A genetic risk score is significantly associated with statin therapy response in the elderly population

Abstract

The ability of statins to strongly reduce low-density lipoprotein cholesterol (LDL-C) varies interindividually and is partially influenced by genetic variants. Based on a comprehensive analysis of 23 single nucleotide polymorphisms (SNPs) known to be associated with pharmacokinetics and dynamics of statins, we developed a genetic risk score to study its impact on the therapy outcome in elderly individuals under at least 5 years statin therapy. The study was performed in a population-based cohort of 1016 elderly individuals, which comprised 168 statin users investigated at age 75 and 80. Using random forest models, the major variants influencing LDL-C levels were summarized in a weighted GRS (wGRS). The wGRS was tested with lipid and glucose outcomes and validated in an independent population-based cohort including 221 statin users. Four SNPs within the APOE cluster (rs7412, rs4420638), ABCC2 (rs2002042) and CELSR/SORT1/PSRC1 (rs646776), displayed a major impact on statin efficacy. The wGRS was significantly associated with lower LDL-C at age 75 and 80. This association was replicated displaying similar results. GRS analysis is a powerful tool to evaluate the additive effects of genetic variants on statin response and to estimate the magnitude of LDL-C reduction to a considerable extent in the older population.

Serum amyloid P component therapeutically attenuates atherosclerosis in mice via its effects on macrophages

“…Finally, we focused on the Psrc 1 gene. Genetic variants near PSRC1 are also associated with serum LDL cholesterol level 27 - 31 and statin treatment efficacy 32 - 34 . Therefore, we suspected that PSRC1 may be a key downstream effector of SAP in macrophages.…”

“…SNP rs599839 in the 3'-UTR region of the PSRC1 gene is significantly associated with moyamoya and atherosclerotic disease in Europeans 40 . Genetic variants near PSRC1 are also associated with serum LDL cholesterol level 27 - 31 and statin treatment efficacy 32 - 34 . In addition to AS, PSRC1 is a susceptibility locus for myocardial infarction 41 - 43 and coronary heart disease 44 - 46 .…”

Clinical evidence of pharmacogenetics of statins: systematic literature review

“…In two RCTs, one data analysis study, one case-control study and one prospective study ApoE (rs429358 and rs7412) had different allele variation e2, e3 and e4. [9,10,14,18,19] The e4 allele carriers showed a poorer response to statin therapy, while e2 and e3 alleles had been associated with greater LDL-C reduction. Eventually, there is little reason to consider pharmacogenetic testing for APOE gene polymorphism to guide treatment with statins.…”

“…Van Der Baan et al (2013) [10] RCT** APOE, ACE, HL, TLR4 gene-gene interactions with statin therapy were identified. Ciuculete et al (2017) [19] Prospective Four SNPs within the APOE cluster (rs7412, rs4420638), ABCC2 (rs2002042) and CELSR/SORT1/PSRC1 (rs646776), displayed a major impact on statin efficacy. Elgwad et al (2018) [23] Prospective Q192R polymorphism of PON1gene had important role in interindividual variety in accomplishment of HDL-C goals in response to statins.…”

“…The literature search was limited by available databases and access. The number of publications in this topic is relatively [9,[13][14][15] X X SLCO1B1 [16,17] X X APOE [9,10,14,18,19] X X PON1 [23,24] X X RYR2 [27] X X RYR2 [17] X X TLR4, [10] LTa C804A, [31] LPA, [9] NPC1L1, [18] HLA-G, [32] CYP3A4*2, [33] eNOS, [33] CYP2D6, [34] ABCB1, [35] CETP, [14] SREBF1,2, [36] KIF16, [37] HMGCR, [14,19] SORT1/CELSR2/PSRC1 [19,24] X X ACE, [10] HL, [10] WDR52, [38] CDH13, [39] CYP3A4*2 [40] X X HLA-DRB1, [17] LILRB5 [25] X X COQ2, [15] GATM [17,30] X X Pharmacogentics of statins Anas S. Aldawsari and Mohammad S. Shawaqfeh scares which made the literature search a real challenge. There were limited numbers of randomised controlled studies and meta-analysis in the topic.…”