Date Published: February 13, 2018
Publisher: Public Library of Science
Author(s): Suzanne A. Al-Bustan, Ahmad Al-Serri, Babitha G. Annice, Majed A. Alnaqeeb, Wafa Y. Al-Kandari, Mohammed Dashti, Farook Thameem.
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.
Dyslipidemia or variation in plasma lipid levels is a global health concern that often leads to metabolic syndrome and subsequently heart disease. Although numerous environmental factors have been shown to increase the risk of hypertriglyceridemia (HTG) and hypercholesterolemia (HC), genetic factors remain unresolved. Different genetic studies on various populations have estimated the heritability values for plasma lipids to range between 40–60% [1–4]. These values are very likely to be influenced by ethnicity. Recent studies [3,5] reported that variation in triglyceride (TG), high density lipoprotein (HDL) and low-density lipoprotein (LDL) in addition to total cholesterol (TC) levels are influenced by specific variants at numerous gene loci that may contribute to the variation of these levels between different populations [1,6]. However, genetic association studies at various gene loci including Genome Wide Association Studies (GWAS) continue to report conflicting results and often reproducibility studies fail to confirm reported findings for specific genetic variants [2–6]. It has been documented that the main reason behind such conflicting results is the selection of variants (especially “rare” variants) that may be ethnic specific and therefore may not yield similar findings between different populations [3,5]. Nonetheless, genetic association of numerous variants at several gene loci involved in the lipid metabolic and transport pathways have been implicated, including lipoprotein lipase (LPL), to influence TG and HDL-C levels [3, 5].
The strength of the present study rests with the inclusion of the whole LPL gene along with its flanking sequence in a bid to identify the effect of variants in an ethnic group that is not well studied. Furthermore, the study identified a novel variant (KUA LPL-27) LPL: g.18704C>A associated with HDL-C, TG and VLDL levels. This allowed the identification of variants that maybe absent or very rare in other populations yet could be a significant contributor to plasma lipid levels. The variants identified and their description in details, which can be used for meta-analysis or for comparison of the Arab ethnicity with other ethnic groups, is summarized (Table D in S2 File). In addition, the comparative analysis allowed formulation of a list of potential variants (Table 6 & Table G in S2 File) that may serve as a guide for selection in genetic association studies of dyslipidemia in relation to different ethnic groups. The study identified a novel SNP in a noncoding region and demonstrated its opposing effect on plasma HDL-C and TG levels and proposed a mode of action for this effect. However, a limitation was the lack of LPL protein levels in the cohort. This would have been highly informative with regards to the effect of KUA LPL-27: g.18704C>A on LPL expression. It is strongly recommended that KUA LPL-27: g.18704C>A be investigated in other ethnic groups as well as to investigate its potential association with clinical manifestations of dyslipidemia such as diabetes mellitus and/or heart disease. In addition, the two novel insertions (LPL: c.249+606dupA in intron and KUA LPL-36InsTTT in intron 7) identified in all the 100 samples of Kuwaiti Arabs re-sequenced presents an opportunity for further analysis in a large cohort to assess their effect on LPL activity or determine their role in the population structure of Arab ethnicity.