Protective association of A-T-T haplotype of <i>DMT1</i> gene against risk of human age-related nuclear cataract

<p><b>Background</b>: Age-related cataract (ARC) is profoundly associated with oxidative stress. Iron plays a pivotal role in generating oxidative stress and promoting deleterious irreversible damage to the macromolecules. Divalent metal transporter 1 (DMT1) mediates the uptake of iron into the cell. Aberrant transcript expression of <i>DMT1</i> gene in lenses of human ARC was reported. The present investigated the genetic association between <i>DMT1</i> gene polymorphisms and risk of ARC.</p> <p><b>Methods</b>: DNA from peripheral blood of ARC subjects (n = 764) and age-matched controls (<i>n</i> = 794) was isolated. Genotyping of three single-nucleotide polymorphisms (SNPs) – rs224589 (C/A), rs1048230 (T/C), and rs2285230 (T/C) – of <i>DMT1</i> gene was performed by polymerase chain reaction (PCR)-restriction fragment length polymorphism technique. Level of <i>DMT1</i> transcript expression was determined by quantitative real-time PCR analysis using RNA from lens epithelial and fiber cells.</p> <p><b>Results</b>: Nuclear cataract showed a higher frequency of CC genotypes (OR = 1.40; 95%CI = 1.01–1.95; <i>p</i> = 0.04) of SNP rs224589 and a significantly lower frequency of A-T-T haplotype (OR = 0.63; 95%CI = 0.42–0.92; <i>p</i> = 0.02) than that of controls. The A-T-T haplotype demonstrated a dominant protective effect against disease risk when compared to the more common haplotype (C-T-T) (<i>p</i> = 0.01). The haplotype pairs C-T-T/C-T-T and A-C-C/A-C-C showed higher level of transcript expression of <i>DMT1</i> than C-T-T/A-T-T haplotype pair (<i>p</i> < 0.05). Further, a novel genetic variation (c.1328A>G; p.N443S) in exon 3 of <i>DMT1</i> gene was observed in a subject with nuclear cataract.</p> <p><b>Conclusions</b>: The results highlighted a protective association of A-T-T haplotype against the risk of ARC.</p>