The principal pathogenesis of MI is the disruption of coronary atherosclerotic plaques , which caused by both individual’s genetic makeup and various environmental factors. Previous studies have demonstrated the effects of LRP6 in early coronary artery disease and abnormal blood lipids including hypercholesterolemia [12–14], indicating the important role of LRP6 in the MI development. Nonetheless, the association between SNPs in LRP6 gene and MI risk is still largely unknown. In this study, we performed a genetic association analysis on the three SNPs (rs2302685 in LRP6, rs6687605 in LDLRAP1 and rs13306731 in SOAT1), and revealed that the LRP6 rs2302685 polymorphism was associated with increased risk of MI in a Chinese Han population, and the association was more remarkable among younger subjects (≤60 years old), which might potentially due to the enhanced LDL-C levels. Taken together, our study suggested that LRP6 rs2302685 might play an important role in the MI pathogenesis.
Though rs2302685 has been considered as a common functional LRP6 polymorphism, and is significantly associated with several human diseases such as Alzheimer’s disease , the effects of this polymorphism on MI risk is still unknown. Nonetheless, Sarzani et al. has reported that the rs2302685 was strongly related to carotid artery atherosclerosis (CAA) in hypertensive patients, indicating that C allele of LRP6 rs2302685 might be an independent risk factor for CAA (OR = 2.08, 95% CI = 1.27-3.41, P = 0.003) . Carotid artery atherosclerosis is closely associated with arterial cardiovascular events, and is a strong predictor of future myocardial infarction, which might share common risk factors [35, 36]. Our data that rs2302685 endowed C allele carriers with significant increased MI risk was in consistent with the results from the above association analysis between rs2302685 and CAA.
Our stratified analyses revealed that the increased risk of LRP6 rs2302685 polymorphism in MI was more evident among younger subjects (≤60 years old), whereas no significant association was observed from the group older than 60 years old (Table 4). In addition, LRP6 rs2302685 only exhibited an association with elevated LDL-C levels in younger individuals, but not in total or older subjects. Weak immune system and relative high level exposure to environmental risk factors in older individuals may account for these. The potential risk of MI in older subjects is more likely due to the aging effects rather than direct genetic effects. Thus, the LRP6 rs2302685 polymorphism might be more influential in early-onset MI, which was similar as the effects of LRP6 R611C variant on early-onset CAD development in an Iranian family .
Previous investigations have demonstrated that LRP6, as a component of LDL cholesterol trafficking complex, was involved in direct LDL uptake ; and the elevated LDL-C levels in LRP6 R611C mutation carriers was likely due to the reduced LDL clearance capacity . Moreover, Tomaszewsk et al. unveiled that T allele of LRP6 rs10845493 polymorphism was associated with 0.14 mmol/L increase in LDL-C levels (SE = 0. 05, P = 0.0038) . In consistent with above findings, our data revealed that the LDL-C levels of the individuals carrying CT/CC genotype were higher than the TT genotype carriers among younger individuals (≤60 years old) (Table 5), which provided a reasonable explanation to the enhanced effects of rs2302685 on MI pathogenesis in younger subjects.
Several limitations herein in this case–control study need to be addressed. First, the case subjects and controls enrolled from hospitals may not represent the general population. Nonetheless, the genotype distribution of the controls was in Hardy-Weinberg equilibrium. Second, the moderate sample size of our study limited the statistical power, especially in the case subjects. Finally, further studies in different population could help to verify the true significance of the association between the rs2302685 polymorphism and the risk of MI. However, our observations provided valuable insights and interesting information and might serve to guide future studies in this area.