Interplay between CARD9 genetic variants and fungal colonization patterns among patients with diabetes

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Background Diabetes mellitus significantly increases susceptibility to opportunistic fungal colonization; however, the genetic architecture underlying this vulnerability in Middle Eastern populations remains underexplored. Caspase recruitment domain-containing protein 9 (CARD9) is a fundamental adaptor in fungal sensing. While CARD9 deficiency is traditionally viewed as a rare pediatric immunodeficiency, we hypothesize that common CARD9 variants serve as significant predisposing factors for fungal burden in the adult diabetic population. Methods A cohort of 107 diabetic participants (49.5% overweight/obese) was screened for fungal colonization across multiple anatomical sites. Targeted sequencing of the CARD9 gene was performed, using a bioinformatics pipeline for heterozygous peak calling (IUPAC ambiguity codes) and Ensembl VEP for variant annotation. Functional impacts were predicted using SIFT, PolyPhen-2, and PyMOL structural modeling. Results Fungal colonization was prevalent, with Aspergillus niger complex (27.9%) being the most frequently identified organism. Genomic analysis identified the N-terminal CARD domain as a mutational “hotspot.” We identified a high prevalence of homozygous damaging variants (52.7%), including p.Arg47His and p.Gly49Asp, which disrupt CARD domain stability. An additional 24.8% of the cohort displayed significant IUPAC-mixed heterozygous signals. Despite these genetic findings, a “paradox of stability” emerged: individuals with the highest microbial scores (4–5) often carried the reference sequence, while multivariate analysis identified obesity (OR: 1.85, p < 0.05) as the primary independent predictor of fungal burden. Conclusion Our findings demonstrate that the diabetic population harbors a widespread, previously unrecognized deficiency in the Dectin-1/CARD9 signaling pathway. This shifts the clinical narrative of CARD9 from a “rare pediatric disease” to a common genetic predisposition in adult patients with diabetes. While metabolic dysregulation may override genetic factors, the high frequency of CARD domain “hotspot” mutations supports a precision medicine approach integrating CARD9 genotyping with metabolic profiling to risk-stratify patients for early antifungal prophylaxis.

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