Ⅰ型自身免疫性肝炎患者细胞因子基因多态性研究

目的 评价肿瘤坏死因子—α(TNF—α)和白细胞介素—10(IL—10)启动了基因的多态性在Ⅰ型自身免疫性肝炎(AIH)易感背景中的作用。 方法 采用聚合酶链反应扩增后寡核苷酸探针杂交法,在Ⅰ型AIH(32例)和健康对照者(48例)中,对2个TNF—α启动子多态性位点(—238和—308)和3个IL—10启动子多态性位点(—1082、—819和—592)进行分析。 结果 Ⅰ型AIH患者中TNF—α启动子—308位点鸟嘌呤(G)被替换为腺嘌呤(A)的频率显著高于健康对照组(53.1％对27.1％,RR=1.05,P<0.05)。TNF-238位点和IL-10启动子3个位点的多态性差异无显著性。 结论 TNF—308位点G被替换为A (TNF—308A)可能是Ⅰ型AIH的发病机制之一。     

I型自身免疫性肝炎患者细胞因子基因多态性研究

目的评价肿瘤坏死因子-α(TNF-α)和白细胞介素-10(IL-10)启动子基因的多态性在I型自身免疫性肝炎(AIH)易感背景中的作用.方法采用聚合酶链反应扩增后寡核苷酸探针杂交法,在I型AIH(32例)和健康对照者(48例)中,对2个TNF-α启动子多态性位点(-238和-308)和3个IL-10启动子多态性位点(-1082、-819和-592)进行分析.结果 I型AIH患者中TNF-α启动子-308位点鸟嘌呤(G)被替换为腺嘌呤(A)的频率显著高于健康对照组(53.1%对27.1%,RR=3.05,P＜0.05).TNF-238位点和IL-10启动子3个位点的多态性差异无显著性.结论TNF-308位点G被替换为A(TNF-308A)可能是I型AIH的发病机制之一.     

白细胞介素-10基因多态性与自身免疫性肝病相关性研究

目的研究白细胞介素10(IL-10)基因启动子区域-592、-819和-1082位单核昔酸多态性与自身免疫性肝病发病之间的关系。方法分别采用聚合酶链反应限制性片段长度多态性分析法(PCRRFLP)和聚合酶链反应一序列特异性引物扩增法(PCRSSP)检测54例自身免疫性肝炎(AIH)，77例原发性胆汁性肝硬化(PBC)患者及160例健康献血员外周血单个核细胞基因组DNA IL-10基因启动子区域3个多态位点-592，-819、-1082的基因多态性，并进行相关性分析。结果54例AIH和77例PBC患者与160例健康对照组的IL-10启动子-1082、-819和592基因型分布的统计学分析表明，差异无显著性。结论IL-10启动子基因多态性与自身免疫性肝病发病之间无显著关联性。     

肺结核患者肿瘤坏死因子-α基因多态性的研究

目的通过病例-对照研究,探讨肿瘤坏死因子-α(TNF-α)基因启动子区-238A/G、-308A/G位点单核苷酸多态性(SNP)与肺结核病的关系。方法采用序列特异性引物PCR(PCR-SSP)及测序技术检测深圳地区汉族人群肺结核患者200例及健康对照者197例TNF-α启动子区-238A/G、-308A/G位点基因多态性。采用直接计数法计算各组基因型频率及等位基因频率,并进行χ2检验;采用SHEsis软件进行单倍型分析。以P值0.05为具有统计学意义。结果2组人群TNF-α启动子区-238A/G、-308A/G位点基因型及等位基因分布频率差异无统计学意义(P0.05);两位点各种单倍型在2组间分布差异无统计学意义(P0.05)。结论TNF-α启动子区-238、-308位点基因多态性与中国汉族人群肺结核病易感性未见关联。     

细胞毒性T淋巴细胞相关抗原-4+49基因多态性与自身免疫性肝病相关

自身免疫性肝炎(autoimmune hepatitis，AIH)和原发性胆汁性肝硬化(primary biliary cirrhosis,PBC)是两组重要的自身免疫性肝病，多基因遗传因素在AIH和PBC的发生发展中起重要作用。细胞毒性T淋巴细胞相关抗原-4(CTLA-4)基因位于染色体2q33区域，其外显子1区基因多态性与高加索人种的AIH和PBC相关。我们采用限制性片段长度多态性分析法(PCR-RFLP)分析了49例AIH和58例PBC患者CTLA-4外显子1区49位A／G单核苷酸多态性，并与正常献血者作比较。     

上海地区非酒精性脂肪性肝炎患者肿瘤坏死因子-α的基因多态性研究

目的:了解非酒精性脂肪性肝炎(NASH)患者肿瘤坏死因子-α(Tumor necrosis factor-alpha,TNF-α)启动子基因多态性在上海人群中的分布及其与疾病的相关性。方法:用聚合酶链反应-限制性片段长度多态性技术检测400例NASH患者和50例健康对照者外周血的TNF-α基因启动子区域-308、-238位点基因多态性。结果:TNF-α基因-308位点在NASH组中变异的G/A基因型频率比健康对照组明显升高(P<0.01,OR=14.667,95%CI 4.436～48.497),而-238位点其基因变异频率两组差异无显著性意义(P>0.05)。结论:TNF-α基因-308位点G/A的突变与NASH易感性相关。     

白细胞介素-1O基因多态性与自身免疫性肝病相关性研究

目的研究白细胞介素-10(IL-10)基因启动子区域-592、-819和-1082位单核苷酸多态性与自身免疫性肝病发病之间的关系.方法分别采用聚合酶链反应-限制性片段长度多态性分析法(PCR-RFLP)和聚合酶链反应-序列特异性引物扩增法(PCR-SSP)检测54例自身免疫性肝炎(AIH)、77例原发性胆汁性肝硬化(PB C)患者及1 60例健康献血员外周血单个核细胞基因组DNA IL-1 0基因启动子区域3个多态位点-592、-819、-1082的基因多态性,并进行相关性分析.结果 54例AIH和7 7例PBC患者与160例健康对照组的IL-10启动子-1082、-819和-592基因型分布的统计学分析表明,差异无显著性.结论 I L-10启动子基因多态性与自身免疫性肝病发病之间无显著关联性.     

肿瘤坏死因子-α基因多态性与非酒精性脂肪性肝病的关系

目的研究肿瘤坏死因子-α(TNF-α)基因-308位点及-238位点多态性在非酒精性脂肪性肝病(NAFLD)患者中的分布,及其在胰岛素抵抗(IR)和 NAFLD 发病中的地位。方法运用聚合酶链反应-限制性片段长度多态性检测117例 NAFLD 患者 TNF-α基因—308位点及—238位点多态性,其中伴肥胖者60例,非肥胖者57例,同时测定患者空腹血清胰岛素(FINS)及空腹血糖,通过体内平衡代谢指数(HOMA)评估 IR,并与120名健康者对照。结果 NAFLD 患者与正常对照组 TNF-α基因-238位点基因多态性分布差异有统计学意义(29.9%比15.8%,P<0.05),而—308位点差异无统计学意义(P>0.05)。NAFLD 患者血清 HOMA-IR、TNF-α明显高于对照者[2.50±0.68比1.16±0.68,(10.54±3.19)ng/L 比(4.54±3.10)ng/L,P<0.01]。FINS、HOMA-IR 在 TNF-α基因-238位点基因变异组明显高于正常基因型组(P<0.05),但在—308位点变异组差异无统计学意义(P>0.05)。NAFLD 患者中无论肥胖或非肥胖患者均较正常对照人群在 TNF-α基因-238位点多态性分布及HOMA-IR、TNF-α差异有统计学意义(P<0.05)。肥胖及非肥胖的 NAFLD 患者之间 HOMA-IR、TNF-α差异无统计学意义(P>0.05)。结论 NAFLD 患者 IR 与其体重关系不显著,非肥胖 NAFLD患者同样有 IR 发生。TNFα基因-238位点 G/A 变异与 IR、NAFLD 易感性相关,TNFα基因-308位点 G/A 的突变与 IR 易感性不相关。NAFLD 发病与 IR、TNF-α密切相关。     

肿瘤坏死因子-238 G/A基因多态性与海南汉族老年脑梗死的关系

目的分析TNFα-238 G/A基因多态性与海南汉族老年脑梗死的关系。方法选择老年脑梗死患者108例为脑梗死组,同期健康体检者121例为对照组,应用PCR技术检测TNFα-238 G/A基因的多态性,并进行比较。结果脑梗死组与对照组TNFα-238 G/A基因GG、GA基因型和等位基因频率差异有统计学意义(χ~2=20.314,P<0.01;χ~2=1044.265,P<0.01);2组中,男性和女性TNFα-238 G/A基因分布差异无统计学意义(P>0.05)。结论 TNFα-238 G/A基因多态性与海南汉族老年脑梗死发病相关。     

强直性脊柱炎与肿瘤坏死因子-α基因启动子-308位点多态性关联研究的Meta分析

目的 探讨强直性脊柱炎（AS）与肿瘤坏死因子（TNF）-α基因启动子-308位点多态性的关联情况。方法检索已发表的有关AS和与TNF—α基因启动子-308位点多态性的文献进行Meta分析。结果 8篇文献共纳入987例AS患者和922名正常对照。综合分析显示不能认为TNF—α启动子-308位点等位基因多态性与AS间存在关联，OR=0．86（0．53，1．38），P=-0．53；东西方人群亚群分析结果显示不能认为东方人群TNF—α启动子-308位点等位基因多态性与AS间存在关联，OR=1．06（0．34，3．33），P=0．91；西方人群TNF—α启动子-308位点等位基因多态性可能与AS间存在关联，OR=0．75（0．59，0．96），P=0．02；在东西方人群不能认为TNF—α启动子-308位点GA＋AA基因型与AS间存在相关关系，OR=0．90（0．52,1．55），P=0．69；TNF—α启动子-308位点等位基因多态性与AS无关联，独立于HLA—B27，OR=0．71（0．42．1．20），P=0．20；在中国人群，TNF—α启动子-308位点等位基因多态性与AS骶髂关节炎严重程度可能存在关联．OR=0．37（0．15,0．90），P=-0．03。结论 Meta分析显示西方人群TNF—α启动子-308位点等位基因多态性可能与AS间存在关联，中国人群TNF—α启动子-308位点等位基因多态性与AS间无关联．但与AS骶髂关节炎严重程度可能存在关联。     

Genetic association of vitamin D receptor polymorphisms with autoimmune hepatitis and primary biliary cirrhosis in the Chinese

BACKGROUND: Autoimmune hepatitis (AIH) and primary biliary cirrhosis (PBC) are two autoimmune diseases of unknown etiology. Genetic factors appear to be involved in the pathogenesis of both diseases. Vitamin D has been shown to exert multiple immunomodulatory effects, which acts through its own receptor (VDR). Polymorphisms of VDR had been implicated in several autoimmune diseases. In the present study, the association between Chinese patients with AIH, PBC and the polymorphisms in exon 2, intron 8 and exon 9 of vitamin D receptor genes was studied. METHODS: Four candidate gene loci were investigated in 49 patients with AIH, 58 patients with PBC, and 160 healthy controls. The VDR polymorphisms were assessed by FokI, BsmI, ApaI, and TaqI endonuclease digestion after specific polymerase chain reaction (PCR) amplification. RESULTS: The result show a significant difference in FokI polymorphism between AIH patients and controls (chi(2) = 5.47, P = 0.019), and a significant association in BsmI polymorphisms between PBC patients and controls (chi(2) = 6.52, P = 0.01). Furthermore the distribution of FokI, BsmI, ApaI, and TaqI gene types differed between Chinese healthy controls and Caucasian healthy controls. CONCLUSION: It is suggested that there is a genetic link of VDR polymorphisms to autoimmune liver diseases such as AIH and PBC in Chinese patients. Further studies are needed to elucidate the mechanisms by which VDR polymorphisms contribute to the lose of immune tolerance in autoimmune diseases.     

Tumour necrosis factor-alpha promoter polymorphisms in primary biliary cirrhosis

BACKGROUND/AIMS: The incidence of primary biliary cirrhosis (PBC) is increased in the close relatives of patients, suggesting that genetic factors play a role in disease susceptibility. Decreased in vitro production of tumour necrosis factor (TNF)-alpha has been reported in PBC patients, suggesting a potential aetiological role for this cytokine. The aim of this study was to examine two biallelic polymorphisms in the promoter region of the TNF-alpha gene, which may play a role in the control of TNF-alpha secretion, as candidate susceptibility loci in PBC. METHODS: The polymorphisms at positions -238 and -308 in the TNF-alpha promoter region were analysed by polymerase chain reaction in 168 unrelated PBC patients and 145 local unrelated, geographically matched normal individuals. All PBC subjects were also genotyped for HLA DR8, a previously identified susceptibility locus in PBC. RESULTS: The -308 TNF1/TNF1 genotype was seen in a similar proportion of PBC patients (66%) and controls (60%). However, this genotype was found significantly more frequently in the 95 PBC patients with more advanced disease (histological stage III/IV) (77%) than in either controls (p<0.01, OR = 2.2 [1.2-4.0]) or the PBC patients with earlier disease (38/73 (52%), p = 0.001 OR 3.1 [1.6-5.9]). Linkage between TNF -308 and HLA DR8 was not seen. No association was found between PBC and the biallelic -238 TNF-alpha polymorphism, either in the whole PBC population or the histological Stage III/IV subgroup. CONCLUSIONS: Our study provides no evidence for involvement of the TNF-alpha -308 or -238 promoter polymorphisms in genetic predisposition to PBC. However, the significantly increased frequency of the -308 TNF1/TNF1 genotype seen in 95 patients with more advanced disease raises the possibility that this allele may be linked to disease progression rather than susceptibility. The finding of different allele frequencies in PBC patients in different disease subgroups emphasises the importance of clinical phenotype/casemix in the design of disease association studies.     

Genetic association of cytokines polymorphisms with autoimmune hepatitis and primary biliary cirrhosis in the Chinese

AIM: To characterize gene polymorphism of several cytokine gene in-patients with AIH and PBC and to analyze the difference of the polymorphism distribution between Chinese patients and healthy controls. METHODS: The study population consisted of 62 patients with AIH, and 77 patients with PBC. The genetic profile of four cytokines was analyzed by restriction fragment length polymorphism after specific PCR amplification (PCR-RFLP) or sequence-specific primers PCR (SSP-PCR). The analyzed gene polymorphism included interleukin-1 (IL-1) (at position +3 953 and IL-1RN intron 2), IL-6 (at position -174), IL-10 promoter (at position -1082, -819, and -592). The control group consisted of 160 healthy blood donors. RESULTS: The majority of Chinese people including patients and healthy controls exhibited IL-1B 1,1 genotype, and there was no significant difference in AIH, PBC patients and controls. There were highly statistically significant differences in the distribution of the IL-1RN gene polymorphism between the patients with PBC compared with controls. The frequency of IL-1RN 1,1 was significantly higher (90.9% vs 79.4%, P=0.03) and the frequency of IL-1RN 1,2 was significantly lower in PBC patients (6.5% vs 17.5%, P=0.01). No statistical difference was observed between AIH patients and controls. All of the 160 healthy controls and 62 cases of AIH patients exhibited IL-6-174GG genotype, and there were four cases, which expressed IL-6-174GC genotype in 77 cases of PBC patients. The frequency of IL-6-174GC was markedly significantly higher in PBC patients compared with controls (5.2% vs 0%, P=0.004). No statistically significant difference was found in the distribution of IL-10 promoter genotype in AIH and PBC patients compared with controls. CONCLUSION: The polymorphisms of IL-1RN and IL-6-174G/C appear to be associated with PBC in Chinese patients.     

Cytotoxic T lymphocyte associated antigen-4 gene polymorphisms confer susceptibility to primary biliary cirrhosis and autoimmune hepatitis in Chinese population

AIM: To investigate the association between Chinese patients with autoimmune hepatitis (AIH), primary biliary cirrhosis (PBC) and the polymorphisms of cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) gene promoter (-318) and exon 1 (+49). METHODS: CTLA-4 promoter (-318 T/C) and exon1 (+49A/G) polymorphisms were genotyped via restriction fragment length polymorphism methods in 62 Chinese AIH patients, 77 Chinese PBC patients and 160 healthy controls. RESULTS: We found a significant association in CTLA-4 gene exon1 49 A/G polymorphism between PBC patients and controls (P = 0.006) and the frequency of G alleles was significantly increased in comparison with controls (P = 0.0046, OR = 1.8). We also found the frequency of C alleles in promoter -318 was significantly increased in AIH patients compared with controls (P = 0.02, OR = 0.41). Although the genotype distribution of the CTLA-4 exon 1-promoter gene was not significantly different between AIH and PBC patients and controls, the occurrence of GG-CC was increased in two groups of patients (AIH: 32.3%, PBC: 37.7%, control: 22.5%). CONCLUSION: Polymorphisms of CTLA-4 gene probably confer susceptibility to AIH and PBC in Chinese population.     

Primary biliary cirrhosis shows association with genetic polymorphism of tumour necrosis factor alpha promoter region.

BACKGROUND/AIMS: Primary biliary cirrhosis is an autoimmune disease in which increased prevalence in first-degree relatives and an association with HLA DR8 suggest a genetic background. TNFalpha is a mediator of inflammation and immunity, and is implicated in the pathogenesis of primary biliary cirrhosis, ex vivo studies having shown reduced production of TNFalpha by lymphocytes from patients. Our group has previously described a biallelic promoter-region polymorphism of the TNFA gene at position -308, and demonstrated that the rare allele, TNF*2, has increased promoter function compared with the common allele, TNF*1. A further biallelic base change has been described in the TNFA gene at -238. We conducted a case-control study to assess association of these gene polymorphisms with primary biliary cirrhosis. METHODS: Ninety-one patients and 213 controls were genotyped for both TNFA loci using restriction fragment length polymorphism analysis of PCR products. RESULTS: The high production TNFA-308*2 allele was significantly under-represented among subjects with primary biliary cirrhosis (27.5% PBC, 41.6% controls, p=0.02, pc=0.04, OR for carriage of TNF*1/*1 genotype=1.89, CI=1.10-3.32). No association was shown with the TNFA -238 polymorphism. CONCLUSION: Primary biliary cirrhosis is associated with reduced carriage of TNF*2. This is in keeping with a protective role of TNFalpha against the disease.     

Fas polymorphisms influence susceptibility to autoimmune hepatitis

BACKGROUND AND AIMS: Genetic factors associated with autoimmune hepatitis (AIH) and primary biliary cirrhosis (PBC), immune-mediated chronic inflammatory liver diseases of unknown etiology, remain to be elucidated. Polymorphisms of the gene encoding Fas have been linked to a variety of autoimmune diseases. We hypothesized that Fas gene polymorphisms might be genetic markers for AIH and PBC. METHODS: To determine the frequency and significance of Fas polymorphisms in patients with AIH and PBC, 74 Japanese AIH patients, 98 Japanese PBC patients, and 132 ethnically matched control subjects were investigated by the use of the Taqman assay. RESULTS: We found significant differences between AIH patients and controls in allele frequencies of Fas-670 (p=0.009), Fas IVS (intervening sequence) 2nt176 (p=0.018), Fas IVS3nt46 (p=0.031), and Fas IVS5nt82 (p=0.013) polymorphisms. Haplotype analysis revealed that one of the haplotypes, GATGC, was associated with increased AIH prevalence. On the other hand, we found no statistically significant differences between PBC patients and controls in allele frequencies of the Fas polymorphisms genotyped in this study. CONCLUSIONS: These results indicate a genetic link of Fas polymorphisms to the development of AIH. Further studies are needed to determine the genetic factors contributing to the development of AIH.     

Genetic association of vitamin D receptor polymorphisms with primary biliary cirrhosis and autoimmune hepatitis.

Autoimmune hepatitis (AIH) and primary biliary cirrhosis (PBC) are immune-mediated chronic inflammatory diseases of the liver of unknown etiology. Genetic factors appear to be involved in the pathogenesis of both diseases. 1,25-Dihydroxyvitamin D(3) has been implicated as an immunomodulator, which acts through its own receptor (VDR). Polymorphisms of the VDR have been linked to a variety of autoimmune diseases. In this study VDR polymorphisms were analyzed in 123 patients with AIH, 74 patients with PBC, and 214 controls. VDR polymorphisms were assessed by BsmI, TaqI, ApaI, and Fok endonuclease digestion after specific polymerase chain reaction (PCR) amplification. We found a significant association between the BsmI polymorphisms in PBC patients in comparison with controls (chi(2) = 9.49, P =.009). Furthermore we detected a significant association of the Fok polymorphims in AIH patients in comparison to controls (chi(2) = 9.71, P =.008) indicating a genetic link of VDR polymorphisms to autoimmune liver diseases such as PBC and AIH in German patients. These findings contribute to the knowledge of the complex events determining immunologic tolerance in the liver. Further studies are needed to elucidate the mechanisms by which the vitamin D receptor contributes to the development of autoimmune diseases.     

Tumor necrosis factor gene polymorphisms and clearance or progression of hepatitis B virus infection.

OBJECTIVES: We evaluated the influence of tumor necrosis factor-alpha (TNF-alpha) promoter gene polymorphisms on clearance of hepatitis B virus (HBV) and outcome of HBV chronic hepatitis. METHODS: Four TNF-alpha promoter polymorphisms (T-1031C, C-863A, G-308A, and G-238A) were evaluated by direct sequencing in 184 chronic HBV carriers hepatitis B surface antigen (HBsAg) positive and 96 controls with documented sero-clearance (HBsAg negativity, positivity for anti-HBs and anti-HBc IgG). Frequencies of single-nucleotide polymorphisms (SNPs) and haplotypes in the control group were compared with those of the chronic carrier group and with clinically defined subgroups of the latter: asymptomatic carriers, patients with compensated hepatitis, decompensated cirrhotics, and patients with hepatocellular carcinoma. Furthermore, subgroups of chronic carriers were compared among them. Results: In the chronic carrier group, the -308 G allele was more frequent in those with a family history of HBV infection (96% vs 88% of those with non-familial transmission). The G/G genotype at position -308 was found in all chronic carriers with decompensated cirrhosis but in only 78% of controls (P=0.01) and was more frequent in decompensated cirrhotics than in the other subgroups. The distribution of TNF-alpha gene polymorphisms in the carrier group was not significantly different from that in the sero-clearance control group. TNF-alpha SNPs at positions -1031/-863 and -863/-238 were in linkage disequilibrium. The TCGG haplotype (-T1031, -C863, -G308, -G238) was significantly associated with end-stage liver disease. CONCLUSION: The TNF-alpha promoter polymorphisms do not appear to be determinant of HBV sero-clearance in southern Italians. The genotype -308G/G and haplotype TCGG are associated with an unfavorable prognosis in patients with chronic HBV infection.     

Tumor necrosis factor-alpha and Interleukin-10 gene promoter polymorphisms in Turkish rheumatoid arthritis patients

Tumor necrosis factor and interleukin 10 have been implicated in the pathogenesis of rheumatoid arthritis (RA). Certain single-nucleotide polymorphisms (SNPs) within the promoter region of the IL-10 and TNF genes have been associated with altered levels of circulating IL10 and TNF. We aimed to explore the association of IL-10 and TNF-alpha polymorphisms in Turkish RA patients. We analyzed the association of TNF-alpha (-308G/A, -238G/A, -376G/A) and IL10 (-1082G/A, -819C/T, -592C/A) polymorphisms in 98 Turkish patients with rheumatoid arthritis and 122 healthy subjects using ARMS-PCR. The correlation of these findings with RF positivity and erosive disease in RA patients was also sought. A significant association was found between having RA and -1082 G allele (p = 0.008; OR = 1.44, 95% CI 1.11-1.86). There was no association between RA and -819C/T polymorphism. Significant differences were observed in IL10 GCC and ACC haplotypes distribution between RA and control subjects (p = 0.006; OR = 1.46, 95% CI 1.13-1.89 and p = 0.011; OR = 1.43, 95% CI 1.09-1.88, respectively). No statistically significant association was found between TNF-alpha 308G/A, -238G/A, -376G/A polymorphisms and RA. No significant association was found between RF positivity and erosive disease and TNF-alpha, IL10 gene polymorphisms. In addition, when combined genotypes were analyzed, no significant difference was found between RA patients and healthy controls. Our findings suggest that IL-10 1082 G/A polymorphism or GCC, ACC haplotypes may be associated with RA in Turkish patients.     

TNF-alpha and hyperandrogenism: a clinical, biochemical, and molecular genetic study

To evaluate the role of TNF-alpha in the pathogenesis of hyperandrogenism, we have evaluated the serum TNF-alpha levels, as well as several polymorphisms in the promoter region of the TNF-alpha gene, in a group of 60 hyperandrogenic patients and 27 healthy controls matched for body mass index. Hyperandrogenic patients presented with mildly increased serum TNF-alpha levels as compared with controls (mean[median] +/- SD: 7.2[7.0] +/- 3.3 pg/ml vs. 5.6[4.4] +/- 4.0 pg/ml, P < 0.02). Although no differences in body mass index and insulin resistance indexes were observed between patients and controls, when subjects were classified by body weight, serum TNF-alpha was increased only in lean patients as compared with lean controls, but this difference was not statistically significant when comparing obese patients with obese controls. The TNF-alpha gene polymorphisms studied here (-1196C/T, -1125G/C, -1031T/C, -863C/A, -857C/T, -316G/A, -308G/A, -238G/A, and -163G/A) were equally distributed in hyperandrogenic patients and controls. However, carriers of the -308A variant presented with increased basal and leuprolide-stimulated serum androgens and 17-hydroxyprogesterone levels when considering patients and controls as a group. No differences were observed in serum TNF-alpha levels, body mass index, and insulin resistance indexes, depending on the presence or absence of these variants. In conclusion, our present results suggest that the TNF-alpha system might contribute to the pathogenesis of hyperandrogenism, independent of obesity and insulin resistance. However, elucidation of the precise mechanisms underlying the relationship between the TNF-alpha system and androgen excess is needed before considering TNF-alpha as a significant contributing factor to the development of hyperandrogenism.