Zahid Ahmad1, Xilong Li2, Jedrek Wosik3, Preethi Mani3, Joye Petr3, George McLeod3, Shatha Murad3, Li Song3, Beverley Adams-Huet2, Abhimanyu Garg4. 1. Division of Nutrition and Metabolic Diseases, Center for Human Nutrition, UT Southwestern Medical Center, Dallas, TX, USA; Department of Internal Medicine, UT Southwestern Medical Center, Dallas, TX, USA. Electronic address: Zahid.ahmad@utsouthwestern.edu. 2. Department of Clinical Sciences, UT Southwestern Medical Center, Dallas, TX, USA. 3. Department of Internal Medicine, UT Southwestern Medical Center, Dallas, TX, USA. 4. Division of Nutrition and Metabolic Diseases, Center for Human Nutrition, UT Southwestern Medical Center, Dallas, TX, USA; Department of Internal Medicine, UT Southwestern Medical Center, Dallas, TX, USA. Electronic address: Abhimanyu.garg@utsouthwestern.edu.
Abstract
BACKGROUND: For patients with autosomal dominant hypercholesterolemia (ADH), it remains unclear whether differences exist in the risk of premature coronary heart disease (CHD) between patients with confirmed mutations in low-density lipoprotein receptor (LDLR) vs those without detectable mutations. OBJECTIVE: This study sought to assess the risk of premature CHD in ADH patients with mutations in LDLR (referred to as familial hypercholesterolemia [FH]) vs those without detectable mutations (unexplained ADH), stratified by sex. METHODS: Comparative study of premature CHD in a multiethnic cohort of 111 men and 165 women meeting adult Simon-Broome criteria for ADH. RESULTS: Women with FH (n = 51) had an increased risk of premature CHD compared with unexplained ADH women (n = 111; hazard ratio [HR], 2.74; 95% confidence interval, 1.40-5.34; P = .003) even after adjustment for lipid levels and traditional CHD risk factors (HR, 2.53 [1.10-5.83]; P = .005). Men with FH (n = 42), in contrast, had a similar risk of premature CHD when compared with unexplained ADH men (n = 66; unadjusted: HR, 1.48 [0.84-2.63]; P = .18; adjusted: HR, 1.04 [0.46-2.37]; P = .72). To address whether mutation status provides additional information beyond LDL-cholesterol level, we analyzed premature CHD risk for FH vs unexplained ADH at various percentiles of LDL-cholesterol: the risk ratios were significant for women at 25th percentile (HR, 4.90 [1.69-14.19]) and 50th percentile (HR, 3.44 [1.42-8.32]) but not at 75th percentile (HR, 1.99 [0.95-4.17]), and were not significant for men at any percentile. CONCLUSIONS: Our findings suggest that genetic confirmation of ADH may be important to identify patient's risk of CHD, especially for female LDLR mutation carriers.
BACKGROUND: For patients with autosomal dominant hypercholesterolemia (ADH), it remains unclear whether differences exist in the risk of premature coronary heart disease (CHD) between patients with confirmed mutations in low-density lipoprotein receptor (LDLR) vs those without detectable mutations. OBJECTIVE: This study sought to assess the risk of premature CHD in ADH patients with mutations in LDLR (referred to as familial hypercholesterolemia [FH]) vs those without detectable mutations (unexplained ADH), stratified by sex. METHODS: Comparative study of premature CHD in a multiethnic cohort of 111 men and 165 women meeting adult Simon-Broome criteria for ADH. RESULTS:Women with FH (n = 51) had an increased risk of premature CHD compared with unexplained ADH women (n = 111; hazard ratio [HR], 2.74; 95% confidence interval, 1.40-5.34; P = .003) even after adjustment for lipid levels and traditional CHD risk factors (HR, 2.53 [1.10-5.83]; P = .005). Men with FH (n = 42), in contrast, had a similar risk of premature CHD when compared with unexplained ADH men (n = 66; unadjusted: HR, 1.48 [0.84-2.63]; P = .18; adjusted: HR, 1.04 [0.46-2.37]; P = .72). To address whether mutation status provides additional information beyond LDL-cholesterol level, we analyzed premature CHD risk for FH vs unexplained ADH at various percentiles of LDL-cholesterol: the risk ratios were significant for women at 25th percentile (HR, 4.90 [1.69-14.19]) and 50th percentile (HR, 3.44 [1.42-8.32]) but not at 75th percentile (HR, 1.99 [0.95-4.17]), and were not significant for men at any percentile. CONCLUSIONS: Our findings suggest that genetic confirmation of ADH may be important to identify patient's risk of CHD, especially for female LDLR mutation carriers.
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