The angiotensin-converting enzyme gene insertion polymorphism: a higher risk for psoriasis in male patients

Dear Editor, Psoriasis is a chronic inflammatory skin disease clinically manifested as well‐defined red, scaly plaques typically located on the scalp, knees or elbows. Angiotensin‐converting enzyme (ACE) is an important circulating enzyme in the renin–angiotensin–aldosterone system that converts angiotensin I into angiotensin II. Angiotensin II has been proven to play a proinflammatory role,1 and also inactivates bradykinin, which has been suggested to play a role in the pathogenesis of psoriasis.2 ACE contains a polymorphism based on the presence (insertion, I) or absence (deletion, D) of a 287‐bp Alu repeat sequence within intron 16, resulting in three genotypes: D/D and I/I homozygotes and I/D heterozygote.3 Several studies have investigated the involvement of ACE alleles and genotypes in psoriasis but the results have been conflicting. The present study is so far one of the largest specifically investigating the association of ACE polymorphisms with psoriasis susceptibility. In total 486 cases of psoriasis and 571 control samples were recruited for the present study. Both patients and controls of matched ethnic background belonged to various castes and tribes from Northern Punjab and Khyber Pakhtunkhwa. Of all the subjects included, 73% of cases and 70% of controls were Punjabi, whereas 16% of cases and 15% of controls were Pathan. The rest of the samples belonged to different castes that were equally represented in the case and control groups. Eighty percent of the cases had plaque psoriasis while 18% had psoriatic arthritis. Patients aged ≤ 40 years were considered as type I patients, whereas those aged > 40 years were considered type II. The demographic characteristics of the patient and control groups are listed in Table 1. Blood was obtained following written informed consent and DNA was isolated using a standard protocol.4 Polymerase chain reaction (PCR) amplification was carried out as described previously.5 6 PCR products were separated on 2% agarose gel and visualized under an ultraviolet transilluminator after staining with ethidium bromide. The fragment size of 190 bp represented allele D (deletion) while the fragment of 490 bp represented allele I (insertion). Odds ratios and 95% confidence intervals were determined by means of an online calculator (http://www.hutchon.net/ConfidOR.htm). Significance at P < 0·05 was calculated using the 2 × 2 χ2‐contingency test with Yates correction (http://vassarstats.net/odds2x2.html). Characteristics of the study group for the ACE association study Values are n (%) unless stated otherwise. aType I, patients aged ≤ 40 years; type II, patients aged > 40 years. Characteristics of the study group for the ACE association study Values are n (%) unless stated otherwise. aType I, patients aged ≤ 40 years; type II, patients aged > 40 years. In the present study the homozygous insertion (I/I) genotype was found to be strongly associated with risk of psoriasis (P < 0·001), whereas the homozygous deletion genotype (D/D) was associated with protection (P = 0·04; Table 2). A similar association with genotype I/I was observed in both type I and type II samples (Table S1; see Supporting Information). However, when the data were analysed on the basis of sex it was found that the genotype I/I and allele I frequencies were significantly higher in male patients (P < 0·001), whereas no association was observed in female patients (Tables S2, S3; see Supporting Information). The genotypic frequency distributions of patients with psoriasis vs. controls and various subgroups are shown in Figure S1 (see Supporting Information). ACE genotype and alleles in patients with psoriasis and controls OR, odds ratio; CI, confidence interval; I/I, homozygous insertion; I/D, heterozygous insertion/deletion; D/D, homozygous deletion. aValues are n (%). ACE genotype and alleles in patients with psoriasis and controls OR, odds ratio; CI, confidence interval; I/I, homozygous insertion; I/D, heterozygous insertion/deletion; D/D, homozygous deletion. aValues are n (%). Tissue ACE can control the cutaneous inflammatory response in psoriasis by degrading bradykinin and substance P, which are strong mediators of inflammation.7 Activation of the kallikrein–kininogen system in plasma and tissue has been associated with psoriasis.8 The insertion allele of ACE has been shown to be associated with lower ACE activity and kinin degradation.9 For this reason, we speculate that changes in ACE activity due to I/D polymorphism, leading to reduced ACE levels in plasma, may augment the activation of the kallikrein–kininogen system, increasing bradykinin levels and related inflammatory metabolites in the skin and subsequently increasing the risk of psoriasis, especially in male patients. Many studies have investigated the association between ACE polymorphisms and susceptibility to psoriasis in white and Asian populations, but the results are inconsistent. However, the present results do support the reserved conclusion of a meta‐analysis showing association of genotype I/I with the disease in Asian patients.10 The discrepancy between the findings in European and Asian populations may be due to the fact that the pathogenesis of psoriasis involves a complicated interaction between genetic and environmental components. Our results showed a novel finding of genotype I/I and allele I frequencies being significantly higher in male Pakistani patients with psoriasis than in the male control group, with no such association in the female group. These sex‐based differences suggest that there may be differences in the renin–angiotensin system of men and women, and that the mechanism might involve the role of sex hormones. Association of ACE I/D polymorphism in Pakistani patients with psoriasis has not been studied before, and the present study is the first such attempt to investigate this association. The present study concluded that the homozygous insertion gene is a risk factor for psoriasis in the Pakistani population in general. Differences in the results compared with some of the previous studies may be due to several factors, such as racial/geographical differences, the number of male and female patients under study and the genetic heterogeneity and multifactorial aetiology of psoriasis. However, most previous studies have shown an association with the insertion polymorphism and psoriasis, and studies that do not show this association typically recruited a smaller number of patients. In addition, our results show for the first time a significant difference between the ACE insertion polymorphism and sex, where there is a significantly higher risk of psoriasis in male individuals carrying two copies of the insertion polymorphism compared with female individuals. Funding sources: no external funding. Conflicts of interest: none declared. Fig S1. Angiotensin‐converting enzyme insertion/deletion genotypes in psoriasis subgroups and controls. Table S1. Angiotensin‐converting enzyme genotype and allele frequencies with respect to age of onset in the psoriasis group. Table S2. Angiotensin‐converting enzyme insertion/deletion polymorphism in male patients with psoriasis and male controls. Table S3. Angiotensin‐converting enzyme insertion/deletion polymorphism in female patients with psoriasis and female controls.