The Genetic Burden of Familial Hypercholesterolemia in the Qatari Population

Abstract

Familial Hypercholesterolemia (FH) is an autosomal dominant disorder characterized by elevated plasma low-density lipoprotein cholesterol (LDL-C) levels affecting the general population between 1:250 and 1:500. A myocardial infarction in an individual younger than 60 years of age is likely to be caused by FH in approximately 2%-3% of cases. The genetic cause of FH is primarily determined by three genes: LDLR, APOB and PCSK9. Around 60-80% of clinically diagnosed FH patients exhibit detectable mutations in one of these three genes. The remaining cases of FH are due to polygenic inheritance or variants in other sporadic genes. Additionally, FH phenocopy disorders exhibit similar clinical or laboratory findings to FH but are not caused by the same canonical genes. Instead, these may be caused by the autosomal recessive genes LDLRAP1, ABCG5, ABCG8, CYP27A1, and LIPA. Despite the high incidence of cardiovascular diseases, knowledge of FH prevalence and its genetic cause has not been well established in the Arabs. So far, only 57 genetic variants have been documented in 17 countries in the Middle East and North Africa, with no FH mutation detected in Qatar. Similarly, another study found that no FH-related mutations were detected in 14 Arab countries, including Qatar. Here, we present the first-large scale study of genetic variation causing FH in 6,140 individuals from the Qatari population, using whole-genome sequences (WGS) from the Qatar Genome Program (QGP) and phenotypic data from the Qatar Biobank (QBB). We combined their genetic and biochemistry data and family history of FH and used established diagnostic criteria to identify the individuals at the risk of FH. We assessed the presence of known deleterious variants in the LDLR, APOB, and PCSK9 genes in these individuals and evaluated novel variants of these genes for pathogenicity. In addition, we examined known and novel pathogenic variants found within autosomal recessive genes associated with FH phenocopy disorders. Finally, we tested the utility of globally established LDL-C SNP risk scores for predicting FH risk in Arab populations. Our results revealed eleven novel alleles within FH-causing genes associated with LDL-C in the Qatari population, with implications for population-specific precision medicine, including developing targeted screening programs and novel diagnostic tests for FH in the greater Middle East.

Date of Award	2022
Original language	American English
Awarding Institution	HBKU College of Health & Life Sciences