Abstract
Background Hp2 alleles of the haptoglobin α–chain polymorphism reduce the anti-oxidant properties and increase the pro-inflammatory actions of this acute-phase protein in a gene-dosage fashion. We hypothesized that the haptoglobin polymorphism might contribute to the increased oxidative stress and low-grade chronic inflammation frequently associated with polycystic ovary syndrome, obesity, and abnormalities of glucose tolerance.Methodology/Principal FindingsSerum haptoglobin and the haptoglobin α–chain polymorphism were determined in 141 patients with polycystic ovary syndrome and 102 non-hyperandrogenic women. Of the whole group of 243 premenopausal women, 117 were obese and 51 showed abnormal glucose tolerance. Although serum haptoglobin concentrations were similar in PCOS patients and controls, the former presented with an increased frequency of Hp2 alleles (62% vs. 52%, P = 0.023). Circulating haptoglobin levels increased with obesity (P<0.001), yet no association was found between obesity and haptoglobin genotypes. No differences were observed in haptoglobin levels or genotype frequencies depending on glucose tolerance. Fifty percent of the variation in serum haptoglobin concentrations was explained by the variability in serum C-reactive protein concentrations, BMI, insulin sensitivity and haptoglobin genotypes.Conclusions/SignificanceSerum haptoglobin concentrations in premenopausal women are largely dependent on the haptoglobin polymorphism and on the presence of obesity, with insulin resistance and chronic inflammation possibly modulating this relationship. The association of polycystic ovary syndrome with Hp2 alleles suggests that the anti-oxidant and anti-inflammatory properties of haptoglobin may be reduced in these patients.
Highlights
Polycystic ovary syndrome (PCOS), a very prevalent syndrome characterized by the association of hyperandrogenism with chronic ovulatory dysfunction in premenopausal women [1,2], is among the most common metabolic associations of both type 1 [3,4] and type 2 diabetes mellitus [5]
As expected by design the patients with PCOS and the nonhyperandrogenic controls showed no statistically significant differences in the mean body mass index (BMI) or in the distribution according to the weight classification (Table 1), yet because PCOS patients were younger than controls (25.466.3 vs 31.767.7 yr respectively, P = 0.001), age was introduced as a covariate in the following analyses
The frequency of women presenting with serum haptoglobin concentrations above the references values for their haptoglobin genotype was similar in both groups
Summary
Polycystic ovary syndrome (PCOS), a very prevalent syndrome characterized by the association of hyperandrogenism with chronic ovulatory dysfunction in premenopausal women [1,2], is among the most common metabolic associations of both type 1 [3,4] and type 2 diabetes mellitus [5]. We have shown that serum ferritin concentrations are increased in PCOS patients independently of chronic inflammation, suggesting increased body iron stores in these women very especially when obesity is present [7]. Haptoglobin, a circulating acute-phase protein that is synthesized in the liver under the influence of several cytokines such as TNF-a and interleukin-6 [14], ameliorates the iron loss and renal injury that follows the liberation of hemoglobin from erythrocytes during processes of intravascular hemolysis. Haptoglobin accomplishes this function by forming soluble complexes with hemoglobin, thereby reducing the generation of oxygen reactive species and ameliorating oxidative stress [14]. We conducted the present study hypothesizing that haptoglobin and its polymorphism might mediate the associations of PCOS with hyperferritinemia and increased body iron stores, obesity and disorders of glucose tolerance
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