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. 2025 Aug 14;26(16):7855.
doi: 10.3390/ijms26167855.

The G-allele of rs10830963 in MTNR1B Exerts Stage-Specific Effects Across the Trajectory of Type 2 Diabetes: A Multi-State Analysis

Yao Huang  1 , Xiuping Dou  1 , Man He  1 , Yang Su  1 , Hualiang Lin  1 , Yin Yang  1
Affiliations

The G-allele of rs10830963 in MTNR1B Exerts Stage-Specific Effects Across the Trajectory of Type 2 Diabetes: A Multi-State Analysis

Yao Huang et al. Int J Mol Sci. .

Abstract

Although the MTNR1B single nucleotide polymorphism rs10830963 has been strongly associated with the onset of type 2 diabetes (T2D), its association with the progression and prognosis of T2D has been understudied. We conducted this prospective analysis based on the UK Biobank cohort study. Microvascular complications (MIC) of T2D in this study included diabetic retinopathy, diabetic neuropathy, and diabetic kidney disease. Macrovascular complications (MAC) of T2D included diabetic coronary artery disease, diabetic cerebrovascular disease, and diabetic peripheral vascular disease. The multi-state model was used to analyze the association between the polymorphism of rs10830963 and the trajectory of T2D. The accelerated failure time (AFT) model was used to assess the association between rs10830963 and the onset of T2D and T2D comorbidities. A total of 283,531 middle- and old-age participants were included. During a median follow-up of 13.7 years, 11,947 participants developed T2D, 1556 participants developed MIC, 1797 participants developed MAC, and 618 participants died. In the additive model, the G risk allele of rs10830963 was significantly associated with an increased risk of the transition from T2D-free to T2D (HR = 1.050, 95% CI: 1.020, 1.079) and a decreased risk of the transition from T2D to MIC (HR = 0.918, 95% CI: 0.850, 0.992), particularly from T2D to diabetic retinopathy (HR = 0.882, 95% CI: 0.782, 0.995). Besides, the G risk allele of rs10830963 accelerated the transition from T2D-free to T2D (Time Ratio [TR] = 0.966, 95% CI: 0.947, 0.986) and slowed down the transition from T2D to MIC (TR = 1.067, 95% CI: 1.030, 1.105). The MTNR1B single nucleotide polymorphism rs10830963 was associated with an increased risk of T2D and a decreased risk of MIC, particularly diabetic retinopathy among T2D individuals. Our results highlight that rs10830963 might play differential roles in the onset and progression of T2D.

Keywords: MTNR1B; diabetic macrovascular complications; diabetic microvascular complications; multi-state model; rs10830963; type 2 diabetes.

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Conflict of interest statement

The authors declare that they have no competing interests.

Figures

Figure 1
Figure 1
Numbers (percentages) of participants in transitions from baseline to T2D, diabetic comorbidities, and all-cause death. T2D, type 2 diabetes; DR, diabetic retinopathy; DN, diabetic neuropathy; DKD, diabetic kidney disease; MIC, diabetic microvascular complications (including DR, DN, or DKD); DCAD, diabetic coronary artery disease; DCVD, diabetic cerebrovascular disease; DPAD, diabetic peripheral vascular disease; MAC, diabetic macrovascular complications (including DCAD, DCVD, or DPAD).
Figure 2
Figure 2
Associations between rs10830963 and transitions from baseline to T2D, T2D comorbidities, and then death. (A) Hazard ratios (95% confidence intervals) for transitions from T2D-free to T2D, from T2D to MIC, and from MIC to all-cause death. (B) Hazard ratios (95% confidence intervals) for transitions from T2D-free to T2D, from T2D to MAC, and from MAC to all-cause death. HR, hazard ratios; CI, confidence interval; T2D, type 2 diabetes; DR, diabetic retinopathy; DN, diabetic neuropathy; DKD, diabetic kidney disease; MIC, diabetic microvascular complications (including DR, DN, or DKD); DCAD, diabetic coronary artery disease; DCVD, diabetic cerebrovascular disease; DPAD, diabetic peripheral vascular disease; MAC, diabetic macrovascular complications (including DCAD, DCVD, or DPAD).
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