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Exploring the genetic basis of chronic periodontitis: a genome-wide association study.

ABSTRACT: Chronic periodontitis (CP) is a common oral disease that confers substantial systemic inflammatory and microbial burden and is a major cause of tooth loss. Here, we present the results of a genome-wide association study of CP that was carried out in a cohort of 4504 European Americans (EA) participating in the Atherosclerosis Risk in Communities (ARIC) Study (mean age-62 years, moderate CP-43% and severe CP-17%). We detected no genome-wide significant association signals for CP; however, we found suggestive evidence of association (P < 5 × 10(-6)) for six loci, including NIN, NPY, WNT5A for severe CP and NCR2, EMR1, 10p15 for moderate CP. Three of these loci had concordant effect size and direction in an independent sample of 656 adult EA participants of the Health, Aging, and Body Composition (Health ABC) Study. Meta-analysis pooled estimates were severe CP (n = 958 versus health: n = 1909)-NPY, rs2521634 [G]: odds ratio [OR = 1.49 (95% confidence interval (CI = 1.28-1.73, P = 3.5 × 10(-7)))]; moderate CP (n = 2293)-NCR2, rs7762544 [G]: OR = 1.40 (95% CI = 1.24-1.59, P = 7.5 × 10(-8)), EMR1, rs3826782 [A]: OR = 2.01 (95% CI = 1.52-2.65, P = 8.2 × 10(-7)). Canonical pathway analysis indicated significant enrichment of nervous system signaling, cellular immune response and cytokine signaling pathways. A significant interaction of NUAK1 (rs11112872, interaction P = 2.9 × 10(-9)) with smoking in ARIC was not replicated in Health ABC, although estimates of heritable variance in severe CP explained by all single nucleotide polymorphisms increased from 18 to 52% with the inclusion of a genome-wide interaction term with smoking. These genome-wide association results provide information on multiple candidate regions and pathways for interrogation in future genetic studies of CP.

SUBMITTER: Divaris K

PROVIDER: S-EPMC3652417 | biostudies-literature | 2013 Jun

REPOSITORIES: biostudies-literature

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Exploring the genetic basis of chronic periodontitis: a genome-wide association study.

Divaris Kimon K Monda Keri L KL North Kari E KE Olshan Andrew F AF Reynolds Lindsay M LM Hsueh Wen-Chi WC Lange Ethan M EM Moss Kevin K Barros Silvana P SP Weyant Robert J RJ Liu Yongmei Y Newman Anne B AB Beck James D JD Offenbacher Steven S

Human molecular genetics 20130304 11

Chronic periodontitis (CP) is a common oral disease that confers substantial systemic inflammatory and microbial burden and is a major cause of tooth loss. Here, we present the results of a genome-wide association study of CP that was carried out in a cohort of 4504 European Americans (EA) participating in the Atherosclerosis Risk in Communities (ARIC) Study (mean age-62 years, moderate CP-43% and severe CP-17%). We detected no genome-wide significant association signals for CP; however, we foun ...[more]

PMID: 23459936

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Project description:Chronic periodontitis (CP) has a genetic component, particularly its severe forms. Evidence from genome-wide association studies (GWASs) has highlighted several potential novel loci. Here, the authors report the first GWAS of CP among a large community-based sample of Hispanics/Latinos. The authors interrogated a quantitative trait of CP (mean interproximal clinical attachment level determined by full-mouth periodontal examinations) among 10,935 adult participants (mean age: 45 y, range: 18 to 76 y) from the Hispanic Community Health Study / Study of Latinos. Genotyping was done with a custom Illumina Omni2.5M array, and imputation to approximately 20 million single-nucleotide polymorphisms was based on the 1000 Genomes Project phase 1 reference panel. Analyses were based on linear mixed models adjusting for sex, age, study design features, ancestry, and kinship and employed a conventional P < 5 × 10-8 statistical significance threshold. The authors identified a genome-wide significant association signal in the 1q42.2 locus ( TSNAX-DISC1 noncoding RNA, lead single-nucleotide polymorphism: rs149133391, minor allele [C] frequency = 0.01, P = 7.9 × 10-9) and 4 more loci with suggestive evidence of association ( P < 5 × 10-6): 1q22 (rs13373934), 5p15.33 (rs186066047), 6p22.3 (rs10456847), and 11p15.1 (rs75715012). We tested these loci for replication in independent samples of European-American ( n = 4,402) and African-American ( n = 908) participants of the Atherosclerosis Risk in Communities study. There was no replication among the European Americans; however, the TSNAX-DISC1 locus replicated in the African-American sample (rs149133391, minor allele frequency = 0.02, P = 9.1 × 10-3), while the 1q22 locus was directionally concordant and nominally significant (rs13373934, P = 4.0 × 10-2). This discovery GWAS of interproximal clinical attachment level-a measure of lifetime periodontal tissue destruction-was conducted in a large, community-based sample of Hispanic/Latinos. It identified a genome-wide significant locus that was independently replicated in an African-American population. Identifying this genetic marker offers direction for interrogation in subsequent genomic and experimental studies of CP.

Project description:Recent genome-wide association studies (GWAS) of chronic periodontitis (CP) offer rich data sources for the investigation of candidate genes, functional elements, and pathways. We used GWAS data of CP (n = 4,504) and periodontal pathogen colonization (n = 1,020) from a cohort of adult Americans of European descent participating in the Atherosclerosis Risk in Communities study and employed a MAGENTA approach (i.e., meta-analysis gene set enrichment of variant associations) to obtain gene-centric and gene set association results corrected for gene size, number of single-nucleotide polymorphisms, and local linkage disequilibrium characteristics based on the human genome build 18 (National Center for Biotechnology Information build 36). We used the Gene Ontology, Ingenuity, KEGG, Panther, Reactome, and Biocarta databases for gene set enrichment analyses. Six genes showed evidence of statistically significant association: 4 with severe CP (NIN, p = 1.6 × 10(-7); ABHD12B, p = 3.6 × 10(-7); WHAMM, p = 1.7 × 10(-6); AP3B2, p = 2.2 × 10(-6)) and 2 with high periodontal pathogen colonization (red complex-KCNK1, p = 3.4 × 10(-7); Porphyromonas gingivalis-DAB2IP, p = 1.0 × 10(-6)). Top-ranked genes for moderate CP were HGD (p = 1.4 × 10(-5)), ZNF675 (p = 1.5 × 10(-5)), TNFRSF10C (p = 2.0 × 10(-5)), and EMR1 (p = 2.0 × 10(-5)). Loci containing NIN, EMR1, KCNK1, and DAB2IP had showed suggestive evidence of association in the earlier single-nucleotide polymorphism-based analyses, whereas WHAMM and AP2B2 emerged as novel candidates. The top gene sets included severe CP ("endoplasmic reticulum membrane," "cytochrome P450," "microsome," and "oxidation reduction") and moderate CP ("regulation of gene expression," "zinc ion binding," "BMP signaling pathway," and "ruffle"). Gene-centric analyses offer a promising avenue for efficient interrogation of large-scale GWAS data. These results highlight genes in previously identified loci and new candidate genes and pathways possibly associated with CP, which will need to be validated via replication and mechanistic studies.

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Exploring the genetic basis of chronic periodontitis: a genome-wide association study.

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Exploring the genetic basis of chronic periodontitis: a genome-wide association study.

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