Further analysis of previously implicated linkage regions for Alzheimer's disease in affected relative pairs

Background Genome-wide linkage studies for Alzheimer's disease have implicated several chromosomal regions as potential loci for susceptibility genes. Methods In the present study, we have combined a selection of affected relative pairs (ARPs) from the UK and the USA included in a previous linkage study by Myers et al. (Am J Med Genet, 2002), with ARPs from Sweden and Washington University. In this total sample collection of 397 ARPs, we have analyzed linkage to chromosomes 1, 9, 10, 12, 19 and 21, implicated in the previous scan. Results The analysis revealed that linkage to chromosome 19q13 close to the APOE locus increased considerably as compared to the earlier scan. However, linkage to chromosome 10q21, which provided the strongest linkage in the previous scan could not be detected. Conclusion The present investigation provides yet further evidence that 19q13 is the only chromosomal region consistently linked to Alzheimer's disease

Increased mRNA Levels of TCF7L2 and MYC of the Wnt Pathway in Tg-ArcSwe Mice and Alzheimer's Disease Brain

Several components in the Wnt pathway, including β-catenin and glycogen synthase kinase 3 beta, have been implied in AD pathogenesis. Here, mRNA brain levels from five-month-old tg-ArcSwe and nontransgenic mice were compared using Affymetrix microarray analysis. With surprisingly small overall changes, Wnt signaling was the most affected pathway with altered expression of nine genes in tg-ArcSwe mice. When analyzing mRNA levels of these genes in human brain, transcription factor 7-like 2 (TCF7L2) and v-myc myelocytomatosis viral oncogene homolog (MYC), were increased in Alzheimer's disease (AD) (P < .05). Furthermore, no clear differences in TCF7L2 and MYC mRNA were found in brains with frontotemporal lobar degeneration, suggesting that altered regulation of these Wnt-related genes could be specific to AD. Finally, mRNA levels of three neurogenesis markers were analyzed. Increased mRNA levels of dihydropyrimidinase-like 3 were observed in AD brain, suggesting that altered Wnt pathway regulation may signify synaptic rearrangement or neurogenesis

Increased mRNA Levels of TCF7L2 and MYC of the Wnt Pathway in Tg-ArcSwe Mice and Alzheimer's Disease Brain

Several components in the Wnt pathway, including β-catenin and glycogen synthase kinase 3 beta, have been implied in AD pathogenesis. Here, mRNA brain levels from five-month-old tg-ArcSwe and nontransgenic mice were compared using Affymetrix microarray analysis. With surprisingly small overall changes, Wnt signaling was the most affected pathway with altered expression of nine genes in tg-ArcSwe mice. When analyzing mRNA levels of these genes in human brain, transcription factor 7-like 2 (TCF7L2) and v-myc myelocytomatosis viral oncogene homolog (MYC), were increased in Alzheimer's disease (AD) (P < .05). Furthermore, no clear differences in TCF7L2 and MYC mRNA were found in brains with frontotemporal lobar degeneration, suggesting that altered regulation of these Wnt-related genes could be specific to AD. Finally, mRNA levels of three neurogenesis markers were analyzed. Increased mRNA levels of dihydropyrimidinase-like 3 were observed in AD brain, suggesting that altered Wnt pathway regulation may signify synaptic rearrangement or neurogenesis

Does APOE explain the linkage of Alzheimer's disease to chromosome 19q13?

We have studied the impact of the apolipoprotein E gene (APOE) on the chromosome 19 linkage peak from an analysis of sib-pairs affected by Alzheimer’s disease. We genotyped 417 affected sib-pairs (ASPs) collected in Sweden and Norway (SWE), the UK and the USA for 10 microsatellite markers on chromosome 19. The highest Zlr (3.28, chromosome-wide P-value 0.036) from the multipoint linkage analysis was located approximately 1 Mb from APOE, at marker D19S178. The linkage to chromosome 19 was well explained by APOE in the whole sample as well as in the UK and USA subsamples, as identity by descent (IBD) increased with the number of ε4 alleles in ASPs. There was a suggestion from the SWE subsample that linkage was higher than would be expected from APOE alone, although the test for this did not reach formal statistical significance. There was also a significant age at onset (aao) effect on linkage to chromosome 19q13 in the whole sample, which manifested itself as increased IBD sharing in relative pairs with lower mean aao. This effect was partially, although not completely, explained by APOE. The aao effect varied considerably between the different subsamples, with most of the effect coming from the UK sample. The other samples showed smaller effects in the same direction, but these were not significant

The methionine synthase reductase 66A>G polymorphism is a maternal risk factor for spina bifida.

Contains fulltext : 51023.pdf (publisher's version ) (Closed access)The methionine synthase reductase (MTRR) enzyme restores methionine synthase (MTR) enzyme activity and therefore plays an essential role in homocysteine remethylation. In some studies, the 66A>G polymorphism in the MTRR gene was associated with increased neural tube defect (NTD) risk. Using a case-control design, we studied the association between the MTRR 66A>G polymorphism and spina bifida risk in 121 mothers, 109 spina bifida patients, 292 control women, and 234 pediatric controls. Possible interactions between the MTRR 66A>G variant and the MTR 2756A>G polymorphism, the MTHFR 677C>T variant, plasma vitamin B12, and plasma methylmalonic acid (MMA) levels were examined in the 121 mothers and 292 control women. Meta-analyses were conducted to set the results of the case-control study in the context of eligible literature on the relation between the MTRR 66A>G variant and NTD risk. Finally, a transmission disequilibrium test was performed for 82 complete mother-father-child triads to test for preferential transmission of the MTRR risk allele. In our case-control study, the MTRR 66A>G polymorphism had no influence on spina bifida risk in children [odds ratio (OR) 0.6, 95% confidence interval (CI) 0.4-1.1]. The MTRR 66GG genotype increased maternal spina bifida risk by 2.1-fold (OR 2.1, 95% CI 1.3-3.3). This risk became more pronounced in combination with the MTHFR 677TT genotype (OR 4.0, 95% CI 1.3-12.5). Moreover, we demonstrate a possible interaction between the MTRR 66GG genotype and high plasma MMA levels (OR 5.5, 95% CI 2.2-13.5). The meta-analyses demonstrated that the maternal MTRR 66GG genotype was associated with an overall 55% (95% CI 1.04-2.30) increase in NTD risk and that the MTRR 66GG genotype did not increase NTD risk in children (OR 0.96, 95% CI 0.46-2.01). These data show that the MTRR 66GG genotype is a maternal risk factor for spina bifida especially when intracellular vitamin B12 status is low

SARS‐CoV‐2‐specific humoral and cellular immunity persists through 9 months irrespective of COVID‐19 severity at hospitalisation

Objectives Humoral and cellular immunity to SARS-CoV-2 following COVID-19 will likely contribute to protection from reinfection or severe disease. It is therefore important to characterise the initiation and persistence of adaptive immunity to SARS-CoV-2 amidst the ongoing pandemic. Methods Here, we conducted a longitudinal study on hospitalised moderate and severe COVID-19 patients from the acute phase of disease into convalescence at 5 and 9 months post-symptom onset. Utilising flow cytometry, serological assays as well as B cell and T cell FluoroSpot assays, we assessed the magnitude and specificity of humoral and cellular immune responses during and after human SARS-CoV-2 infection. Results During acute COVID-19, we observed an increase in germinal centre activity, a substantial expansion of antibody-secreting cells and the generation of SARS-CoV-2-neutralising antibodies. Despite gradually decreasing antibody levels, we show persistent, neutralising antibody titres as well as robust specific memory B cell responses and polyfunctional T cell responses at 5 and 9 months after symptom onset in both moderate and severe COVID-19 patients. Conclusion Our findings describe the initiation and, importantly, persistence of cellular and humoral SARS-CoV-2-specific immunological memory in hospitalised COVID-19 patients long after recovery, likely contributing towards protection against reinfection.Medicin