Genome scan for loci regulating HDL cholesterol levels in Finnish extended pedigrees with early coronary heart disease

• Published in: European journal of human genetics : EJHG Vol. 18; no. 5; pp. 604 - 613
• Main Authors: KANGAS-KONTIO, Tiia, KAKKO, Sakari, TAMMINEN, Minna, VON ROHR, Peter, HOESCHELE, Ina, JUVONEN, Tatu, KERE, Juha, SAVOLAINEN, Markku J
• Format: Journal Article
• Language: English
• Published: Basingstoke Nature Publishing Group 01.05.2010
• Subjects: Age of Onset; Biological and medical sciences; Cardiology. Vascular system; Cardiovascular disease; Cholesterol; Cholesterol, HDL - genetics; Chromosome 10; Chromosome 17; Chromosome 4; Chromosome 6; Chromosome Mapping; Chromosomes; Classical genetics, quantitative genetics, hybrids; Coronary Disease - epidemiology; Coronary Disease - genetics; Coronary heart disease; Female; Finland - epidemiology; Fundamental and applied biological sciences. Psychology; General aspects. Genetic counseling; Genetic Loci - genetics; Genetic Predisposition to Disease; Genetics of eukaryotes. Biological and molecular evolution; Genome, Human - genetics; Genome-Wide Association Study; Genomes; Heart; Heart diseases; Heritability; Human; Humans; Lipoproteins (high density); Lod Score; Low density lipoprotein; Male; Medical genetics; Medical sciences; Medicin och hälsovetenskap; Middle Aged; Molecular and cellular biology; Mortality; Pedigree; Peroxisome proliferator-activated receptors; Quantitative trait loci; Quantitative Trait Loci - genetics; Statistics, Nonparametric; Studies; Europe; Finland; United States > US; Genetic mapping; Family study; Pathogenesis; Polygenic; Cardiovascular disease; Early stage; Lipoprotein; Coronary heart disease; Genetic determinism; Cholesterol; Vascular disease; linkage analysis; Pedigree; complex trait; Atherosclerosis; Genetic linkage; Finnish; Genetics; Genome; Locus
• ISSN: 1018-4813; 1476-5438; 1476-5438
• DOI: 10.1038/ejhg.2009.202

Coronary heart disease (CHD) is the leading cause of mortality in Western societies. Its risk is inversely correlated with plasma high-density lipoprotein cholesterol (HDL-C) levels, and approximately 50% of the variability in these levels is genetically determined. In this study, the aim was to carry out a whole-genome scan for the loci regulating plasma HDL-C levels in 35 well-defined Finnish extended pedigrees (375 members genotyped) with probands having low HDL-C levels and premature CHD. The additive genetic heritability of HDL-C was 43%. A variance component analysis revealed four suggestive quantitative trait loci (QTLs) for HDL-C levels, with the highest LOD score, 3.1, at the chromosomal locus 4p12. Other suggestive LOD scores were 2.1 at 2q33, 2.1 at 6p24 and 2.0 at 17q25. Three suggestive loci for the qualitative low HDL-C trait were found, with a nonparametric multipoint score of 2.6 at the chromosomal locus 10p15.3, 2.5 at 22q11 and 2.1 at 6p12. After correction for statin use, the strongest evidence of linkage was shown on chromosomes 4p12, 6p24, 6p12, 15q22 and 22q11. To search for the underlying gene on chromosome 6, we analyzed two functional and positional candidate genes (peroxisome proliferator-activated receptor-delta (PPARD), and retinoid X receptor beta, (RXRB)), but found no significant evidence of association. In conclusion, we identified seven chromosomal regions for HDL-C regulation exceeding the level for suggestive evidence of linkage.