Polygenic risk scores for low-density lipoprotein cholesterol and familial hypercholesterolemia

Abstract

Familial hypercholesterolemia (FH) is an autosomal dominant monogenic disorder characterized by elevated levels of lowdensity lipoprotein cholesterol (LDL-C) and an increased risk of premature coronary artery disease (CAD). Recently, it has been shown that a high polygenic risk score (PRS) could be an independent risk factor for CAD in FH patients of European ancestry. However, it is uncertain whether PRS is also useful for risk stratification of FH patients in East Asia. We recruited and genotyped clinically diagnosed FH (CDFH) patients from the Kanazawa University Mendelian Disease FH registry and controls from the Shikamachi Health Improvement Practice genome cohort in Japan. We calculated PRS from 3.6 million variants of each participant (imputed from the 1000 Genome phase 3 Asian dataset) for LDL-C (PRS LDLC ) using a genomewide association study summary statistic from the BioBank Japan Project. We assessed the association of PRS LDLC with LDL-C and CAD among and within monogenic FH, mutation negative CDFH, and controls. We tested a total of 1223 participants (376 FH patients, including 173 with monogenic FH and 203 with mutation negative CDFH, and 847 controls) for the analyses. PRS LDLC was significantly higher in mutation negative CDFH patients than in controls (p = 3.1 × 10 −13 ). PRS LDLC was also significantly linked to LDL-C in controls (p trend = 3.6 × 10 −4 ) but not in FH patients. Moreover, we could not detect any association between PRS LDLC and CAD in any of the groups. In conclusion, mutation negative CDFH patients demonstrated significantly higher PRS LDLC than controls. However, PRS LDLC may have little additional effect on LDL-C and CAD among FH patients.

Applicability of polygenic risk scores in endometriosis clinical presentation

“…On the other hand, PRS is not enough to estimate the risk of coronary artery disease since non-genetic risk factors, such as age and environmental factors, are also involved [ 33 ]. When studying the association between PRS of low-density lipoprotein cholesterol (LDL-C) with circulating LDL-C levels and coronary artery disease, there were no associations within a cohort of patients with familial hypercholesterolemia [ 34 ]. Accordingly, PRSs are predictive of colorectal cancer in the general population but not in the Lynch syndrome [ 35 ].…”

“…Then, PRS was calculated as it is implemented in PLINK software [ 34 ] (version 1.9), using unweighted (presence of the risk allele) and weighted (using the beta value of the effect of the risk allele) methods.…”

Association between Vitamin Intake and Chronic Kidney Disease According to a Variant Located Upstream of the PTGS1 Gene: A Cross-Sectional Analysis of Shika Study

“…Genome-wide SNP genotyping was executed using the Japonica Array v2 [ 18 ] (TOSHIBA Co., Ltd., Tokyo, Japan). Quality control (QC) procedures for the obtained genome-wide SNP genotype data have been described elsewhere [ 19 ]. In brief, SNP genotype data and participants were filtered according to gender identity between karyotypes and the questionnaire, call rates, the Hardy–Weinberg equilibrium test, inbreeding coefficient, cryptic relatedness, and population structure.…”

Genetic Determinants of Plasma Low-Density Lipoprotein Cholesterol Levels: Monogenicity, Polygenicity, and “Missing” Heritability

“…A PRS using 10 LDL-c-raising alleles explained 3.4% of the variance in LDL-c in three European cohorts [ 125 ]. Another PRS with 37 SNVs explained 6.0% of the variation in plasma LDL-c levels in the Atherosclerosis Risk in Communities (ARIC) cohort, comprising white and black people from four US communities [ 126 ], whereas a PRS including 3.6 million variants explained 3.5% of the LDL-c variability in a Japanese ADH cohort [ 127 ]. Regarding the use of PRSs in clinical practice, an important question that has not yet been resolved is the definition of what constitutes a “high” score—the top quartile, the top decile, or another calculated cutoff point.…”

“…Studies of ADH patients without LDL , APOB , or PCSK9 pathogenic mutations showed that 20%–80% presented high PRSs relative to a control population [ 60 , 127 , 129 , 131 , 133 , 134 , 135 , 136 , 137 ]. Although each variant had a small effect, the accumulation of LDL-c-raising variants could lead to a phenotype similar to that of monogenic ADH [ 138 ].…”