10.11648.j.sjcm.20130202.15

Science Journal of Clinical Medicine
2013; 2(2): 58-63
Published online April 2, 2013 (http://www.sciencepublishinggroup.com/j/sjcm)
doi: 10.11648/j.sjcm.20130202.15
The immunogenetic analysis of acne vulgaris
Anis Irawan Anwar1, Indropo Agusni2, Muh. Nasrum Massi3, Irawan Yusuf4
1Dermatology and Venereology Department, Faculty of medicine Hasanuddin University, Makassar, Indonesia 2Dermatology and Venereology Department, Faculty of medicine Airlangga University, Surabaya, Indonesia 3Microbiology Department Faculty of medicine Hasanuddin University, Makassar, Indonesia; and Physiology 4Department, Faculty of medicine Hasanuddin University, Makassar, Indonesia Email address
[email protected] (A. Irawan Anwar)
To cite this article
Anis Irawan Anwar , Indropo Agusni, Muh. Nasrum Massi , Irawan Yusuf. The Immunogenetic Analysis of Acne Vulgaris. Science Jour-
nal of Clinical Medicine. Vol. 2, No. 2, 2013, pp. 58-63. doi: 10.11648/j.sjcm.20130202.15
Abstract: Polymorphisms that occur in the CYP1A1, CYP17 and TNF-α genes affects hyperkeratinzation process, se-
bum production and inflammation in acne vulgaris. Polymorphisms of CYP1A1, CYP17 and TNF-α genes can be identified
by using PCR and sequencing techniques. The aim of this study is to demonstrate the role of polymorphisms of CYP1A1,
CYP17, and TNF-α genes and the interaction polimorphisms of CYP1A1, CYP17 and TNF-α genes to severe acne vulgaris.
This study was conducted as an observational study with case-control method, in 64 patients with severe acne, and as con-
trols 73 patients with mild acne and healthy people. Criteria based on Combined Acne Severity Classification. Biospesimen
blood 1 ml taken from vena mediana cubiti then performed PCR and sequencing to determine the sequence of nucleotides
in DNA fragments. The conclution from the study shows that polymorphisms of CYP1A1, CYP17, TNF-α genes and the
interaction polimorphisms of CYP1A1, CYP 17 and TNF-α genes is not a risk factor for severe acne vulgaris, but polymor-
phism of CYP1A1 gene is a risk factor for acne vulgaris.
Keywords: Severe Acne Vulgaris, Polymorphisms of CYP1A1, CYP17, and TNF-α genes, Interactions polymorphisms
of CYP1A1, CYP 17 and TNF-α genes
Sudirohusodo Hospital there were 22 visits (21% of all AV 1. Introduction
patient visit), in Dr. Moh. Hoesin Palembang Hospital there were 20 visits (6% of all AV patients visit), and Dr. Sardjito Acne vulgaris (AV) is a common skin disease, as well as Yogyakarta Hospital there were 97 visits (9% of all AV on our society in Indonesia (1). Acne does not threaten life but it often become a cosmetic problem in the form of se- Acne can be caused by several factors, such as excess vere AV resulting scar formation, and often leads to psy- sebum production, follicular hyperkeratinization, prolifera- chological complains, and even lead to lack of confidence tion of Propionibacterium acnes (P. acnes), inflammation, in a person (1, 2). In a study conducted by Abdel-Hafez et al (2009) demonstrated psychiatric symptoms such as anxiety, Several genes that may influence the occurrence of AV depression, paranoia, and psychosis related to AV and including gene CYP 1A1, CYP 17 and TNF-α. Research showed negative effect on the quality of life of patients (3). conducted in Germany showed that CYP 1A1 gene poly- Acne vulgaris is a chronic inflammatory pilosebaceous morphisms causing the lack of an active natural retinoids follicle disease, characterized by comedones, papules, pus- resulting in follicular hiperkeratinization resulting AV (7). tules, nodules, and sometimes scars. Acne primarily affects CYP17 gene that encodes cytochrome P450c17α is an en- the face, neck, upper trunk and upper arms (4). Acne vulga- zyme in androgen biosynthesis that mediates the activity of ris is mainly found in adolescence and adulthood, and often steroid 17α-hydroxylase and 17, 20-lyase. The presence of at a younger age or older (1). In the United States this dis- CYP 17 gene polymorphism affects the activity of the en- ease affects 40-50 million people each year (5), and the zyme CYP 17 that will change the levels of androgen, number of visits to the dermatologist are at 20% of all visits progesterone and estrogen hormones. Androgens increase (6). From the medical record at several hospitals in Indone- sebum production and follicular keratosis which plays an sia in 2008, obtained a high number of AV patients visits in important role in the development of acne (8). Tumor necro- some hospitals in Indonesia, among others, Dr Wahidin Science Journal of Clinical Medicine 2013, 2(2): 58-63 sis factor-alpha (TNF-α) is one of the proinflammatory 3. Results
cytokines that initiate and regulate the flow of cytokines during the inflammatory response. The factors that cause The number of samples in this study were 137 people changes in the production of TNF-α may influence the de- consisting of 53 males (38.7%) and 84 females (61.3%). gree of inflammation. The existence of polymorphism in The sample consisted of 64 patients with severe AV, 31 the TNF-α gene can increase the production of TNF-α and males (48.4%) and 33 females (51.6%) and 73 patients with aggravate AV (9). Expression of TLR2 and TNF-α by kera- mild AV and healthy individuals, 22 males (31.1%) and 51 tinocytes induced by P. acnes in acne inflammatory phase Table 1 shows that from 64 people with severe AV, there The results of CYP 1A1, CYP 17 and TNF-α gene poly- were 31 (51%) who had a GG genotype, compared to 30 morphisms in AV is still very limited, and the results of (50%) with mild AV and healthy individuals. GA genotype research that has been done in Makassar who get results are in severe AV are at 30% compared to 70% in mild AV and not statistically significant between CYP 17 gene polymor- healthy individuals. While the AA genotype in severe AV phisms and progression of severe acne, prompted us to per- 58.3% compared to 41.7% in light AV and healthy individ- form research on gene polymorphisms CYP 1A1, CYP genes 17 and TNF-α genes and their interactions in AV. Table 1. Distribution of CYP1A1 genotype on the severe AV group and
mild AV and healthy individuals group.
2. Material and Methods
Genotype CYP 1A1
Total (%)
This study is an observational study with case-control method, in which the cases were severe acne patients and the controls were patients with mild acne and healthy people. The study was conducted in the Department of Dermatology and Venereology Hasanuddin University, Wa-hidin Sudirohusodo Hospital and network hospitals, labora- 61 (100,0) 40 (100,0) 36 (100,0) 137 (100,0) tory of Microbiology, Faculty of Medicine Hasanuddin Note. Pearson Chi-Square p = 0,032 University in Makassar, and laboratory Eijkman in Jakarta in March 2010-September 2011. Tabel 2 shows that from 64 people with severe AV, there The study population was divided into two characters, were 20 (46,5%) who had CC genotype, compared to 23 namely the case with the following inclusion criteria: pa- (53,5%) with mild AV and healthy individual. TC genotype tients with severe acne based on Combined Acne Severity exist in 44,7% severe acne compared to 55,3% in mild AV Classification criteria, those are assessed by a dermatolo- and healthy individual. While the TT genotype 48.9% in gist and patients signed the informed consent. While the severe AV compared to 51.1% of mild AV and healthy indi- excluded case criteria were: patients with severe acne who received antibiotics and anti-inflammatory medication for 1 month, patients with severe acne who use hormonal contra- Tabel 2. Distribution of CYP17 genotype on the severe AV group and mild
ceptives, patient with severe acne who smoke, patients with AV and healthy individuals group. severe acne who are pregnant and breastfeeding. Inclusion CYP 17 genotype
criteria for the control group were patients with mild acne Total (%)
and healthy people on the same age with the case and agreed to and signed informed consent. As for the exclu- sion criteria for the control group were mild acne patients who received antibiotics and anti-inflammatory medication for 1 month, patients with mild acne who use hormonal contraceptives, patients with mild acne who are smokes, 43 (100,0) 47 (100,0) 47 (100,0) 137 (100,0) and patients with mild acne who are pregnant and breast- Note: Pearson Chi-Square p = 0,918 feeding. Determination of the sample based on the table of Rochat et al, with OR = 3.5, the value of α = 0.05, β = 0.1, Tabel 3 shows that from 64 people with severe AV, there and f = 0.30 is 56. In this study, severe acne cases collected were 3 (37,5%) who had AA genotype, compared to 5 (62,5%) with mild AV and healthy individual. GA genotype Blood specimens were taken 1 mL of 64 patients with exist in 55,6% severe acne compared to 44,4% in mild AV severe acne as cases and 73 patients with mild acne and and healthy individual. While the GG genotype 46.7% in healthy controls. The specimen will then be treated DNA severe AV compared to 53.3% of mild AV and healthy indi- isolation (sediment) for PCR testing. PCR method is pre- pared using DNA extract as a positive control and sterile The results of analysis of the interaction between geno- type, whether it is in the CYP 1A1, CYP 17, and TNF-α gene in severe AV, showed that the difference was not sta- Anis Irawan Anwar et al: The immunogenetic analysis of acne vulgaris sembling follicular keratosis Darier and pityriasis rubra pilaris (11). Hiperkeratinization follicular epithelium is one Table 3. Distribution of TNF-α genotype on the severe AV group and mild
important factor in the pathogenesis of acne (12). AV and healthy individuals group. Study conducted by Paraskevaidis et al in Germany TNF-α genotype
about the role of CYP 1A1 gene polymorphisms in acne Total (%)
showed normal frequency of m2 mutations from adenine to guanine substitution (A to G) result a change of isoleucine to valine amino acid which increases the activity of the enzyme. Another study focused on the development of can- cer bronchogenic also found the effect of the polymorphism of CYP 1A1 gene by increasing the activity of the enzyme Ket: Pearson Chi-Square p = 0,757 Cytochrome P450c17 is an enzyme in the synthesis of sexual steroids. This enzyme catalyzes the 17α- 4. Discussion
hydroxylation of pregnenolone and progesterone. Enzyme activity is required in the synthesis of androgens and estro- In this study found that the group with the genotype GG, gens. CYP17 gene is a gene that codes for this enzyme (13). GA and AA give a substantial proportion of the occurrence Varian of polymorphic P450c17 gene (CYP17) encode this of cases of acne vulgaris (Table 1), but the proportion of enzyme can lead to changes in the activity of CYP17 (14). cases with genotype AA higher than genotypes GG and GA. The role of androgens in the pathogenesis of acne has GG and GA genotype at position that gives the proportion been known. (8). There is evidence that androgenic stimu- of controls more than the AA genotype, this is a question to lation of sebaceous glands important role play in the occur- rence of acne (15). However, the actual genetic reasons, Combined genotypes GG and GA show properties AV how androgen effect on acne is still not clear (8). protection against the occurrence of severe cases with ER CYP17 gene in this research is done as study by He et al, of 0.85 (95% CI: 0.69 to 1.04). The fact shows the nature of in which the results obtained homozygous frequency C which is not in line with expectations (GG and GA geno- allele CYP17 gene in a group of severe AV in men was types as risk factors). The answer may lie in the selection of significantly higher than the control group. this study can mild AV were included in the control group, it may be the be concluded that the homozigositosis CYP17-34C / C may genotypes GG and GA as the initial trigger pain (mild AV) increase the risk of severe acne in men (8). should be grouped together with severe AV. Further analy- In this study, mutations of CYP17 gene occur with nuc- sis of the patients with grouping mild and severe AV as leotide substitution T / C at the 5 'untranslated region (UTR) cases and healthy individuals as controls. The results of the CYP17 promoter. Alleged that the substitution T / C will analysis between GG and AA genotype of CYP1A1 gene increase the rate of transcription of this enzyme in the CC showed that individuals who have the GG genotype of genotype due to increased activity of promoters (14) and CYP1A1 genes have ER 1.04 times (95% CI: 0.69 to 1.55) the consequence is an excessive production of glucocorti- than individuals who have genotype AA CYP1A1 gene. coids (13). Fiegelson and Haiman et al get estrogen levels The results of the analysis between GA and AA genotype of were higher in women with the A2 allele (allele C) CYP17 CYP1A1 gene showed that individuals who had GA geno- type of CYP1A1 gene have ER 0.71 times (95% CI: 0.47 to In this study was found the group with CC and TC geno- 1.07) than individuals who have genotype AA CYP1A1 type are not a risk factor for severe AV if compared with gene. The Further analysis showed true GG genotype as a the TT genotype, although the CC genotype had higher risk factor and genotyping GA can not be proven as a risk androgen levels. Research by Cibula et al did not show a positive relationship between androgen production and Theoretically, groups with genotypes GG and GA CYP severity of acne in women over the age of 17 years (18). 1A1gene has a natural retinoid levels were lower than in Another study examined the association between CYP17 the group with AA genotype. This occurance due to the gene polymorphism in women using PCR have also been increased activity of the enzyme in the metabolism and carried out by Tian et al used 3 genotyping androgen- inactivation of ATRA to 4-oxo-retinoic acid, so that active related gene CYP 17 and the results showed significant natural retinoids will be reduced. Deficiency of active natu- results between the genotypes of androgen is A2, A2 of the ral retinoids on the skin can cause abnormal differentiation CYP17 gene in 34 bp where there is a single base polymor- and hiperkeratinization sebosit follicular canal (7). It is well phism on changes from T to C in the untranslated region known that vitamin A deficiency resulted in a variety of (UTR) of the CYP17 gene. The effect of increased risk of epithelial metaplasia is accompanied by an increase in cell acne in women with higher levels of androgens (19). proliferation and hyperkeratosis of the skin. From several This study found no statistical relationship polymor- studies in animals and infants with vitamin A deficiency, phism with severe AV because acne is a disease that is in- suggesting that vitamin A deficiency causes a disease re- fluenced by a variety of factors, mainly by environmental Science Journal of Clinical Medicine 2013, 2(2): 58-63 well as the minor allele at position -308 increased in pa- In this study the use of TNF-α gene promoter at position tients with acne. G nucleotide replacement in the TNF-α -308 and the obtained results from 64 people with severe gene at position -308 are associated with increased tran- AV, there are 3 people (37.5%) who had AA genotype, scriptional activity of TNF-α and increased levels of circu- compared with 5 (62.5%) with severe AV and healthy indi- lating TNF-α (22). Substitution of guanine (G) to adenine viduals. GA genotype present in 55.6% severe AV com- (A) is also associated with increased susceptibility suffer- pared to 44.4% by mild AV and healthy individuals. While ing from chronic inflammatory diseases, including acne the GG genotype in severe AV compared with mild AV 46.7% vulgaris (9). Some diseases are associated with polymor-and 53.3% of healthy individuals (statistical test p = 0.757). phism in the TNF-α gene at position -308 one of them is From these results it can be seen GG genotype frequency breast cancer (23), chronic hepatitis B (22) dan schizophre- distributions predominantly found in the severe AV and mild groups and healthy individuals, and there was no sig- Various other related studies identified a single nucleo- nificant difference in genotype distribution in both groups tide polymorphism in the TNF-α gene promoter humans so that it can be interpreted that there is no relationship have been reported, and found an association between in- between genotype distribution of TNF-α with severe AV. creased susceptibility to various diseases. Research in Chile This is consistent with research conducted Baz K et al by Cuenca J et al against TNF-α genotyping conclude that (2008) in 113 patients with acne, 30 of them with severe there is a difference in the spread of allele TNF-α and eth- AV and GG genotype distribution obtained in 16 (53.3%), nic populations that have a high proportion of allele TNF-α genotype GA in 12 (40.0%) and genotype AA in 2 (6.7%) is also likely to have increased the incidence of multiple compared with 32 patients with mild AV GG genotype dis- metabolic diseases predisposing to chronic, degenerative tribution of 16 (50.0%), genotype GA 15 (46.8%) and the diseases, inflammatory and autoimmune diseases. This AA genotype 1 (3.2%) with the results of statistical tests (p indicates that there is a diversity of results of each minor = 0.463) (9). Based on statistical tests, our study found no alleles of several different tribes and populations and significant association between TNF-α gene polymor- changes in one or two copies of chromosome 6 in the pro- phisms with severe AV events (p = 0.757). This suggests moter region of the TNF gene cluster contained in the HLA that TNF-α gene polymorphism is not a risk factor for se- class III genes may lead to increased risk of various diseas- vere AV. In accordance with the results of the study in Tur- es (25). From the results of our study and compared with key found the severity of acne vulgaris genotype was not some previous studies that have been published can be con- associated with TNF-α. This can be caused by the expres- cluded that TNF-α gene polymorphism at position -308 in sion of TNF-α genotype is associated with individual HLA touch with a person suffering from acne vulgaris vulnera- (20) and is also influenced by the ethnic as found in the bility, but not related to the degree of severity of acne vul- study by Baz K et al in several different ethnic, found also that the frequency of heterozygotes genotif G / A is very Therefore, further discussion is necessary to see the ef- low on spare Asia (8-18%) when compared with research fects of retinoid therapy in severe AV group. Retinoid ther- apy is given in the form of topical tretinoin 0.05 to 0.1% In this study, all the results of sequencing compared to and / or oral isotretinoin. The proportion of patients with full sequencing TNFα gene promoter along the 605 base- severe AV who got improvement after retinoid therapy, pair (bp) referral of the gene bank using the BLAST pro- with GG genotype of CYP1A1 gene 50%, while those with gram (alert-2) from the webside: NBCI, and in our study the AA genotype of CYP1A1 gene as much as 42.9%. This with a sample of 64 patients with severe AV, we found 3 suggests that administration of retinoids in severe AV pa- (4.7%) mutations at position -308. Thus the discovery of tients with CYP1A1 gene polymorphisms provide a better the G allele frequency in TNF-α gene promoter -308 domi- outcome than severe AV patients without CYP1A1 gene nant position when compared with the frequency of allele A. polymorphisms, which are consistent with the theory that From the frequency distribution of genotypes, mutant AA the group with the GG and GA genotypes of CYP 1A1 genotype was found by 3 (4.7%) which is in line with re- gene has a lower natural retinoid levels than in group with search conducted in Turkey Baz K et al who found 4 (3.5%) the AA genotype, thus, giving retinoid provide improve- of 113 patients with acne mutations and research conducted ments in severe AV patients with CYP1A1 gene polymor- by Szabo K et al in Romania that found 4 (1.8%) of 229 patients with acne mutation (9, 21). Some research on the This study still remains questions thet has not been com- analysis of allele frequencies of TNF-α was reported by pleted answered. From the three gene polymorphisms stu- Szabo et al in position 1031 T> C,-857C> T,-863C> A,- died, only further analysis of CYP1A1 gene polymor- 308G> A and-238g> A suspected role in the development phisms showing the GG genotype of CYP1A1 gene as a of the inflammatory reaction in acne vulgaris . Results ob- risk factor for acne vulgaris. Theoretically, individuals with tained no significant differences in allele frequencies be- the GG genotype of CYP1A1 gene can be fall into active tween cases and controls at the position -1031, -861, -238 natural retinoid deficiency (7). Therefore, further discus- SNPs, whereas at position -857 and -308 obtained signifi- sion is necessary to see the effects of retinoid therapy in cant results (p = 0.010) between allele C major and acne, as severe AV group. Retinoid therapy is given in the form of Anis Irawan Anwar et al: The immunogenetic analysis of acne vulgaris topical tretinoin 0.05 to 0.1% and / or oral isotretinoin. The factor for severe AV. It is need to perform a measurement of proportion of patients with severe AV who got improve- natural retinoids, the 4-oxo retinoic acid, the rate of sebum, ment after retinoid therapy, with GG genotype of CYP1A1 the hormones androgen and TNF-α level in relation to the gene 50%, while those with the AA genotype of CYP1A1 influence of CYP1A1 gene polymorphisms, gene CYP17 gene as much as 42.9%. This suggests that administration and TNF-α gene expression in the creation of severe AV. of retinoids in severe AV patients with CYP1A1 gene po- Should be examined other genes that may play a role in the lymorphisms provide a better outcome than severe AV pa- tients without CYP1A1 gene polymorphisms, which are consistent with the theory that the group with the GG and GA genotypes of CYP 1A1 gene has a lower natural retino- References
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