Familial hypercholesterolemia. The determination of phenotype

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Jansen, A.C.M.

Publication date

2003

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Citation for published version (APA):

Jansen, A. C. M. (2003). Familial hypercholesterolemia. The determination of phenotype.

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Generall introduction

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Generall introduction

Heterozygouss Familial Hypercholesterolemia (FH) is a common (1:500) inherited autosomal codominantt disorder of lipoprotein metabolism. Clinically, FH is characterized by elevated levelss of total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C) and the presence off tendon xanthomas, xanthelasmata and/or an arcus cornealis. The elevated LDL-C levels stronglyy predispose for premature atherosclerotic disease.

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Manyy years later, in 1938, Muller, a Norwegian physician, associated the xanthomas with a highh incidence of premature atherosclerosis and revealed the dominant inheritance pattern off the disease.2 Later, Khachadurian (1964) confirmed these findings, and, in addition, demon-stratedd the existence of the less severe heterozygous and more severe homozygous forms of FH.33 In the years thereafter, it became evident that an increased level of LDL-C was the hallmarkk of the disease. Intrigued by the autosomal codominant inheritance pattern, it were Goldsteinn and Brown (assistant-professors of Medicine at the University of Texas) who, in 1972,, set out to unravel the underlying defect in FH. Their studies led to the discovery of the LDL-receptor,, a cell surface receptor for LDL, and to the elucidation of the mechanism by whichh this receptor carries LDL particles into cells through coated vesicles. They soon found thatt FH is caused by genetic defects in the LDL-receptor." In 1985, Goldstein and Brown were rewardedd the Nobel Prize in Physiology or Medicine for these findings.

Thee LDL-receptor gene locus is located on the short arm of chromosome 19 and spans 45 kb withh 18 exons and 17 introns. At present, more than 900 sequence variations in this gene are documentedd and still new mutations are identified continuously. Mutations have been categorizedd in different classes. The so-called 'null-alleles' result in failure to produce any protein,, while other mutations lead to impairment of binding capacity, post-translational processingg or recycling. Due to this impaired function of the LDL-receptor, LDL-C is insufficiently takenn up by the receptor in the liver and LDL-C concentration in plasma will rise to approximately twice-normall levels. This leads to excessive deposition of cholesterol in the arterial wall and peripherall tissues, often leading to accelerated atherosclerosis and premature cardiovascular diseasee (CVD).

Untreated,, around 75% of male FH patients suffer from coronary artery disease (CAD) beforee the age of 60 years.57 Characteristically, the mean age of CVD onset is between 40 andd 45 years in male FH patients and in female FH patients 10 years later.811 Strikingly, althoughh FH is monogenic, the phenotypic expression, in terms of onset and severity of atheroscleroticc disease, varies considerably and the CVD burden as a consequence of FH differss considerably from patient to patient.

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Chapterr 1

Thiss was already recognized in 1966 when Harlan et al. reported a normal mean survival in 16911691 individuals of a single large FH kindred of nine generations.12 Recently, this was confirmedd by three different mortality studies, carried out in the United Kingdom and The Netherlands.13155 In addition to patients with serious excess CVD mortality, many patients weree observed to have a normal lifespan.

Inn the first study, performed in the UK in 1991, 526 Lipid Clinic patients, recruited into the Simonn Broome Register of Familial Hyperlipidemia, were prospectively followed up for 10 years.. '3 Remarkably, there was a 100-fold increase in mortality from coronary heart disease andd a nearly 10-fold increase in total mortality. A striking finding was the diminishing mortality riskk from coronary heart disease with increasing age. In both men and women aged over 600 at registration there was no increase in the standardized mortality ratio for coronary heartt disease or all cause mortality.

Inn the second study, in a large pedigree with the V408M mutation that had been traced backk to a single pair of ancestors in the 19th century, all-cause mortality had been documented overr eight generations.14 Seventy deaths had occurred among the 250 people analysed {forr 6950 person years). The standardised mortality ratio was low in the period 1830-1869 (0.58),, but rose between 1935 and 1989 (to a maximum of 1.78). The study also found thatt some subjects, who must have carried the FH gene, enjoyed a normal life span. The differencess in mortality, both over time and within generations demonstrate the important interactionss with environmental and genetic factors.

Thee third study addressed all-cause mortality in 855 untreated first-degree relatives of 113 unrelatedd Dutch FH patients.15 As in the previous study, many carriers of a LDL-receptor mutationn reached a normal life span, but mortality varied with age, gender, family history off CVD and ,strikingly, again calendar time. In this study, individuals withh a family history of CVDD had a significantly higher mortality risk than individuals without. Probably, such families aree characterized by clustering, genetic and environmental, risk factors.

FHH is a common disease that affects many individuals in most societies. More in-depth knowledgee of risk factors that influence the clinical phenotype is urgently needed. A more precisee estimate of an FH individual's risk profile could enable the physician to identify thosee patients at very high risk, that need strict medical follow-up and adherence to intensive combinationn drug regimens, whereas patients at lower risk could probably benefit from statinss and/or lifestyle advices only. Such knowledge could have major consequences for thee welfare of the individual patients, as well as for society at large.

Manyy previous studies have focused on the role of classical risk factors.101628 In general, all studiess found the CVD risk to increase for male gender, age and smoking. Unfortunately, thesee studies yielded conflicting data on the influence of classical risk factors such as hypertension'1 0 1 6'8 2 3 2 77 and diabetes1613'23'2723, possibly explained by small study sizes. Therefore,, the role of these well-known risk factors, at least for the general population,

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iss not well established in FH.

Onee parameter that affects the incidence of coronary artery disease in FH heterozygotes may bee the plasma level of lipoprotein(a), which consists of an LDL particle attached to an additional protein,, apoprotein(a), through a disulfide bond to the apolipoprotein B-100 component. Again,, study results in FH have been conflicting.'5'18'2""6'29"34

Inn addition, high-density lipoprotein cholesterol (HDL-C) metabolism seems very important in thee development of atherosclerosis in patients with heterozygous Familial Hypercholesterolemia. Mostt studies found low HDL-C levels to increase risk in FH20'23'24'26'30'35'36, although some studies failedd to show a relationship22-27,33'37 or detected effects in subgroup analyses only.1517 Moreover,, the class of receptor mutation and resulting defective protein are also suggested too influence the clinical phenotype.253841 Recently, in the first large and unselected FH cohort,, CVD risk varied largely among different types of mutations, with carriers of null-alleless having the most atherogenic lipid profile, combined with the most severe increased risk.422 This undoubtedly emphasizes an important role of mutation type in the clinical expressionn of FH. However, even within subjects that share an identical gene defect, the clinicall presentation still differs substantially, so the genetic make-up of an FH individual is certainlyy not the sole factor that determines absolute risk of CVD mortality.

Additionall genetic variation outside the LDL-receptor locus is also presumed to play an importantt role in the clinical phenotype of this disorder. Studies in the general population andd in patients with atherosclerotic disease have shown that mutations in genes involved in lipoproteinn metabolism, blood pressure regulation, homocysteine metabolism, coagulation, fibrinolysis,, cell adhesion, inflammation and plaque stability increase an individuals CVD risk.. In FH, so far, only a few small case-control studies have been carried out, studying the rolee of one or only several polymorphisms. Large studies that simultaneously examine many polymorphismss in a host of genes do not exist for FH patients.

Alreadyy in 1977, Heiberg and Slack found an 0.7 combined correlation coefficient for tntrafamiliall correlations of age at death due to coronary heart disease for heterozygous sib pairss and cousins of 172 FH kindreds. According to the authors, this pointed at 'a condition causedd by a single mutant gene influenced by many modifying genes'. They ended their paperr with the phrase 'Further genetic work must be undertaken to elucidate the importance off genetic heterogeneity in FH'. Now 25 years later and only with the DNA techniques of today,, their proposal could be effectuated at a large scale and the results are described in this thesis. .

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Chapterr 1

Outlinee of this thesis

Thee large variability in the clinical phenotype of FH, in terms of severity and time of onset of cardiovascularr symptoms, is not well understood. Further studies with the purpose of unravellingg the underlying mechanisms are urgently warranted for this common disorder andd this formed the rationale for the current thesis. The specific objective of the research describedd in this thesis was to elucidate the contribution of genetic risk factors to the occurrencee of CVD in patients with heterozygous FH.

Inn general, the clinical phenotype of FH is supposed to be influenced by environmental and metabolicc factors, the type of LDL-receptor mutation and the co-inheritance of other genetic factors.. In Chapter 2 an overview is presented of recent developments in this field. Inn order to investigate the role of genetic variability, extensive clinical information and DNA sampless were collected from a large cohort of 2400 FH patients from 27 Lipid Clinics throughoutt the Netherlands. The research project received the working title 'GIRaFH-study' (Geneticc Identification of Risk Factors in Familial Hypercholesterolemia). The collection of a veryy large, well-defined cohort provided the possibility to describe the role of classical risk factors,, such as smoking and the presence of hypertension and diabetes mellitus, as well as thee influence of metabolic factors, such as plasma levels of lipoproteins, lipoprotein(a) and homocysteine,, as described in Chapter 3.

Forr inclusion of FH patients in the GIRaFH study, we used a combination of strict FH clinical criteria.. Nevertheless, we arrived at differences between two subgroups within our cohort; thosee patients with established LDL-receptor mutations and those without, but both included onn the basis of clinical criteria. This has led us to examine and present these differences in

Chapterr 4

Inn the process of designing the GIRaFH study we performed a systematic search of the publishedd literature for the design, execution and reporting of retrospective studies using medicall records for data collection. No comprehensive guidelines were found for the executionn or reporting of such studies. Therefore, we decided to develop a set of guidelines whichh we discuss in Chapter 5.

Duringg the last decade, many polymorphisms in genes involved in lipid metabolism, blood pressuree regulation, coagulation and hemostasis, homocysteine metabolism, endothelial function,, cell adhesion, inflammation and plaque stability have been characterized and associatedd with CVD in the general population. In FH, so far, only very limited data are availablee on the role of these genes in the occurrence of CVD. In Chapter 6 the contribution too CVD risk of 65 polymorphisms in 36 candidate genes in more than 2000 FH patients of thee large GIRaFH cohort is reported. The relationships of these candidate susceptibility geness with mortality in the parents of GIRaFH participants is analysed in Chapter 7.

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Loww plasma HDL-C levels have been postulated as an independent risk factor in FH patients. Inn this thesis, we could confirm a major role of low HDL-C levels in the development of CVD inn FH. Therefore, in Chapter 8 we investigated the underlying genetic determinants of plasmaa HDL-C levels in FH.

Hyperhomocysteinemiaa is associated with atherosclerosis, but a causal relationship is still vehementlyy debated. In Chapter 9 we assessed the relation between plasma homocysteine levels,, the methylenetetrahydrofolate reductase (MTHFR) genotype and the occurrence of CVDD and intima media thickness (IMT) measurements, a well validated non-invasive method

i r t r ^ tt r\i - 3 t k _{Q r n c r l o r r i ! ; i ( ; ;}

Paraoxonasee (PON-1) is a HDL-associated enzyme that may protect against atherosclerosis. Inn Chapter 10 we evaluated the role of paraoxonase plasma levels and the role of several functionall polymorphisms in the paraoxonase gene and the association with CVD in FH. Thee overall results of this thesis are summarized and discussed in Chapter 11.

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