Correlation of oestrogen receptor gene polymorphism with gouty arthritis

Gout represents a group of diseases characterised by hyperuricaemia, arthritis, and uric acid crystal formation. Men have a higher level of serum uric acid and are more susceptible to gout than women. The lower serum urate values in women of reproductive age compared with their male counterparts have been ascribed to lower renal postsecretory uric acid reabsorption.¹ An increase in ratios of testosterone to oestradiol has been reported to be associated with hyperuricaemia.²

The oestrogen receptor gene is located at chromosome 6q25.1 and has a thymine–adenine (TA) dinucleotide repeat polymorphism 1174 bp upstream from exon 1. This polymorphism has been shown to be associated with menopausal osteoporosis,³ coronary artery disease⁴ and rheumatoid arthritis.⁵ The androgen receptor has three main functional domains that are located at Xq11–12, near the centromere of the X chromosome. Binding of the androgen receptor–androgen complex activates the expression of other genes (transactivation). This transactivation activity depends on the transactivation domain of the protein encoded by exon 1, which contains a polymorphic CAG repeat sequence. Previous studies have shown that the CAG repeat is associated with inflammatory arthritis, such as rheumatoid arthritis⁶ and ankylosing spondylitis,⁷ and severity of coronary artery disease in men.⁸

Methods and results

In this study, we enrolled 196 patients (181 men and 15 women) with gout according to the 1977 revised American College of Rheumatology criteria.⁹ In addition, 102 unrelated, healthy people (57 men and 45 women) living in central Taiwan served as control subjects. Informed consent was obtained from all subjects who participated in this study. Genomic DNA was prepared from peripheral blood using a genomic DNA isolation reagent kit (Genomarker, Taipei, Taiwan). The oestrogen receptor gene TA repeats and androgen receptor gene CAG repeats in patients and controls were typed by polymerase chain reaction.

The frequency distribution of the oestrogen receptor gene polymorphism in patients with gouty arthritis and healthy controls is presented in fig 1. Patients with gout had significantly shorter oestrogen receptor gene TA repeats than their sex‐matched controls (men: mean 14.9 v 17.2, p<0.001; women: mean 14.8 v 17.0, p = 0.002; table 1). We further classified the patients and controls into groups with shorter TA repeats (⩽18) and longer TA repeats (>18 repeats). The frequency of the shorter TA repeats (⩽18) was considerably higher in patients with gout than in healthy controls (data not shown).

Figure 1 Frequency distribution of oestrogen receptor gene thymine–adenine (TA) repeats polymorphism in patients with gout and healthy controls.

Table 1 Mean (SD) of the oestrogen receptor gene thymine–adenine repeats and androgen receptor gene CAG repeats for patients with gout and healthy controls.

Group	Women			Men
	n	Mean (SD)	p Value	n	Mean (SD)	p Value
OR gene TA repeats
Control	90	17.0 (3.8)	0.002	114	17.2 (4.0)	<0.001
Gout	30	14.8 (3.0)		362	14.9 (2.1)
AR gene CAG repeats
Control	84	22.0 (2.8)	0.928	55	21.4 (2.9)	0.300
Gout	30	21.9 (2.9)		181	21.9 (2.9)

AR, androgen receptor; OR, oestrogen receptor; TA, thymine–adenine.

Discussion

Our findings suggest that the oestrogen receptor gene TA repeat polymorphism is associated with the risk of developing gout in both men and women. In men, the risk is more consistently correlated with decreasing length of TA repeats. The protective effect of long TA repeats increases dramatically as the frequency of TA repeats increases in men. On the basis of the reports mentioned earlier, we conjecture that longer oestrogen receptor gene TA repeats increase the transactivational activity of the oestrogen receptor, facilitating uric acid excretion and thereby decreasing the susceptibility to gout. However, the speculation will need to be confirmed by further studies.