ASIC2 is a Novel Locus for Severe Gingival Inflammation

Objectives: Little is known regarding genetic determinants of severe gingival inflammation. We conducted a genome-wide association study (GWAS) to identify novel single nucleotide polymorphisms (SNPs) and genentic loci using severe gingival inflammation (GI) as the clinical phenotype.
Methods: A GWAS was performed among 4077 Caucasian (European American) adults, which is a subset of The Dental Atherosclerosis Risk In Communities (ARIC) cohort. Complete full-mouth periodontal characterization was undertaken and GI scores were used as the single clinical phenotype of interest in this analysis, irrespective of the periodontal diagnosis (gingivitis or periodontitis). Genotyping was performed with the Affymetrix 6.0 array platform and an imputed set of 2.5 million markers was interrogated. The severe GI trait was defined using the 90^th percentile of GI≥2 extent score (GIGE2). Genetic models were adjusted for examination center, sex, age and 10 ancestry principal components, and a conventional genome-wide significance threshold of 5x10^-8 was used. Pathway analysis was performed using Ingenuity Pathway Analysis (IPA).
Results: We found one SNP (rs11652874, minor allele frequency=6.5%) intronic to the ASIC2 (acid sensing ionic channel-2) gene on chromosome 17 significantly associated with severe gingival inflammation (OR=2.1; 95% confidence interval=1.6-2.7; p=3.9x10^-8). This association did not persist among subjects whose plaque index was below the median. ASIC-2 is a neuroprotein that regulates signaling at the neurovascular junction to mediate vasodilation. IPA provided further support for the importance of the ASIC protein, associated molecules (e.g., neurexin-1 alpha and neuroligin-1), and the ASIC2-associated pathway in the context of GI.
Conclusions: A common genetic variation in ASIC2 is significantly associated with severe GI, irrespective of periodontal diagnosis. This finding will require independent validation and replication. The heterogeneity of the association according to plaque score suggests that this may be a plaque-dependent susceptibility trait.