Sequence variation in the CHAT locus shows no association with late-onset Alzheimer's disease

There is substantial evidence for a susceptibility gene for late-onset Alzheimer's disease (AD) on chromosome 10. One of the characteristic features of AD is the degeneration and dysfunction of the cholinergic system. The genes encoding choline acetyltransferase (ChAT) and its vesicular transporter (VAChT), CHAT and SLC18A3 respectively, map to the linked region of chromosome 10 and are therefore both positional and obvious functional candidate genes for late-onset AD. We have screened both genes for sequence variants and investigated each for association with late-onset AD in up to 500 late-onset AD cases and 500 control DNAs collected in the UK. We detected a total of 17 sequence variants. Of these, 14 were in CHAT, comprising three non-synonymous variants (D7N in the S exon, A120T in exon 5 and L243F in exon 8), one synonymous change (H547H), nine single-nucleotide polymorphisms in intronic, untranslated or promoter regions, and a variable number of tandem repeats in intron 7. Three non-coding SNPs were detected in SLC18A3. None demonstrated any reproducible association with late-onset AD in our samples. Levels of linkage disequilibrium were generally low across the CHAT locus but two of the coding variants, D7N and A120T, proved to be in complete linkage disequilibrium.

Antioxidants and oxidative stress in BAL fluid of atopic asthmatic children

Earlier studies in adults have indicated that increased oxidative stress may occur in the blood and airways of asthmatic subjects. Therefore the aim of this study was to compare the concentrations of antioxidants and protein carbonyls in bronchoalveolar lavage fluid of clinically stable atopic asthmatic children (AA, n = 78) with our recently published reference intervals for nonasthmatic children (C, n = 124). Additionally, lipid peroxidation products (malondialdehyde) in bronchoalveolar lavage fluid and several antioxidants in plasma were determined. Bronchoalveolar lavage concentrations (median and interquartile range) of ascorbate [AA: 0.433 (0.294-0.678) versus C: 0.418 (0.253-0.646) micromol/L], urate [AA: 0.585 (0.412-0.996) versus C: 0.511 (0.372-0.687) micromol/L], alpha-tocopherol [AA: 0.025 (0.014-0.031) versus C: 0.017 (0.017-0.260) micromol/L], and oxidized proteins as reflected by protein carbonyls [AA: 1.222 (0.970-1.635) versus C: 1.243 (0.813-1.685) nmol/mg protein] were similar in both groups (p > 0.05 in all cases). The concentration of protein carbonyls correlated significantly with the number of eosinophils, mast cells, and macrophages in AA children only. Concentrations of oxidized proteins and lipid peroxidation products (malondialdehyde) correlated significantly in AA children (r = 0.614, n = 11, p = 0.044). Serum concentrations of ascorbate, urate, retinol, alpha-tocopherol, beta-carotene, and lycopene were similar in both groups whereas alpha-carotene was significantly reduced in asthmatics. Overall, increased bronchoalveolar lavage eosinophils indicate ongoing airway inflammation, which may increase oxidatively modified proteins as reflected by increased protein carbonyl concentrations.