Oral Health as a Risk Factor for Spontaneous Intracerebral Hemorrhage: A Mendelian Randomization Analysis
Cyprien Rivier1, Santiago Clocchiatti-Tuozzo2, Shufan Huo1, Daniela Renedo1, Maximiliano Hawkes3, N. Abimbola Sunmonu4, Kevin Sheth5, Guido Falcone6
1Yale University, 2Yale University, Department of Neurology, 3University of Nebraska Medical Center, 4Yale Neurology, 5Yale University Division of Neuro and Critical Care, 6Yale School of Medicine
Objective:
We hypothesize that genetically-determined poor oral health increases the risk of ICH.
Background:
Poor oral health is a highly prevalent and modifiable risk factor that is associated with higher risk of cardiovascular disease, including ischemic stroke. However, the relationship between oral health and spontaneous intracerebral hemorrhage (ICH) has not been studied.
Design/Methods:
We conducted a two-sample Mendelian Randomization (MR) study using summary statistics from the largest genome-wide associations studies of oral health and ICH conducted to date. As genetic instruments (e.g., genetic risk variants for oral health), we identified 105 independent single nucleotide polymorphisms known to be associated with higher risk of caries, dentures and missing teeth at genome wide levels (p<5x10-8). The primary analysis employed summary statistics-based MR to assess the relationship between poor oral health and risk of ICH in any brain location. Secondary analyses evaluated deep and lobar ICH separately.
Results:
The primary analysis using the inverse variance-weighted MR method showed that genetically-increased risk of poor oral health was associated with a higher risk of ICH (OR 2.34, [1.08-5.06], p=0.029). Secondary analyses indicated a more potent association with deep ICH (OR 3.20 [1.34-7.6], p=0.008), whereas the link with lobar ICH was not statistically significant (OR 1.32 [0.53-3.27], p=0.543). Sensitivity analyses detected no horizontal pleiotropy in our findings (MR-PRESSO global test p-values >0.05).
Conclusions:
Genetically-determined poor oral health is associated with an increased risk of ICH, particularly in the case of deep ICH. Because gene-disease associations are less prone to confounding, our results suggest that this association is causal. However, further analyses are needed to validate these results and identify the mediating mechanisms. Because oral health is an easily modifiable process, it may be a promising target for very early interventions focused on mitigating the risk of hemorrhagic stroke.