A Novel Mutation in the FECH Gene in a Czech Family with Erythropoietic Protoporphyria and a Population Study of IVS3-48C Variant Contributing to the Disease.

Erythropoietic protoporphyria (EPP), a chronic erythropoietic porphyria, is characterized by excess accumulation of protoporphyrin, particularly in erythroid cells. EPP inheritance is complex, almost always associated with two molecular defects. In most EPP patients, clinical expression requires coinheritance of a private ferrochelatase (FECH) mutation trans- to a hypomorphic FECH*IVS3-48C allele. This leads to a decrease of FECH activity below the critical threshold. This is characterized by cutaneous photosensitivity in early childhood such as itching, burning, swelling and redness in sun-exposed areas. Hepatic failure occurs in some patients (about 1-10 % of EPP patients), which may necessitate liver transplantation. We investigated a Czech family with two patients with manifested EPP in four generations. We found a novel mutation, c.84G >A, in the FECH gene in four individuals including proband and his mother (G84A transition in exon 2; p.W28*). Both clinically manifested probands inherited the hypomorphic IVS3-48C allele as well, while two clinically latent individuals with FECH mutation did not. To address the question whether the relatively low incidence of EPP in the Czech Republic might be due to lower frequency of the IVS3-48C allele, we screened for the frequency of the low expression allele in a control Czech (West Slaves) Caucasian population. Such study has not been performed in any Slavic population. Among 312 control individuals, there were no IVS3-48C/C (c.68-23C-T) homozygotes; 35 IVS3-48C/T heterozygous individuals were detected. The frequency of IVS3-48C allele was thus found to be 5.5 % in the Czech population, comparable to most West Caucasian populations.

Stress perception and (GT)n repeat polymorphism in haem oxygenase 1 promoter are both risk factors in development of eating disorders.

Haem oxygenase 1 (HO-1) plays a pivotal role in metabolic stress protecting cells in dependence on reactive oxygen species. This study investigated a potential gene environment interaction between the (GT)n repeat HO1 polymorphism and the stress perception in patients with eating disorder and in controls. Stress perception and (GT)n polymorphism were measured in 127 patients with eating disorders and in 78 healthy controls using Stress and Coping Inventory and genotyping. Based on the inventory, overall, specific and weighted stress scores were defined. Clinical stress score was generated according to the patient's history and interviews. According to our hypothesis, 1) all stress scores describing subjective stress perception were significantly higher in patients compared to controls (P ≤ 0.001; P ≤ 0.002; P ≤ 0.001), 2) the L/L genotype of GT promoter repeats (L < 25 GT repeats, S < 25 GT repeats) in the patients was associated with higher overall (P ≤ 0.001), specific (P ≤ 0.010) and weighted stress score (P ≤ 0.005) compared to the L/S variant, and 3) Pearson's correlation of clinical versus objective stress scores showed not very tight relationship (0.198; 0.287; 0.224, respectively). We assume potential risk of the L allele of HO1 promoter polymorphism for the stress response and contribution of the subjective stress perception together with the L/L genotype to the development of eating disorder. Decreased HO1 expression in the presence of L/L genotype plus more intensive stress perception in the patients can lead to secondary stress, with increasing severity of the symptoms and aggravation of the disease.

Polymorphisms in serotonin-related genes in anorexia nervosa. The first study in Czech population and metaanalyses with previously performed studies.

Anorexia nervosa is a serious psychiatric disorder characterized by the inability to maintain normal body weight. The frequently studied polymorphisms in the serotonin 5-HT2A receptor gene (-1438A/G) and in serotonin transporter 5-HTT gene (LPR, VNTR) have led to controversial results in different populations. The aim of the study was to address association of the above-mentioned polymorphisms with anorexia nervosa in the Czech population. We genotyped a well-defined group of 75 patients with anorexia nervosa (average age of 25.39 years, SD 6.18; average BMI 14.65 (SD 1.38)). The control group consisted of 65 Caucasian healthy females (average age 25.76 years, SD 5.12; average BMI 20.69, SD 1.85). The 5-HT2A receptor -1438A/G polymorphism analysis showed a trend for the association with odds ratios for risk allele A being in the same direction. In combination with a previously published Polish cohort, the allelic test reached a suggestive borderline (P = 0.0362, chi2 statistics, 1 df). In meta-analysis which included all published results for allelic tests, the resulting P value was highly significant (0.0003, chi2 statistics, 1 df). Using quantitative association of 5-HTR2A polymorphism with BMI in the Czech sample, a borderline association (P = 0.055) was observed. In 5-HTT, LPR polymorphism analysis, unlike in 5-HT2A, neither allelic nor quantitative association with BMI for the bi-allelic 5-HTT marker was observed. Results of this study support previous reports of a significant role of the A allele (-1438A/G, 5-HT2A receptor) as a risk factor in anorexia nervosa.

Does bilirubin level correspond to interaction of c.-3279T>G and A(TA)7TAA variants in UGT1A1 gene?

Promoter variants c.-3279T>G and A(TA)7TAA show decreased level of expression of UDP-glucuronosyl transferase 1A1 (UGT1A1) and consequently reduced activity of the enzyme catalyzing glucuronidation of bilirubin in hepatocytes. Thus, coincidental occurence of both variants should lead to increase of hyperbilirubinemia or contribute to its manifestation. In this study, investigation of both variants in 101 patients and 84 controls in a Caucasian population was performed and the results were compared with serum bilirubin levels. Despite high linkage disequilibrium between the loci (D' = 0.91, r(2) = 0.69), we have proven an interaction between the variants increasing the odds ratio for [(TA)7]+c.[-3279T>G] homozygotes to 54.2.