ORIGINAL ARTICLE

Gene–environment interaction between adiponectin gene polymorphisms and environmental factors on the risk of diabetic retinopathy Yuan Li1†, Qun Hong Wu1*, Ming Li Jiao1†, Xiao Hong Fan1, Quan Hu2, Yan Hua Hao1*, Ruo Hong Liu3, Wei Zhang4, Yu Cui1, Li Yuan Han5† 1

Department of Social Medicine, School of Public Health, Harbin Medical University, Harbin, 3Wenhua Community Clinics, Qiqihar, 4The First Hospital of Qiqihar, Heilongjiang Province, 5Department of Preventive Medicine, Medical School of Ningbo University, Ningbo, Zhejiang Province, China, and 2Department of Community Health Sciences, University of Calgary, Calgary, Alberta, Canada

Keywords Adiponectin, Diabetic retinopathy, Gene–environment interaction *Correspondence Qun Hong Wu and Yan Hua Hao Tel: +86-0451-87502851 Fax: +86-0451-87502853 E-mail addresses: wuqunhong@163. com, [email protected] J Diabetes Invest 2015; 6: 56–66 doi: 10.1111/jdi.12249

ABSTRACT Aims/Introduction: To evaluate whether the adiponectin gene is associated with diabetic retinopathy (DR) risk and interaction with environmental factors modifies the DR risk, and to investigate the relationship between serum adiponectin levels and DR. Materials and Methods: Four adiponectin polymorphisms were evaluated in 372 DR cases and 145 controls. Differences in environmental factors between cases and controls were evaluated by unconditional logistic regression analysis. The model-free multifactor dimensionality reduction method and traditional multiple regression models were applied to explore interactions between the polymorphisms and environmental factors. Results: Using the Bonferroni method, we found no significant associations between four adiponectin polymorphisms and DR susceptibility. Multivariate logistic regression found that physical activity played a protective role in the progress of DR, whereas family history of diabetes (odds ratio 1.75) and insulin therapy (odds ratio 1.78) were associated with an increased risk for DR. The interaction between the C-11377 G (rs266729) polymorphism and insulin therapy might be associated with DR risk. Family history of diabetes combined with insulin therapy also increased the risk of DR. No adiponectin gene polymorphisms influenced the serum adiponectin levels. Serum adiponectin levels did not differ between the DR group and non-DR group. Conclusions: No significant association was identified between four adiponectin polymorphisms and DR susceptibility after stringent Bonferroni correction. The interaction between C-11377G (rs266729) polymorphism and insulin therapy, as well as the interaction between family history of diabetes and insulin therapy, might be associated with DR susceptibility.

INTRODUCTION Diabetic retinopathy (DR), one of the most prominent pathological microvascular complications of type 2 diabetes, is the leading cause of blindness among people of working age in developed countries1,2. The prevalence of DR in diabetics is †These authors contributed equally to this article. Received 21 August 2013; revised 17 February 2014; accepted 8 May 2014

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approximately 37% in China3, where DR currently places a large public health and economic burden on the country. Adiponectin has been shown to play a protective role in preventing macrovascular disorders, and has gained considerable attention because of its involvement in cardiovascular disease4; however, the role of adiponectin in the development of DR is largely unknown. Endothelial dysfunction pathways are thought to play an important role in the pathogenesis of

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ORIGINAL ARTICLE Gene–environment interaction analysis

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DR5, and in vitro data have shown that adiponectin is an adipocyte-specific secretory protein that modulates endothelial cell functions6,7, endothelial cell dysfunction is thought to play a major role in the development of diabetic microangiopathy. As adiponectin is involved in the modulation of angiogenesis, it could be a new candidate gene involved in promoting the progression of DR. Nowadays, the examination of gene–environment interactions is increasingly popular. Although the traditional logistic regression model is often used to detect interactions, it is difficult to evaluate potential higher-order interactions when dealing with greater dimensional data; however, the multifactor dimensionality reduction (MDR) method makes this possible, which is very powerful to detect high-order gene–environment interactions in studies with relatively small sample sizes8, and to detect interactions without main effects9. A susceptibility locus for metabolic syndrome and diabetes was previously mapped to human chromosome 3q2710, where the adiponectin gene is located11,12. As little is known about the possible role of the adiponectin gene and its interaction with environmental factors on DR risk, we chose to genotype C-11377G (rs266729; 50 flanking region), A-4034C (rs822394; intron 1) to tag block 1, and G276T (rs1501299; intron 2) and T45G (rs2241766; exon 2) to tag block 2, because these are the four most common polymorphisms and are able to tag all common haplotypes at the adiponectin locus. These common haplotypes (frequency >5%) account for more than 70% of the haplotypes at this locus13. Furthermore, these four polymorphisms have been extensively studied regarding their functionality and relationship with diabetes11–13. The polymorphisms of C-11377G (rs266729), G276T (rs1501299) and T45G (rs2241766) have been proved to be associated with type 2 diabetes14–16. Our previous study involving 36,974 cases and 68,838 controls also showed that C-11377G (rs266729) might be associated with type 2 diabetes risk17. The adiponectin gene has been shown to be related to serum adiponectin levels among various ethnicities18–20. In epidemiological studies, serum levels of adiponectin predicted the risk of type 2 diabetes21–23, evidence suggests that the genetic variations in adiponectin gene might affect the serum adiponectin levels and cause insulin resistance. Both G alleles of T45G (rs2241766) and G276T (rs1501299) are associated with the lower serum adiponectin levels in type 2 diabetes patients15,24,25. Thus, the adiponectin gene gains much more importance in its relationship with diabetes and serum adiponectin levels. However, the role of adiponectin in the pathogenesis of DR is still largely unknown. Relevant clinical studies have been inconclusive26–28. Therefore, we investigated the possible role of serum adiponectin levels and adiponectin gene polymorphisms in the development of DR, and we attempted to detect whether the gene–environment interaction modifies DR risk.

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MATERIALS AND METHODS Study Population

This was a population-based cross-sectional study. Chinese patients with type 2 diabetes were consecutively recruited between January 2011 and December 2011 from the Wenhua community clinics of Qiqihar City, China. Considering the possible influence of duration of diabetes, non-DR patients with shorter diabetes duration might develop DR later on, we excluded all the non-DR patients with duration of diabetes G, A -4034C, +276G>T –11377C>G, A -4034C, +45T>G, +276G>T Environment–environment interaction model Family history of diabetes Family history of diabetes, insulin therapy Duration of diabetes, family history of diabetes, insulin therapy Gene–environment interaction model Insulin therapy C-11377G (rs266729), insulin therapy Family stress, history of hypertension, insulin therapy G276T (rs1501299), family stress, family history of diabetes, insulin therapy

P-value permutation test

0.58 0.55 0.56 0.57

0.56 0.51 0.53 0.49

10/10 6/10 9/10 10/10

0.82 0.95 1.70 0.96

(0.61–1.08) (0.39–2.12) (0.74–3.67) (0.39–2.12)

0.63 0.65 0.65

0.64 0.68 0.65

10/10 10/10 8/10

2.82 (2.29–3.53 3.29 (2.34–4.26) 2.89 (2.12–4.52)

0.63 0.64 0.65 0.67

0.63 0.65 0.62 0.62

10/10 10/10 7/10 6/10

2.01 2.53 1.95 2.13

0.12 0.89 0.17 0.92 0.001 0.001 0.001

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Gene-environment interaction between adiponectin gene polymorphisms and environmental factors on the risk of diabetic retinopathy.

To evaluate whether the adiponectin gene is associated with diabetic retinopathy (DR) risk and interaction with environmental factors modifies the DR ...
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