title: Resequencing of LPL in African Blacks and associations with lipoprotein-lipid levels.
abstract: Genome-wide association studies have identified several loci associated with plasma lipid levels but those common variants together account only for a small proportion of the genetic variance of lipid traits. It has been hypothesized that the remaining heritability may partly be explained by rare variants with strong effect sizes. Here, we have comprehensively investigated the associations of both common and uncommon/rare variants in the lipoprotein lipase (LPL) gene in relation to plasma lipoprotein-lipid levels in African Blacks (ABs). For variant discovery purposes, the entire LPL gene and flanking regions were resequenced in 95 ABs with extreme high-density lipoprotein cholesterol (HDL-C) levels. A total of 308 variants were identified, of which 64 were novel. Selected common tagSNPs and uncommon/rare variants were genotyped in the entire sample (n=788), and 126 QC-passed variants were evaluated for their associations with lipoprotein-lipid levels by using single-site, haplotype and rare variant (SKAT-O) association analyses. We found eight not highly correlated (r(2)<0.40) signals (rs1801177:G>A, rs8176337:G>C, rs74304285:G>A, rs252:delA, rs316:C>A, rs329:A>G, rs12679834:T>C, and rs4921684:C>T) nominally (P<0.05) associated with lipid traits (HDL-C, LDL-C, ApoA1 or ApoB levels) in our sample. The most significant SNP, rs252:delA, represented a novel association observed with LDL-C (P=0.002) and ApoB (P=0.012). For TG and LDL-C, the haplotype analysis was more informative than the single-site analysis. The SKAT-O analysis revealed that the bin (group) containing 22 rare variants with MAF≤0.01 exhibited nominal association with TG (P=0.039) and LDL-C (P=0.027). Our study indicates that both common and uncommon/rare LPL variants/haplotypes may affect plasma lipoprotein-lipid levels in general African population.
authors: Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA, USA.
authors: Dilek
authors: D
authors: Pirim
authors: 1] Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA, USA [2] Department of Biostatistics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA, USA.
authors: Xingbin
authors: X
authors: Wang
authors: Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA, USA.
authors: Zaheda H
authors: ZH
authors: Radwan
authors: Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA, USA.
authors: Vipavee
authors: V
authors: Niemsiri
authors: Department of Epidemiology, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA, USA.
authors: Clareann H
authors: CH
authors: Bunker
authors: Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA, USA.
authors: M Michael
authors: MM
authors: Barmada
authors: Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA, USA.
authors: M Ilyas
authors: MI
authors: Kamboh
authors: Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA, USA.
authors: F Yesim
authors: FY
authors: Demirci
mesh_terms: D000328:Adult; D000483:Alleles; D016632:Apolipoprotein A-I / Q000097:blood / Q000235:genetics*; D001055:Apolipoproteins B / Q000097:blood / Q000235:genetics*; D044383:Black People; D008076:Cholesterol, HDL / Q000097:blood / Q000235:genetics; D008078:Cholesterol, LDL / Q000097:blood / Q000235:genetics; D005260:Female; D015870:Gene Expression; D005787:Gene Frequency; D015894:Genome, Human; D055106:Genome-Wide Association Study; D006239:Haplotypes; D006801:Humans; D050356:Lipid Metabolism / Q000235:genetics; D008071:Lipoprotein Lipase / Q000097:blood / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009549:Nigeria; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D017422:Sequence Analysis, DNA; D014280:Triglycerides / Q000097:blood / Q000235:genetics
chemical_list: D016632:Apolipoprotein A-I; D001055:Apolipoproteins B; D008076:Cholesterol, HDL; D008078:Cholesterol, LDL; D014280:Triglycerides; C548261:LPL protein, human; D008071:Lipoprotein Lipase
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