The Genetics of Lipid Lowering Drugs and Diet Network (GOLDN)

Size: px

Start display at page:

Download "The Genetics of Lipid Lowering Drugs and Diet Network (GOLDN)"

Pauline Dickerson
5 years ago
Views:

1 The Genetics of Lipid Lowering Drugs and Diet Network (GOLDN) Recruitment The majority of participants in the GOLDN Study were re-recruited from threegenerational pedigrees from two National Heart, Lung and Blood Institute (NHLBI) Family Heart Study (FHS) field centers (Minneapolis, MN and Salt Lake City, UT). 1 The NHLBI FHS is a multicenter, population-based study of genetic and environmental determinants of cardiovascular disease and associated risk factors. For the GOLDN Study, we extended pedigrees by targeting offspring of the original FHS probands siblings who were not included in the original FHS sampling. Additional, genetically related pedigree members were recruited as well, specifically targeting large sibships. Sixty percent of those who were eligible to participate completed the study protocol. We collected clinical measurements in related individuals before and after exposure to a high-fat meal in order to assess baseline TGs and postprandial TG response and related phenotypes. Clinical measurements were also collected in all individuals before and after exposure to the drug fenofibrate. Participants were given a 28-day supply of fenofibrate as 160 mg tablets (TriCor, Abbott Laboratories, Chicago, IL) and informed to take one fenofibrate tablet with a breakfast meal once daily for a minimum of 21 days. Exclusion criteria included the following: fasting TGs 1500 mg/dl; recent history (six months) of myocardial infarction, coronary bypass surgery, coronary angioplasty or PTCA; self report of a positive history of liver, kidney, pancreas, or gall bladder disease, or a history of malabsorption of nutrients; current use of insulin or warfarin; serum concentrations of aspartate aminotransferase (AST) exceeding 52 U/L in males or 42 U/L in females; serum concentrations of alanine transaminase (ALT) exceeding 66 U/L in males or 44 U/L in females; glomerular filtration rate <30 ml/min/1.73 m 2 estimated from the MDRD equation; pregnant women or women of childbearing potential not using contraception; and women nursing a child. Individuals who reported current use of prescription and/or over-the-counter (OTC) hypolipidemic drugs or dietary supplements known to influence lipid values (e.g., fish oil, flaxseed oil, niacin, etc.) were required to consult with their physician for approval to discontinue 1

2 these lipid-lowering agents for 4 weeks prior to study participation. Written informed consent was obtained from each participant at his/her screening visit. This protocol was approved by the Institutional Review Boards at the University of Minnesota, the University of Utah and Tufts University. Adverse events were monitored, and all incidents were reviewed by the local Principal Investigator, with any serious adverse events reported to the Institutional Review Boards at the University of Minnesota or the University of Utah and the NHLBI. Interventions and clinic visits In brief, the study has been conducted in five visits. Visit 0: the first screening took place. Visit 1: one blood draw for the baseline 4-8 weeks later after visit 0. One day after visit 1, visit 2 was conducted for the first PPL challenge (see below) before fenofibrate trial. Three blood draws were took from each subject: 0 hours before drinking shake, 3.5 hours after drinking shake, and 6 hours after drinking shake. Fenofibrate was dispended to subjects. Each subject took 160 mg per day for three weeks. After drug intervention, visit 3 was performed for one blood draw for the baseline after drug trial (3-4 weeks after visit 2). One day after visit 3, visit 4 was conducted for the second PPL challenge after fenofibrate trial; three blood draws: 0 hours before drinking shake, 3.5 hours after drinking shake, and 6 hours after drinking shake. Three blood draws from visit 2 and 4 were used to measure postprandial TG. The data used in this study was recorded in visit 2 and 4. Participants were asked to fast for 12 hours and abstain from using alcohol for 24 hours before visiting the clinic. For all study participants, the clinical exam included anthropometric and blood pressure measurements. After a five minute rest, blood pressure was measured in duplicate, one minute apart, in the right arm (except for those women who reported right-side mastectomy), with an oscillometric device (Dinamap Pro Series 100, GE Medical Systems, Waukesha, WI, USA); measures were averaged. Weight was measured with a beam balance and hip measurements were made at maximal hip girth and waist measures at the umbilicus. BMI was calculated as weight (kg)/height 2 (m 2 ). Questionnaires were administered to solicit demographic and lifestyle information; 2

3 medical history; current prescription, OTC, and non-traditional medication use. An interviewer-administered, direct data entry system was created 3 for the Diet History Questionnaire developed by the National Cancer Institute (NCI) to quantify usual dietary intake. The PPL study fat-challenge consisted of a meal following the protocol of Patsch et al. 2. This high-fat meal was consumed after fasting laboratory measurements were collected. The meal, which participants were instructed to consume within 15 minutes, had 700 Calories/m 2 body surface area (2.93 MJ/m 2 body surface area); 3% of Calories were derived from protein, 14% from carbohydrate, and 83% from fat sources. The cholesterol content and the ratio of polyunsaturated to saturated fat was 240 mg and 0.06, respectively. The average person consumed 175 ml heavy whipping cream (39.5% fat), and 7.5 ml of powdered, instant, non-fat, dry milk. The mixture was blended with water ice and 15 ml of chocolate- or strawberry-flavored syrup to increase palatability. Blood samples were drawn immediately before (time 0) and at 3.5 and 6 hours after consuming this high-fat meal. For the duration of the 6-hour study period, participants were instructed to take nothing by mouth except water, unsweetened coffee or tea, or sugarless soft drinks and to abstain from exercise and strenuous physical work until the final blood sample was obtained. All high-fat meals were administered in the early morning, usually between 0630 and 0900 hours. 1. Higgins M, Province M, Heiss G, Eckfeldt J, Ellison RC, Folsom AR, Rao DC, Sprafka JM, Williams R. NHLBI Family Heart Study:objectives and design. Am J Epidemiol. 1996;143(12): Patsch JR, Miesenbock G, Hopferwieser T, Muhlberger V, Knapp E, Dunn JK, Gotto AM, Jr., Patsch W. Relation of triglyceride metabolism and coronary artery disease. Studies in the postprandial state. Arterioscler Thromb. Nov 1992;12(11):

4 3. Morgan D. SAS/AFR, metadata, and the National Cancer Institutes Diet History Questionnaire: How to build a computer-assisted interview. Western Users of SAS Software, Eleventh Annual Conference. San Francisco;

5 Supplement table 1. Lipid response to fenofibrate according to APOA5-1131T>C genotypes Before Drug After Drug Response Genotype Mean (SE) p-value Mean (SE) p-value Mean (SE) Adjusted p-value* p-value** Triglycerides (Log) (mg/dl) TT 2.22 (0.04) (0.03) (0.02) TC+CC 2.31 (0.05) 2.09 (0.04) (0.03) HDL-C (mg/dl) TT 45.5 (1.7) (1.9) (0.8) TC+CC 43.1 (2.2) 46.8 (2.3) 3.8 (0.8) LDL-C (mg/dl) TT (4.7) (4.7) (3.4) TC+CC (4.9) (5.7) -5.0 (5.4) Total Cholestrol (mg/dl) TT (5.9) (5.5) (3.4) TC+CC (6.2) (6.4) (4.5) log CRP (mg/dl) TT (0.148) (0.150) (0.121) TC+CC (0.170) (0.200) (0.194) *Adjusted for covariates: family relationships, gender, age, BMI, smoking, alcohol consumption, physical activity, post-menopausal status, hormone use, and drugs for lowering cholesterol, diabetes, and hypertension **Adjusted for the baseline and covariates Sample size: N (TT)=699, N (TC+CC)=89 5

6 Supplement table 2. Fenofibrate effects on lipoprotein subclasses according to APOA5 genotypes Before Drug After Drug Response SNPs Genotype Mean (SE) p-value Mean (SE) p-value Mean (SE) p-value log Chylomicron 56C>G CC (0.036) (0.043) (0.047) (mg/dl) CG+GG (0.042) (0.045) (0.050) -1131T>C TT (0.037) (0.042) (0.048) TC+CC (0.039) (0.049) (0.050) log VLDL total 56C>G CC (0.050) (0.046) (0.036) (mg/dl) CG+GG (0.059) (0.057) (0.043) -1131T>C TT (0.050) (0.047) (0.036) TC+CC (0.069) (0.060) (0.043) log VLDL-large 56C>G CC 1.50 (0.08) (0.08) (0.06) (mg/dl) CG+GG 1.64 (0.10) 1.32 (0.09) (0.07) -1131T>C TT 1.51 (0.08) (0.08) (0.06) log VLDLintermediate TC+CC 1.60 (0.10) 1.37 (0.10) (0.07) 56C>G CC 1.75 (0.08) (0.07) (0.07) (mg/dl) CG+GG 1.90 (0.09) 1.40 (0.09) (0.10) -1131T>C TT 1.75 (0.08) (0.07) (0.08) TC+CC 1.91 (0.10) 1.45 (0.09) (0.07) log VLDL-small 56C>G CC 1.01 (0.06) (0.06) (0.06) (mg/dl) CG+GG 1.04 (0.07) 0.92 (0.07) (0.07) -1131T>C TT 1.01 (0.06) (0.06) (0.06) TC+CC 1.08 (0.07) 0.97 (0.07) (0.08) HDL-large 56C>G CC (1.74) (1.70) (0.94) (mg/dl) CG+GG (1.82) (1.85) (1.12) -1131T>C TT (1.73) (1.70) (0.94) TC+CC (2.24) (2.19) (1.14) log HDLintermediate 56C>G CC (0.096) (0.085) (0.084) (mg/dl) CG+GG (0.115) (0.092) (0.087) -1131T>C TT (0.097) (0.085) (0.081) TC+CC (0.111) (0.090) (0.098) log IDL 56C>G CC (0.087) (0.074) (0.087) (mg/dl) CG+GG (0.104) (0.092) (0.118) -1131T>C TT (0.087) (0.075) (0.090) TC+CC (0.104) (0.084) (0.104) LDL-large 56C>G CC 49.8 (5.8) (4.9) (5.5) (mg/dl) CG+GG 41.8 (6.7) 56.4 (5.0) 15.0 (6.4) -1131T>C TT 49.5 (5.9) (4.8) (5.6) TC+CC 42.5 (7.2) 56.8 (5.4) 13.2 (7.4) log LDL-Medium Small 56C>G CC (0.060) (0.042) (0.050) (mg/dl) CG+GG (0.070) (0.048) (0.066) -1131T>C TT (0.060) (0.042) (0.052) TC+CC (0.076) (0.049) (0.061) log Total LDL-small 56C>G CC 1.74 (0.06) (0.04) (0.05) (mg/dl) CG+GG 1.80 (0.06) 1.68 (0.05) (0.06) -1131T>C TT 1.74 (0.06) (0.04) (0.05) TC+CC 1.80 (0.07) 1.69 (0.06) (0.06) log LDL-very small 56C>G CC 1.54 (0.06) (0.04) (0.05) (mg/dl) CG+GG 1.57 (0.07) 1.54 (0.05) (0.06) -1131T>C TT 1.54 (0.06) (0.04) (0.05) TC+CC 1.59 (0.07) 1.53 (0.06) (0.06) *Adjusted for covariates: family relationships, gender, age, BMI, smoking, alcohol consumption, physical activity, post-menopausal status, hormone use, and drugs for lowering cholesterol, diabetes, and hypertension Sample size: N (CC)=703, N (CG+GG) = 87; N (TT)=699, N (TC+CC)=89. 6

STUDY OVERVIEW KEY TAKEAWAYS

STUDY OVERVIEW KEY TAKEAWAYS Avocado fruit on postprandial markers of cardio-metabolic risk: A randomized controlled dose response trial in overweight and obese men and women Britt Burton-Freeman, Eunyoung Park, Indika Edirisinghe