MT-ND1 Variants and Protective Haplotypes in Egyptian Chronic Kidney Disease: An Integrated Targeted Mitochondrial Analysis

<title>Abstract</title> <p>Background Chronic kidney disease (CKD) is a global health problem increasingly linked to mitochondrial dysfunction. However, mitochondrial DNA (mtDNA) variants remain poorly studied, particularly in understudied populations with renal disease. Methods We conducted a case-control study in an Egyptian cohort of 45 CKD patients and 14 controls, using targeted sequencing of selected mitochondrial genes spanning 600–4600 bp. Results Single-variant, burden, haplotype, and network analyses revealed two distinct mitochondrial signatures separating CKD patients from controls. CKD showed enrichment of MT-ND1 variants, especially rs397515509 (35.6% cases vs. 0% controls, OR = ∞, p = 0.0068). Controls exhibited higher heteroplasmic variability in 16S rRNA (Δ = −28.9%), indicating greater mitochondrial tolerance. Protective haplotypes centered on rs28358576 reduced CKD risk, with larger haplotypes showing stronger cumulative protection (OR = 0.08–0.13). CKD patients also had higher total and homoplasmic variant burden. Conclusion Network analysis identified rs397515509 as a key variant linked to energy metabolism, oxidative stress, and apoptosis. Despite limited power and conservative bias (λ = 0.355), major associations showed large effect sizes, supporting mtDNA patterns as potential biomarkers of CKD susceptibility and resilience. The sequence data have been deposited in GenBank under accession numbers PZ760239–PZ760428.</p>