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

Abstract

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.

Figure 1

(a) Results of the genome-wide quantitative analysis. All genotyped markers were included in the analysis. The x axis indicates the distance (cM) from the p-terminus and the y axis indicates the LOD score. Chr, chromosome. (b) Results of the genome-wide qualitative analysis. All the statistics calculated before adding markers to the regions with LOD score ⩾1.5 are presented in the figure. The x axis indicates the distance (cM) from the p-terminus and the y axis indicates the NPL score. Chr, chromosome.

Figure 1

(a) Results of the genome-wide quantitative analysis. All genotyped markers were included in the analysis. The x axis indicates the distance (cM) from the p-terminus and the y axis indicates the LOD score. Chr, chromosome. (b) Results of the genome-wide qualitative analysis. All the statistics calculated before adding markers to the regions with LOD score ⩾1.5 are presented in the figure. The x axis indicates the distance (cM) from the p-terminus and the y axis indicates the NPL score. Chr, chromosome.

Figure 2

Results showing suggestive evidence of linkage (LOD/NPL score ⩾2.0) in the case of six chromosomes in quantitative analysis (HDL-C as a continuous variable, age and sex as covariates) or in qualitative analysis (subjects having their measured HDL-C levels in the lowest 10th percentile for the general population were coded as affected). Only the results of the MAX-TREE statistics (most powerful at detecting linkage to a dominant trait) or NPL_ALL scores (most powerful at detecting linkage to an additive trait) are reported here for the qualitative analysis, but the results of the other statistics were consistent with these assessments. The x axis indicates the distance (cM) from the first genotyped marker and the y axis indicates the LOD/NPL score. Chr, chromosome. , quantitative multipoint analysis; , qualitative multipoint analysis, NPL_ALL; The same analysis in the initial scan (no additional markers); qualitative multipoint analysis, MAX-TREE; , qualitative multipoint analysis with overweight (BMI>25) subjects with low HDL-C coded as affected, NPL-ALL; , quantitative two-point analysis with sex, age and BMI (for Chr6) as covariates; , qualitative two-point analysis.