PIDEMIOLOGICAL STUDIES CONSIStently demonstrate that a low plasma level of high-density lipoprotein (HDL) cholesterol is associated with increased risk of ischemic heart disease (IHD). 1 However, whether HDL cholesterol is a primary causal factor in the pathogenesis of IHD is unclear. Data from observational studies are potentially confounded by other factors related to low HDL cholesterol levels that may contribute independently to increases in cardiovascular events. One such factor is plasma triglycerides, 2 a marker for the presence of atherogenic remnant lipoproteins. 3-5 Mendelian randomization, which is the random assortment of genes from parents to offspring that occurs during gamete formation, provides a method of assessing whether modifiable exposures are causally related to increased risk of IHD. 6 Thus, studies of genetic disorders that lower HDL cholesterol without increases in plasma triglycerides and remnant lipoproteins provide an ideal system in which to assess the consequences of isolated, lifelong low HDL cholesterol levels. A genetic disorder that fulfills such a criterion is Tangier disease, which is due to loss-of-function mutations in the adenosine triphosphatebinding cassette transporter A1 (ABCA1; GenBank No. AF275948) gene and results in unmeasurable HDL cholesterol levels in homozygotes and half-normal HDL cholesterol levels in heterozygotes. Family studies of homozygotes or heterozygotes for these severe HDL de-Author Affiliations are listed at the end of this article.

Multiple common and rare alleles in APOB contribute to plasma levels of LDL cholesterol in the general population, although the effects of common alleles and haplotypes are modest.

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 5 95) and lowest 1% (n 5 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.-Stene, M. C., R. Levels of HDL cholesterol are inversely related to risk of ischemic heart disease in the general population (1, 2). 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 (3).Twin and family studies suggest that approximately half of the variation in HDL cholesterol is genetically determined (4-7). A new susceptibility locus for familial hypoalphalipoproteinemia (Online Mendelian Inheritance in Man 604091) on chromosome 11q23 was identified in Utah pedigrees (8); 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 Krü ppel-associated box (KRAB) repression domain, and eight zinc finger (Cys 2 His 2 ) DNA binding motifs, a typical domain architecture for transcription factors (9). ZNF202 target genes are mainly involved in lipid and, particularly, HDL cholesterol metabolism (10-12), 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 ...