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Genetic polymorphisms of a novel vascular susceptibility gene, Ninjurin2 (NINJ2), are associated with a decreased risk of Alzheimer's disease.

ABSTRACT: BACKGROUND: Accumulated evidences have shown that vascular risk factors, e.g., hypertension, diabetes mellitus and hyperlipidemia, may be related to the risk of dementia. This study investigated the association between genetic polymorphisms of a vascular susceptibility gene, Ninjurin2 (NINJ2), and the risk of dementia, which has not been explored previously. METHODS: A total of 275 Alzheimer's disease (AD) patients and 119 vascular dementia (VaD) patients aged 50 or older were recruited from three teaching hospitals from 2007 to 2010. Healthy controls (n?=?423) with the same age of cases were recruited from the health checkup and volunteers worked at the hospital during the same time period. Five common (frequency >5%) haplotype-tagging single nucleotide polymorphisms (htSNPs) in NINJ2 were genotyped to test for the association between sequence variants of NINJ2 and dementia risk, and how vascular risk factors modify this association. RESULTS: Homozygosity of two NINJ2 SNPs was significantly associated with a decreased risk of AD [rs11833579: adjusted odds ratio (AOR)?=?0.43; 95% confidence interval (CI)=?0.23-0.80; rs12425791: AOR=?0.33, 95% CI=?0.12-0.96]. Five common haplotypes (cumulative frequency=?97%) were identified. The global test for the association between NINJ2 haplotypes and AD was significant (p?=?0.03). Haplotype CAGGA was significantly associated with a decreased risk of AD (AOR=?0.32, 95% CI=?0.11-0.94). No associations were observed for VaD. CONCLUSION: Inherited polymorphisms of the vascular susceptibility gene NINJ2 were associated with AD risk.

SUBMITTER: Lin KP

PROVIDER: S-EPMC3108950 | biostudies-literature | 2011

REPOSITORIES: biostudies-literature

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Genetic polymorphisms of a novel vascular susceptibility gene, Ninjurin2 (NINJ2), are associated with a decreased risk of Alzheimer's disease.

Lin Kun-Pei KP Chen Shih-Yuan SY Lai Liang-Chuan LC Huang Yi-Ling YL Chen Jen-Hau JH Chen Ta-Fu TF Sun Yu Y Wen Li-Li LL Yip Ping-Keung PK Chu Yi-Min YM Chen Wei J WJ Chen Yen-Ching YC

PloS one 20110606 6

<h4>Background</h4>Accumulated evidences have shown that vascular risk factors, e.g., hypertension, diabetes mellitus and hyperlipidemia, may be related to the risk of dementia. This study investigated the association between genetic polymorphisms of a vascular susceptibility gene, Ninjurin2 (NINJ2), and the risk of dementia, which has not been explored previously.<h4>Methods</h4>A total of 275 Alzheimer's disease (AD) patients and 119 vascular dementia (VaD) patients aged 50 or older were recru ...[more]

PMID: 21674003

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Project description:Identification of genetic polymorphisms causing increased antibiotic resistance in bacterial pathogens traditionally has proceeded from observed phenotype to defined mutant genotype. The availability of large collections of microbial genome sequences that lack antibiotic susceptibility metadata provides an important resource and opportunity to obtain new information about increased antimicrobial resistance by a reverse genotype-to-phenotype bioinformatic and experimental workflow. We analyzed 26,465 genome sequences of Streptococcus pyogenes, a human pathogen causing 700 million infections annually. The population genomic data identified amino acid changes in penicillin-binding proteins 1A, 1B, 2A, and 2X with signatures of evolution under positive selection as potential candidates for causing decreased susceptibility to β-lactam antibiotics. Construction and analysis of isogenic mutant strains containing individual amino acid replacements in penicillin-binding protein 2X (PBP2X) confirmed that the identified residues produced decreased susceptibility to penicillin. We also discovered the first chimeric PBP2X in S. pyogenes and show that strains containing it have significantly decreased β-lactam susceptibility. The novel integrative reverse genotype-to-phenotype strategy presented is broadly applicable to other pathogens and likely will lead to new knowledge about antimicrobial agent resistance, a massive public health problem worldwide. IMPORTANCE The recent demonstration that naturally occurring amino acid substitutions in Streptococcus pyogenes PBP2X are sufficient to cause severalfold reduced susceptibility to multiple β-lactam antibiotics in vitro raises the concern that these therapeutic agents may become compromised. Substitutions in PBP2X are common first-step mutations that, with the incremental accumulation of additional adaptive mutations within the PBPs, can result in high-level resistance. Because β-lactam susceptibility testing is not routinely performed, the nature and extent of such substitutions within the PBPs of S. pyogenes are poorly characterized. To address this knowledge deficit, polymorphisms in the PBPs were identified among the most comprehensive cohort of S. pyogenes genome sequences investigated to date. The mutational processes and selective forces acting on the PBPs were assessed to identify specific substitutions likely to influence β-lactam susceptibility and to evaluate factors posited to be impediments to resistance emergence.

Dataset Information

Genetic polymorphisms of a novel vascular susceptibility gene, Ninjurin2 (NINJ2), are associated with a decreased risk of Alzheimer's disease.

Publications

Genetic polymorphisms of a novel vascular susceptibility gene, Ninjurin2 (NINJ2), are associated with a decreased risk of Alzheimer's disease.

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