Dysfunctional innate immune responsiveness to Porphyromonas gingivalis lipopolysaccharide in diabetes.

INTRODUCTION: Type 1 diabetes is a major risk factor for the development of severe periodontal disease. As diabetes increases in severity, so does the susceptibility to and severity of periodontitis. People with diabetes who have periodontal disease have a harder time maintaining healthy blood glucose levels. Macrophages play an important role in both diabetes and periodontitis. Previous research comparing bone-marrow-derived macrophages (BM-Mvarphi) from diabetic non-obese diabetic (NOD) mice and control mice illustrates that a dysregulation in cytokine, Toll-like receptor (TLR) expression, and cell signaling occurs in the diabetic state. METHODS: This study examines the effect of chronic hyperglycemia on BM-Mvarphi TLR expression and activation, cell signaling, cytokine production, and phagocytic function in the diabetic state, when challenged with the periodontal stimulus Porphyromonas gingivalis lipopolysaccharide (LPS) to further understand how diabetes and associated hyperglycemia may contribute to the increased susceptibility of people with diabetes to periodontitis. RESULTS: When BM-Mvarphi, obtained from diabetic NOD mice, are stimulated with P. gingivalis LPS under hyperglycemic conditions the following changes occur: reduced messenger RNA expression and cell surface expression of TLR2, reduced messenger RNA expression and protein production of tumor necrosis factor-alpha, reduced signal transduction, and a reduction in phagocytic function. All the activity of BM-Mvarphi from diabetic NOD mice was restored when differentiation and stimulation occurred under normoglycemic conditions. DISCUSSION: Diabetic patients in a hyperglycemic state may be generating macrophages that are inherently immunocompromised, contributing to an environment allowing periodontal infections to flourish. As a consequence, people with diabetes who maintain proper control of blood sugar levels may experience an increased immunological benefit when challenged with a periodontal infection.

SNPing away at complex diseases: analysis of single-nucleotide polymorphisms around APOE in Alzheimer disease.

There has been great interest in the prospects of using single-nucleotide polymorphisms (SNPs) in the search for complex disease genes, and several initiatives devoted to the identification and mapping of SNPs throughout the human genome are currently underway. However, actual data investigating the use of SNPs for identification of complex disease genes are scarce. To begin to look at issues surrounding the use of SNPs in complex disease studies, we have initiated a collaborative SNP mapping study around APOE, the well-established susceptibility gene for late-onset Alzheimer disease (AD). Sixty SNPs in a 1.5-Mb region surrounding APOE were genotyped in samples of unrelated cases of AD, in controls, and in families with AD. Standard tests were conducted to look for association of SNP alleles with AD, in cases and controls. We also used family-based association analyses, including recently developed methods to look for haplotype association. Evidence of association (P

Analysis of association at single nucleotide polymorphisms in the APOE region.

The discussion of the prospects of using a dense map of single nucleotide polymorphisms (SNPs) to identify disease genes with association analysis has been extensive. However, there is little empiric evidence to support this strategy. To begin to examine the practical issues surrounding this methodology, we identified 10 SNPs in the region immediately surrounding the apolipoprotein E locus (APOE), an established susceptibility gene for Alzheimer disease. Our goal was to examine patterns of allelic association to begin to investigate the question of whether APOE could have been identified using SNPs. Our strongest evidence of association was at the 2 SNPs immediately flanking APOE.

Linkage of a gene causing familial focal segmental glomerulosclerosis to chromosome 11 and further evidence of genetic heterogeneity.

Focal segmental glomerulosclerosis (FSGS) is a pathological entity characterized by proteinuria, nephrotic syndrome, and the progressive loss of renal function. It is a common cause of end-stage renal disease (ESRD). Recently, familial forms of FSGS have been identified. Two families with autosomal dominant FSGS were evaluated for linkage using 351 genomic microsatellite markers. Linkage, multipoint analysis, and tests for heterogeneity were performed on the subsequent results. In addition, three small families were used for haplotype analysis. Evidence for linkage was found on chromosome 11q21-q22 for the largest family, with a maximum lod score of 9.89. The gene is currently localized to an 18-cM area between flanking markers D11S2002 and D11S1986. The disease in a second family was not linked to this locus or to a previously described locus on chromosome 19q13. There were no shared haplotypes among affected individuals in the three smaller families. Our findings demonstrate that genetic heterogeneity is prevalent in FSGS in that at least three genes cause the FSGS phenotype. Identification of the genes that cause familial FSGS will provide valuable insights into the molecular basis and pathophysiology of FSGS.

Confirmation of a second locus for CMT2 and evidence for additional genetic heterogeneity.

The Charcot-Marie-Tooth (CMT) neuropathies are a group of disorders exhibiting neurophysical, pathological and genetic heterogeneity. CMT2 is a diagnostic subtype of this group of disorders characterized by variable expression and age-of-onset and normal or slightly diminished nerve conduction velocities. Previously, linkage and heterogeneity had been reported in CMT2 with linked families localizing to chromosome 1p (CMT2A). Recently a second CMT2 locus has been described on chromosome 7 in a single large CMT2 family (CMT2D). We have performed pedigree linkage analysis on 15 CMT2 families (N = 371 individuals, 106 affected family members) and have confirmed linkage to chromosome 7. Furthermore, using both admixture and multipoint linkage analysis we show conclusive evidence for additional heterogeneity within this clinical subtype with evidence of families that exclude linkage to both the CMT2D and CMT2A regions. In addition, unlike the previous report we found no obvious consistent clinical differences between the linked family types.