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.

Figure 1

Two-point maximum LOD scores (from parametric linkage analysis with either a dominant or recessive mode of inheritance or from ASP analysis) obtained for each chromosome in different study samples, using the FCHL trait. Gray columns show the two-point results for the Dutch families with FCHL, white columns show the results for the Finnish families with FCHL, and black columns show the results for the combined data analysis of the Dutch and Finnish families with FCHL. The marker resulting in the highest LOD score on each chromosome is indicated for each study group, and its position from pter (in cM) is given in parentheses. The complete genomewide two-point results are available for all five traits at the authors' Web site.

Figure 2

Parametric multipoint results for chromosome 16q24.1, obtained using the HDL-C trait and a recessive mode of inheritance. The analysis was performed using the “Location Score” option of the SimWalk2 program and allowing for heterogeneity. Dutch = the study group of the Dutch families with FCHL; Finns = the Finnish families with FCHL; combined = the Dutch and Finnish families with FCHL; combined + HDL-C = the Dutch and Finnish families with FCHL, as well as the Finnish families with low HDL-C. The α values for the peak location scores of the Dutch, Finns, combined, and combined + HDL-C families were 0.80, 0.70, 0.75, and 0.50, respectively.

Figure 3

Conservation between mouse and human sequences in the genomic region of the FOXC2 gene. The SNP located in the putative promoter of the FOXC2 gene (−512) is shown in detail. The comparison between the genomic sequences of human and mouse was performed using the VISTA program.