Oral and non-oral lichen planus show genetic heterogeneity and differential risk for autoimmune disease and oral cancer

Abstract

Lichen planus (LP) is a T-cell-mediated inflammatory disease affecting squamous epithelia in many parts of the body, most often the skin and oral mucosa. Cutaneous LP is usually transient and oral LP (OLP) is most often chronic, so we performed a large-scale genetic and epidemiological study of LP to address whether the oral and non-oral subgroups have shared or distinct underlying pathologies and their overlap with autoimmune disease. Using lifelong records covering diagnoses, procedures, and clinic identity from 473,580 individuals in the FinnGen study, genome-wide association analyses were conducted on carefully constructed subcategories of OLP (n = 3,323) and non-oral LP (n = 4,356) and on the combined group. We identified 15 genome-wide significant associations in FinnGen and an additional 12 when meta-analyzed with UKBB (27 independent associations at 25 distinct genomic locations), most of which are shared between oral and non-oral LP. Many associations coincide with known autoimmune disease loci, consistent with the epidemiologic enrichment of LP with hypothyroidism and other autoimmune diseases. Notably, a third of the FinnGen associations demonstrate significant differences between OLP and non-OLP. We also observed a 13.6-fold risk for tongue cancer and an elevated risk for other oral cancers in OLP, in agreement with earlier reports that connect LP with higher cancer incidence. In addition to a large-scale dissection of LP genetics and comorbidities, our study demonstrates the use of comprehensive, multidimensional health registry data to address outstanding clinical questions and reveal underlying biological mechanisms in common but understudied diseases.

Keywords: autoimmune disease; genetics; hypothyroidism; lichen planus; oral cancer; oral lichen planus.

Graphical abstract

Figure 1

Categorization of lichen planus subgroups in FinnGen

Figure 2

UpSet plot showing the intersection of genital LP (GEN_LP) and cutaneous LP (CUT_LP) with the oral (ORAL_LP) and non-oral (NONORAL_LP) subgroups Intersections with fewer than five individuals are not displayed due to data-protection regulations.

Figure 3

Excess comorbidities between LP oral and non-oral subgroupings and other diseases in FinnGen Error bars represent 95% CI on the estimated effect. (^∗243 OLP-affected individuals with a leukoplakia diagnosis within one month have been removed from the tongue cancer analysis.) Data are presented in Table S1.

Figure 4

Genome-wide significant loci from meta-analysis of UKBB-FG, FG all LP, FG OLP, and FG non-OLP Traditional Manhattan plots aligned are available as Figure S1.