Table1_Effect of causative genetic variants on atherosclerotic cardiovascular disease in heterozygous familial hypercholesterolemia patients.docx

BackgroundHeterozygous familial hypercholesterolemia (HFH) is an autosomal dominant genetic disorder leading to a lifetime exposure to high low-density lipoprotein cholesterol (LDL-c) level and an increased risk of premature atherosclerotic cardiovascular disease (ASCVD). We evaluate the effect of a causative genetic variant to predict ASCVD in HFH patients undergoing treatment.Materials and methodsA retrospective cohort was conducted on 289 patients with possible, probable, and definite diagnosis of HFH according to Dutch Lipid Clinic Network Score and in whom DNA analyses were performed and mean LDL-c level was above 155 mg/dl. The study population was divided into groups based on the presence or not of a causative variant (pathogenic or likely pathogenic). We observed each of the study’s participants for the occurrence of ASCVD.ResultsA causative variant was detected in 42.2% of study participants, and ASCVD has occurred in 21.5% of HFH patients. The incidence of ASCVD (27% vs. 17.4%, p = 0.048) and the mean of LDL-c under an optimal medical treatment (226 ± 59 mg/dl vs. 203 ± 37 mg/dl, p = 0.001) were higher in HFH-causative variant carriers than others. After adjusting on confounders, ASCVD was positively associated with LDL-c level [OR = 2.347; 95% (1.305–4.221), p = 0.004] and tends toward a negative association with HDL-c level [OR = 0.140; 95% (0.017–1.166), p = 0.059]. There is no more association between the detection of a causative variant and the occurrence of ASCVD [OR = 1.708; 95% (0.899–3.242), p = 0.102]. Kaplan Meier and log rank test showed no significant differences in event-free survival analysis between study groups (p = 0.523).ConclusionIn this study population under medical care, it seems that the presence of a causative variant did not represent an independent predictor of adverse cardiovascular outcomes in HFH patients, and LDL-c level played an undisputable causal role.</p

Adjusted HR for mortality in type 2 diabetic compared with non-diabetic subjects.

<p>HR: Hazard Ratio; CI: Confidence Interval; (1) Reference: Non-diabetic subjects; (2) Reference: Toulouse; (3) Reference: 35–44 years.</p>£<p>HR for type 2 diabetics with metformin alone or with sulfonylureas (alone or in combination) = 1.85 [1.07–3.20] (p = 0.027);</p><p>* As compared with <6 years duration of diabetes (among diabetics). Duration of diabetes is composed of 3 categories (<6 years, ≥6 years and non-diabetic subjects);</p><p>** Diabetes with renal, ophthalmic, neurological, peripheral arterial disease or atherosclerotic cardiovascular disease.</p

Main baseline characteristics of participants.

<p>Of type 2 diabetic subjects, 12 were receiving other hypoglycaemic treatments. SD: Standard Deviation; IQR: Inter-Quartile Range;</p>£<p>Diabetes was assessed for subjects with fasting blood glucose ≥7.7 mmol/l (140 mg/dl) or under hypoglycaemic drug treatment;</p>££<p>Diabetic subjects treated with metformin alone;</p>£££<p>Diabetics with sulfonylureas or insulin alone or in combination;</p><p>* Diabetes with renal, ophthalmic, neurological, peripheral arterial disease or atherosclerotic cardiovascular disease;</p><p>** Among diabetics.</p

Risk for ankle-brachial index <0.90 according to <i>LIPC</i> genotypes in CAD patients.

1<p>Adjusted for smoking, diabetes, physical activity and heart rate.</p><p>All interactions between ankle-brachial index, <i>LIPC</i> genotypes and variables of adjustment were non-significant.</p>2<p>Area under the curve (AUC) for adjusted model: 0.73, corrected AUC after bootstrap validation: 0.72.</p>3<p>False discovery rate method was used to correct for multiple comparisons for subgroup analyses. Corrected p values are shown.</p

Risk for CAD according to <i>LIPC</i> genotypes.

1<p>Adjusted for diabetes, hypertension, dyslipidemia, smoking, alcohol consumption, physical activity, CRP, HDLc, Lp(a), triglycerides and ABI.</p>2<p>Area under the curve (AUC) for adjusted model: 0.91; corrected AUC after bootstrap validation: 0.90.</p>3<p>Area under the curve (AUC for adjusted model: 0.92; corrected AUC after bootstrap validation: 0.91.</p

Characteristics according to ankle-brachial index status in CAD patients.

*<p>Log transformed data.</p><p>Mean (standard deviation) or % (n).</p

Lipids, lipoproteins and metabolic markers according to <i>LIPC</i> genotypes and case-control design.

*<p>Analyses were performed on log transformed data.</p

Additional file 1: Table S1. of Serum levels of mitochondrial inhibitory factor 1 are independently associated with long-term prognosis in coronary artery disease: the GENES Study

Vital status according to administered medication in coronary artery disease patients (n = 577). Table S2. Correlation between IF1 and HDL, measured by standard method and NMR spectroscopy in coronary artery disease patients (n = 212). Table S3. Comparison between coronary artery disease patients included in the study and non-included patients. (DOCX 31 kb

Schematic diagram of the case-cohort design in MORGAM.

<p>Outline of the selection of individuals in the MORGAM dataset. The subcohort and all CHD cases who were genotyped (N = 4818) were chosen from the full cohort. We restricted the validation analysis to 4209 men with complete genotype data for > = 11 SNPs with the remaining SNP data multiply imputed.</p

Association between LPA haplotypes and CHD in MORGAM.

<p>While MORGAM associations conditioned on a different allele set, haplotypic combinations are consistent with those reported in ref which are given here for comparison. Association was tested with a model adjusted for cohort and Framingham coefficients. Haplotypic ORs were used as coefficients for GRS1.</p