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• W1992670435 abstract "We investigated the effects of single nucleotide polymorphisms (SNPs) of the hepatic lipase gene (LIPC) on plasma HDL-cholesterol (HDL-C) levels in Turks, a population with low levels of HDL-C. All exons and six evolutionarily conserved regions from 28 Turkish subjects were sequenced. We found 51 SNPs, nine of which were novel. Those 51 SNPs and SNPs from the National Center for Biotechnology Information dbSNP were evaluated by bioinformatics approaches. The population frequencies and linkage disequilibrium among SNPs from HapMap were combined with results from transcriptional factor prediction tools and the literature to select SNPs for genotyping. We found that five tagging LIPC SNPs, two reported here for the first time, were significantly associated with plasma HDL-C levels in both men and women (n = 2,612). These results were replicated in a separate Turkish cohort (n = 1,164). Plasma HDL-C levels were higher in subjects homozygous for the minor alleles of rs4775041, rs1800588 (–514C>T), and rs11858164 and lower in subjects homozygous for the minor alleles of rs11856322 and rs2242061. These SNPs seemed to have independent and additive effects on plasma HDL-C levels (1.5–5.2 mg/dl). Hepatic lipase activity in a subset (n = 260) of the main cohort was also significantly associated with all five SNPs. Thus, five LIPC SNPs, two novel, are associated with plasma HDL-C levels and hepatic lipase activity in two cohorts of Turkish subjects. We investigated the effects of single nucleotide polymorphisms (SNPs) of the hepatic lipase gene (LIPC) on plasma HDL-cholesterol (HDL-C) levels in Turks, a population with low levels of HDL-C. All exons and six evolutionarily conserved regions from 28 Turkish subjects were sequenced. We found 51 SNPs, nine of which were novel. Those 51 SNPs and SNPs from the National Center for Biotechnology Information dbSNP were evaluated by bioinformatics approaches. The population frequencies and linkage disequilibrium among SNPs from HapMap were combined with results from transcriptional factor prediction tools and the literature to select SNPs for genotyping. We found that five tagging LIPC SNPs, two reported here for the first time, were significantly associated with plasma HDL-C levels in both men and women (n = 2,612). These results were replicated in a separate Turkish cohort (n = 1,164). Plasma HDL-C levels were higher in subjects homozygous for the minor alleles of rs4775041, rs1800588 (–514C>T), and rs11858164 and lower in subjects homozygous for the minor alleles of rs11856322 and rs2242061. These SNPs seemed to have independent and additive effects on plasma HDL-C levels (1.5–5.2 mg/dl). Hepatic lipase activity in a subset (n = 260) of the main cohort was also significantly associated with all five SNPs. Thus, five LIPC SNPs, two novel, are associated with plasma HDL-C levels and hepatic lipase activity in two cohorts of Turkish subjects. Low levels of plasma HDL-cholesterol (HDL-C) are an independent risk factor for coronary heart disease (1Gordon D.J. Probstfield J.L. Garrison R.J. Neaton J.D. Castelli W.P. Knoke J.D. Jacobs Jr., D.R. Bangdiwala S. Tyroler H.A. High-density lipoprotein cholesterol and cardiovascular disease. Four prospective American studies.Circulation. 1989; 79: 8-15Google Scholar, 2Jacobs Jr., D.R. Mebane I.L. Bangdiwala S.I. Criqui M.H. Tyroler H.A. High density lipoprotein cholesterol as a predictor of cardiovascular disease mortality in men and women: the follow-up study of the Lipid Research Clinics Prevalence Study.Am. J. Epidemiol. 1990; 131: 32-47Google Scholar), the leading cause of death worldwide (3Murray C.J.L. Lopez A.D. Mortality by cause for eight regions of the world: Global Burden of Disease study.Lancet. 1997; 349: 1269-1276Google Scholar). Plasma HDL-C levels are strongly influenced by genetics, as demonstrated in extensive epidemiological, family, and association studies. Heritability estimates of total HDL-C have been reported as 0.20–0.69 (4Mahaney M.C. Blangero J. Rainwater D.L. Comuzzie A.G. VandeBerg J.L. Stern M.P. MacCluer J.W. Hixson J.E. A major locus influencing plasma high-density lipoprotein cholesterol levels in the San Antonio Family Heart Study: segregation and linkage analyses.Arterioscler. Thromb. Vasc. Biol. 1995; 15: 1730-1739Google Scholar, 5Knoblauch H. Bauerfeind A. Toliat M.R. Becker C. Luganskaja T. Günther U.P. Rohde K. Schuster H. Junghans C. Luft F.C. et al.Haplotypes and SNPs in 13 lipid-relevant genes explain most of the genetic variance in high-density lipoprotein and low-density lipoprotein cholesterol.Hum. Mol. Genet. 2004; 13: 993-1004Google Scholar, 6Yu Y. Wyszynski D.F. Waterworth D.M. Wilton S.D. Barter P.J. Kesäniemi Y.A. Mahley R.W. McPherson R. Waeber G. Bersot T.P. et al.Multiple QTLs influencing triglyceride and HDL and total cholesterol levels identified in families with atherogenic dyslipidemia.J. Lipid Res. 2005; 46: 2202-2213Google Scholar). Recently, a genome scan for atherogenic dyslipidemia by the multinational Genetic Epidemiology of Metabolic Syndrome project (7Wyszynski D.F. Waterworth D.M. Barter P.J. Cohen J. Kesäniemi Y.A. Mahley R.W. McPherson R. Waeber G. Bersot T.P. Sharma S.S. et al.Relation between atherogenic dyslipidemia and the Adult Treatment Program-III definition of metabolic syndrome (Genetic Epidemiology of Metabolic Syndrome Project).Am. J. Cardiol. 2005; 95: 194-198Google Scholar) found significant linkage to plasma HDL-C levels on chromosome 15q22-23 in Turkish families; the reported heritability estimate for this trait in these families was 0.80 (6Yu Y. Wyszynski D.F. Waterworth D.M. Wilton S.D. Barter P.J. Kesäniemi Y.A. Mahley R.W. McPherson R. Waeber G. Bersot T.P. et al.Multiple QTLs influencing triglyceride and HDL and total cholesterol levels identified in families with atherogenic dyslipidemia.J. Lipid Res. 2005; 46: 2202-2213Google Scholar). The hepatic lipase gene (LIPC) is located on chromosome 15q22, suggesting that variation(s) within this gene might be responsible for or contribute to the linkage peak in Turkish families. Hepatic lipase is primarily synthesized by hepatocytes and is at the surface of liver sinusoids. It has both triglyceride lipase and phospholipase activities and is involved at different steps of lipoprotein metabolism (8Mahley R.W. Weisgraber K.H. Bersot T.P. Disorders of lipid metabolism.in: Kronenberg H.M. Melmed S. Polonsky K.S. Larsen P.R. Williams Textbook of Endocrinology. Saunders, Philadelphia2008: 1589-1653Google Scholar). High hepatic lipase activity is associated with low plasma HDL-C levels (8Mahley R.W. Weisgraber K.H. Bersot T.P. Disorders of lipid metabolism.in: Kronenberg H.M. Melmed S. Polonsky K.S. Larsen P.R. Williams Textbook of Endocrinology. Saunders, Philadelphia2008: 1589-1653Google Scholar). Several single nucleotide polymorphisms (SNPs) in LIPC showed significant associations with plasma HDL-C (9Guerra R. Wang J. Grundy S.M. Cohen J.C. A hepatic lipase (LIPC) allele associated with high plasma concentrations of high density lipoprotein cholesterol.Proc. Natl. Acad. Sci. USA. 1997; 94: 4532-4537Google Scholar, 10Couture P. Otvos J.D. Cupples L.A. Lahoz C. Wilson P.W.F. Schaefer E.J. Ordovas J.M. Association of the C–514T polymorphism in the hepatic lipase gene with variations in lipoprotein subclass profiles: the Framingham Offspring Study.Arterioscler. Thromb. Vasc. Biol. 2000; 20: 815-822Google Scholar, 11Murtomäki S. Tahvanainen E. Antikainen M. Tiret L. Nicaud V. Jansen H. Ehnholm C. Hepatic lipase gene polymorphisms influence plasma HDL levels. Results from Finnish EARS participants.Arterioscler. Thromb. Vasc. Biol. 1997; 17: 1879-1884Google Scholar, 12Andersen R.V. Wittrup H.H. Tybjærg-Hansen A. Steffensen R. Schnohr P. Nordestgaard B.G. Hepatic lipase mutations, elevated high-density lipoprotein cholesterol, and increased risk of ischemic heart disease: the Copenhagen City Heart Study.J. Am. Coll. Cardiol. 2003; 41: 1972-1982Google Scholar, 13Kathiresan S. Melander O. Anevski D. Guiducci C. Burtt N.P. Roos C. Hirschhorn J.N. Berglund G. Hedblad B. Groop L. et al.Polymorphisms associated with cholesterol and risk of cardiovascular events.N. Engl. J. Med. 2008; 358: 1240-1249Google Scholar, 14Vega G.L. Gao J. Bersot T.P. Mahley R.W. Verstraete R. Grundy S.M. White A. Cohen J.C. The –514 polymorphism in the hepatic lipase gene (LIPC) does not influence androgen-mediated stimulation of hepatic lipase activity.J. Lipid Res. 1998; 39: 1520-1524Google Scholar) and hepatic lipase activity (12Andersen R.V. Wittrup H.H. Tybjærg-Hansen A. Steffensen R. Schnohr P. Nordestgaard B.G. Hepatic lipase mutations, elevated high-density lipoprotein cholesterol, and increased risk of ischemic heart disease: the Copenhagen City Heart Study.J. Am. Coll. Cardiol. 2003; 41: 1972-1982Google Scholar, 15Nie L. Wang J. Clark L.T. Tang A. Vega G.L. Grundy S.M. Cohen J.C. Body mass index and hepatic lipase gene (LIPC) polymorphism jointly influence postheparin plasma hepatic lipase activity.J. Lipid Res. 1998; 39: 1127-1130Google Scholar, 16Nie L. Niu S. Vega G.L. Clark L.T. Tang A. Grundy S.M. Cohen J.C. Three polymorphisms associated with low hepatic lipase activity are common in African Americans.J. Lipid Res. 1998; 39: 1900-1903Google Scholar, 17Hegele R.A. Tu L. Connelly P.W. Human hepatic lipase mutations and polymorphisms.Hum. Mutat. 1992; 1: 320-324Google Scholar). The most frequently examined, –514C>T (rs1800588), is located in the promoter region and is in perfect linkage disequilibrium (LD) with the SNPs –763A>G (rs1077835), –710C>T (rs1077834), and –250G>A (rs2070895) (9Guerra R. Wang J. Grundy S.M. Cohen J.C. A hepatic lipase (LIPC) allele associated with high plasma concentrations of high density lipoprotein cholesterol.Proc. Natl. Acad. Sci. USA. 1997; 94: 4532-4537Google Scholar), which are also associated with plasma HDL-C levels (9Guerra R. Wang J. Grundy S.M. Cohen J.C. A hepatic lipase (LIPC) allele associated with high plasma concentrations of high density lipoprotein cholesterol.Proc. Natl. Acad. Sci. USA. 1997; 94: 4532-4537Google Scholar). Other linkage studies also suggested the importance of the LIPC locus on chromosome 15q22 in determining HDL-C levels (9Guerra R. Wang J. Grundy S.M. Cohen J.C. A hepatic lipase (LIPC) allele associated with high plasma concentrations of high density lipoprotein cholesterol.Proc. Natl. Acad. Sci. USA. 1997; 94: 4532-4537Google Scholar, 18Cohen J.C. Wang Z. Grundy S.M. Stoesz M.R. Guerra R. Variation at the hepatic lipase and apolipoprotein AI/CIII/AIV loci is a major cause of genetically determined variation in plasma HDL cholesterol levels.J. Clin. Invest. 1994; 94: 2377-2384Google Scholar, 19Allayee H. Dominguez K.M. Aouizerat B.E. Krauss R.M. Rotter J.I. Lu J. Cantor R.M. de Bruin T.W.A. Lusis A.J. Contribution of the hepatic lipase gene to the atherogenic lipoprotein phenotype in familial combined hyperlipidemia.J. Lipid Res. 2000; 41: 245-252Google Scholar). Recent genome-wide association (GWA) studies (20Willer C.J. Sanna S. Jackson A.U. Scuteri A. Bonnycastle L.L. Clarke R. Heath S.C. Timpson N.J. Najjar S.S. Stringham H.M. et al.Newly identified loci that influence lipid concentrations and risk of coronary artery disease.Nat. Genet. 2008; 40: 161-169Google Scholar, 21Kathiresan S. Melander O. Guiducci C. Surti A. Burtt N.P. Rieder M.J. Cooper G.M. Roos C. Voight B.F. Havulinna A.S. et al.Six new loci associated with blood low-density lipoprotein cholesterol, high-density lipoprotein cholesterol or triglycerides in humans.Nat. Genet. 2008; 40: 189-197Google Scholar, 22Kooner J.S. Chambers J.C. Aguilar-Salinas C.A. Hinds D.A. Hyde C.L. Warnes G.R. Gómez Pérez F.J. Frazer K.A. Elliott P. Scott J. et al.Genome-wide scan identifies variation in MLXIPL associated with plasma triglycerides.Nat. Genet. 2008; 40: 149-151Google Scholar) showed the importance of variants at the LIPC locus; five SNPs, rs4775041, rs261332, rs10468017 (20Willer C.J. Sanna S. Jackson A.U. Scuteri A. Bonnycastle L.L. Clarke R. Heath S.C. Timpson N.J. Najjar S.S. Stringham H.M. et al.Newly identified loci that influence lipid concentrations and risk of coronary artery disease.Nat. Genet. 2008; 40: 161-169Google Scholar), rs1800588 (21Kathiresan S. Melander O. Guiducci C. Surti A. Burtt N.P. Rieder M.J. Cooper G.M. Roos C. Voight B.F. Havulinna A.S. et al.Six new loci associated with blood low-density lipoprotein cholesterol, high-density lipoprotein cholesterol or triglycerides in humans.Nat. Genet. 2008; 40: 189-197Google Scholar), and rs11858164 (22Kooner J.S. Chambers J.C. Aguilar-Salinas C.A. Hinds D.A. Hyde C.L. Warnes G.R. Gómez Pérez F.J. Frazer K.A. Elliott P. Scott J. et al.Genome-wide scan identifies variation in MLXIPL associated with plasma triglycerides.Nat. Genet. 2008; 40: 149-151Google Scholar), were associated with plasma HDL-C levels. The rs4775041 variant was in strong LD with rs10468017 and rs1800588 (–514C>T) was in strong LD with rs261332, but rs11858164 was not in LD with any of them. Thus, three unlinked tagging-SNPs in the LIPC locus were strongly associated with plasma HDL-C levels (20Willer C.J. Sanna S. Jackson A.U. Scuteri A. Bonnycastle L.L. Clarke R. Heath S.C. Timpson N.J. Najjar S.S. Stringham H.M. et al.Newly identified loci that influence lipid concentrations and risk of coronary artery disease.Nat. Genet. 2008; 40: 161-169Google Scholar, 21Kathiresan S. Melander O. Guiducci C. Surti A. Burtt N.P. Rieder M.J. Cooper G.M. Roos C. Voight B.F. Havulinna A.S. et al.Six new loci associated with blood low-density lipoprotein cholesterol, high-density lipoprotein cholesterol or triglycerides in humans.Nat. Genet. 2008; 40: 189-197Google Scholar, 22Kooner J.S. Chambers J.C. Aguilar-Salinas C.A. Hinds D.A. Hyde C.L. Warnes G.R. Gómez Pérez F.J. Frazer K.A. Elliott P. Scott J. et al.Genome-wide scan identifies variation in MLXIPL associated with plasma triglycerides.Nat. Genet. 2008; 40: 149-151Google Scholar). Although hundreds of thousands of SNPs can be examined simultaneously in GWA studies, significant SNPs might be markers for known or unknown functional SNPs (23McCarthy M.I. Abecasis G.R. Cardon L.R. Goldstein D.B. Little J. Ioannidis J.P.A. Hirschhorn J.N. Genome-wide association studies for complex traits: consensus, uncertainty and challenges.Nat. Rev. Genet. 2008; 9: 356-369Google Scholar). Turks, whether living in Turkey or abroad, have very low plasma HDL-C levels (24Mahley R.W. Palaoğlu K.E. Atak Z. Dawson-Pepin J. Langlois A-M. Cheung V. Onat H. Fulks P. Mahley L.L. Vakar F. et al.Turkish Heart Study: lipids, lipoproteins, and apolipoproteins.J. Lipid Res. 1995; 36: 839-859Google Scholar, 25Mahley R.W. Can S. Özbayrakçı S. Bersot T.P. Tanir S. Palaoğlu K.E. Pépin G.M. Modulation of high-density lipoproteins in a population in Istanbul, Turkey, with low levels of high-density lipoproteins.Am. J. Cardiol. 2005; 96: 547-555Google Scholar, 26Tezcan S. Altıntaş H. Sönmez R. Akinci A. Doğan B. Çakır B. Bilgin Y. Klör H.U. Razum O. Cardiovascular risk factor levels in a lower middle-class community in Ankara, Turkey.Trop. Med. Int. Health. 2003; 8: 660-667Google Scholar, 27Porsch-Oezçueruemez M. Bilgin Y. Wollny M. Gediz A. Arat A. Karatay E. Akinci A. Sinterhauf K. Koch H. Siegfried I. et al.Prevalence of risk factors of coronary heart disease in Turks living in Germany: the Giessen Study.Atherosclerosis. 1999; 144: 185-198Google Scholar, 28Bersot T.P. Vega G.L. Grundy S.M. Palaoğlu K.E. Atagündüz P. Özbayrakçi S. Gökdemir O. Mahley R.W. Elevated hepatic lipase activity and low levels of high density lipoprotein in a normotriglyceridemic, nonobese Turkish population.J. Lipid Res. 1999; 40: 432-438Google Scholar) and 25–30% higher hepatic lipase activity and mass (28Bersot T.P. Vega G.L. Grundy S.M. Palaoğlu K.E. Atagündüz P. Özbayrakçi S. Gökdemir O. Mahley R.W. Elevated hepatic lipase activity and low levels of high density lipoprotein in a normotriglyceridemic, nonobese Turkish population.J. Lipid Res. 1999; 40: 432-438Google Scholar, 29Shohet R.V. Vega G.L. Bersot T.P. Mahley R.W. Grundy S.M. Guerra R. Cohen J.C. Sources of variability in genetic association studies: insights from the analysis of hepatic lipase (LIPC).Hum. Mutat. 2002; 19: 536-542Google Scholar). Plasma HDL-C levels and hepatic lipase activity association with the promoter variant, –514C>T (rs1800588), have been reported in the Turkish population (14Vega G.L. Gao J. Bersot T.P. Mahley R.W. Verstraete R. Grundy S.M. White A. Cohen J.C. The –514 polymorphism in the hepatic lipase gene (LIPC) does not influence androgen-mediated stimulation of hepatic lipase activity.J. Lipid Res. 1998; 39: 1520-1524Google Scholar, 29Shohet R.V. Vega G.L. Bersot T.P. Mahley R.W. Grundy S.M. Guerra R. Cohen J.C. Sources of variability in genetic association studies: insights from the analysis of hepatic lipase (LIPC).Hum. Mutat. 2002; 19: 536-542Google Scholar). In this study, we investigated in detail the association between LIPC SNPs and plasma HDL-C levels in over 3,750 participants in two separate cohorts in the Turkish Heart Study (THS), a large, cross-sectional epidemiological survey of the Turkish population (24Mahley R.W. Palaoğlu K.E. Atak Z. Dawson-Pepin J. Langlois A-M. Cheung V. Onat H. Fulks P. Mahley L.L. Vakar F. et al.Turkish Heart Study: lipids, lipoproteins, and apolipoproteins.J. Lipid Res. 1995; 36: 839-859Google Scholar, 25Mahley R.W. Can S. Özbayrakçı S. Bersot T.P. Tanir S. Palaoğlu K.E. Pépin G.M. Modulation of high-density lipoproteins in a population in Istanbul, Turkey, with low levels of high-density lipoproteins.Am. J. Cardiol. 2005; 96: 547-555Google Scholar). All exons and six evolutionarily conserved regions of LIPC were sequenced to detect polymorphisms. There are more than 1,000 SNPs (dbSNP 128) in the LIPC locus. To assess and choose the SNPs for genotyping, HapMap and other resources were used for frequencies and LD among SNPs, and the results were combined with those from comparative genomic resources and transcriptional factor prediction tools. Study samples with complete biodata were randomly selected from THS participants. The first cohort (n = 2,612) included subjects whose samples were collected between 1990 and 1995 (24Mahley R.W. Palaoğlu K.E. Atak Z. Dawson-Pepin J. Langlois A-M. Cheung V. Onat H. Fulks P. Mahley L.L. Vakar F. et al.Turkish Heart Study: lipids, lipoproteins, and apolipoproteins.J. Lipid Res. 1995; 36: 839-859Google Scholar). The second cohort (n = 1,164) included subjects whose samples were collected between 2000 and 2003 (25Mahley R.W. Can S. Özbayrakçı S. Bersot T.P. Tanir S. Palaoğlu K.E. Pépin G.M. Modulation of high-density lipoproteins in a population in Istanbul, Turkey, with low levels of high-density lipoproteins.Am. J. Cardiol. 2005; 96: 547-555Google Scholar) and were used mainly to verify results obtained with the first cohort. Detailed biodata and blood samples were collected for each subject after an overnight fast. Plasma lipids were measured as described (24Mahley R.W. Palaoğlu K.E. Atak Z. Dawson-Pepin J. Langlois A-M. Cheung V. Onat H. Fulks P. Mahley L.L. Vakar F. et al.Turkish Heart Study: lipids, lipoproteins, and apolipoproteins.J. Lipid Res. 1995; 36: 839-859Google Scholar). The protocols were approved by the Committee on Human Research of the University of California, San Francisco, and were in accordance with the Helsinki Declaration. Informed consent was obtained. Subjects who were taking lipid-lowering medication, had a history of diabetes mellitus, or had a plasma triglyceride level >800 mg/dl were excluded. Primers (supplementary Table I) were designed to amplify across the LIPC promoter and all exons, including intron/exon splicing boundaries. Six evolutionarily conserved regions (ECRs; two upstream of the gene and four in intron 1) were also selected for sequencing (see below for selection criteria). DNA from 28 subjects (16 with low HDL-C and 12 with high HDL-C levels) was sequenced to identify polymorphisms in LIPC. DNA sequences were aligned and analyzed with Sequencher DNA analysis software (GeneCodes, Ann Arbor, MI). LIPC is a very large gene and over 1,000 SNPs are found in and around LIPC with different frequencies and validation status (Ensembl BioMart, dbSNP 128). We sequenced about 9–10% of the LIPC locus. To choose and prioritize SNPs in the unsequenced parts of the LIPC locus, we used several bioinformatics tools. First, we used information from HapMap (30The International HapMap Consortium A second generation human haplotype map of over 3.1 million SNPs.Nature. 2007; 449: 851-861Google Scholar), Perlegen (31Hinds D.A. Stuve L.L. Nilsen G.B. Halperin E. Eskin E. Ballinger D.G. Frazer K.A. Cox D.R. Whole-genome patterns of common DNA variation in three human populations.Science. 2005; 307: 1072-1079Google Scholar), and Applied Biosystems SNP Browser 3.5 (32De La Vega F.M. Isaac H.I. Scafe C.R. A tool for selecting SNPs for association studies based on observed linkage disequilibrium patterns.Pac. Symp. Biocomput. 2006; 11: 487-498Google Scholar), in which the frequency and LD information among SNPs were available for various populations. Data from other projects in our laboratory show that Turks more closely resemble Europeans than other populations with respect to allele frequency and we used the relevant populations from these sources. Second, because over half of the bases in ECRs in mammals appear to be functional (33The ENCODE Project Consortium Identification and analysis of functional elements in 1% of the human genome by the ENCODE pilot project.Nature. 2007; 447: 799-816Google Scholar), we examined SNPs in those regions with an ECR browser (34Ovcharenko I. Nobrega M.A. Loots G.G. Stubbs L. ECR Browser: a tool for visualizing and accessing data from comparisons of multiple vertebrate genomes.Nucleic Acids Res. 2004; 32: W280-W286Google Scholar) and the UCSC browser for PhastCon conservation scores (35Siepel A. Bejerano G. Pedersen J.S. Hinrichs A.S. Hou M. Rosenbloom K. Clawson H. Spieth J. Hillier L.W. Richards S. et al.Evolutionarily conserved elements in vertebrate, insect, worm, and yeast genomes.Genome Res. 2005; 15: 1034-1050Google Scholar). Third, the transcriptional factor binding prediction tool (TRANSFAC) (36Matys V. Fricke E. Geffers R. Gößling E. Haubrock M. Hehl R. Hornischer K. Karas D. Kel A.E. Kel-Margoulis O.V. et al.TRANSFAC®: transcriptional regulation, from patterns to profiles.Nucleic Acids Res. 2003; 31: 374-378Google Scholar) was used to identify SNPs that may associate with allele-specific transcription factor recruitment. To speed up this process, we developed a web-based database resource, Delta-MATCH, which can determine in silico whether a SNP alters transcription factor binding sites between two sets of alleles. We also used PReMod, which analyzes information from phylogenetically conserved regions and transcription factor binding sites to predict regulatory modules (37Blanchette M. Bataille A.R. Chen X. Poitras C. Laganière J. Lefèbvre C. Deblois G. Giguère V. Ferretti V. Bergeron D. et al.Genome-wide computational prediction of transcriptional regulatory modules reveals new insights into human gene expression.Genome Res. 2006; 16: 656-668Google Scholar). Fourth, possible microRNA binding sites were also evaluated (UCSC genome browser), and all results and data were harmonized to prioritize the selection of regions for sequencing or SNPs for genotyping. SNPs from published reports were also evaluated in detail. Polymorphisms were genotyped with TaqMan genotyping assays (ABI, Applied Biosystems, Foster City, CA) or by restriction fragment length analysis. Methodological details and primer sequences are available on request. The average genotyping call rate exceeded 97% and the estimated genotyping error rate, determined by analysis of duplicate samples, was about 1%. Data were analyzed with SPSS 10.0, PLINK v1.05 (38Purcell S. Neale B. Todd-Brown K. Thomas L. Ferreira M.A.R. Bender D. Maller J. Sklar P. de Bakker P.I.W. Daly M.J. et al.PLINK: a tool set for whole-genome association and population-based linkage analyses.Am. J. Hum. Genet. 2007; 81: 559-575Google Scholar), Microsoft Access, and Microsoft Excel. Associations between genotypes, lipids, and other parameters were analyzed separately for males and females. Because triglyceride levels were not normally distributed, log-transformed values were used for statistical comparison; untransformed mean values are reported here. Univariate ANOVA was used to calculate adjusted HDL-C levels. Log-transformed triglyceride level, body mass index (BMI), smoking (number of cigarettes/day), alcohol consumption (nondrinkers, 1–5 drinks/week, >5 drinks/week), and age were included as covariates, and genotype score was included as a fixed factor in the model (GLM Univariate, SPSS 10.0). Genotype-lipid association analyses were conducted with an additive model, including covariates, for genotypic effects implemented in PLINK. Corrections for multiple testing were conducted with a permutation test (50,000 permutations) using PLINK. The proportion of variation in plasma HDL-C level from each SNP was estimated from partial regression coefficients (39Corbex M. Poirier O. Fumeron F. Betoulle D. Evans A. Ruidavets J.B. Arveiler D. Luc G. Tiret L. Cambien F. Extensive association analysis between the CETP gene and coronary heart disease phenotypes reveals several putative functional polymorphisms and gene-environment interaction.Genet. Epidemiol. 2000; 19: 64-80Google Scholar). Unadjusted mean values and association results with an additive model for genotypic effects, including permutation results, are presented in the supplementary tables. Hardy-Weinberg equilibrium was tested with Haploview 4.1 (40Barrett J.C. Fry B. Maller J. Daly M.J. Haploview: analysis and visualization of LD and haplotype maps.Bioinformatics. 2005; 21: 263-265Google Scholar). Mean values and frequencies between males and females were compared with the t-test and chi-square analysis, respectively. P < 0.05 was considered significant. The demographic and biochemical characteristics of the 1990–1995 and 2000–2003 cohorts are shown in Table 1. In both groups and in men and women, the plasma HDL-C levels were low and total cholesterol/HDL-C ratios were high.TABLE 1Demographic and biochemical characteristics of THS participants by gender (samples collected between 1990–1995 and 2000–2003)1990–1995 Cohort2000–2003 CohortMales(n = 1549)Females(n = 1063)PMales(n = 474)Females(n = 690)PAge (years)42.1 ± 13.242.2 ± 14.9NS44.1 ± 13.144.4 ± 13.9NSBMI (kg/m2)26.1 ± 3.926.6 ± 5.4<0.0528.1 ± 3.829.9 ± 5.4<0.05HDL-C (mg/dl)35.7 ± 7.541.2 ± 9<0.00138.7 ± 8.547.0 ± 9.4<0.001Total cholesterol (mg/dl)183 ± 44183 ± 42NS182 ± 37184 ± 43NSTotal cholesterol/HDL-C ratio5.8 ± 2.94.5 ± 1.4<0.015.0 ± 1.64.0 ± 1.9<0.01LDL-C (mg/dl)126 ± 41116 ± 39<0.05112 ± 33113 ± 35NSTriglycerides (mg/dl)153 ± 107110 ± 70<0.001155 ± 105118 ± 67<0.001Systolic blood pressure (mm Hg)125 ± 23122 ± 21NS132 ± 20133 ± 22NSDiastolic blood pressure (mm Hg)82 ± 1481 ± 13NS84 ± 1285 ± 13NSConsumption of alcohol (%)aOne or more drinks per week.29.85.6<0.00136.79.6<0.001Cigarette smoking (%)bOne or more cigarettes per day.56.624<0.00167.225.2<0.001Values shown are means ± SD or percentages. Means were compared by t-test, and percentages were analyzed by chi-square test. NS, not significant.a One or more drinks per week.b One or more cigarettes per day. Open table in a new tab Values shown are means ± SD or percentages. Means were compared by t-test, and percentages were analyzed by chi-square test. NS, not significant. Fifty-one SNPs with rare allele frequencies (<1% to 49%) were identified by sequencing DNA from 28 subjects. Nine of these SNPs were novel. Four additional SNPs were selected with other approaches. Two SNPs (rs2242061 and rs11632627) were selected using Delta-MATCH, a program that uses TRANSFAC database matrices (36Matys V. Fricke E. Geffers R. Gößling E. Haubrock M. Hehl R. Hornischer K. Karas D. Kel A.E. Kel-Margoulis O.V. et al.TRANSFAC®: transcriptional regulation, from patterns to profiles.Nucleic Acids Res. 2003; 31: 374-378Google Scholar) and aims to predict which polymorphisms may modulate transcription factor binding in an allele-specific manner. The rs2242061 (C/T) SNP is predicted to modulate the binding of the vitamin D receptor (VDR) transcription factor (C score = 0. 8594; T score = 0. 8075; VDR threshold score = 0.8590). Similarly, rs11632627 (A/G) is predicted to modulate the binding of the GATA transcription factor (A score = 1.0000; G score = 0. 7263; GATA threshold score = 1.0000). The other two tagging SNPs (rs4775041 and rs11858164) were selected for genotyping because they were significantly associated with plasma HDL-C levels in GWA studies (21Kathiresan S. Melander O. Guiducci C. Surti A. Burtt N.P. Rieder M.J. Cooper G.M. Roos C. Voight B.F. Havulinna A.S. et al.Six new loci associated with blood low-density lipoprotein cholesterol, high-density lipoprotein cholesterol or triglycerides in humans.Nat. Genet. 2008; 40: 189-197Google Scholar, 22Kooner J.S. Chambers J.C. Aguilar-Salinas C.A. Hinds D.A. Hyde C.L. Warnes G.R. Gómez Pérez F.J. Frazer K.A. Elliott P. Scott J. et al.Genome-wide scan identifies variation in MLXIPL associated with plasma triglycerides.Nat. Genet. 2008; 40: 149-151Google Scholar). Rs numbers, chromosomal and gene locations, allele frequencies, and nucleotide changes for all 55 SNPs are presented in supplementary Table II. After examining the rare allele frequencies and LD (D′, r2) among all these SNPs, we selected 35 SNPs for follow-up. LD among the SNP pairs and the frequency data from available sources were also evaluated in the selection process (30The International HapMap Consortium A second generation hum" @default.
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• W1992670435 title "Polymorphisms in the hepatic lipase gene affect plasma HDL-cholesterol levels in a Turkish population" @default.
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