No association between the alpha2-macroglobulin (A2M) deletion and Alzheimer's disease, and no change in A2M mRNA, protein, or protein expression

A polymorphism consisting of a deletion near the 5' splice site of exon 18 on the alpha2-macroglobulin (A2M) gene (A2M-2) has been suggested to be associated with Alzheimer's disease (AD) in family-based studies. We studied the A2M-2 allele together with the ApoE alleles in a large series on patients with AD (n = 449) and age-matched controls (n = 349). Neuropathologically confirmed diagnoses were available in 199 cases (94 AD and 107 control cases). We found no increase in A2M-2 genotype or allele frequencies in AD (27.5% and 14.6%) versus controls (26.4% and 14.9%). In contrast, a marked increase (p < 0.0001) in ApoE epsilon4 genotype or allele frequencies was found in AD (66.6% and 41.2%) as compared with controls (29.8% and 16.5%), suggesting sufficient statistical power in our sample. No relation was found between the A2M-2 and the ApoE epsilon4 allele. No change in A2M exon 17-18 mRNA size or sequence or A2M protein size was found in cases carrying the A2M-2 deletion, suggesting that there is no biological consequences of the A2M intronic deletion. No change in A2M protein level in cerebrospinal fluid was found in AD, suggesting that the A2M-2 allele does not effect the A2M protein expression in the brain. The lack of an association between the A2M-2 allele and AD in the present study, and the lack of abnormalities in the A2M mRNA or protein suggest that the A2M-2 allele is not associated with AD

Identifying mutation regions for closely related individuals without a known pedigree

<p>Abstract</p> <p>Background</p> <p>Linkage analysis is the first step in the search for a disease gene. Linkage studies have facilitated the identification of several hundred human genes that can harbor mutations leading to a disease phenotype. In this paper, we study a very important case, where the sampled individuals are closely related, but the pedigree is not given. This situation happens very often when the individuals share a common ancestor 6 or more generations ago. To our knowledge, no algorithm can give good results for this case.</p> <p>Results</p> <p>To solve this problem, we first developed some heuristic algorithms for haplotype inference without any given pedigree. We propose a model using the parsimony principle that can be viewed as an extension of the model first proposed by Dan Gusfield. Our heuristic algorithm uses Clark’s inference rule to infer haplotype segments.</p> <p>Conclusions</p> <p>We ran our program both on the simulated data and a set of real data from the phase II HapMap database. Experiments show that our program performs well. The recall value is from 90% to 99% in various cases. This implies that the program can report more than 90% of the true mutation regions. The value of precision varies from 29% to 90%. When the precision is 29%, the size of the reported regions is three times that of the true mutation region. This is still very useful for narrowing down the range of the disease gene location. Our program can complete the computation for all the tested cases, where there are about 110,000 SNPs on a chromosome, within 20 seconds.</p