Chronic Periodontitis Genome-wide Association Study in the Hispanic Community Health Study / Study of Latinos

Abstract

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 communitybased 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.

Genomics of periodontal disease and tooth morbidity

“…In that study, the investigators discovered and subsequently replicated the association of rs1537415, located in the glycosyltransferase gene ( GLT6D1 ), with aggressive periodontitis. More recently, Sanders et al reported a significant association of a relatively rare TSNAX‐DISC1 noncoding RNA polymorphism (rs149133391) with chronic periodontitis among Hispanic/Latino people and subsequently replicated it among an independent sample of African‐Americans. Other studies have implicated numerous loci without reaching genome‐wide statistical significance levels and/or demonstrating replication in an independent cohort.…”

“…Some of the limitations of genome‐wide association studies for periodontitis are related to the sample size of the study and the inherent complexity in defining the trait. A commonly cited limitation in the periodontal genome‐wide association study literature is the relatively modest sample sizes of individual studies compared with reports for other common complex diseases, ranging between a few hundred and up to 10 000‐17 000 participants . This has been somewhat overcome by the establishment of the Gene‐Lifestyle Interactions and Dental Endpoints consortium and a recent report of periodontitis and dental caries genome‐wide association studies among over half a million individuals .…”

Identification of genetic risk factors of aggressive periodontitis using genomewide association studies in association with those of chronic periodontitis

“…One genetic risk factor, SNP rs149133391 in TSNAX‐DISC1 , has been identified to have genomewide significant association with CP through a Hispanic case‐control GWAS (n = 10 935) with a P ‐value of 7.9 × 10 −9 . rs149133391 also showed association with African American CP subjects (n = 4314) with a P ‐value of 9.1 × 10 −3 through a replication study . Since rare variants occur less frequently, association studies require larger sample sizes to achieve the necessary statistical power.…”

“…A case‐control GWAS of CP in Hispanic subjects (n = 10 935) identified three rare variants: rs75715012 in NELL1 (MAF: 0.089), rs186066047 in IRXI (MAF:0.003), and rs79308117 in ASHIL (MAF:0.005) with P ‐values of 1.1 × 10 −7 , 1.7 × 10 −7 and 2.8 × 10 −7 , respectively. It also identified one common variant, rs10456847 in RNF144B (MAF:0.330) with a P ‐value of 2.6 × 10 −7 . It is worth noting that despite the small P ‐values, the rare variant associations could be false positives since the sample lacked the statistical power to discover rare‐variant associations.…”

“…A single nucleotide polymorphism (SNP) in interleukin‐1 ( IL‐1 ) was the first identified genetic risk factor for AgP . However, subsequent studies with improved statistical power using samples from homogeneous populations did not validate associations between IL‐1 variants and periodontitis . Subsequently, several genes have been identified as genetic risk factors for AgP, but the full complement of associated genes has not been fully elucidated.…”