Comparative analysis of SNPs associated with COVID-19 and chronic liver disease identifies DPP9 as a candidate genetic marker for Long COVID

Long COVID is a multisystemic condition characterized by persistent symptoms after acute SARS-CoV-2 infection, whose biological mechanisms are not yet fully understood. Host genetic factors may be associated, and the sharing of genetic architecture with other chronic diseases such as viral hepatitis B and C may aid in understanding this disease. A cross-sectional study was conducted including 150 individuals stratified into two groups: (i) Long COVID and (ii) chronic viral hepatitis B and C. Eighteen single nucleotide polymorphisms (SNPs) previously associated with COVID-19 severity and inflammatory pathways were genotyped using TaqMan® real-time PCR assays. The analyses of genetic association models were performed using multivariate logistic regression adjusted for gender, self-reported skin color, and comorbidities. Mental health scales for assessing depression (Beck), anxiety (Hamilton), fatigue, and post-COVID functional scale were used both to define the syndrome and for subsequent analyses of the genotypic profile probably associated with Long COVID. Among all the SNPs analyzed, rs12610495 (A/G) in the DPP9 gene was the only variant consistently associated with Long COVID. After adjustment for sex, self-reported skin color, and hepatitis status, carriers of the G variant allele demonstrated increased odds of Long COVID under the dominant model (OR = 2.66; 95% CI: 1.08–6.57; p = 0.029) and the overdominant model (OR = 2.96; 95% CI: 1.17–7.52; p = 0.018). The association was more pronounced in women (OR = 3.30; 95% CI: 1.08–10.07). Exploratory analyses of mental and functional outcomes did not reach statistical significance, although a higher frequency of functional limitation and fatigue was observed among carriers of the G allele. This study suggests that DPP9 rs12610495 is associated with Long COVID, previously associated only with severe acute COVID, demonstrating that individuals carrying the rs12610495 G variant allele had higher odds of developing Long COVID. The inclusion of viral hepatitis as a chronic inflammatory condition for comparison contributed to the identification of shared genetic archetypal among diseases, revealing the possible role of DPP9 with Long COVID and highlighting this gene as a relevant target for future validation studies.