Evidence of a Genetic Susceptibility Locus Influencing Interindividual Variation in Triglycerides: The NHLBI Family Heart Study

P06 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.

Natural Hybrids of Phytophthora nicotianae and Phytophthora cactorum Demonstrated by Isozyme Analysis and Random Amplified Polymorphic DNA

Three similar isolates of Phytophthora (Phytophthora sp-h) were obtained from diseased Spathiphyllum and Primula plants. Cultural characteristics did not fit any known description of Phytophthora species. The Phytophthora sp-h isolates are papillate, are homothallic, possess 80 to 86% amphigynous antheridia, and have a maximum temperature for growth of 36.5°C. Isozyme analysis of the Phytophthora sp-h isolates revealed a three-banded pattern with malic enzyme and a three-banded pattern with malate dehydrogenase on the second putative locus. The fastest band at both enzyme loci comigrated with the single P. nicotianae band, the slowest band comigrated with the single P. cactorum (and also P. pseudotsugae) band, and one band in between was concluded to represent the heterodimeric isozyme. The random amplified polymorphic DNA patterns of the Phytophthora sp-h isolates almost exclusively consisted of bands that were also present in either P. nicotianae or P. cactorum. Southern hybridization showed that bands specific for P. nicotianae were present as comigrating bands in the Phytophthora sp-h isolates. The same was found for species-specific bands of P. cactorum. It is concluded that the three Phytophthora sp-h isolates represent interspecific hybrids, P. nicotianae being the one parent and P. cactorum the other. Analysis of mito-chondrial DNA with restriction enzymes revealed banding patterns in all the Phytophthora sp-h isolates identical with those of P. nicotianae, confirming that indeed P. nicotianae was one of the parents.

Meta-Analysis of Linkage Data under Worst-Case Conditions: A Demonstration Using the Human OB Region

To date, few methods have been developed explicitly for meta-analysis of linkage analyses. Moreover, the methods that have been developed or suggested generally depend on certain ideal situations and have not been widely applied. In this article, we apply standard statistical theory and meta-analytic techniques in novel ways to five published papers discussing the evidence of linkage of body mass index (BMI) to the region of the human genome containing the OB gene. These methods are “inference based,” meaning that they allow one to make statements about the statistical significance of the entire body of evidence. As currently developed, they do not allow specific statements to be made about the amount of variance explained by any putative locus or allow precise confidence intervals to be placed around the putative location of a linked locus. By applying these techniques to the literature on linkage in the human OB gene region, we are able to show that the evidence for linkage somewhere in the region is extremely strong (P = 1.5 × 10−5).