The association between paraoxonase 1 activity and the susceptibilities of diabetes mellitus, diabetic macroangiopathy and diabetic microangiopathy

Abstract We carried out this meta‐analysis to explore the influence of paraoxonase 1 activity on the susceptibility of diabetes mellitus (DM), diabetic macroangiopathy and diabetic microangiopathy. Relevant studies were identified from PubMed, Web of Science and CNKI without language limitation, following the inclusion and exclusion criteria. Statistical analyses were implemented with the STATA 12.0 statistical software. Thirty‐six case‐control studies were included in the meta‐analyses, in which 35 for the association between paraoxonase 1 activity and DM risk, 8 for diabetic macroangiopathy and 7 for diabetic microangiopathy. Paraoxonase 1 activity was significantly associated with the susceptibility of DM in pooled population (SMD = −1.37, 95% CI = −1.79 ∼ −0.96, P = .000), and Asians (SMD = −2.00, 95% CI = −2.56 ∼ −1.44, P = .000), but not in non‐Asians (SMD = −0.44, 95% CI = −0.91 ∼ 0.03, P = .069). However, marked heterogeneity was existed (I2 = 98.10%, P = .000) and subgroup analyses failed to investigate the sources of heterogeneity. Then, meta‐regression was performed and found that ethnicity could explain the observed between‐study heterogeneity (P = .002). Meanwhile, significant associations were found between paraoxonase 1 activity and diabetic macroangiopathy (SMD = −1.06, 95% CI = −1.63 ∼ −0.48, P = .000) and diabetic microangiopathy (SMD = −0.72, 95% CI = −1.32 ∼ −0.13, P = .018). In conclusion, paraoxonase 1 activity plays important roles in the risk of DM, diabetic macroangiopathy and microangiopathy with ethnicity differences. Further studies with large sample and well design are needed to confirm these results.

and development of DM, such as genetic, psychological, lifestyle and environment. Among these influential factors in DM, the serum level, the activity and gene polymorphisms of paraoxonase 1 played important roles in the susceptibility of DM. Paraoxonase 1, a member of hydrolases with a glycoprotein structure, is a 354 aa glycoprotein of about 45 kD that is synthesized in the liver, released to the blood and binds to the high-density lipoprotein in calcium-dependent manner. 4 Paraoxonase 1 has been demonstrated approximately 200 nucleotide polymorphisms, such as Q192R polymorphism, which was significantly associated with the susceptibility to T2DM by meta-analysis. 5  It has been reported that paraoxonase 1 activity was decreased in heart disease, 6 Subsequently, there were some studies on the associations between paraoxonase 1 activity and the susceptibilities of DM and DM complications. However, the previously published results remain contentious. Therefore, to firmly demonstrate the association of paraoxonase 1 activity (paraoxon as substrate) with the susceptibility to DM, diabetic macroangiopathy and diabetic microangiopathy, we performed this meta-analysis of data from thirty-six studies.

| METHODS
We carried out literature searches in PubMed, Web of Science and China National Knowledge Internet (CNKI) without language limitation, using the following key words: "PON1" or "paraoxonase 1," "diabetes" or "diabetes mellitus" or "DM" or "T2DM" or "T1DM," and "activity." On the other hand, relevant articles were hand searched to identify additional reports.

| Inclusion and exclusion criteria
The following criteria were used to select articles included in this meta-analysis: (1) published as original case-control studies; (2) paraoxonase 1 activity was detected in serum using paraoxon as the substrate; (3) reported an association between paraoxonase 1 activity and the susceptibilities of DM, diabetic macroangiopathy and/or diabetic F I G U R E 1 Flow diagram of the search strategy and study selection microangiopathy. When the same series of patients were used in more than one article, we used the latest and most complete one.

| Data extraction
WDL and WCF screened all searched articles and extracted data from all eligible publications independently. For each study, we carefully extracted the following information: name of the first author, published year, country, ethnicity, type of DM, type of control and paraoxonase 1 activity (mean AE SD) in each group. If there were any discrepancies, an agreement was reached after discussion; otherwise, another author was consulted to resolve the dispute.
T A B L E 1 Characteristics of studies included in this meta-analysis for the relationship between paraoxon activity and diabetes risk

Author
Year The unit of paraoxonase 1 activity is U/mL.

| Statistical analysis
Paraoxonase 1 activity in each group was described as mean AE SD.
Standard mean differences (SMD) were used to evaluate the associa-  Two studies used the same case series, respectively, so the most recent publication was included. 8,16 Lastly, 36 case-control studies were included in the meta-analyses.  Thirty-four publications were written in English, and two were written in Chinese. 17,18 The detailed information is shown in Tables 1 and 2. The first author, published year, country, ethnicity, the types and numbers of cases and controls, and levels of paraoxonase 1 activity for each study were presented.

| Paraoxonase 1 activity and DM risk
As shown in Table 1 Table 3).
There was no significant publication bias existed, demonstrated by funnel plot and Egger's test (P = .116, data not shown).

| DISCUSSION
Our meta-analysis firstly demonstrated the associations between paraoxonase 1 activity and DM, diabetic macroangiopathy and diabetic microangiopathy by polling the individual data set. In the overall meta-analysis of paraoxonase 1 activity, susceptibility of DM significantly increased with low levels of paraoxonase 1 activity, but strong between-study heterogeneity was found. Therefore, to F I G U R E 3 A, Forest plot for the association between paraoxonase 1 activity with diabetic macroangiopathy; B, Forest plot for the association between paraoxonase 1 activity with diabetic microangiopathy address the substantial heterogeneity, subgroup analyses on ethnicity, type of control and type of DM were conducted. But significant heterogeneity was still existed. Then, meta-regression was performed using the following covariates: published year, sample size, ethnicity, type of control and type of DM and the results showed that ethnicity could explain the observed between-study heterogeneity. In addition, subgroup analysis showed significant associations between paraoxonase 1 activity and DM in Asian group, but not in non-Asian group. Paraoxonase 1 activity was different from ethnicity, and significantly higher in Malays and Chinese than Indians. 22 A recent meta-analysis on the associations of paraoxonase 1 Q192R/L55M genetic polymorphisms with susceptibility of T2DM also suggested a significant ethnicity differences. 5 There are huge racial and regional differences in the genetic polymorphisms of In this meta-analysis, there existed some limitations. First, only articles with English and Chinese language were included in this study, some publication bias may exist. Second, significant heterogeneity was found in our analysis about the association between paraoxonase 1 activity and susceptibility of DM and diabetic complications, and for DM, ethnicity might explain some of the sources of between-study heterogeneity. But there were only 8 and 7 articles included for analysis of the association between paraoxonase 1 activity and diabetic macroangiopathy and microangiopathy, respectively, so we failed to find the sources of heterogeneity. Thus, large sample and welldesigned studies needed to demonstrate the result in the further.
In conclusion, paraoxonase 1 activity plays important roles in the risk of DM, diabetic macroangiopathy and microangiopathy with ethnicity differences. Further studies with large sample and well design are needed to confirm these results.

ACKNOWLEDG EMENTS
This research was supported by the National Natural Science Foundation of China (No. 81701962).

CONFLI CT OF INTEREST
All authors declared that there were no potential conflict of interests.

S U P P O R T I N G I N F O R M A T I O N
Additional supporting information may be found online in the Supporting Information section at the end of the article.
How to cite this article: Wu D, Wu C, Zhong Y.