Background: A previous work has discovered that LRP5 and LRP6 locus are linked to the risk of ABM in postmenopausal women with type 2 diabetes mellitus (T2DM). This study aimed to investigate the role of LRP5-LRP6 SNP and gene-gene and gene-environment interactions in the development of ABM in postmenopausal women with type 2 diabetes mellitus . Methods:A total of 272 postmenopausal women, comprising 166 patients with abnormal bone mass (ABM) and 106 controls with normal bone mass, were recruited based on BMD results. BMD of the lumbar spine 1-4 (L1-4) and femoral neck (FN) was measured by dual-energy X-ray (DEXA), and polymorphisms and gene frequency distributions of LRP5 rs2306862, rs41494349, and LRP6 rs10743980, rs2302685 were determined by time-of-flight mass spectrometry (MALDI-TOF MS). Results:1) Logistic regression analysis showed that the risk of ABM was higher for the CT and CT/TT genotypes than for the CC genotype at the rs2306862 locus of the LRP5 gene (OR=2.353, 95%CI=1.039-6.186; OR=2.434, 95%CI=1.071, 5.531; P<0.05). TC genotype at the rs2302685 locus of the LRP6 gene has a higher risk of ABM than TT genotype (OR=2.951, 95%CI=1.030-8.457, P<0.05). 2) Polymorphisms at the rs2306862&rs10743980, rs41494349&rs2302685&rs10743980 SNPs were synergistic with the development of ABM and were risk factors for the development of ABM (P<0.05). Polymorphisms at rs2306862, rs2302685, rs41494349&rs2302685& rs10743980 SNPs were synergistic with the occurrence of ABM and were risk factors for the occurrence of ABM (P<0.05). There was an interaction between gene polymorphism & age at each locus at menopause and the occurrence of ABM (P>0.05). Conclusion:These findings indicate that LRP5-rs2306862 and LRP6-rs2302685 polymorphisms, gene-gene, and gene-age interactions are associated with an increased risk of ABM in postmenopausal women with type 2 diabetes mellitus.

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Objectives To assess LRP5-/6 gene polymorphisms and its association with risk of abnormal bone mass (ABM) in postmenopausal women. Methods The study recruited 166 patients with ABM (case group) and 106 patients with normal bone mass (control group) based on bone mineral density (BMD) results. Multi-factor dimensionality reduction (MDR) was used to analyze the interaction between the Low-density lipoprotein receptor-related protein 5 (LRP5) gene (rs41494349, rs2306862) and the Low-density lipoprotein receptor-related protein 6 (LRP6) gene (rs10743980, rs2302685) and the subjects’ clinical characteristics of age and menopausal years. Results (1) Logistic regression analysis showed that the subjects with the CT or TT genotype at rs2306862 had a higher risk of ABM than those with the CC genotype (OR = 2.353, 95%CI = 1.039–6.186; OR = 2.434, 95%CI = 1.071, 5.531; P < 0.05). The subjects with the TC genotype at rs2302685 had a higher risk of ABM than those with the TT genotype (OR = 2.951, 95%CI = 1.030–8.457, P < 0.05). (2) When taking the three Single-nucleotide polymorphisms (SNPs) together, the accuracy was the highest with the cross-validation consistency of 10/10 (OR = 1.504, 95%CI:1.092–2.073, P < 0.05), indicating that the LRP5 rs41494349 and LRP6 rs10743980, rs2302685 were interactively associated with the risk of ABM. (3) Linkage disequilibrium (LD) results revealed that the LRP5 (rs41494349,rs2306862) were in strong LD (D′ > 0.9, r2 > 0.3). AC and AT haplotypes were significantly more frequently distributed in the ABM group than in the control group, indicating that subjects carrying the AC and AT haplotypes were associated with an increased risk of ABM (P < 0.01). (4) MDR showed that rs41494349 & rs2302685 & rs10743980 & age were the best model for ABM prediction. The risk of ABM in “high-risk combination” was 1.00 times that of “low-risk combination”(OR = 1.005, 95%CI: 1.002–1.008, P < 0.05). (5) MDR showed that there was no significant association between any of the SNPs and menopausal years and ABM susceptibility. Conclusion These findings indicate that LRP5-rs2306862 and LRP6-rs2302685 polymorphisms and gene–gene and gene–age interactions may increase the risk of ABM in postmenopausal women. There was no significant association between any of the SNPs and menopausal years and ABM susceptibility.