Serum paraoxonase (PON1) 55 and 192 polymorphism and paraoxonase activity and concentration in non-insulin dependent diabetes mellitus
Introduction
The oxidative modification of low-density lipoprotein (LDL) in the artery wall is currently believed to be central to the pathogenesis of atherosclerosis [1]. Therefore, mechanisms that prevent the oxidation of low density lipoprotein (LDL) have received increasing attention in recent years. One such mechanism is the prevention of LDL-oxidation by high-density lipoprotein (HDL) [2]. HDL appears to decrease the accumulation of lipid-peroxides on LDL by a mechanism that is, at least in part, enzymatic [3]. We have subsequently shown that the HDL-associated enzyme, paraoxonase (PON1), is one of the enzymes of HDL responsible for its ability to prevent the accumulation of lipid-peroxides on LDL 4, 5. These findings have since been confirmed by others [6]. PON1 has previously received most attention because it is the enzyme present in the serum of mammals (as opposed to insects), which is responsible for resistance to organophosphate toxicity [7]. Serum PON1 activity is decreased in subjects, who have had a myocardial infarction [8], and in both insulin dependent and non-insulin dependent diabetes (IDDM and NIDDM), particularly so when it is complicated by neuropathy [9]. Also, streptozotocin-induced diabetes results in a progressive decrease in serum paraoxonase activity [10]. This evidence has given rise to speculation that decreased PON1 activity is associated with the increased lipid-peroxidation found in diabetes and could therefore contribute to excess mortality from coronary heart disease (CHD) and that it might be a factor determining predisposition to neuropathy, either because lipid peroxidation is also important in neural damage or because of increased susceptibility to low levels of organophosphates encountered in the everyday environment [9].
Paraoxonase (aryldialkylphosphatase [E.C. 3.1.8.1]) is a calcium dependent serum esterase that is synthesised by the liver and hydrolyses aromatic carboxylic acid esters and organophosphate insecticides and nerve gases 11, 12. Purified human PON1 has a molecular mass of 43–45 kDa and contains up to three carbohydrate chains that account for 15.8% of its weight [13]. PON1 is associated with a specific HDL sub-species also containing apolipoprotein (apo) A1 and clusterin which may explain the weak but statistically significant association with total HDL 11, 12. PON1 activity is genetically determined by two alleles at a single autosomal locus 14, 15, an amino acid substitution at position 192 giving rise to two alloenzymes, the low activity A-type (glycine at position 192) and the high activity B-type (arginine at position 192). There also exists a second polymorphism of the human PON1 gene affecting amino acid 55 giving a leucine (L allele) substitution for methionine (M allele). Initially it was reported that this polymorphism had no apparent effect on PON1 enzyme activity 14, 15. However, a later study carried out in a population with NIDDM showed that the L/M polymorphism affects PON1 activity [16], and we have recently found that in a healthy non-diabetic population both PON1 activity and specific activity are affected by the 55 polymorphism [17].
One study of the relationship of the PON1 192 polymorphism to plasma lipid and lipoprotein concentrations in non-diabetic populations suggested that the A-phenotype may be associated with decreased serum apo B and triglyceride concentrations [18]. In another in the Hutterite Brethren, a genetically closed society, the 192 AA genotype was also associated with increased serum concentration of HDL and decreased serum total cholesterol, triglycerides and LDL compared to the 192 BB genotype [19].
In three case-control studies the PON1 BB genotype was found to be present with an increased frequency in CHD in both NIDDM and non-diabetic patients with CHD 20, 21, 22, although in other studies the association was not found 23, 24. Nonetheless the association of the BB genotype with CHD in some reports is intriguing, because this genotype is responsible for an alloenzyme of PON1 with the highest activity towards paraoxon, which might be expected to provide most protection of LDL against lipid-peroxidative damage, if a similar activity polymorphism was exhibited towards lipid peroxides. However, recently we have shown that HDL isolated from BB homozygotes, although most active in the hydrolysis of paraoxon is much less effective at protecting LDL against lipid-peroxidation than HDL from either AA homozygotes or AB heterozygotes. [25]. This has therefore prompted us to re-examine the effect of NIDDM on serum PON1 activity and also to investigate the interaction between NIDDM and both the 192 and the 55 polymorphism and PON1 activity. Furthermore there have been no studies directly comparing the effect of either of the polymorphisms on PON1 and lipoproteins in NIDDM and controls from the same geographical area. We have, therefore, also compared the distribution of both the PON1 192 and PON1 55 polymorphisms and their effect on PON1 activity, concentration and serum lipid and lipoprotein parameters in a NIDDM population and compared it to healthy, non-diabetic controls.
Section snippets
Subjects
The NIDDM population comprised 252 unselected patients who were attending the Manchester Diabetes Centre. Diabetes mellitus was diagnosed according to the 1980 World Health Organisation Expert Committee Report [26]. There were 209 patients of European descent and 43 of Asian Indian descent. Ninety three individuals were free of diabetic complications and 159 individuals had one or more complication (124 with peripheral neuropathy, 82 with nephropathy, 101 with retinopathy and 23 with coronary
Demographic details of the study populations
The NIDDM group were on average older and were significantly more obese than the control subjects (Table 1). The NIDDM population had moderately good glycaemic control as judged by HbA1c. Age, BMI and HbA1c did not differ significantly between males and females.
Serum PON1 in the study populations
Both the median serum PON1 activity (P<0.01) and concentrations (P<0.001) were significantly decreased in the NIDDM population compared to the control subjects (Table 1). There was no significant difference in the PON1 specific activity.
Discussion
These data confirm and extend our previous observations of low PON1 activity in NIDDM [9], despite an increased frequency of the B-allele (high activity) in NIDDM. We have also confirmed an effect of the PON1 55 polymorphism on PON1 activity. In both controls and NIDDM subjects AA/MM homozygotes have the lowest PON1 activity and BB/LL the highest suggesting that the effect of the two polymorphisms on activity were cumulative. In NIDDM subjects the PON1 concentration was also affected by the 55
Acknowledgements
This study was supported in part by grants from the Medical Research Council (BM), The British Heart Foundation (SA) and The British Diabetic Association (KJ).
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