no association of MTHFR genotype or dietary folate/B-vitamins with CVD. In addition, there were no gene-diet or gene-homocysteine interactions in relation to CVD.

Conclusions: In this large-scale prospective study, the association of homocysteine with CVD was markedly attenuated after adjusting for risk factors and was not modified by MTHFR 677C>T or intake of folate or B-vitamins.
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http://dx.doi.org/10.1373/clinchem.2006.083881DOI Listing
May 2007