Late-onset Alzheimer's disease (LOAD) is a multifactorial neurodegenerative disorder that corresponds to most Alzheimer's disease (AD) cases. Inflammation is frequently related to AD, whereas microglial cells are the major phagocytes in the brain and mediate the removal of Aβ peptides. Microglial cell dsyregulation might contribute to the formation of amyloid plaques, a hallmark of AD. Genome-wide association studies have reported genetic loci associated with the inflammatory pathway involved in AD. Among them, rs3865444 CD33, rs3764650 ABCA7, rs6656401 CR1, and rs610932 MS4A6A variants in microglial genes are associated with LOAD. These variants are proposed to participate in the clearance of Aβ peptides. However, their association with LOAD was not validated in all case-control studies. Thus, the present work aimed to assess the involvement of CD33 (rs3865444), ABCA7 (rs3764650), CR1 (rs6656401), and MS4A6A (rs610932) with LOAD in a sample from southeastern Brazil. The genotype frequencies were assessed in 79 AD patients and 145 healthy elders matched for sex and age. We found that rs3865444 CD33 acts as a protective factor against LOAD. These results support a role for the inflammatory pathway in LOAD.

Genome-wide association studies (GWAS) have associated several genetic variants with late-onset Alzheimer's disease (LOAD), a neurodegenerative disease. Among those, rs3764650 ABCA7, rs6656401 CR1, and rs744373 BIN1 were associated as risk factors for LOAD, while rs11136000 CLU and rs610932 MS4A6A were protective. Recently, several case-control studies have investigated the association of these polymorphisms with AD. However, not all meta-analyses analyzed these variants across different ethnic groups. Therefore, we performed an updated meta-analysis of rs3764650 ABCA7, rs6656401 CR1, rs744373 BIN1, rs11136000 CLU, and rs610932 MS4A6A variants associated with LOAD, considering different ethnic populations. We utilized samples from 38 articles, comprising a total of 24,771 patients and 35,324 controls obtained through the PubMed database. Odds ratios (ORs) with 95% confidence intervals (CI) for polymorphisms were calculated by allelic comparison as an additive genetic model. We validated the risk for LOAD with BIN1 (rs744373), CR1 (rs6656401), and ABCA7 (rs376465), as well as the protective association for MS4A6A (rs610932) and CLU (rs11136000) variants.

ABSTRACT. Osteogenesis imperfecta (OI) is a genetic disease characterized by bone deformities and fractures. Most cases are caused by autosomal dominant mutations in the type I collagen genes COL1A1 and COL1A2; however, an increasing number of recessive mutations in other genes have been reported. The LEPRE1, CRTAP, and PPIB genes encode proteins that form the P3H1/CRTAP/CypB complex, which is responsible for posttranslational modifications of type I collagen. In general, mutations in these genes lead to severe and lethal phenotypes of recessive OI. Here, we describe sixteen genetic variations detected in LEPRE1, CRTAP, and PPIB from 25 Brazilian patients with OI. Samples were screened for mutations on single-strand conformation polymorphism gels and variants were determined by automated sequencing. Seven variants were detected 15849 P3H1/CRTAP/CyPB and osteogenesis imperfecta ©FUNPEC-RP www.funpecrp.com.br Genetics and Molecular Research 14 (4): 15848-15858 (2015) in patients but were absent in control samples. LEPRE1 contained the highest number of variants, including the previously described West African allele (c.1080+1G>T) found in one patient with severe OI as well as a previously undescribed p.Trp675Leu change that is predicted to be disease causing. In CRTAP, one patient carried the c.558A>G homozygous mutation, predicted as disease causing through alteration of a splice site. Genetic variations detected in the PPIB gene are probably not pathogenic due to their localization or because of their synonymous effect. This study enhances our knowledge about the mutational pattern of the LEPRE1, CRTAP, and PPIB genes. In addition, the results strengthen the proposition that LEPRE1 should be the first gene analyzed in mutation detection studies in patients with recessive OI.

Osteogenesis Imperfecta (OI) is a heterogeneous genetic disorder characterized by bone fragility and fracture. Mutations in 20 distinct genes can cause OI, and therefore, the genetic diagnosis of OI is frequently difficult to obtain because of the great number of genes that can be related with this disease. Studies that report the most frequently mutated genes in OI patients can help to improve molecular strategies for diagnosis of the disease. In order to characterize the mutation profile of OI in Brazilian patients, we analyzed 30 unrelated patients through SSCP screening, NGS gene panel, and/or Sanger sequencing for the 11 most frequently mutated genes in the database of mutations, including COL1A1 , COL1A2, P3H1 , CRTAP , PPIB , SERPINH1 , SERPINF1 , FKBP10, SP7, WNT1 and IFITM5 . Disease-causing variants were identified in COL1A1 , COL1A2 , FKBP10, P3H1, and IFITM5 . A total of 28 distinct mutations were identified, including seven novel changes. Our data show that the analysis of these five genes is able to detect at least 95% of causative mutations in OI disorder from Brazilian population. However, it has to be taken into considerations that distinct populations can have different frequencies of disease-causing variants. Hence, it is important to replicate this study in other groups.

ABSTRACT. Osteogenesis imperfecta (OI) is a heterogeneous disorder that causes fragility, deformity, and fractures in bones. A large number of genes that are associated with the disease have been identified in the last decade; this makes the genetic diagnosis of OI more difficult. To improve our knowledge of the genetic mutation profile in OI we used single-stranded conformation polymorphism screening and automated sequencing to investigate the SERPINH1, FKBP10, and SERPINF1 genes, which are related to recessive OI, in 23 unrelated Brazilian patients. Nine rare changes and four common polymorphisms were detected. Most changes were benign genetic variants. In general, changes in the SERPINH1 and SERPINF1 genes were synonymous polymorphisms or missense changes located in non-coding regions. A pathogenic change was found in the FKBP10 gene. The characterization of mutations related to OI in distinct populations can improve our knowledge of the genetic aspects of OI and help us develop molecular strategies for the diagnosis of the disease.