Since, as an exploratory study, we did not correct for multiple comparisons, definitive interpretation of these findings will require confirmation in larger cohort studies. Nevertheless, our findings support multiple pathways being involved in host response to IPD. Recent studies also suggest that additional genes in the toll-like receptor-signaling pathway may influence response to IPD. Furthermore, the collectin MBL2 had variants overrepresented in pneumococcal bacteremia and meningitis, but not for overall IPD. This suggests the possibility of syndrome-specific host genetic associations, but our study was underpowered to definitively evaluate this. For this analysis, we took an indirect association approach by selecting and genotyping SNPs that are either causative SNPs or in LD with the causative SNP. The latter situation most likely applies to the majority of SNPs found associated with IPD in this study, as 18 of the 27 associated SNPs are located in introns. Furthermore, of the four SFTPD variants associated with IPD in either EA and/or AA , all are intronic. Notably, in AMN107 Src-bcr-Abl inhibitor SeattleSNPs EA, rs17886286 and rs1998374 are in complete or high LD with rs3088308, a coding INCB18424 JAK inhibitor non-synonymous SNP, while in SeattleSNPs AA, these SNPs have little to no LD with rs3088308 and are not associated with IPD in AA. The two SFTPD variants that are associated with IPD in AA are in moderate LD with a different coding non-synonymous SNP, rs4469829, which is monomorphic in EA. Furthermore, SFTPD variant rs721917, a non-synonymous SNP known to reduce serum levels of SP-D in EA, is in LD with rs1998374 in AA but not EA. Thus, differences in LD patterns between ancestral populations may help to explain the disparate signals observed in EA compared to AA. Our primary goal was to assess the feasibility of cross-linking surveillance data with an nDBS repository to perform tagSNP genomic studies, and toward this end we were highly successful: 82% of surveillance cases were linked to an nDBS, and 88% of samples successfully genotyped. Several key issues associated with this experience deserve emphasis. First, the completeness of IPD case surveillance in ABCs through use of active surveillance methods and routine audits of laboratory records combined with the overall low incidence of IPD in the general population support our assumption that controls were at low risk of having had IPD outside the surveillance time-period. Second, efficient linking of surveillance cases to nDBS samples was critical to minimize bias, but this linkage depends on consent requirements for nDBS use, which differ by state and continue to evolve.

MPO and IgG are products of neutrophils and B cells respectively, cells types supposedly to not be primarily affect by the interference with CCR1 and CCR5 EX 527 promoted by met-RANTES. In accordance with such hypothesis, 5 mg dose of met- RANTES treatment reduced the number of both Gr1+ and CD19+ cells in the infected periodontal tissues. In addition, it is important to mention that the expression of the antimicrobial enzyme iNOS was also greatly diminished by the 5 mg met- RANTES dose. Taken together, the reduction in the innate and adaptive antimicrobial LDN-193189 in vivo response is possible responsible for the increase in the bacterial load found in periodontal tissues. Accordingly, MPO, iNOS and IgG are supposed to contribute to the killing of periodontal bacteria. Therefore, it is possible to conclude that an excessive downregulation of host response by the high met-RANTES doses significantly impair host response overcoming the protective effect presented by lower doses. In fact, the significant increase in serum CRP levels reinforces the compromised host response presented by mice treated with high met-RANTES doses. In this setting, an important question refers to nature and intensity of host response required to assure a proper defense against the periodontopathogens. Since a series of therapeutic proposals targets the modulation of host response, the exact determination of the leukocyte subsets, cytokines and antimicrobial factors really involved in the control of periodontal infection is fundamental to direct future host-targeted therapies. When the results presented here are compared with a previous study of our group, were a mice strain selected for minimal inflammatory response was evaluated , interesting information arise. AIRmin strain and the C57BL/6 mice treated with 5 mg met-RANTES dose present similar inflammatory and bone loss scores, and also similar production of IL-1b and TNF-a. However, AIRmin strain efficiently controls the experimental periodontal infection, a finding associated with higher IFN-c production than met-RANTES-treated mice. Also, while MPO and iNOS levels were similar in AIRmin strain and met- RANTES-treated mice, 5 mg met-RANTES treatment resulted in lower IgG response than observed in AIRmin strain. In accordance with previous studies , these results point to important roles of IFN-c and antibody production in the control of periodontal infection. Therefore, it is possible to suggest that immunoregulatory strategies aimed to control PD should not interfere with these mediators.