Abstract
Abstract Introduction Insomnia is associated with neurodegenerative diseases. Concentration levels of some metabolites are associated with pathophysiologic changes, possibly in a sex-specific manner. Thus, serum metabolite levels are useful for understanding insomnia-related pathophysiological changes and how they potentially relate to neurodegenerative disease. Methods The Hispanic Community Health Study/Study of Latinos (HCHS/SOL) is a longitudinal cohort study following self-reported Hispanic/Latino individuals in the U.S. At baseline, insomnia symptoms were captured using the Women Health Initiative Insomnia Rating Scale (WHIIRS), insomnia being defined as WHIIRS≥9. Metabolites were measured using blood serum from the baseline exam in independent discovery and replication datasets. In discovery, metabolite associations with WHIIRS and with insomnia were estimated in linear regression. Significant associations (FDR p-values< 0.05) were tested in the replication dataset and considered replicated if their p-value< 0.05 and the direction of association matched with the discovery analysis. Associations were further studied for gender interaction. All analyses were adjusted for age, self-reported gender, study center, and Hispanic/Latino background. Results 3,895 individuals participated in the discovery analysis, and 2,121 in replication analysis. Female individuals were aged 46.5 on average (SD 15.1) and 35% had insomnia, while male individuals were aged 44.8 (14.8) and 24% had insomnia. After quality control, 767 metabolites were tested for association. Six metabolites were associated with WHIIRS (FDR< 0.05) in the gender-combined analysis. Three were xenobiotics which were on the benzoate or salicylic acid metabolism pathway. Of the 6 metabolite associations, two replicated (p-value< 0.05): hydrocinnamate and indolepropionate. These two metabolites had spearman correlation of 0.44. Higher levels of both metabolites were associated with lower WHIIRS, showing stronger associations in females (interaction p-value =0.04 for hydrocinnamate and p-value=0.13 for indolepropionate). Associations remained essentially unchanged in a model further adjusting for hypertension and diabetes. When removing 534 individuals who self-reported using sleeping pills at least once a week, the associations attenuated slightly: from an effect estimates of -0.0075 to -0.0069 (hydrocinnamate) and from -0.0082 to -0.0068 (indolepropionate). Conclusion Among the HCHS/SOL target population, insomnia symptom severity is associated with a lower concentrations of some plasma metabolite levels which are important antioxidant needed in preventing oxidative stress and neurodegeneration. Support (if any) R01HL161012.