scholarly journals Premature Coronary Artery Disease and Familial Hypercholesterolemia: Need for Early Diagnosis and Cascade Screening in the Indian Population

2012 ◽  
Vol 2012 ◽  
pp. 1-4 ◽  
Author(s):  
N. Setia ◽  
I. C. Verma ◽  
B. Khan ◽  
A. Arora
Keyword(s):  
Heart Disease ◽  
Familial Hypercholesterolemia ◽  
Genetic Factors ◽  
Age Of Onset ◽  
Ldl Receptor ◽  
Premature Coronary Artery Disease ◽  
Cascade Screening ◽  
Cholesterol Levels ◽  
Premature Cad ◽  
Artery Disease

Cardiovascular disease (CVD) is the leading cause of death in India, accounting for 28% of mortality. The average age of onset of CVD is younger (below 55 years) among Indians than in other populations. This may be due to bad lifestyle, genetic factors, or both. Hypertension, smoking, diabetes, and physical inactivity have been identified as modifiable risk factors for heart disease. Hypercholesterolemia is the most common and treatable cause of heart disease. Genetic factors that lead to hypercholesterolemia have not been fully studied in India. Familial Hypercholesterolemia results from mutations in the LDL receptor, ApoB, PCSK9, and ApoE genes. There is an urgent need to screen subjects with premature CAD and their relatives in India for the presence of FH, identify the mutations that lead to high cholesterol, and carry out cascade screening in the at-risk relatives. Those harbouring mutations in the above genes can be treated to lower the cholesterol levels, prevent early CVD, and avoid death. A programme based on these lines has been initiated in Delhi.

Abstract 12689: Targeted Exon Sequencing of Lipid-related Genes in Patients With Clinically Diagnosed Familial Hypercholesterolemia

Circulation ◽  
2020 ◽  
Vol 142 (Suppl_3) ◽  
Author(s):  
Takeshi Okada ◽  
Masahiro Koseki ◽  
Makoto Nishida ◽  
Katsunao Tanaka ◽  
Hiroyasu Inui ◽  
...  
Keyword(s):  
Familial Hypercholesterolemia ◽  
Ldl Receptor ◽  
University Hospital ◽  
Premature Coronary Artery Disease ◽  
Apolipoprotein C3 ◽  
Pathogenic Variants ◽  
History Of ◽  
Premature Cad ◽  
Artery Disease ◽  
Selection Of

Background: Familial hypercholesterolemia (FH) is at high risk of premature coronary artery disease (CAD). Japan Atherosclerosis Society (JAS) has published original criteria for FH. Patients are diagnosed clinical FH if at least 2 of the following criteria are satisfied: i) LDL-C ≥ 180 mg/dL, ii) Tendon/ skin xanthomas, iii) History of FH or premature CAD within 2nd degree blood relatives. Although it is easy to apply these criteria for FH-suspected patients, in fact, we are not sure whether other lipid-related genes may be overlapped in addition to those of conventional FH genes such as LDL receptor (LDLR), apolipoprotein B (APOB), and proprotein convertase subtilisin/kexin type 9 (PCSK9). Methods and Results: Ninety-one heterozygous FH (HeFH) patients in Osaka University Hospital, who met the clinical FH criteria of JAS were enrolled after obtaining informed consent. Genomic DNA for each patient was extracted from peripheral blood cells. Targeted exon sequencing was performed to investigate 36 lipid-related genes including conventional FH genes. We have defined pathogenic variants if they fulfilled i) rare protein truncating variants, ii) rare damaging missense variants, and iii) ClinVar-registered pathogenic or likely pathogenic variants. Among 91 HeFH patients (52.9 ± 14.7 years), 41 patients (45.1%) were males. We have identified LDLR pathogenic variants in 61 patients (67.0%) and PCSK9 variants in 1 patient (1.1%). Among these 62 patients, 22 patients (35.5%) additionally have pathogenic variants of other lipid-related genes, which include apolipoprotein E2 (APOE2) in 1 patient, apolipoprotein E4 (APOE4) in 10 patients, ATP-binding cassette subfamily G member 5 (ABCG5) in 2 patients, apolipoprotein C3 (APOC3) in 1 patient, and CD36 in 10 patients. As for remaining 29 patients without conventional FH gene variants, 13 patients (44.8%) have pathogenic variants of other lipid-related genes, which include APOE4 in 11 patients, apolipoprotein E5 (APOE5) in 1 patient, and variants of ABCG5 in 1 patient. Conclusion: We have identified several variants of lipid-related genes in addition to conventional FH genes in HeFH patients diagnosed according to JAS criteria. These variants may affect the atherogenicity of patients and selection of medication.

scholarly journals Familial Hypercholesterolaemia Diagnosis and Management

2018 ◽  
Vol 13 (1) ◽  
pp. 14 ◽  
Author(s):  
Rodrigo Alonso ◽  
Leopoldo Perez de Isla ◽  
Ovidio Muñiz-Grijalvo ◽  
Jose Luis Diaz-Diaz ◽  
Pedro Mata ◽  
...  
Keyword(s):  
Ldl Cholesterol ◽  
Familial Hypercholesterolaemia ◽  
Receptor Gene ◽  
Ldl Receptor ◽  
Premature Coronary Artery Disease ◽  
Cascade Screening ◽  
Adequate Treatment ◽  
Clinical Criteria ◽  
Disease Mutations ◽  
Artery Disease

Familial hypercholesterolaemia is the most common monogenic disorder associated with premature coronary artery disease. Mutations are most frequently found in the LDL receptor gene. Clinical criteria can be used to make the diagnosis; however, genetic testing will confirm the disorder and is very useful for cascade screening. Early identification and adequate treatment can improve prognosis, reducing negative clinical cardiovascular outcomes. Patients with familial hypercholesterolaemia are considered at high cardiovascular risk and the treatment target is LDL cholesterol <2.6 mmol/l or at least a 50 % reduction in LDL cholesterol. Patients require intensive treatment with statins and ezetimibe and/or colesevelam. Recently, proprotein convertase subtilisin/kexin type 9 inhibitors have been approved for the management of familial hypercholesterolaemia on top of statins.

scholarly journals Mutational Spectrum of LDLR and PCSK9 Genes Identified in Iranian Patients With Premature Coronary Artery Disease and Familial Hypercholesterolemia

2021 ◽  
Vol 12 ◽  
Author(s):  
Arman Moradi ◽  
Majid Maleki ◽  
Zahra Ghaemmaghami ◽  
Zahra Khajali ◽  
Feridoun Noohi ◽  
...  
Keyword(s):  
Coronary Artery Disease ◽  
Coronary Artery ◽  
Familial Hypercholesterolemia ◽  
Genetic Disorder ◽  
Premature Coronary Artery Disease ◽  
Double Mutation ◽  
The Family ◽  
Premature Cad ◽  
Artery Disease ◽  
Iranian Patients

Familial hypercholesterolemia (FH) is a common, yet underdiagnosed, genetic disorder characterized by lifelong elevated low-density lipoprotein cholesterol levels, which can increase the risk of early-onset coronary artery disease (CAD). In the present study, we screened the nucleotide variations of the LDLR and PCSK9 genes, as well as a part of the APOB gene, in Iranian patients with FH and premature CAD to find the genetic cause of the disorder. Fifteen unrelated individuals with a clinical diagnosis of FH and premature CAD were recruited. Direct DNA sequencing was applied to screen the whole coding exons and exon–intron boundaries of the LDLR and PCSK9 genes and the main parts of their introns, together with exon 26 of the APOB gene. The pathogenicity of the identified mutations was investigated via either segregation analyses in the family or in silico predictive software. Six different point mutations (p.Cys148Tyr, p.Cys216Tyr, p.Cys302Trp, p.Cys338Trp, p.Leu479Gln, and p.G593Afs∗72) in LDLR and a double mutation (p.Asp172His and p.Ala53Val) in both LDLR and PCSK9 genes were identified in seven families with clinically diagnosed FH (43%), whereas no pathogenic mutations were found in eight families with clinically diagnosed FH. This study is the first to identify 1 pathogenic mutation in the LDLR gene (c.1014C &gt; G [p.Cys338Trp]) and to cosegregate it from the affected individual in the family. No mutations were found in the APOB gene, whereas several silent mutations/polymorphisms were identified in the LDLR and PCSK9 genes. Genetic testing and reports on nucleotide alterations in the Iranian population are still limited. Our findings not only further confirm the significant role of FH in the incidence of premature CAD but also enlarge the spectrum of LDLR and PCSK9 variations and exhibit the heterogeneity of FH in Iranians. In patients with no mutation in the examined genes, the disease could be begotten either by a polygenic cause or by gene defects occurring in other related genes and regions not targeted in this study.

Risk Factors for Coronary Artery Disease in Children: Recognition, Evaluation, and Therapy

1980 ◽  
Vol 2 (5) ◽  
pp. 131-138
Author(s):  
C. J. Glueck ◽  
M. J. Mellies ◽  
R. C. Tsang ◽  
J. A. Morrison
Keyword(s):  
Risk Factors ◽  
Coronary Heart Disease ◽  
Heart Disease ◽  
Eating Habits ◽  
Plasma Cholesterol ◽  
Saturated Fat ◽  
Cholesterol Levels ◽  
Chd Risk ◽  
Artery Disease ◽  
Atherosclerosis Prevention

PEDIATRIC GENESIS OF ATHEROSCLEROSIS Atherosclerosis results from a variety of pathophysiologic disturbances, some currently recognized, and many undoubtedly not yet recognized, which in aggregate are identified as risk factors. Genetic and environmental influences conjointly affect the incidence and the severity of these risk factors and, thus, coronary heart disease (CHD) risk. Prophylaxis should be designed to prevent or retard the development of arterial plaques. This suggests that diagnostic and preventive efforts should begin in childhood. Eating habits are also probably established in childhood, allowing their early modification. The atherosclerotic plaque appears to have its genesis in childhood. The data from wartime autopsies confirm the presence of mature atherosclerotic lesions by the end of the second decade and emphasize the importance of primary atherosclerosis prevention beginning in the first and second decades. While there are clearly genetic factors in CHD, variation in rates in differing geographic areas appears less likely to be related to genetic than to environmental differences. Marked differences in plasma cholesterol levels are found in children in different geographic areas, generally paralleling pediatric cholesterol and saturated fat intake and the incidence of adult coronary heart disease. The relationships of elevated total plasma cholesterol levels to the incidence of coronary heart disease are clearly established in adults.

scholarly journals A case of familial hypercholesterolemia with premature coronary artery disease

Heart India ◽  
2018 ◽  
Vol 6 (4) ◽  
pp. 156
Author(s):  
DigvijayDeeliprao Nalawade ◽  
JaywantM Nawale ◽  
AjayS Chaurasia ◽  
Dhirendra Tiwari
Keyword(s):  
Coronary Artery Disease ◽  
Coronary Artery ◽  
Familial Hypercholesterolemia ◽  
Premature Coronary Artery Disease ◽  
Artery Disease

Abstract 18995: Statins in Familial Hypercholesterolemia - Effects on Coronary Artery Disease and All-cause Mortality

Circulation ◽  
2015 ◽  
Vol 132 (suppl_3) ◽  
Author(s):  
Joost Besseling ◽  
Gerard K Hovingh ◽  
John J Kastelein ◽  
Barbara A Hutten
Keyword(s):  
Coronary Artery Disease ◽  
Coronary Artery ◽  
Familial Hypercholesterolemia ◽  
Lipid Lowering ◽  
Premature Coronary Artery Disease ◽  
Lipid Lowering Therapy ◽  
Time Varying ◽  
All Cause Mortality ◽  
Artery Disease

Introduction: Heterozygous familial hypercholesterolemia (heFH) is characterized by high levels of low-density lipoprotein cholesterol (LDL-C) and increased risk for premature coronary artery disease (CAD) and death. Reduction of CAD and mortality by statins has not been properly quantified in heFH. The aim of the current study is to determine the effect of statins on CAD and mortality in heFH. Methods: All adult heFH patients identified by the Dutch FH screening program between 1994 and 2014 and registered in the PHARMO Database Network were eligible. Of these patients we obtained hospital, pharmacy (in- and outpatient), and mortality records in the period between 1995 and 2015. The effect of statins (time-varying) on CAD and all-cause mortality was determined using a Cox proportional hazard model, while correcting for the use of other lipid-lowering therapy, thrombocyte aggregation inhibitors, antihypertensive and antidiabetic medication (all time-varying). Furthermore, we used inverse probability for treatment weighting (IPTW) to account for differences between statin-treated and untreated patients regarding history of CAD before follow-up, age at start of follow-up and age of screening, as well as body mass index, LDL-C and triglycerides. Results: Of the 25,479 identified heFH patients, 11,021 gave informed consent to obtain their medical records, of whom 2,447 could be retrieved. We excluded 766 patients younger than 18. The remaining 1,681 heFH patients comprised our study population and these had very similar characteristics as compared to the 23,798 excluded FH patients, e.g. mean (SD) LDL-C levels were 214 (74) vs. 203 (77) mg/dL. Among 1,151 statin users, there were 133 CAD events and 15 deaths during 10,115 statin treated person-years, compared to 17 CAD events and 9 deaths during 4,965 person-years in 530 never statin users (combined rate: 14.6 vs. 5.2, respectively, p<0.001). After applying IPTW to account for indication bias and correcting for use of other medications, the hazard ratio of statin use for CAD and all-cause mortality was 0.61 (0.40 - 0.93). Conclusions: In heFH patients, statins lower the risk for CAD and mortality by 39%.

Genesis of Statins

2009 ◽  
Author(s):  
Jie Jack Li
Keyword(s):  
Heart Disease ◽  
Thyroid Hormone ◽  
Large Scale ◽  
Hormone Treatment ◽  
Blood Cholesterol ◽  
Heart Attacks ◽  
Cholesterol Levels ◽  
The 1950S ◽  
Loss Of Libido ◽  
Artery Disease

As evidence grew that high blood cholesterol levels were linked to heart disease, scientists in both academia and industry began to look for drugs to lower cholesterol as early as the 1950s. Before Akira Endo discovered the first statin, mevastatin, in the 1970s, many things, including hormones, vitamins, and resins, were tried to lower cholesterol. Some worked, and some did not. Thyroid hormone was one of the fi st drugs used for that purpose. The cholesterol-lowering properties of dextro-thyroxine were discovered by serendipity. At one point, surgical removal of part of the thyroid gland had been used to relieve angina, the pain brought on by exercise in coronary artery disease. Doctors observed that thyroid removal also raised the blood cholesterol level, which in turn sped up arterial degeneration. By deduction, the doctors reasoned that taking thyroid hormone should then decrease blood cholesterol levels. Initial clinical trials proved this theory, and dextro-thyroxine was used to lower cholesterol beginning in the 1950s, when thyroid extract became a standard treatment for hypercholesterolemic (high cholesterol) patients. Unfortunately, too much thyroid hormone made patients tremble all the time. Later, a large-scale, long-term clinical trial named the “Coronary Drug Project” established the association of dextro-thyroxine with ischemic heart disease as a severe side eff ect in men. As a consequence, thyroid hormone treatment was discontinued. Women, in contrast to men, enjoy natural cardiac protection through the action of the female sex hormones, the estrogens. In 1930, a minute quantity of estrogen was isolated from the ovaries of 80,000 sows. In the 1950s, reports appeared that estrogen could lower blood cholesterol levels even more effectively than nicotinic acid, another anticholesterol drug used at the time. Unfortunately, men on estrogen for too long began to develop feminine traits, including breast enlargement and loss of libido, and other side effects, although they did acquire relative immunity from heart attacks until late in life. Due to the lack of safe and effiicacious drugs, some doctors seemed willing to take their chances with estrogens.

scholarly journals Genetics of Hypercholesterolemia: Comparison Between Familial Hypercholesterolemia and Hypercholesterolemia Nonrelated to LDL Receptor

2020 ◽  
Vol 11 ◽  
Author(s):  
Estíbaliz Jarauta ◽  
Ana Ma Bea-Sanz ◽  
Victoria Marco-Benedi ◽  
Itziar Lamiquiz-Moneo
Keyword(s):  
Cardiovascular Risk ◽  
Familial Hypercholesterolemia ◽  
Genetic Defect ◽  
Genetic Diagnosis ◽  
Ldl Receptor ◽  
Lipid Lowering ◽  
Atherosclerotic Cardiovascular Disease ◽  
Single Nucleotide Variants ◽  
Cascade Screening ◽  
The Moment

Severe hypercholesterolemia (HC) is defined as an elevation of total cholesterol (TC) due to the increase in LDL cholesterol (LDL-C) &gt;95th percentile or 190 mg/dl. The high values of LDL-C, especially when it is maintained over time, is considered a risk factor for the development of atherosclerotic cardiovascular disease (ASCVD), mostly expressed as ischemic heart disease (IHD). One of the best characterized forms of severe HC, familial hypercholesterolemia (FH), is caused by the presence of a major variant in one gene (LDLR, APOB, PCSK9, or ApoE), with an autosomal codominant pattern of inheritance, causing an extreme elevation of LDL-C and early IHD. Nevertheless, an important proportion of serious HC cases, denominated polygenic hypercholesterolemia (PH), may be attributed to the small additive effect of a number of single nucleotide variants (SNVs), located along the whole genome. The diagnosis, prevalence, and cardiovascular risk associated with PH has not been fully established at the moment. Cascade screening to detect a specific genetic defect is advised in all first- and second-degree relatives of subjects with FH. Conversely, in the rest of cases of HC, it is only advised to screen high values of LDL-C in first-degree relatives since there is not a consensus for the genetic diagnosis of PH. FH is associated with the highest cardiovascular risk, followed by PH and other forms of HC. Early detection and initiation of high-intensity lipid-lowering treatment is proposed in all subjects with severe HC for the primary prevention of ASCVD, with an objective of LDL-C &lt;100 mg/dl or a decrease of at least 50%. A more aggressive reduction in LDL-C is necessary in HC subjects who associate personal history of ASCVD or other cardiovascular risk factors.

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