A novel LPL intronic variant: g.18704C>A identified by re-sequencing Kuwaiti Arab samples is associated with high-density lipoprotein, very low-density lipoprotein and triglyceride lipid levels

Abstract

The role interethnic genetic differences play in plasma lipid level variation across populations is a global health concern. Several genes involved in lipid metabolism and transport are strong candidates for the genetic association with lipid level variation especially lipoprotein lipase (LPL). The objective of this study was to re-sequence the full LPL gene in Kuwaiti Arabs, analyse the sequence variation and identify variants that could attribute to variation in plasma lipid levels for further genetic association. Samples (n = 100) of an Arab ethnic group from Kuwait were analysed for sequence variation by Sanger sequencing across the 30 Kb LPL gene and its flanking sequences. A total of 293 variants including 252 single nucleotide polymorphisms (SNPs) and 39 insertions/deletions (InDels) were identified among which 47 variants (32 SNPs and 15 InDels) were novel to Kuwaiti Arabs. This study is the first to report sequence data and analysis of frequencies of variants at the LPL gene locus in an Arab ethnic group with a novel “rare” variant (LPL:g.18704C>A) significantly associated to HDL (B = -0.181; 95% CI (-0.357, -0.006); p = 0.043), TG (B = 0.134; 95% CI (0.004–0.263); p = 0.044) and VLDL (B = 0.131; 95% CI (-0.001–0.263); p = 0.043) levels. Sequence variation in Kuwaiti Arabs was compared to other populations and was found to be similar with regards to the number of SNPs, InDels and distribution of the number of variants across the LPL gene locus and minor allele frequency (MAF). Moreover, comparison of the identified variants and their MAF with other reports provided a list of 46 potential variants across the LPL gene to be considered for future genetic association studies. The findings warrant further investigation into the association of g.18704C>A with lipid levels in other ethnic groups and with clinical manifestations of dyslipidemia.

Genetic association of LPL rs1121923 and rs258 with plasma TG and VLDL levels

“…Despite consistency in the implication of LPL and variation in lipid levels with associated clinical manifestations 2,16–22 , the effect of many of the significant variants identified were not observed in different populations and ethnic groups 2,3,5,6,8,9,12,13 . It has been suggested that the role of LPL and its variants be further investigated in different populations with reference to ethnic backgrounds 2 .…”

“…Although numerous studies have demonstrated the complex etiology of dyslipidemia implicating a variety of environmental factors such as nutrition, conflicting results persist with regards to the role of genetic factors. More recently, studies have indicated that the heritably of plasma lipid levels is not only influenced by numerous genetic variants but also by ethnicity 2–6 . In fact, Deo et al .…”

“…(2010) indicated that both common and rare genetic variants could explain 41.6% of total variation in HTG with common genetic variants explaining 20.8% (specifically for 7 gene loci) and the rare genetic variants explaining only 1.1% (at 4 gene loci) while the other associated factors explained 19.7% of the cases 7 . Among all these studies, the gene for lipoprotein lipase ( LPL ) has always been implicated with a significant influence on one or multiple variations in lipid parameters 2–4,6–9 .…”

“…The LPL gene codes for the 475-amino acid enzyme responsible for the hydrolysis of triglycerides to free fatty acid and is an important catalyst in lipid metabolism and transport pathways. The gene has been fully mapped to chromosome 8q22 and has been fully sequenced in different ethnic groups 2,5,6,10–12 . The gene spans 30Kb including 10 exons with the first exon encoding the 5′ untranslated region (UTR) and signal peptide and the last exon encoding the full 3′ UTR.…”

“…The gene spans 30Kb including 10 exons with the first exon encoding the 5′ untranslated region (UTR) and signal peptide and the last exon encoding the full 3′ UTR. Most of the gene comprises noncoding sequences mainly localized to intron 1 6,10 . Some studies have reported associations of numerous variants in both the coding and the non-coding regions, especially in introns 2, 3, 5, 6 and 8 with variation in lipid levels 2,5,6,10–15 .…”