The PF4/PPBP/CXCL5 Gene Cluster Is Associated with Periodontitis

被引:31
作者
Shusterman, A. [1 ]
Munz, M. [2 ,3 ]
Richter, G. [2 ]
Jepsen, S. [4 ]
Lieb, W. [5 ]
Krone, B. [6 ]
Hoffman, P. [7 ,8 ]
Laudes, M. [9 ]
Wellmann, J. [10 ]
Berger, K. [10 ]
Kocher, T. [11 ]
Offenbacher, S. [12 ]
Divaris, K. [13 ,14 ]
Franke, A. [15 ]
Schreiber, S. [9 ,15 ]
Dommisch, H. [2 ]
Weiss, E. [16 ]
Schaefer, A. S. [2 ]
Houri-Haddad, Y. [1 ]
Iraqi, F. A. [17 ]
机构
[1] Hebrew Univ Jerusalem, Dept Prosthodont, Hadassah Fac Dent Med, Jerusalem, Israel
[2] Charite, Inst Dent & Craniofacial Sci, Dept Periodontol & Synopt Med, Berlin, Germany
[3] Univ Med Ctr Schleswig Holstein, Inst Integrat & Expt Genom, Campus Lubeck, Lubeck, Germany
[4] Univ Bonn, Dept Periodontol Operat & Prevent Dent, Bonn, Germany
[5] Univ Kiel, Inst Epidemiol, Biobank Popgen, Kiel, Germany
[6] Univ Clin Essen, Inst Med Informat Biometry & Epidemiol, Essen, Germany
[7] Univ Bonn, Inst Human Genet, Bonn, Germany
[8] Univ Hosp Basel, Dept Biomed, Germany & Human Genom Res Grp, Basel, Switzerland
[9] Univ Clin Schleswig Holstein, Clin Internal Med, Kiel, Germany
[10] Univ Munster, Inst Epidemiol & Social Med, Munster, Germany
[11] Univ Med Greifswald, Dent Sch, Dept Restorat Dent Periodontol Endodontol Prevent, Unit Periodontol, Greifswald, Germany
[12] Univ North Carolina Chapel Hill, Sch Dent, Dept Periodontol, Chapel Hill, NC USA
[13] Univ North Carolina Chapel Hill, Sch Dent, Dept Pediat Dent, Chapel Hill, NC USA
[14] Univ North Carolina Chapel Hill, Gillings Sch Global Publ Hlth, Dept Epidemiol, Chapel Hill, NC USA
[15] Univ Kiel, Inst Clin Mol Biol, Kiel, Germany
[16] Tel Aviv Univ, Maurice & Gabriella Goldschleger Sch Dent Med, Sackler Fac Med, Tel Aviv, Israel
[17] Tel Aviv Univ, Dept Clin Microbiol & Immunol, Sackler Fac Med, IL-69978 Tel Aviv, Israel
基金
以色列科学基金会; 美国国家卫生研究院;
关键词
QTL mapping; association; genetic; alveolar bone loss; mice model; GWAS; GENOME-WIDE ASSOCIATION; RISK-FACTORS; DISEASE; SUSCEPTIBILITY; EXPRESSION; STATES;
D O I
10.1177/0022034517706311
中图分类号
R78 [口腔科学];
学科分类号
1003 ;
摘要
Periodontitis is a common dysbiotic inflammatory disease with an estimated heritability of 50%. Due to the limited sample size of available periodontitis cohorts and the underlying trait heterogeneity, genome-wide association studies (GWAS) of chronic periodontitis (CP) have been unsuccessful in discovering susceptibility factors. A strategy that combines agnostic GWAS with a well-powered candidate-gene approach has the potential to discover novel loci. We combined RNA-seq data from gingival tissues with quantitative trait loci (QTLs) that were identified in a F-2-cross of mice resistant and susceptible to infection with oral bacterial pathogens. Four genes, which were located within the mapped QTLs, showed differential expression. The chromosomal regions across the human orthologous were interrogated for putative periodontitis-associated variants using existing GWAS data from a German case-control sample of aggressive periodontitis (AgP; 651 cases, 4,001 controls), the most severe and early onset form of periodontitis. Two haplotype blocks, one upstream to the coding region of UGT2A1 (rs146712414, P = 9.1 x 10(-5); odds ratio [OR], 1.34; 95% confidence interval [CI], 1.16-1.56) and one downstream of the genes PF4/PPBP/CXCL5 (rs1595009, P = 1.3 x 10(-4); OR, 1.32; 95% CI, 1.15-1.52), were associated with AgP. The association of rs1595009 was validated in an independent cohort of CP of European Americans (1,961 cases and 1,864 controls; P = 0.03; OR, 1.45; 95% CI, 1.01-1.29). This association was further replicated in another sample of 399 German CP cases (disease onset <60 y of age) and 1,633 controls (P = 0.03; OR, 1.75; 95% CI, 1.06-2.90). The combined estimates of association from all samples were P = 2.9 x 10(-5) (OR, 1.2; 95% CI, 1.1-1.3). This study shows the strength of combining QTL mapping and RNA-Seq data from a mouse model with association studies in human case-control samples to identify genetic risk variants of periodontitis.
引用
收藏
页码:945 / 952
页数:8
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