The genetic response to short-term interventions affecting cardiovascular function: rationale and design of the Heredity and Phenotype Intervention (HAPI) Heart Study.

BACKGROUND: The etiology of cardiovascular disease (CVD) is multifactorial. Efforts to identify genes influencing CVD risk have met with limited success to date, likely because of the small effect sizes of common CVD risk alleles and the presence of gene by gene and gene by environment interactions. METHODS: The HAPI Heart Study was initiated in 2002 to measure the cardiovascular response to 4 short-term interventions affecting cardiovascular risk factors and to identify the genetic and environmental determinants of these responses. The measurements included blood pressure responses to the cold pressor stress test and to a high salt diet, triglyceride excursion in response to a high-fat challenge, and response in platelet aggregation to aspirin therapy. RESULTS: The interventions were carried out in 868 relatively healthy Amish adults from large families. The heritabilities of selected response traits for each intervention ranged from 8% to 38%, suggesting that some of the variation associated with response to each intervention can be attributed to the additive effects of genes. CONCLUSIONS: Identifying these response genes may identify new mechanisms influencing CVD and may lead to individualized preventive strategies and improved early detection of high-risk individuals.

Physical activity and the association of common FTO gene variants with body mass index and obesity.

BACKGROUND: Common FTO (fat mass and obesity associated) gene variants have recently been associated with body mass index (BMI) and obesity in several large studies. The role of lifestyle factors (such as physical activity) in those with an underlying FTO genetic predisposition is unknown. METHODS: To determine if FTO variants are associated with BMI in Old Order Amish (OOA) individuals, and to further determine whether the detrimental associations of FTO gene variants can be lessened by increased physical activity, a total of 704 healthy OOA adults were selected from the Heredity and Phenotype Intervention (HAPI) Heart Study, an investigation of gene x environment interactions in cardiovascular disease, for whom objective quantified physical activity measurements were available and for whom 92 single-nucleotide polymorphisms (SNPs) in FTO were genotyped. RESULTS: Twenty-six FTO SNPs were associated with BMI (P = .04 to <.001), including rs1477196 (P < .001) and rs1861868 (P < .001), 2 SNPs in moderate linkage disequilibrium in the OOA (D' = 0.82; r(2) = 0.36). Stratified analyses of rs1861868 revealed its association with BMI to be restricted entirely to those subjects with low sex- and age-adjusted physical activity scores (P < .001); in contrast, the SNP had no effect on those with above-average physical activity scores (P = .29), with the genotype x physical activity interaction achieving statistical significance (P = .01). Similar evidence for interaction was also obtained for rs1477196. CONCLUSIONS: Our results strongly suggest that the increased risk of obesity owing to genetic susceptibility by FTO variants can be blunted through physical activity. These findings emphasize the important role of physical activity in public health efforts to combat obesity, particularly in genetically susceptible individuals.

Two cases of thyroid storm-associated cholestatic jaundice.

OBJECTIVE: To describe the association of the rare and serious complication of jaundice with severe thyrotoxicosis, a potentially lethal endocrine disorder. METHODS: We report the clinical, laboratory, and pathologic findings of 2 cases of severe jaundice (total bilirubin levels: 35.2 mg/dL in case 1 and 42 mg/dL in case 2) associated with thyroid storm in the absence of a history of liver disease, thionamide exposure, or congestive heart failure. We also present other relevant reports available in the literature. RESULTS: Case 1 was a 38-year-old woman who presented with nausea, vomiting, fatigue, pruritus, and frequent nonbloody diarrhea. She was transferred to our institution because of worsening hyperbilirubinemia. Case 2 was a 35-year-old woman admitted to a community hospital with thyroid storm and jaundice. Upon transfer to our institution, the patient was unconscious, mechanically ventilated, and in atrial fibrillation. In case 2, liver biopsy results revealed diffuse hepatocellular ballooning with intrahepatic cholestasis with mild portal lymphocytic infiltration. Both patients presented with severe cholestatic jaundice in the absence of congestive heart failure; underlying liver disease (infectious or autoimmune); or previous exposure to thionamides, other hepatotoxic agents, or complementary and alternative medications. In both cases, jaundice responded to therapy with antithyroid medications. Both patients eventually underwent thyroidectomy with complete resolution of the jaundice. CONCLUSION: The data strongly suggest that in these patients, the hepatic dysfunction was primarily due to hyperthyroidism. These cases indicate that the mere presence of hyperbilirubinemia during severe thyrotoxicosis should not per se delay the use of potentially life-saving thionamides once a thorough evaluation for other causes of liver disease has been completed.