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Genetic Contribution of SCARB1 Variants to Lipid Traits in African Blacks: a Candidate Gene Association Study Vipavee Niemsiri1, Xingbin Wang1, Dilek Pirim1, Zaheda H

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Genetic Contribution of SCARB1 Variants to Lipid Traits in African Blacks: a Candidate Gene Association Study Vipavee Niemsiri1, Xingbin Wang1, Dilek Pirim1, Zaheda H Niemsiri et al. BMC Medical Genetics (2015) 16:106 DOI 10.1186/s12881-015-0250-6 RESEARCH ARTICLE Open Access Genetic contribution of SCARB1 variants to lipid traits in African Blacks: a candidate gene association study Vipavee Niemsiri1, Xingbin Wang1, Dilek Pirim1, Zaheda H. Radwan1, Clareann H. Bunker2, M. Michael Barmada1, M. Ilyas Kamboh1*† and F. Yesim Demirci1*† Abstract Background: High-density lipoprotein cholesterol (HDL-C) exerts many anti-atherogenic properties including its role in reverse cholesterol transport (RCT). Scavenger receptor class B member 1 (SCARB1) plays a key role in RCT by selective uptake of HDL cholesteryl esters. We aimed to explore the genetic contribution of SCARB1 to affecting lipid levels in African Blacks from Nigeria. Methods: We resequenced 13 exons and exon-intron boundaries of SCARB1 in 95 individuals with extreme HDL-C levels using Sanger method. Then, we genotyped 147 selected variants (78 sequence variants, 69 HapMap tagSNPs, and 2 previously reported relevant variants) in the entire sample of 788 African Blacks using either the iPLEX Gold or TaqMan methods. A total of 137 successfully genotyped variants were further evaluated for association with major lipid traits. Results: The initial gene-based analysis demonstrated evidence of association with HDL-C and apolipoprotein A-I (ApoA-I). The follow-up single-site analysis revealed nominal evidence of novel associations of nine common variants with HDL-C and/or ApoA-I (P < 0.05). The strongest association was between rs11057851 and HDL-C (P = 0.0043), which remained significant after controlling for multiple testing using false discovery rate. Rare variant association testing revealed a group of 23 rare variants (frequencies ≤1%)associatedwithHDL-C(P = 0.0478). Haplotype analysis identified four SCARB1 regions associated with HDL-C (global P <0.05). Conclusions: To our knowledge, this is the first report of a comprehensive association study of SCARB1 variations with lipid traits in an African Black population. Our results showed the consistent association of SCARB1 variants with HDL-C across various association analyses, supporting the role of SCARB1 in lipoprotein-lipid regulatory mechanism. Keywords: African continental ancestry group, Candidate gene association study, Genetic variation, Haplotypes, Lipids, SCARB1 protein, human, Sequence analysis, DNA Background correlated with the development of CHD. There is a Abnormal lipid and lipoprotein levels are a major risk strong genetic basis for lipoprotein-lipid levels with her- factor for coronary heart disease (CHD) [1], the leading itability estimates of 40–80 % [3]. A large number of cause of death worldwide [2]. Elevated low-density genes and genetic variants associated with lipid traits lipoprotein cholesterol (LDL-C) levels and decreased have been discovered in genome-wide association stud- high-density lipoprotein cholesterol (HDL-C) levels are ies (GWAS) [4–6]. Most of the common variants (minor allele frequency [MAF] ≥5 %) identified by GWAS have modest effects on lipid levels, and have overall a small * Correspondence: [email protected]; [email protected] † contribution to total genetic variance of lipid traits Equal contributors 1Department of Human Genetics, Graduate School of Public Health, (~25–30 % of the heritability) [4–8]. A portion of the University of Pittsburgh, 130 DeSoto Street, Pittsburgh, PA 15261, USA missing heritability of lipid traits could be explained by Full list of author information is available at the end of the article © 2015 Niemsiri et al. Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Niemsiri et al. BMC Medical Genetics (2015) 16:106 Page 2 of 30 low frequency (LoF)/rare variants (MAF <5 %) as sug- Methods gested by recent studies [9–11]. Study population HDL, the smallest and densest (d =1.063–1.21 g/mL) The present study was carried out on 788 African Black class of lipoprotein particles, has a variety of anti- subjects from Benin City, Nigeria, who were recruited as atherogenic properties [12]. One of the HDL properties part of a population-based epidemiological study on to protect against CHD is mediated by reverse choles- CHD risk factors. Detailed information on the study de- terol transport (RCT) from peripheral tissues back to sign and population description is provided elsewhere the liver [13]. Scavenger receptor class B member 1 [41]. In brief, 788 recruited subjects were healthy civil (SCARB1, protein; SCARB1, gene) serves as a HDL-C servants (37.18 % females) from three government min- receptor in RCT that mediates selective uptake of istries of the Edo state in Benin City, Nigeria, aged HDL-C cholesteryl esters (CE) by the liver and free between 19 and 70 years, including 464 junior staff cholesterol efflux from cells to HDL-C [14]. SCARB1 is (non-professional staff with salary grades 1–6), and 324 also implicated in the metabolism of apolipoprotein B senior staff (professional and administrative staff with (ApoB)-containing particles [15–21]. salary grades 7–16). The summary features, including The SCARB1 gene (Entrez Gene ID: 949) is located on biometric and quantitative data of the entire sample of human chromosome 12, and is abundantly expressed in 788 subjects are given in Table 1 and Additional file 1: liver and steroidogenic tissues [22, 23]. The role of Table S1. SCARB1 in HDL-C and ApoB-containing lipoproteins For resequencing, 95 individuals with extreme HDL- metabolism has been established in animal studies. The C levels (within the upper and lower 10th percentiles of disruption of SCARB1 is associated with increased HDL- HDL-C distribution) were chosen from the entire sample C levels and decreased CE uptake [24–26]. Whereas the of 788 African Blacks. Resequencing sample comprised of overexpression of SCARB1 reduces levels of HDL-C, 48 individuals with high HDL-C levels (≥90th percentile, ApoA-I, very low-density lipoprotein cholesterol (VLDL- range 68.30–99.00 mg/dL; Table 1) and 47 individuals C), LDL-C, and ApoB [15–17, 19] and promotes the with low HDL-C levels (≤10th percentile, range 10.30– hepatic uptake of CE as well as the biliary secretion of 35.00 mg/dL; Table 1). The University of Pittsburgh Insti- HDL-C [15, 27]. The SCARB1 expression is also signifi- tutional Review Board approved the study protocol. All cantly associated with hepatic VLDL-triglycerides (TG) participants gave their informed consent. and VLDL-ApoB production. Hepatic VLDL cholesterol production together with VLDL clearance is enhanced in Lipid and apolipoprotein measurements response to SCARB1 overexpression [21]. In contrast, At least 8-hour fasting blood samples were collected reduced hepatic VLDL-TG and VLDL-ApoB production from all participants. Serum specimens were separated is associated with SCARB1 knockout status [18, 20, 21]. by centrifugation of blood samples and then stored at In humans, three SCARB1 mutations (rs397514572 −70 °C for 6–12 months until ready for testing. Lipid [p.Ser112Phe], rs187831231 [p.Thr175Ala], and and apolipoprotein measurements included total choles- rs387906791 [p.Pro297Ser]; MIM: 601040) have been terol, HDL-C, TG, ApoA-I, and ApoB and were done reported to be associated with significantly increased with standard assays at the Heinz Nutrition Laboratory, HDL-C levels [28, 29]. Moreover, several genetic studies University of Pittsburgh under the Centers for Disease have demonstrated the association of common SCARB1 Control Lipid Standardization Program [41]. LDL-C was variation with lipoprotein-lipid levels [5, 28–39] and sub- calculated with the Friedewald equation [42] when TG clinical atherosclerosis [40]. levels were less than 400 mg/dL. To our knowledge, no genetic study has exclusively investigated the association between SCARB1 and lipid PCR and sequencing traits in native African populations to date. The object- Genomic DNA was isolated from clotted blood using ive of this study was to resequence all 13 exons and the standard DNA extraction procedure. All 13 SCARB1 exon-intron boundaries of SCARB1 in 95 African exons (isoform 1, NM_005505), exon-intron boundaries, Blacks from Nigeria with extreme HDL-C levels for and 1 kb of each of 5′ and 3′ flanking regions on variant discovery and then to genotype selected variants chromosome 12 (hg19, chr12: 125,262,175-125,348,519) intheentiresampleof788AfricanBlacks,followedby were polymerase chain reaction (PCR) amplified and genotype-phenotype association analyses with five major sequenced. Specific primers were designed using the Pri- lipid and apolipoprotein (Apo) traits (HDL-C, LDL-C, TG, mer3 software (Whitehead Institute for Biomedical ApoA-I and ApoB). Because our initial gene-based ana- Research, http://bioinfo.ut.ee/primer3-0.4.0/) to cover 13 lysis demonstrated evidence of association with HDL-C target regions, resulting in 14 amplicons, including two and ApoA-I, our subsequent analyses focused on these overlapping amplicons for the largest last exon 13. PCR two traits. reaction and cycling conditions are available upon
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