Evidence of a Genetic Susceptibility Locus Influencing Interindividual Variation in Triglycerides: The NHLBI Family Heart Study
Genomic regions have been linked to hypertriglyceridemia associated with familial syndromes, such as familial combined hyperlipidemia. However, there is little information regarding chromosomal regions harboring susceptibility genes for more common forms of hypertriglyceridemia. Significant linkage of triglycerides (TGs) was recently identified on chromosome 15 in Mexican Americans (LOD=3.88). As part of the NHLBI-sponsored Family Heart Study (FHS), a genome-wide linkage analysis was done to replicate this finding or to identify other quantitative trait loci for TGs. Multi-generational families were recruited (a) at excess risk of early onset myocardial infarction and (b) randomly selected from Framingham, Atherosclerosis Risk in Communities, and Utah Family Tree Studies. The largest families were selected for genomic analysis (105 families, family size=8.6). Microsatellite markers (n=369), approximately equally spaced throughout the genome (CHLC-10), were typed by the NHLBI Mammalian Genotyping Service. TGs were measured in participants fasting for at least 12 hours. TGs were adjusted for sex, age and age 2 , and log-transformed to normalize the distribution. The search for quantitative trait loci for TGs was carried out using a multipoint model-free variance components method implemented in GENEHUNTER. The mean age was 60 years and 52% were female. The mean triglyceride value in the family members was 146 (±85) mg/dl in men and 155 (±102) mg/dl in women. Evidence for linkage was identified on chromosome 4 (LOD=3.23 (p<.0003) at position 35cM from the pter). Further evidence for linkage was found on chromosome 15 (LOD=1.90 (p<.007) at position 36cM from the pter), which overlaps the genomic region identified in Mexican Americans. In conclusion, we found significant evidence for linkage of TGs to a region on chromosome 4 in families either randomly recruited or at high risk of early onset coronary heart disease. This putative locus appears to have a major influence on the interindividual variation in triglycerides. Finally, these data add support for the existence of a putative locus for TGs on chromosome 15.