AUTHOR=Gratton Jasmine , Finan Chris , Hingorani Aroon D. , Humphries Steve E. , Futema Marta 

TITLE=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

JOURNAL=Frontiers in Genetics

VOLUME=13

YEAR=2022

URL=https://www.frontiersin.org/journals/genetics/articles/10.3389/fgene.2022.845498

DOI=10.3389/fgene.2022.845498

ISSN=1664-8021

ABSTRACT=<p><bold>Background</bold>: Monogenic familial hypercholesterolaemia (FH) is an autosomal dominant disorder characterised by elevated low-density lipoprotein cholesterol (LDL-C) concentrations due to monogenic mutations in <italic>LDLR</italic>, <italic>APOB</italic>, <italic>PCSK9</italic>, and <italic>APOE</italic>. 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.</p><p><bold>Objectives</bold>: 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&gt;4.9 mmol/L).</p><p><bold>Methods</bold>: 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 (<italic>n</italic> = 353,166), SA (<italic>n</italic> = 7,016), and BC (<italic>n</italic> = 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&gt;4.9 mmol/L) and LDL-C.</p><p><bold>Findings</bold>: 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, <italic>p</italic> &lt; 2.2 × 10<sup>−16</sup>], and BC [3.42 (±0.90) mmol/L] participants (<italic>p</italic> &lt; 2.2 × 10<sup>−16</sup>). There were significant differences in the mean (±SD) 12-SNP score between WB [0.90 (±0.23)] and BC [0.72 (±0.25), <italic>p</italic> &lt; 2.2 × 10<sup>−16</sup>], and WB and SA participants [0.86 (±0.19), <italic>p</italic> &lt; 2.2 × 10<sup>−16</sup>]. In all three ethnic groups the 12-SNP score was associated with measured LDL-C [<italic>R</italic><sup>2</sup> (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.</p><p><bold>Interpretation</bold>: 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.</p>