Functional Iron-Transport Genes—TF and TMPRSS6—As Genetic Determinants of Transferrin and Fasting Glucose in a Kazakh Adult Cohort: A Whole-Exome Sequencing Pilot Study
International Journal of Molecular Sciences, cilt.27, sa.12, 2026 (SCI-Expanded, Scopus)
- Yayın Türü: Makale / Tam Makale
- Cilt numarası: 27 Sayı: 12
- Basım Tarihi: 2026
- Doi Numarası: 10.3390/ijms27125374
- Dergi Adı: International Journal of Molecular Sciences
- Derginin Tarandığı İndeksler: Science Citation Index Expanded (SCI-EXPANDED), Scopus, EMBASE, MEDLINE, Academic Search Ultimate (EBSCO), Biomedical Reference Collection: Corporate Edition (EBSCO), Health Research Premium Collection (ProQuest)
- Anahtar Kelimeler: candidate-gene association study, iron metabolism, Kazakh population, metabolic syndrome, TF rs12769, TMPRSS6 haplotype, transferrin
- Erciyes Üniversitesi Adresli: Evet
Özet
Iron metabolism has long been linked to metabolic syndrome (MetS), but it is still unclear at which step—iron sensing, hepcidin regulation, export, transport, or storage—genetic variation matters the most. There are almost no studies on iron metabolism genes in Kazakhs in particular. Using whole-exome sequencing (WES) data from 96 Kazakh adults (52 with MetS), we examined 18 SNPs across six iron metabolism genes—HFE, SLC40A1, TMPRSS6, FTL, TFR2, and TF. Associations with iron biomarkers and MS components were tested by linear regression adjusted for age, sex, and BMI, with FDR correction, haplotype analysis, and bootstrap mediation analysis. Significant effects clustered at two distinct steps of iron metabolism: hepcidin regulation (TMPRSS6) and iron transport (TF). The T allele of TF rs12769 raised serum transferrin (β = +0.32 g/L; p_FDR = 0.002) while lowering both TSAT (β = −4.25%) and ferritin (β = −0.36 log-units); haplotype analysis confirmed rs12769 as the driver. The TMPRSS6 C–G–C haplotype was associated with lower fasting glucose (β = −1.19 mmol/L; p = 0.023), and TF rs12769 emerged as a robust FDR-significant determinant of serum transferrin (p_FDR = 0.002). Bootstrap mediation analysis (5000 iterations) showed that the TMPRSS6 effect on glucose is not mediated by ferritin, serum iron, transferrin, TSAT, or sTfR (all ACME p > 0.20), while Total and Direct Effects remained robust (p ≤ 0.054). In Kazakhs, iron-metabolism genes appear to influence fasting glucose through direct mechanisms not captured by the standard iron biomarker panel; alternative pathways involving hepatic enzymes, hepcidin, or inflammation warrant investigation in larger cohorts.