title: Combined analysis of genome scans of dutch and finnish families reveals a susceptibility locus for high-density lipoprotein cholesterol on chromosome 16q.
abstract: Several genomewide screens have been performed to identify novel loci predisposing to unfavorable serum lipid levels and coronary heart disease (CHD). We hypothesized that the accumulating data of these screens in different study populations could be combined to verify which of the identified loci truly harbor susceptibility genes. The power of this strategy has recently been demonstrated with other complex diseases, such as inflammatory bowel disease and asthma. We assessed the largely unknown genetic background of CHD by investigating the most common dyslipidemia predisposing to CHD, familial combined hyperlipidemia (FCHL), affecting 1%-2% of Western populations and 10%-20% of families with premature CHD. To be able to perform a combined data analysis, we unified the diagnostic criteria for FCHL and its component traits and combined the data from two genomewide scans performed in two populations, the Finns and the Dutch. As a result of our pooled data analysis, we identified three chromosomal regions, on chromosomes 2p25.1, 9p23, and 16q24.1, exceeding the statistical significance level of a LOD score >2.0. The 2p25.1 region was detected for the FCHL trait, and the 9p23 and 16q24.1 regions were detected for the low high-density lipoprotein cholesterol (HDL-C) trait. In addition, the previously recognized 1q21 region also obtained additional support in the other study sample, when the triglyceride trait was used. Analysis of the 16q24.1 region resulted in a statistically significant LOD score of 3.6 when the data from Finnish families with low HDL-C were included in the analysis. To search for the underlying gene in the 16q24.1 region, we investigated a novel functional and positional candidate gene, helix/forkhead transcription factor (FOXC2), by sequencing and by genotyping of two single-nucleotide polymorphisms in the families.
authors.affiliation: Department of Human Genetics, David Geffen School of Medicine at the University of California-Los Angeles, Los Angeles, CA 90095, USA. ppajukanta@mednet.ucla.edu
authors.forename: Päivi
authors.initials: P
authors.lastname: Pajukanta
authors.forename: Hooman
authors.initials: H
authors.lastname: Allayee
authors.forename: Kelly L
authors.initials: KL
authors.lastname: Krass
authors.forename: Ali
authors.initials: A
authors.lastname: Kuraishy
authors.forename: Aino
authors.initials: A
authors.lastname: Soro
authors.forename: Heidi E
authors.initials: HE
authors.lastname: Lilja
authors.forename: Rebecca
authors.initials: R
authors.lastname: Mar
authors.forename: Marja-Riitta
authors.initials: MR
authors.lastname: Taskinen
authors.forename: Ilpo
authors.initials: I
authors.lastname: Nuotio
authors.forename: Markku
authors.initials: M
authors.lastname: Laakso
authors.forename: Jerome I
authors.initials: JI
authors.lastname: Rotter
authors.forename: Tjerk W A
authors.initials: TW
authors.lastname: de Bruin
authors.forename: Rita M
authors.initials: RM
authors.lastname: Cantor
authors.forename: Aldons J
authors.initials: AJ
authors.lastname: Lusis
authors.forename: Leena
authors.initials: L
authors.lastname: Peltonen
mesh_terms: D008076:Cholesterol, HDL / Q000097:blood*; D002874:Chromosome Mapping; D002885:Chromosomes, Human, Pair 16; D003327:Coronary Disease / Q000453:epidemiology / Q000235:genetics*; D004276:DNA, Satellite / Q000235:genetics; D005819:Genetic Markers; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D015894:Genome, Human; D005838:Genotype; D005858:Germany; D006801:Humans; D006950:Hyperlipidemia, Familial Combined / Q000235:genetics*; D008126:Lod Score; D009426:Netherlands; D012307:Risk Factors
chemical_list: D008076:Cholesterol, HDL; D004276:DNA, Satellite; D005819:Genetic Markers