The evulation of the relationship between CYP3A4, CYP2D6, MRD1gene variants and disease severity in children with familial mediterraneanfever

Familial Mediterranean Fever (FMF), the most common Mendelian autoinflammatory syndrome, is an autosomal recessive pattern of inheritance and results from Mediterranean Fever (MEFV) gene mutations. Colchicine is the principle treatment for FMF. CYP3A4 and CYP2D6 (members of CYP450 enzyme family) and MDR1, a transport protein, are responsible for the colchicine metabolism. In our study, we evaluated the relationship between changes in CYP2D6, MDR1 and CYP3A4 genes and clinical characteristics, colchicine dose and treatment resistance in children with FMF. A total of 124 children followed up with FMF diagnosis and using colchicine, and 60 healthy children were included in the study. MDR1 c.3435C>T (rs1045642), CYP3A41b c.-392G>A (rs2740574), CYP2D6*4 c.1934G>A (rs3892097) and CYP2D6*3 c.2637Adel (rs35742686) variants were analyzed by PCR method. Demographic characteristics, treatments, clinical data and MEFV genotypes of the patients were evaluated. Of the patients included in the study, 55 were female (44.4%) and 69 were male; the mean age was 11.41±4.2 years; The follow-up period was 56.5±52.9 months. The mean age of the control group was 9.15±4.8 years (3-18 years) and the gender distribution was similar to the patient group. Of the patients, 41.8% were of Mediterranean origin. Most of the patients (69.4%) were presented with moderate symptoms according to ISSF. Fifty (40.3%) patients had homozygous, 47 (37.9%) compound heterozygous and 27 (21.8%) heterozygous MEFV gene mutations. The most common MEFV mutation was M694V and the second most common mutation was M694V / R2020Q. The most common MEFV mutation in the colchicine resistant group was M694V homozygous (62.5%). All patients were on colchicine. Thirty-four patients (27.4%) were receiving colchicine at a dose of >1.2 mg/m2/day while the disease was under control. Colchicine 53 resistance was observed in 16 patients (12.9%). Five of these patients were on magnesium containing colchicine. Five of them were taking canakinumab. MDR1 variant distribution was similar in both groups (p = 0.838). When the allele distribution was examined, 63.9% of the patient group and 70% of the control group had T alleles. As MDR1 variant and allele distribution and colchicine resistance were evaluated, no significant relationship was found. When the relationship with colchicine dose was examined, colchicine dose was found to be lower in TT variant and T allele (p=0,046). This result was associated with the lack of TT variant P-glycoprotein pump synthesis and higher blood colchicine levels. When the variant distributions were evaluated according to ISSF values, the scores in the mutant group were significantly higher than those of the wild type patients (p = 0.016), and this result was associated with colchicine nonresponsiveness in the literature. When the CYP3A41b variant distribution was examined, similar to the previous studies, heterozygous changes were observed in 2.4% and 3.3% of the patient and control groups, respectively. Additionally, no mutant changes were detected in groups. The comparison of colchicine resistance and allele distribution were compared with variant distribution, there was 33% colchicine resistance in G allele and 13% in A allele. Regarding colchicine use, most of the patients with G allele (66%) were using colchicine at a dose of <1.2 mg/m2/day. The difference in the distribution between the groups was not statistically significant. For CYP2D6 * 4, the frequency of heterozygote and mutant genes in the patient and control groups was similar to previous studies with the values 33.6% / 3.2% and 21.6% / 2.7%, respectively. When the allele and variant distribution of colchicine resistance was examined, there was no direct relationship between colchicine resistance and A and G alleles. For the association between colchicine dose and variant distribution, the colchicine dose (mg/kg/day) was significantly lower in the pathological allele (mutant) compared to other variants (p = 0.011, p = 0.033). It was concluded that the pathological AA variant would provide a higher blood colchicine level as being a slow metabolizer. Thus, a lower dose of colchicine would be sufficient for treatment management in this group. For CYP2D6 * 3, similar with the studies in the literature, it was found to be wild type in all subjects, that is, there was no pathological allele gene. The data suggest that variations in genes encoding enzymes involved in colchicine metabolism alter the dose of colchicine required to control the disease. Key Words: FMF, colchicine, genetic variation