CRP Genetic Variant Is Associated With Diabetic Retinopathy
CRP Genetic Variant Is Associated With Diabetic Retinopathy
In the present study, we investigated the association of CRP variants with DR in Chinese patients with T2DM. It's the first time to our knowledge to investigate the association between CRP variants with DR. Our results revealed that rs2808629 was significantly associated with the risk of DR in Chinese patients with T2DM. This association remained significant after adjusting for multiple comparisons. Moreover, the correlation of rs2808629 with DR stayed significant after adjusting for confounding factors, including duration of diabetes, HbA1c, blood pressure, BMI and sex, implying that this SNP is an independent genetic factor for susceptibility to DR. It has been reported in several studies that CRP genetic variants were associated with serum CRP levels. rs2808629 was identified to be associated with serum CRP levels in a previous genome-wide association study. Therefore, it is plausible that the effect of rs2808629 on susceptibility to DR is because of its influence on serum CRP levels. However, further studies are needed for confirmation.
As an acute phase reactant, CRP production increases in response to a variety of systemic events such as infection, trauma, or autoimmune inflammatory diseases. Among other systemic inflammatory mediators, CRP has been widely accepted as a potent risk indicator, independently predicting future cardiovascular events in the last decades. On the other hand, given the increasingly recognized link between chronic inflammation and microvascular complications, the relationship between CRP and DR has been investigated in some studies. However, results from limited studies on possible association of CRP with DR are inconsistent. In the Hoorn study, a large population-based cohort study of 625 adults, higher CRP was associated with the prevalence of any DR. Another prospective study of inflammatory biomarkers and risk of DR in the Diabetes Control and Complications Trial also indicated that after adjusting for known risk factors, increasing quintiles of baseline high-sensitivity CRP (hsCRP) level may be associated with higher risks of incident clinically significant macular edema and the development of macular hard exudates. However, report from the Wisconsin Epidemiologic Study of Diabetic Retinopathy (WESDR), a longitudinal population based study of persons with type 1 diabetes, did not find any association between CRP and DR. Similar results were reported by the Multi-ethnic Study of Atherosclerosis (MESA). Besides, Lim et al. reported that patients with higher levels of CRP were less likely to have DR in the Singapore Malay Eye Study (SiMES), a cross-sectional study on 718 persons with diabetes. Nevertheless, emerging evidence supports CRP as an active participant instead of a mere bystander in the pathogenesis of DR. CRP could inhibit endothelium-dependent nitric oxide-mediated dilation in retinal arterioles, thus potentially facilitating the development of retinal vascular diseases. Besides, CRP could stimulate leucocyte-endothelium interactions, decrease endothelial nitric oxide, and impair the number and function of endothelial progenitor cells, thereby promoting endothelial dysfunction, which is another important mediator in the development of diabetic microvascular complications. Taken together, these findings imply that genetic variants of CRP may exert significant effects on DR. And our study found a common variant of CRP, rs2808629, was significantly associated with DR in the Chinese patients with T2DM.
Some limitations should be noted in our study. Firstly, although the association of rs2808629 with DR remained significant after adjusting for multiple comparisons (empirical P = 0.029), we still cannot fully exclude the possibility that the association detected was a false positive. But considering the power of our study samples and the effect of this SNP, the possibility of a false positive is limited. Secondly, rs2808629 locates in the downstream of CRP, and we suppose that it may participate in the susceptibility to DR through its effects on regulating CRP expression or it may be just a genetic marker in linkage disequilibrium with the causal variant(s). However, further studies are needed to reveal the underlying mechanism. Thirdly, although we found association of CRP variant with DR in Chinese patients with T2DM, whether this effect is restricted to T2DM is still unknown and needs to be investigated in studies among patients with type 1 diabetes and other ethnic groups.
Discussion
In the present study, we investigated the association of CRP variants with DR in Chinese patients with T2DM. It's the first time to our knowledge to investigate the association between CRP variants with DR. Our results revealed that rs2808629 was significantly associated with the risk of DR in Chinese patients with T2DM. This association remained significant after adjusting for multiple comparisons. Moreover, the correlation of rs2808629 with DR stayed significant after adjusting for confounding factors, including duration of diabetes, HbA1c, blood pressure, BMI and sex, implying that this SNP is an independent genetic factor for susceptibility to DR. It has been reported in several studies that CRP genetic variants were associated with serum CRP levels. rs2808629 was identified to be associated with serum CRP levels in a previous genome-wide association study. Therefore, it is plausible that the effect of rs2808629 on susceptibility to DR is because of its influence on serum CRP levels. However, further studies are needed for confirmation.
As an acute phase reactant, CRP production increases in response to a variety of systemic events such as infection, trauma, or autoimmune inflammatory diseases. Among other systemic inflammatory mediators, CRP has been widely accepted as a potent risk indicator, independently predicting future cardiovascular events in the last decades. On the other hand, given the increasingly recognized link between chronic inflammation and microvascular complications, the relationship between CRP and DR has been investigated in some studies. However, results from limited studies on possible association of CRP with DR are inconsistent. In the Hoorn study, a large population-based cohort study of 625 adults, higher CRP was associated with the prevalence of any DR. Another prospective study of inflammatory biomarkers and risk of DR in the Diabetes Control and Complications Trial also indicated that after adjusting for known risk factors, increasing quintiles of baseline high-sensitivity CRP (hsCRP) level may be associated with higher risks of incident clinically significant macular edema and the development of macular hard exudates. However, report from the Wisconsin Epidemiologic Study of Diabetic Retinopathy (WESDR), a longitudinal population based study of persons with type 1 diabetes, did not find any association between CRP and DR. Similar results were reported by the Multi-ethnic Study of Atherosclerosis (MESA). Besides, Lim et al. reported that patients with higher levels of CRP were less likely to have DR in the Singapore Malay Eye Study (SiMES), a cross-sectional study on 718 persons with diabetes. Nevertheless, emerging evidence supports CRP as an active participant instead of a mere bystander in the pathogenesis of DR. CRP could inhibit endothelium-dependent nitric oxide-mediated dilation in retinal arterioles, thus potentially facilitating the development of retinal vascular diseases. Besides, CRP could stimulate leucocyte-endothelium interactions, decrease endothelial nitric oxide, and impair the number and function of endothelial progenitor cells, thereby promoting endothelial dysfunction, which is another important mediator in the development of diabetic microvascular complications. Taken together, these findings imply that genetic variants of CRP may exert significant effects on DR. And our study found a common variant of CRP, rs2808629, was significantly associated with DR in the Chinese patients with T2DM.
Some limitations should be noted in our study. Firstly, although the association of rs2808629 with DR remained significant after adjusting for multiple comparisons (empirical P = 0.029), we still cannot fully exclude the possibility that the association detected was a false positive. But considering the power of our study samples and the effect of this SNP, the possibility of a false positive is limited. Secondly, rs2808629 locates in the downstream of CRP, and we suppose that it may participate in the susceptibility to DR through its effects on regulating CRP expression or it may be just a genetic marker in linkage disequilibrium with the causal variant(s). However, further studies are needed to reveal the underlying mechanism. Thirdly, although we found association of CRP variant with DR in Chinese patients with T2DM, whether this effect is restricted to T2DM is still unknown and needs to be investigated in studies among patients with type 1 diabetes and other ethnic groups.
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