Rs4862705 in the melatonin receptor 1A gene is associated with renal function decline in type 1 diabetes individuals

Abstract

Aim: The pathogenesis of chronic diabetes complications has oxidative stress as one of the major elements, and single-nucleotide polymorphisms (SNPs) in genes belonging to antioxidant pathways modulate susceptibility to these complications. Considering that melatonin is a powerful antioxidant compound, our aim was to explore, in a longitudinal cohort study of type 1 diabetes (T1D) individuals, the association of microvascular complications and SNPs in the gene encoding melatonin receptor 1A (MTNR1A).

Methods: Eight SNPs in MTNR1A were genotyped in 489 T1D individuals. Besides cross-sectional analyses of SNPs with each one of the microvascular complications (distal polyneuropathy, cardiovascular autonomic neuropathy, retinopathy, and diabetic kidney disease), a longitudinal analysis evaluated the associations of SNPs with renal function decline in 411 individuals followed up for a median of 8 years. In a subgroup of participants, the association of complications with urinary 6-sulfatoxymelatonin (aMT6s) concentration was investigated.

Results: The group of individuals with a renal function decline ≥ 5 mL min^-1 1.73 m^-2 year^-1 presented a higher frequency of the A allele of rs4862705 in comparison with nondecliners, even after adjustment for confounding variables (OR = 1.84, 95% CI = 1.20-2.82; p = 0.0046). No other significant associations were found.

Conclusions: This is the first study showing an association between a variant in a gene belonging to the melatonin system and renal function decline in the diabetic setting.

Keywords: antioxidant activity; diabetes-related complications; diabetic kidney disease; genetic polymorphism; melatonin receptors; type 1 diabetes mellitus.