Genetic Susceptibility to Lipid Levels and Lipid Change Over Time and Risk of Incident Hyperlipidemia in Chinese Populations

Abstract

Background-Multiple genetic loci associated with lipid levels have been identified predominantly in Europeans, and the issue of to what extent these genetic loci can predict blood lipid levels increases over time and the incidence of future hyperlipidemia remains largely unknown. Methods and Results-We conducted a meta-analysis of genome-wide association studies of lipid levels in 8344 subjects followed by replication studies including 14 739 additional individuals. We replicated 17 previously reported loci. We also newly identified 3 Chinese-specific variants in previous regions (HLA-C, LIPG, and LDLR) with genome-wide significance. Almost all the variants contributed to lipid levels change and incident hyperlipidemia >8.1-year follow-up among 6428 individuals of a prospective cohort study. The strongest associations for lipid levels change were detected at LPL, TRIB1, APOA1-C3-A4-A5, LIPC, CETP, and LDLR (P range from 4.84×10 -4 to 4.62×10 -18), whereas LPL, TRIB1, ABCA1, APOA1-C3-A4-A5, CETP, and APOE displayed significant strongest associations for incident hyperlipidemia (P range from 1.20×10 -3 to 4.67×10 -16 ). The 4 lipids genetic risk scores were independently associated with linear increases in their corresponding lipid levels and risk of incident hyperlipidemia. A C-statistics analysis showed significant improvement in the prediction of incident hyperlipidemia on top of traditional risk factors including the baseline lipid levels. Conclusions-These findings identified some evidence for allelic heterogeneity in Chinese when compared with Europeans in relation to lipid associations. The individual variants and those cumulative effects were independent risk factors for lipids increase and incident hyperlipidemia.

Interaction of GCKR, MLXIPL and FADS Genes Polymorphisms with Obesity in the Occurrence of Childhood Metabolic Syndrome

“…Previous studies have shown the association between GCKR rs1260333 and lipid levels, triglyceride, insulin resistance and metabolic syndrome (35,36). But results of a study in a pediatric population have demonstrated that though this SNP was associated with hypertriglyceridemia in children, the triglyceride increasing allele has protective effect for insulin resistance (37).…”

Genome-wide association study of metabolic syndrome in Korean populations

“…Rs1260326, which is a non-synonymous variant in GCKR, and rs1260333, located downstream of GCKR, were reported to have inverse effects on TG and glucose levels in European descent populations [26][27][28]. The association between these two SNPs and TG level is validated in Chinese and Japanese [29,30]. Moreover, TG-increasing alleles of GCKR variants rs1260326 and rs1260333 lowered insulin and HOMA-IR and reduced the risk of insulin resistance in Chinese [31].…”

“…This enzyme catalyzes the synthesis of retinoic acid from retinaldehyde and retinoic acid, the active derivative of vitamin A, is a hormonal signaling molecule that functions in normal organ development [35]. Variants of the ALDH1A2 gene was associated with lipid traits in previous several Asian studies [29,36]. The LIPC gene provides instructions for making hepatic lipase, which helps with the conversion of very low-density lipoprotein (VLDL) to LDL.…”

Identification of eight genetic variants as novel determinants of dyslipidemia in Japanese by exome-wide association studies

“…Among the 69 loci associated with HDL-cholesterol–related traits in the present study, 16 loci—12q24.1 [24], 16q13 [15, 16], CETP [15, 16], APOA5 [16], LIPC [16, 17], HECTD4 [24], LILRB2 [8], LPL [15, 16], 8p21.3 [15, 16], LOC101928635 [10, 17], BUD13 [16], ZPR1 [23], ABCA1 [10, 16], 11q23.3 [16], OAS3 [24], and CD36 [25]—were previously shown to be related to the blood HDL-cholesterol level or hypo–HDL-cholesterolemia (Supplementary Table 17). Among the 32 loci associated with LDL-cholesterol–related traits in the present study, nine loci— APOE [26], APOC1 [27], APOB [16, 17], PCSK9 [17], PSRC1 [12, 28], CELSR2 [10, 16], 1p13.3 [16], ABO [17], and 9q34.2 [8, 17]—were previously shown to be related to the circulating LDL-cholesterol concentration or hyper–LDL-cholesterolemia (Supplementary Table 18). …”

“…Among the 24 loci associated with triglyceride-related traits in the present study, 13 loci— BUD13 [15], 11q23.3 [16], APOA5 [15, 16], ZPR1 [16], APOA4 [15, 17], LPL [15, 17], 8p21.3 [15, 18], SIK3 [19, 20], GCKR [16], 2p23 [17, 21], C2orf16 [22], 8q24.1 [23], and LOC101929011 [21]—were previously shown to be related to the circulating triglyceride level or hypertriglyceridemia (Supplementary Table 16). Among the 69 loci associated with HDL-cholesterol–related traits in the present study, 16 loci—12q24.1 [24], 16q13 [15, 16], CETP [15, 16], APOA5 [16], LIPC [16, 17], HECTD4 [24], LILRB2 [8], LPL [15, 16], 8p21.3 [15, 16], LOC101928635 [10, 17], BUD13 [16], ZPR1 [23], ABCA1 [10, 16], 11q23.3 [16], OAS3 [24], and CD36 [25]—were previously shown to be related to the blood HDL-cholesterol level or hypo–HDL-cholesterolemia (Supplementary Table 17). Among the 32 loci associated with LDL-cholesterol–related traits in the present study, nine loci— APOE [26], APOC1 [27], APOB [16, 17], PCSK9 [17], PSRC1 [12, 28], CELSR2 [10, 16], 1p13.3 [16], ABO [17], and 9q34.2 [8, 17]—were previously shown to be related to the circulating LDL-cholesterol concentration or hyper–LDL-cholesterolemia (Supplementary Table 18).…”