Zinc Finger Protein 202, genetic variation, and HDL cholesterol in the general population

Zinc Finger Protein 202 (ZNF202) is a transcriptional repressor that binds elements found predominantly in genes involved in HDL metabolism. We tested the following hypotheses: 1) frequencies of single-nucleotide polymorphisms (SNPs) and haplotypes in ZNF202 differ between individuals with low and high HDL cholesterol; and 2) SNPs in ZNF202 affect HDL cholesterol levels in the general population. We screened the promoter and protein-coding exons of ZNF202 in individuals with the highest 1% (n = 95) and lowest 1% (n = 95) HDL cholesterol among 9,259 Danish adults. None of the 10 SNPs identified differed in frequency as single sites or as haplotypes between low and high HDL cholesterol groups. In accordance with this, seven mutations were equally frequent (4–5%) in individuals with low or high HDL cholesterol. Finally, for all five SNPs identified in the coding region, we determined the association of genotype with HDL cholesterol in 9,259 individuals from the general population. Four SNPs were not associated with variation in HDL cholesterol, although c.*2T>G homozygosity was associated with a discrete effect on HDL cholesterol in men. We show that genetic variation in ZNF202 is common in the general population. However, SNPs in the protein-coding region of ZNF202 do not make a major contribution to HDL cholesterol levels. Zinc Finger Protein 202 (ZNF202) is a transcriptional repressor that binds elements found predominantly in genes involved in HDL metabolism. We tested the following hypotheses: 1) frequencies of single-nucleotide polymorphisms (SNPs) and haplotypes in ZNF202 differ between individuals with low and high HDL cholesterol; and 2) SNPs in ZNF202 affect HDL cholesterol levels in the general population. We screened the promoter and protein-coding exons of ZNF202 in individuals with the highest 1% (n = 95) and lowest 1% (n = 95) HDL cholesterol among 9,259 Danish adults. None of the 10 SNPs identified differed in frequency as single sites or as haplotypes between low and high HDL cholesterol groups. In accordance with this, seven mutations were equally frequent (4–5%) in individuals with low or high HDL cholesterol. Finally, for all five SNPs identified in the coding region, we determined the association of genotype with HDL cholesterol in 9,259 individuals from the general population. Four SNPs were not associated with variation in HDL cholesterol, although c.*2T>G homozygosity was associated with a discrete effect on HDL cholesterol in men. We show that genetic variation in ZNF202 is common in the general population. However, SNPs in the protein-coding region of ZNF202 do not make a major contribution to HDL cholesterol levels. Levels of HDL cholesterol are inversely related to risk of ischemic heart disease in the general population (1Stampfer M.J. Sacks F.M. Salvini S. Willett W.C. Hennekens C.H. A prospective study of cholesterol, apolipoproteins, and the risk of myocardial infarction.N. Engl. J. Med. 1991; 325: 373-381Crossref PubMed Scopus (1025) Google Scholar, 2Genest Jr., J. Marcil M. Denis M. Yu L. High density lipoproteins in health and in disease.J. Investig. Med. 1999; 47: 31-42PubMed Google Scholar). The HDL particle is responsible for the delivery of cellular cholesterol from peripheral tissues to the liver and is thus a key component in reverse cholesterol transport (3Tall A.R. Breslow J.L. Rubin E.M. Genetic disorders affecting plasma high-density lipoproteins.in: Scriver C.R. Beaudet A.L. Sly W.S. Valle D. The Metabolic and Molecular Bases of Inherited Disease. McGraw-Hill, New York2001: 2915-2936Google Scholar). Twin and family studies suggest that approximately half of the variation in HDL cholesterol is genetically determined (4Friedlander Y. Kark J.D. Stein Y. Biological and environmental sources of variation in plasma lipids and lipoproteins: the Jerusalem Lipid Research Clinic.Hum. Hered. 1986; 36: 143-153Crossref PubMed Scopus (30) Google Scholar, 5Hunt S.C. Hasstedt S.J. Kuida H. Stults B.M. Hopkins P.N. Williams R.R. Genetic heritability and common environmental components of resting and stressed blood pressures, lipids, and body mass index in Utah pedigrees and twins.Am. J. Epidemiol. 1989; 129: 625-638Crossref PubMed Scopus (264) Google Scholar, 6Perusse L. Despres J.P. Tremblay A. Leblanc C. Talbot J. Allard C. Bouchard C. Genetic and environmental determinants of serum lipids and lipoproteins in French Canadian families.Arteriosclerosis. 1989; 9: 308-318Crossref PubMed Google Scholar, 7Prenger V.L. Beaty T.H. Kwiterovich P.O. Genetic determination of high-density lipoprotein-cholesterol and apolipoprotein A-1 plasma levels in a family study of cardiac catheterization patients.Am. J. Hum. Genet. 1992; 51: 1047-1057PubMed Google Scholar). A new susceptibility locus for familial hypoalphalipoproteinemia (Online Mendelian Inheritance in Man 604091) on chromosome 11q23 was identified in Utah pedigrees (8Kort E.N. Ballinger D.G. Ding W. Hunt S.C. Bowen B.R. Abkevich V. Bulka K. Campbell B. Capener C. Gutin A. et al.Evidence of linkage of familial hypoalphalipoproteinemia to a novel locus on chromosome 11q23.Am. J. Hum. Genet. 2000; 66: 1845-1856Abstract Full Text Full Text PDF PubMed Scopus (46) Google Scholar); this region contains the Zinc Finger Protein 202 (ZNF202) gene. ZNF202 is functionally characterized by a SRE-ZBP, CT-finS1, AW-1, Number 18 (SCAN) oligomerization domain, a Kruäppel-associated box (KRAB) repression domain, and eight zinc finger (Cys2His2) DNA binding motifs, a typical domain architecture for transcription factors (9Collins T. Stone J.R. Williams A.J. All in the family: the BTB/POZ, KRAB, and SCAN domains.Mol. Cell. Biol. 2001; 21: 3609-3615Crossref PubMed Scopus (287) Google Scholar). ZNF202 target genes are mainly involved in lipid and, particularly, HDL cholesterol metabolism (10Wagner S. Hess M.A. Ormonde-Hanson P. Malandro J. Hu H. Chen M. Kehrer R. Frodsham M. Schumacher C. Beluch M. et al.A broad role for the zinc finger protein ZNF202 in human lipid metabolism.J. Biol. Chem. 2000; 275: 15685-15690Abstract Full Text Full Text PDF PubMed Scopus (74) Google Scholar, 11Porsch-Ozcurumez M. Langmann T. Heimerl S. Borsukova H. Kaminski W.E. Drobnik W. Honer C. Schumacher C. Schmitz G. The zinc finger protein 202 (ZNF202) is a transcriptional repressor of ATP binding cassette transporter A1 (ABCA1) and ABCG1 gene expression and a modulator of cellular lipid efflux.J. Biol. Chem. 2001; 276: 12427-12433Abstract Full Text Full Text PDF PubMed Scopus (85) Google Scholar, 12Langmann T. Schumacher C. Morham S.G. Honer C. Heimerl S. Moehle C. Schmitz G. ZNF202 is inversely regulated with its target genes ABCA1 and apoE during macrophage differentiation and foam cell formation.J. Lipid Res. 2003; 44: 968-977Abstract Full Text Full Text PDF PubMed Scopus (29) Google Scholar), suggesting that this transcriptional repressor might be important in the determination of HDL cholesterol levels in the general population. However, it is largely unknown to what extent ZNF202 varies genetically in the general population and whether such genetic variation influences HDL cholesterol levels. We tested the following hypotheses: 1) frequencies of single-nucleotide polymorphisms (SNPs) and haplotypes in ZNF202 differ between individuals with low and high HDL cholesterol levels; and 2) SNPs in the protein-coding region of ZNF202 affect HDL cholesterol levels in the general population. To increase the likelihood of identifying genetic variation with significant effects on HDL cholesterol levels, we screened the promoter and protein coding regions of ZNF202 (∼2 kb) in 95 individuals with the 1% lowest and in 95 individuals with the 1% highest HDL cholesterol levels for age and gender from a general population sample, the Copenhagen City Heart Study (n = 9,259). All SNPs identified in and around the protein-coding region were genotyped in the entire general population sample, and the effect on HDL cholesterol and apolipoprotein A-I (apoA-I) levels was determined. The Copenhagen City Heart Study is a prospective cardiovascular population study of individuals selected based on the Central Population Register Code to reflect the adult Danish general population aged 20 to 80+ years. In 1991–1994, 9,259 participants (55% women) gave blood for DNA analyses (13Appleyard M. Tybjærg-Hansen A. Jensen G. Schnohr P. Nyeboe J. The Copenhagen City Heart Study, Østerbroundersøgelsen. A book of tables with data from the first examination (1976–78) and a five year follow-up (1981–83). The Copenhagen City Heart Study Group.Scand. J. Soc. Med. Suppl. 1989; 41: 1-160PubMed Google Scholar, 14Schnohr P. Jensen G. Lange P. Scharling H. Appleyard A. The Copenhagen City Heart Study, Østerbroundersøgelsen. Tables with data from the third examination 1991–1994.Eur. Heart J. 2001; 3: 1-83Google Scholar). More than 99% were white and of Danish descent. This study was approved by the local ethical committee: Nos. 100.2039/91 and 01-421/94, Copenhagen and Frederiksberg committee. All participants gave written informed consent. For the genetic screening of ZNF202 (GenBank accession number NM_003455), we selected individuals from the Copenhagen City Heart Study with the 1% lowest (n = 95) and 1% highest (n = 95) HDL cholesterol levels for age and gender (in 10 year age groups). Consequently, the cutoff levels for HDL cholesterol depend upon the seven age groups for each gender (15Frikke-Schmidt R. Nordestgaard B.G. Jensen G.B. Tybjærg-Hansen A. Genetic variation in ABC transporter A1 contributes to HDL cholesterol in the general population.J. Clin. Invest. 2004; 114: 1343-1353Crossref PubMed Scopus (232) Google Scholar). We previously showed that by screening these groups with extreme phenotypes, we increased the likelihood of identifying mutations and SNPs (rare frequency of and with on HDL cholesterol levels in the general population (15Frikke-Schmidt R. Nordestgaard B.G. Jensen G.B. Tybjærg-Hansen A. Genetic variation in ABC transporter A1 contributes to HDL cholesterol in the general population.J. Clin. Invest. 2004; 114: 1343-1353Crossref PubMed Scopus (232) Google Scholar). the of a all five SNPs identified in or around the protein-coding region by screening ZNF202 were genotyped in the entire general population (n = and the effect of each on variation in HDL cholesterol and levels was determined as effects of variation the and as effects the data from the third examination of the Copenhagen City Heart Study In tables and data for the general population are for individuals in the five for all SNPs were (n = of 9,259). DNA was from blood DNA The ZNF202 gene contains exons the ZNF202 protein (10Wagner S. Hess M.A. Ormonde-Hanson P. Malandro J. Hu H. Chen M. Kehrer R. Frodsham M. Schumacher C. Beluch M. et al.A broad role for the zinc finger protein ZNF202 in human lipid metabolism.J. Biol. Chem. 2000; 275: 15685-15690Abstract Full Text Full Text PDF PubMed Scopus (74) Google Scholar). were of the ZNF202 promoter of T. Schumacher C. Morham S.G. Honer C. Heimerl S. Moehle C. Schmitz G. ZNF202 is inversely regulated with its target genes ABCA1 and apoE during macrophage differentiation and foam cell formation.J. Lipid Res. 2003; 44: 968-977Abstract Full Text Full Text PDF PubMed Scopus (29) Google Scholar), all exons number (10Wagner S. Hess M.A. Ormonde-Hanson P. Malandro J. Hu H. Chen M. Kehrer R. Frodsham M. Schumacher C. Beluch M. et al.A broad role for the zinc finger protein ZNF202 in human lipid metabolism.J. Biol. Chem. 2000; 275: 15685-15690Abstract Full Text Full Text PDF PubMed Scopus (74) Google Scholar), and of the was by were on Genetic The was to genotype the general population for all five SNPs identified in and around the coding were for all five SNPs were for individuals of the of 9,259 and were to plasma levels of cholesterol, HDL cholesterol, and from in frequencies between individuals with low and high HDL cholesterol were were from = is the frequency of the for a of sites and and are the of the in that M.A. and J.L. M.A. to in New Scholar). was as S. D. The of linkage between the apolipoprotein J. Hum. Genet. Google Scholar). levels for were by the frequencies were the L. M. of frequencies in a Biol. Google Scholar). The association of ZNF202 genotype with variation in HDL cholesterol and levels was determined by with as a on a was were not for of individuals with the lowest 1% and highest 1% HDL cholesterol levels and of the general population are in in the low HDL cholesterol levels, levels, and were than individuals in the high HDL cholesterol or in the general of individuals from the general population with the lowest 1% and highest 1% HDL cholesterol levels and of the general population HDL (n = HDL (n = Population (n = cholesterol cholesterol extreme 20 were mass index apolipoprotein are extreme 20 were in a new apolipoprotein are SNPs and and mutations and were identified in or the protein-coding regions of the gene and in the region of and a between and and a between and is in the SCAN domain, to be important for and are in the A domain, important for transcriptional The by these are in of ZNF202 and are between is in the zinc finger in a and is between c.*2T>G is of the the and not variation in protein-coding and of ZNF202 in individuals from the general population with extreme HDL cholesterol of HDL (n = HDL (n = in the Population (n = promoter binding promoter zinc finger binding promoter to and to to to finger Kruäppel-associated AW-1, Number Zinc Finger Protein for the of variation in the promoter region and is to Langmann et T. Schumacher C. Morham S.G. Honer C. Heimerl S. Moehle C. Schmitz G. ZNF202 is inversely regulated with its target genes ABCA1 and apoE during macrophage differentiation and foam cell formation.J. Lipid Res. 2003; 44: 968-977Abstract Full Text Full Text PDF PubMed Scopus (29) Google Scholar), the transcription for the of variation in and around the protein-coding region and for affecting protein is to and for the of human Genet. 2001; PubMed Scopus Google Scholar), A in the = 1) in from and protein c.*2T>G = to in the the SNPs are characterized by than of a of (rare frequency are characterized by or of a of (rare frequency in a new of human ZNF202 and and protein For the was of the SCAN domain in the domain and zinc finger are and The identified in this study are SNPs are in and mutations are in that are in all KRAB, Kruäppel-associated AW-1, Number Zinc Finger Protein for the of variation in the promoter region and is to Langmann et T. Schumacher C. Morham S.G. Honer C. Heimerl S. Moehle C. Schmitz G. ZNF202 is inversely regulated with its target genes ABCA1 and apoE during macrophage differentiation and foam cell formation.J. Lipid Res. 2003; 44: 968-977Abstract Full Text Full Text PDF PubMed Scopus (29) Google Scholar), the transcription for the of variation in and around the protein-coding region and for affecting protein is to and for the of human Genet. 2001; PubMed Scopus Google Scholar), A in the = 1) in from and protein c.*2T>G = to in the the SNPs are characterized by than of a of (rare frequency are characterized by or of a of (rare frequency Four SNPs and and mutations and were identified in the promoter region and of and are in a in a binding in a zinc finger binding T. Schumacher C. Morham S.G. Honer C. Heimerl S. Moehle C. Schmitz G. ZNF202 is inversely regulated with its target genes ABCA1 and apoE during macrophage differentiation and foam cell formation.J. Lipid Res. 2003; 44: 968-977Abstract Full Text Full Text PDF PubMed Scopus (29) Google Scholar), and in a promoter Four of these seven not Four were identified in SNPs and new from in to the and the of these be to affect A of genetic were identified in the promoter and in and around the protein-coding region of ZNF202 frequencies from to in the low and high HDL cholesterol groups. SNPs frequencies were identified in HDL cholesterol of were new and None of these 10 SNPs differed in frequency between individuals with the lowest 1% and the highest 1% HDL cholesterol levels. the seven mutations frequencies were identified in individuals in the low HDL in individuals in the high HDL and was in HDL groups the frequencies of mutations in ZNF202 in the low and high HDL groups were of the five SNPs in and around the coding region that haplotypes for of all haplotypes in the low HDL cholesterol and for in the high HDL cholesterol However, of these haplotypes differed in frequency between the low and high HDL suggesting that not affect HDL cholesterol frequencies of SNPs in and around the protein-coding region of ZNF202 in individuals from the general population with the lowest 1% and highest 1% HDL cholesterol HDL (n = HDL (n = single of SNPs are in the following to and c.*2T>G in the the in the are to frequency in the low HDL cholesterol The all and from the common the c.*2T>G in a new single of SNPs are in the following to and c.*2T>G in the the in the are to frequency in the low HDL cholesterol The all and from the common the c.*2T>G the of a we genotyped the general population (n = for all SNPs in and around the protein-coding region and frequencies of these five SNPs from 1% to in the general population frequencies not differ from by of variation the for each of the five SNPs with HDL cholesterol and levels are by gender in In (n = homozygosity for in the was associated with in HDL cholesterol of = = = and a in = = = were for the the genotype association with levels significant with five = = None of the SNPs and were associated with variation in HDL cholesterol or levels. To these we tested the effect of the c.*2T>G on HDL cholesterol and levels in by five this this we found association between c.*2T>G genotype and HDL cholesterol in of five and association between c.*2T>G genotype and levels in of five association between genotype and levels significant = was tested for the five SNPs in and around the coding region and genotyped in individuals from the general population was for all However, frequencies between SNPs 1% to these be with linkage between ZNF202 SNPs in and around the protein-coding region of ZNF202 in the general population (n = are as from to = = = is the frequency of the for a of sites and and are the of the in that is and is that that each locus that the locus with the common the For all linkage in a new are as from to = = = is the frequency of the for a of sites and and are the of the in that is and is that that each locus that the locus with the common the For all linkage the to genetic variation in ZNF202 affecting HDL cholesterol levels in the general we a in we screened of the promoter and all protein-coding exons of the ZNF202 gene in individuals with extreme HDL cholesterol levels selected from a of the general population (n = 9,259). We genotyped the entire general population for the five SNPs in and around the protein coding region and determined the association with HDL cholesterol and levels. in this study the 1) we identified new genetic SNPs and seven of were in transcription binding sites in the and were 2) common SNPs in and around the coding region and haplotypes these SNPs not in individuals with low and high HDL cholesterol levels; these SNPs not a major effect on HDL cholesterol and levels in the general as single sites or as the and mutations in ZNF202 were equally frequent in individuals with low or high HDL cholesterol levels. This is the first study to the genetic variation in the promoter and in and around the protein-coding region of ZNF202 in a number of individuals with low or high HDL cholesterol levels and to the role of ZNF202 in HDL metabolism in the general population. ZNF202 identified in a low hypoalphalipoproteinemia locus (8Kort E.N. Ballinger D.G. Ding W. Hunt S.C. Bowen B.R. Abkevich V. Bulka K. Campbell B. Capener C. Gutin A. et al.Evidence of linkage of familial hypoalphalipoproteinemia to a novel locus on chromosome 11q23.Am. J. Hum. Genet. 2000; 66: 1845-1856Abstract Full Text Full Text PDF PubMed Scopus (46) Google Scholar, C. G. G. M. Molecular and of a new gene zinc finger PubMed Scopus Google Scholar), and in studies suggest that ZNF202 is a transcriptional repressor of key genes in HDL cholesterol (10Wagner S. Hess M.A. Ormonde-Hanson P. Malandro J. Hu H. Chen M. Kehrer R. Frodsham M. Schumacher C. Beluch M. et al.A broad role for the zinc finger protein ZNF202 in human lipid metabolism.J. Biol. Chem. 2000; 275: 15685-15690Abstract Full Text Full Text PDF PubMed Scopus (74) Google Scholar), genetic variation in ZNF202 might affect HDL cholesterol levels in plasma and a role in the of in the general population. However, the data suggest that genetic variation in and around the protein-coding region of ZNF202 is not a major of HDL cholesterol or levels in the general population. We all previously SNPs in the promoter and coding region of the gene as as new in the promoter and a in The was the frequent of the SNPs identified in and around the coding region, suggesting that we not important SNPs were identified in the protein-coding region, and and and in the The is in the SCAN domain of The SCAN domain is important for and thus ZNF202 M. Langmann T. Heimerl S. Borsukova H. Kaminski W.E. Drobnik W. Honer C. Schumacher C. Schmitz G. The zinc finger protein 202 (ZNF202) is a transcriptional repressor of ATP binding cassette transporter A1 (ABCA1) and ABCG1 gene expression and a modulator of cellular lipid efflux.J. Biol. Chem. 2001; 276: 12427-12433Abstract Full Text Full Text PDF PubMed Scopus (85) Google Scholar, C. H. Honer C. Ding W. J. Ballinger D. Bowen B.R. et SCAN domain Biol. Chem. 2000; 275: Full Text Full Text PDF PubMed Scopus Google Scholar, R. Bowen B.R. is a that binds its SCAN J. Google Scholar). However, was not between and and are was equally between the HDL cholesterol suggesting that this not affect HDL cholesterol levels. This was in individuals from the general association between genotype and HDL cholesterol levels was and are in the A domain, important repressor The A domain is and selected to be for repression R. A. D. The domain of zinc finger transcriptional PubMed Scopus Google Scholar). is between and the of the is between human with the protein as is to to be for the repressor of the A domain R. A. D. The domain of zinc finger transcriptional PubMed Scopus Google Scholar); it is that a in this affect with protein to repressor However, was identified in high and low HDL cholesterol groups with frequencies and showed association with HDL cholesterol levels in the general population. c.*2T>G is a common in the of the In in the general homozygosity to be associated with levels of HDL cholesterol and with and However, this association was not and be to a the association with levels significant for in a population to or the association between homozygosity and low HDL cholesterol and levels be The data for SNPs and protein-coding and in individuals and protein-coding exons of ZNF202 to haplotypes with frequencies of and with frequencies of In of individuals with low and high HDL cholesterol, we five SNPs in individuals the protein-coding exons to five haplotypes with frequencies of and with frequencies of in 2) of SNPs in exons from the for to data not haplotypes in Finally, we SNPs the protein-coding exons to haplotypes in data that the haplotypes are found in the groups of we common Four new mutations were identified in and around the protein-coding region, of were The were in functionally important of ZNF202 in the A domain and in the zinc finger domain is between not a in is between not between However, a from a to might the of the zinc finger and the DNA binding The by we screened individuals with extreme HDL cholesterol levels previously in the of mutations with effects and SNPs with effects on HDL cholesterol levels, by of the SNPs in groups with extreme (15Frikke-Schmidt R. Nordestgaard B.G. Jensen G.B. Tybjærg-Hansen A. Genetic variation in ABC transporter A1 contributes to HDL cholesterol in the general population.J. Clin. Invest. 2004; 114: 1343-1353Crossref PubMed Scopus (232) Google Scholar, A. R. to low plasma levels of HDL 2004; PubMed Scopus Google Scholar). such a frequency between extreme groups on the of the the frequency of the the of of the effect of the (in this on HDL cholesterol or and whether this effect is equally in In this we this to whether genetic variation in ZNF202 HDL cholesterol, the of ZNF202 target genes a role in HDL metabolism. However, ZNF202 is a transcriptional repressor of the genetic variation in ZNF202 a effect on the than genetic variation in the gene HDL cholesterol levels are by environmental and among body mass index and genetic variation in genes and This is in study by the significant increase in in the low HDL with the high HDL in and in with and and by in the low HDL that were to than in high HDL we from in studies (15Frikke-Schmidt R. Nordestgaard B.G. Jensen G.B. Tybjærg-Hansen A. Genetic variation in ABC transporter A1 contributes to HDL cholesterol in the general population.J. Clin. Invest. 2004; 114: 1343-1353Crossref PubMed Scopus (232) Google that by individuals in the low HDL with and we to of the with mutations associated with low HDL cholesterol, we to for age and gender in the extreme HDL groups. we individuals with in the low HDL we to five of mutations identified in the low HDL The high HDL HDL cholesterol we that a of these in such as and that are associated with increased HDL cholesterol levels. Finally, we screened a of the promoter all protein-coding exons and the of the that affecting gene or in or exons affecting gene In of important for gene a in was identified in the gene J. M. A. J. P. L. and for Genet. PubMed Scopus (74) Google Scholar). In we show that genetic variation in ZNF202 is common in the general population. However, SNPs in and around the protein-coding region of ZNF202 do not make a major contribution to HDL cholesterol levels in the general population. The for The the in the This was by the Danish Heart the Danish Research and and the Research Copenhagen

Fetched live from OpenAlex and de-inverted. Abstracts are not stored in this database: the inverted indexes are 8.6 GB of the frame’s 9.3 GB of text, and the host has 13 GB free.