Genome-Wide Linkage Analysis of Pulse Pressure in Mexican Americans
Pulse pressure, a measure of aortic stiffness, has recently been shown to be a strong predictor of cardiovascular mortality in both normotensives and hypertensives. It is also an important predictor of left ventricular hypertrophy. Unfortunately, little is known about the genetic etiology of pulse pressure. To address this problem we performed genetic analysis on 46 randomly ascertained families (1306 individuals) in the San Antonio Family Heart Study. Pulse pressure (PP) was defined as the difference between systolic and diastolic blood pressure. Likelihood methods were used to construct a model that had both single-locus and polygenic components. The single-locus component included sex-specific and genotype-specific effects of both age and body mass index (BMI). Using this model we then performed two-point linkage analysis of 10 large families (440 individuals), which were a randomly chosen subset of the initial 46 families, that have been genotyped for 396 polymorphic markers. Results showed that when the model contained only the polygenic component and simple effects of the covariates then the heritability of PP is .21. Adding the single-locus component was highly significant (p<.0001). In addition, within the single-locus component, the sex-specific and genotype-specific effects of age and BMI were also highly significant (p<.002). This full model accounted for 73% of the total variation of PP. Linkage analysis of this model with each marker showed four markers with lodscores > 1.9, which is the Lander-Kruglyak standard for suggestive linkage. D21S1439 had a lodscore of 2.78 with a recombination fraction (θ) of 0.02. D7S1799 had a lodscore of 2.04 (θ=0.01). D8S1100 had a lodscore of 1.98 (θ=0.08) and D18S844 had a lodscore of 1.95 (θ=0.11). We conjecture that pulse pressure is affected by several major genes and that together these genes account for the highly significant genotype-specific single-locus effect observed here. Supported by HL54707 and HL45522.