LDL-C Concentrations and the 12-SNP LDL-C Score for Polygenic Hypercholesterolaemia in Self-Reported South Asian, Black and Caribbean Participants of the UK Biobank

Abstract

Background: Monogenic familial hypercholesterolaemia (FH) is an autosomal dominant disorder characterised by elevated low-density lipoprotein cholesterol (LDL-C) concentrations due to monogenic mutations in LDLR, APOB, PCSK9, and APOE. Some mutation-negative patients have a polygenic cause for elevated LDL-C due to a burden of common LDL-C-raising alleles, as demonstrated in people of White British (WB) ancestry using a 12-single nucleotide polymorphism (SNP) score. This score has yet to be evaluated in people of South Asian (SA), and Black and Caribbean (BC) ethnicities.Objectives: 1) Compare the LDL-C and 12-SNP score distributions across the three major ethnic groups in the United Kingdom: WB, SA, and BC individuals; 2) compare the association of the 12-SNP score with LDL-C in these groups; 3) evaluate ethnicity-specific and WB 12-SNP score decile cut-off values, applied to SA and BC ethnicities, in predicting LDL-C concentrations and hypercholesterolaemia (LDL-C>4.9 mmol/L).Methods: The United Kingdom Biobank cohort was used to analyse the LDL-C (adjusted for statin use) and 12-SNP score distributions in self-reported WB (n = 353,166), SA (n = 7,016), and BC (n = 7,082) participants. To evaluate WB and ethnicity-specific 12-SNP score deciles, the total dataset was split 50:50 into a training and testing dataset. Regression analyses (logistic and linear) were used to analyse hypercholesterolaemia (LDL-C>4.9 mmol/L) and LDL-C.Findings: The mean (±SD) measured LDL-C differed significantly between the ethnic groups and was highest in WB [3.73 (±0.85) mmol/L], followed by SA [3.57 (±0.86) mmol/L, p < 2.2 × 10−16], and BC [3.42 (±0.90) mmol/L] participants (p < 2.2 × 10−16). There were significant differences in the mean (±SD) 12-SNP score between WB [0.90 (±0.23)] and BC [0.72 (±0.25), p < 2.2 × 10−16], and WB and SA participants [0.86 (±0.19), p < 2.2 × 10−16]. In all three ethnic groups the 12-SNP score was associated with measured LDL-C [R2 (95% CI): WB = 0.067 (0.065–0.069), BC = 0.080 (0.063–0.097), SA = 0.027 (0.016–0.038)]. The odds ratio and the area under the curve for hypercholesterolaemia were not statistically different when applying ethnicity-specific or WB deciles in all ethnic groups.Interpretation: We provide information on the differences in LDL-C and the 12-SNP score distributions in self-reported WB, SA, and BC individuals of the United Kingdom Biobank. We report the association between the 12-SNP score and LDL-C in these ethnic groups. We evaluate the performance of ethnicity-specific and WB 12-SNP score deciles in predicting LDL-C and hypercholesterolaemia.

Impact of 12-SNP and 6-SNP Polygenic Scores on Predisposition to High LDL-Cholesterol Levels in Patients with Familial Hypercholesterolemia

“…Discordant results among different populations suggest that the polygenic score for LDL-c levels should be tailored to the genetic background of each population. In fact, ethnicity has been demonstrated to be relevant for the distribution of score values and for the association with LDL-c levels [20,43].…”

“…This score was then further refined to reduce the number of SNPs to 6 without losing its performance, according to the original study [17]. Different polygenic scores have been developed to meet the genetic background of different populations, highlighting that a single LDL-c score or a single cut-off cannot be universally used [18][19][20].…”

Cardiovascular Immunotoxicity Associated with Immune Checkpoint Inhibitors in Metastatic Melanoma

“…Novel lipid-lowering drugs, such as PCSK9 inhibitors, could be proposed, as Quagliariello [ 35 ] did, putting forward the argument that PCSK9 inhibition in patients with cancer treated with ICI therapies enables a reduction in atherosclerotic cardiovascular events and potentially improves ICs-related anticancer functions. This meta-analysis did not have the sensitivity to determine whether subjects who developed dyslipidemia under immunotherapy were carriers of a predisposing genetic mutation [ 36 ].…”

Polygenic risk score for hypercholesterolemia in a Brazilian familial hypercholesterolemia cohort

“…Gratton et al. (2022) [ 15 ] demonstrated that this PRS had better performance in individuals with UK Black and Caribbean and White ancestries than Asians individuals and proposed the hypothesis of the adoption of a specific-ethnic decile cut-off value than a general one. Likewise, as shown by Toft-Nielsen and colleagues [ 23 ], FH prevalence diverge among different ancestries, being more prevalent in Black and White than Asian individuals.…”

“…Currently, the replication of this PRS has already been carried out in at least 6 European countries, in Israel and Korea, and in all studies, the score was significantly associated with LDL-c values [ 13 , 14 ]. In addition, a recent study showed this score distribution and association with LDL-C in three different UK ethnic groups [ 15 ].…”