The Novel ASIC2 Locus is Associated with Severe Gingival Inflammation

Abstract

An increasing body of evidence suggests a significant genetic regulation of inflammatory response mechanisms; however, little is known regarding the genetic determinants of severe gingival inflammation (GI). We conducted a genome-wide association study of severe GI among 4077 European American adults, participants in the Dental Atherosclerosis Risk In Communities cohort. The severe GI trait was defined dichotomously using the 90^th percentile of gingival index ≥2 extent score. Genotyping was performed with the Affymetrix 6.0 array platform and an imputed set of 2.5 million markers, based on HapMap Phase II CEU build 36, was interrogated. Genetic models were based on logistic regression and controlled for ancestry (10 principal components), sex, age, and examination center. One locus on chromosome 17 met genome-wide statistical significance criteria-lead single nucleotide polymorphism (SNP): rs11652874 [minor allele frequency=0.06, intronic to ASIC2 (acid sensing ionic channel-2, formerly named ACCN1); odds ratio=2.1, 95% confidence interval=1.6-2.7, p=3.9×10^-8]. This association persisted among subjects with severe periodontitis and was robust to adjustment for microbial plaque index. Moreover, the minor [G] allele was associated with higher levels of severe GI in stratified analyses among subsets of participants with high load of either "red" or "orange" complex pathogens, although this association was not statistically significant. While these results will require replication in independent samples and confirmation by mechanistic studies, this locus appears as a promising candidate for severe gingival inflammation. Our findings suggest that genetic variation in ASIC2 is significantly associated with severe gingival inflammation and the association is plaque-independent.

Keywords: Periodontal Disease(s)/Periodontitis; bacteria; genetics; genomics; gingivitis; plaque/plaque biofilms.

Figure 1.

rs11652874 in the ASIC2 gene locus is associated with severe gingival inflammation. (A) Manhattan plot of genome-wide association analysis results of severe gingival inflammation (binary trait based on EGIGE2q90) in the Atherosclerosis Risk in Communities cohort (n = 4,077). (B) Locus zoom visualization of the 17q11.2 locus (ASIC2, lead SNP: rs11652874) flanking ±400 kb. The vertical axis represents the log₁₀-transformed P value for each SNP. A schematic representation of the ASIC2 gene exons in relation to the lead SNP (rs11652874) is shown in the inset. (C) Locus zoom visualization of the 17q11.2 locus flanking a zoomed-in ±25-kb region. SNP, single-nucleotide polymorphism.

Figure 2.

Association of rs11652874 polymorphisms (minor allele [G] carriers vs. noncarriers) with gingival inflammation extent score ≥2 (EGIGE2) stratified by chronic periodontitis diagnosis (case status classification per the American Academy of Periodontology and Centers for Disease Control and Prevention), adjusting for (A) age, sex, ancestry (10 principal components), and examination center and (B) microbial plaque levels, age, sex, ancestry (10 principal components), and examination center.

Figure 3.

Comparison of severe gingival inflammation extent scores (EGIGE2) by levels of 8 periodontal pathogens in the red and orange complexes as determined by DNA checkerboard; bacterial loads were dichotomized into high level (the top quartile) and low level (lowest 3 quartiles) and stratified by genotypes at rs11652874. A.a, Aggregatibacter actinomycetemcomitans (formerly Actinobacillus actinomycetemcomitans); B.f, Tannerella forsythia (formerly Bacteriodes forsythus); C.r, Campylobacter rectus; F.n, Fusobacterium nucleatum; P.g, Porphorymonas gingivalis; P.i, Prevotella intermedia; P.n, Prevotella nigrescens; T.d, Treponema denticola.