Investigating Known Pathogenic Variants for Familial Hypercholesterolemia in a Samoan Population

Familial Hypercholesterolemia (FH) is a genetic condition that makes it difficult for an individual to remove excess cholesterol from their blood. As a result, these individuals have elevated LDL-cholesterol levels and their risk of developing premature cardiovascular disease increases 20-fold. FH affects 1 in 250 people globally; however, 90% of cases remain undiagnosed. Although the prevalence of cardiovascular disease in Samoa is relatively high, the prevalence of FH and previously identified risk alleles for FH in Samoa are unknown. FH is treatable and, in other countries, implementation of screening programs has identified at-risk individuals and enabled them to receive lipid-lowering medications. No studies have been done to estimate the prevalence of FH risk alleles and subsequently, the usefulness of a screening program. In this study, I estimated the frequency of known FH pathogenic variants in three genes for FH (LDLR, APOB, and PCSK9) in 3475 Samoan adults, aged 24.5 – 65, from a population-based research study, and assessed whether these FH risk alleles were associated with LDL-cholesterol levels over 190 mg/dL—a hallmark of FH. In addition, I assessed the proportion of individuals with elevated LDL-cholesterol levels, as well as the effects of comorbidities, such as obesity, on LDL- and total cholesterol levels. Six known pathogenic FH variants were present among the 3475 individuals in this study. However, individuals with four of these variants did not have elevated LDL-cholesterol levels of >190 mg/dL, although individuals who were heterozygous for variants APOB rs760832994 or PCSK9 rs371488778 had LDL-cholesterol levels greater than 170 mg/dL. However, the mean of LDL-cholesterol levels among all participants was 130 mg/dL, which is above the recommended maximum of 100 mg/dL. Finally, 135 individuals (3.9% of the participants) had LDL-cholesterol levels >190 mg/dL. Although other factors that contribute to high LDL-cholesterol levels must be taken into account, such as diet, exercise, and comorbidities like diabetes, this result is a good indication that at least one individual in this sample may have a previously unknown or novel pathogenic variant for FH based on the global prevalence of FH of 1 in 250 people. The public health significance of this study is that, based on these results, implementing a genetic screening program in Samoa for FH is not advisable at this time; however, because almost 4% of the population has elevated LDL-cholesterol levels, a screening program based off of cholesterol testing may be beneficial