Ailesel Hiperkolesteroleminin Genetik Nedenlerinin Araştırılması

Abstract

Familial hypercholesterolemia is a genetic disease characterized by high plasma cholesterol levels and early cardiovascular disease development. Main objectives of the study were to evaluate the genetic causes of familial hypercholesterolemia and to detect the relationship between genetic causes and the clinical findings. For these purpouses, 52 patients diagnosed with familial hypercholesterolemia according to the Simon Broome Criteria were included. At the beginning, the LDLR gene of all patients was sequenced by Sanger method. After that, Sanger sequencing was performed respectively, for exons 26 and 29 of APOB gene and PCSK9 gene in the patients who did not have a causal LDLR mutations. As a result of Sanger sequencing, pathogenic LDLR mutations of which two of them had not been described before were detected in 28 patients. In the remaining 24 patients, MLPA was performed to detect LDLR copy number changes and a homozygous duplication of exon 11-12 of LDLR gene was found in a patient. In the patients without molecular diagnosis, a NGS panel was performed to comprhensively evaluate the genes related to the disease. Disease-related mutations were detected in the LDLRAP1 in a patient and APOE in two patients. A synonymous mutation found in LDLR gene was identified to cause splice site changes by RNA study and classified as pathogenic. While a monogenic cause was detected in 33 patients, 1 patient had a variant of unknown significance in the LDLR. There was no monogenic cause detected in 18 patients. In addition to effort for detection of monogenic causes of the disease, studies were also conducted to asses polygenic etiology. For this purpose, previously reported 12 SNP were genotyped. To genotype 28 patients that found to have a mutation in LDLR gene at beginning of the study, Sanger sequencing was performed. For the remaining patients, the NGS panel were used. After genotyiping, Two polygenic risk scores (PRS) were calculated in the mutation positive/mutation negative patient groups and the control group by using 12 SNP and 6 SNP (a subset of 12 SNP). The means of the calculated PRS were compared between the groups. By this way, the role of polygenic effects on the disease was evaluated for the first time in the Turkish population. As a result, similar to the different population studies, mutation negative patients were found to have higher mean PRS than control group and mutation positive patients in Turkish population. Besides, probable effects of the polygenic determinants to occuarance of the monogenic disease were identifed. The effects of the genetic etiology on the clinical and biochemical parameters were also investigated. Finally, according to molecular findings, genetic counselling were provided and the patients were directed to the related clinics for treatment and management of the disease.