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Published on: December 28, 2017
Interplay between CARD9 genetic variants and fungal colonization patterns among patients with diabetes
Aiah M Khateb1,2,3, Rahaf Ghazi Alharbi4, Lujain Alsweed5
1Department of Clinical Laboratory Sciences, College of Applied Medical Science, Taibah University, Madina, Saudi Arabia.
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.
Insights
Common Caspase Recruitment Domain-containing protein 9 (CARD9) variants are a frequent genetic predisposition for fungal infections in adults with diabetes. Obesity is also a key factor, suggesting a precision medicine approach for risk stratification.
Area of Science:
- Immunology
- Genetics
- Mycology
Background:
- Diabetes mellitus increases susceptibility to fungal infections.
- The genetic basis for this vulnerability in Middle Eastern populations is not well understood.
- Caspase recruitment domain-containing protein 9 (CARD9) is crucial for fungal sensing, but its role in adult diabetic populations is understudied.
Purpose of the Study:
- To investigate the prevalence of fungal colonization in diabetic individuals.
- To identify common CARD9 gene variants associated with fungal burden in this population.
- To explore the interplay between genetic predisposition and metabolic factors in fungal susceptibility.
Main Methods:
- Screening 107 diabetic participants for fungal colonization.
- Targeted sequencing of the CARD9 gene.
- Bioinformatic analysis including heterozygous peak calling and variant annotation.
- Functional impact prediction using SIFT, PolyPhen-2, and structural modeling.
Main Results:
- Fungal colonization was common, with Aspergillus niger complex identified frequently.
- The CARD9 N-terminal CARD domain was a mutational hotspot, with high prevalence of damaging homozygous variants (52.7%).
- Obesity, not CARD9 variants, emerged as the primary independent predictor of fungal burden, presenting a paradox of stability.
Conclusions:
- Diabetic populations exhibit a widespread, unrecognized deficiency in the Dectin-1/CARD9 signaling pathway.
- CARD9 variants represent a common genetic predisposition to fungal infections in adults with diabetes, challenging the view of it as a rare pediatric disease.
- Integrating CARD9 genotyping with metabolic profiling may enable precision medicine for early antifungal prophylaxis in at-risk patients.
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