Genetics of human coronary heart disease

Because the classic CHD risk factors such as serum cholesterol, smoking, hypertension and diabetes mellitus are incomplete predictors of CHD, additional risk factors based on molecular genetics have been intensively investigated. The two main methods of investigation to date are genome-wide linkage studies and case-control association studies. Whole-genome association studies using ultra high-throughput genotyping have yet to report, although are expected to do so within the next 2-3 years. Most studies to date have focused either on identifying genes that predispose to the traditional risk factors, or on direct linkage and association to the phenotype of CHD per se. We shall focus here on genetic studies of the CHD phenotype itself. The genetics of lipid risk factors has been reviewed above and the genetics of other CHD risk factors including diabetes and hypertension are reviewed in other chapters in this book (Chapters 23, 25).

Genome-wide studies for coronary heart disease

Five independent, genome-wide screens for CHD have been published on Finnish, Mauritian, Australian and European families with various gene localizations reported (Francke et al., 2001; Harrap et al., 2002; Broeckel et al., 2002; Helgadottir et al., 2004; BHF Family Heart Study Research Group, 2005). Most studies have been inconclusive with no LOD score achieving the threshold for genome-wide statistical significance although one study (involving Western European families) localised a new CHD QTL on chromosome 14 with a significant LOD score of 3.9 (Broeckel etal., 2002). This region does not overlap with existing QTLs for other CHD risk factors or intermediate phenotypes, raising the possibility that, whilst the role of existing risk factors in this QTL are not excluded, this QTL may act through a presently unknown mechanism.

The heritability of known risk factors that were included in this linkage study (including type 2 diabetes mellitus and hypertension) was high, suggesting that these intermediate phenotypes are genetically determined to a moderately high extent. However, whereas age, gender, diabetes and hypertension contributed significantly to the myocardial infarction phenotype, high cholesterol levels did not. Since many of the individuals in the study were on lipid-lowering therapy, this suggests that hypercholesterolemia now appears to be a less significant risk factor for myocardial infarction than diabetes and hypertension.

The genome scan in Icelandic subjects localized a susceptibility gene for both myocardial infarction and stroke to chromosome 13 and identified the likely gene as 5-lipoxygenase activating protein (FLAP) (Helgadottir et al., 2004). The FLAP gene product converts 5-lipoxygenase to leukotriene B4, a powerful inflammatory cytokine, emphasising the importance of inflammation in CHD pathogen-esis, and raising the possibility of new therapeutic strategies targeting this and other genes in inflammatory pathways.

A meta-analysis was applied to four of the CHD genome-wide studies (Chiodini and Lewis, 2003). The genetic region 3q26-27 showed the strongest evidence for linkage (P=0.0001), which is one of the regions of linkage found in the Mauritian population (Francke et al., 2001). This result is of interest, and the subject of further investigation, given the existence of several candidate genes involved in the homeostasis of glucose and lipid metabolism in this chromosomal region and the important association between CHD and the metabolic syndrome.

Informative mutations have also been found by utilizing families that demonstrate Mendelian pattern of inheritance for CHD. Wang and colleagues carried out a genome scan in a single family demonstrating a rare autosomal dominant pattern of inheritance for CHD (Wang et al., 2003). The cause of the CHD phenotype in this kindred was proposed to be a deletion of seven amino acids in a member of the myocyte enhancer factor-2 family of transcription factors (MEF2A). The MEF2A protein showed strong expression in the endothelium of coronary arteries, but how this deletion gives rise to the CHD phenotype remains to be determined. Since the original observations of Wang et al., the association of MEF2A with CHD has both been challenged and replicated (Altshuler and Hirschhorn, 2005; Topol, 2005). Although debate therefore exists on the definitive nature of these findings, the data imply that genes in the MEF2A signalling pathway, as well as genes regulating endothelial development and function, may be important in the pathophysiology of CHD.

Candidate gene studies for coronary heart disease

When selecting candidate genes, investigators must choose from a very large number of potential factors that may contribute to the CHD phenotype. These are generally deduced from knowledge of the pathophysiological pathways involved. As a consequence, genes involved in lipid metabolism, the renin-angiotensin-aldosterone system, thrombosis, insulin resistance, inflammation and endothelial function represent potential candidates for CHD. A full survey of candidate genes is beyond the scope of this article and has been reviewed elsewhere (Navarro-Lopez, 2002). Therefore only a small number of illustrative examples of candidate genes shown to be associated with CHD will be given.

One of the best-studied genetic variants is the insertion/deletion (I/D) polymorphism of the angiotensin converting enzyme (ACE) gene. ACE is predominantly found in the vascular endothe-lium of endothelial cells and catalyzes the generation of angiotensin II from angiotensin I and the degradation of bradykinin. The ACE polymorphism is characterized by the presence or absence of an

Alu sequence of 287 base pairs in intron 16. It gives rise to three different genotypes: II/ID/DD with carriers of the D allele having an increase in plasma, cardiac and tissue ACE activity. In 1992, the association of the DD genotype with an increased risk of myocardial infarction was reported (Cambien et al., 1992). As with many candidate gene studies, this association has been variably reproduced. In particular a large prospective population study performed by Lindpaintner and colleagues did not confirm the association (Lindpaintner et al., 1995).

Factor VII participates with tissue factor at the onset of the coagulation cascade. A reduction in factor VII levels reduces the propensity to thrombosis. Two polymorphisms have been implicated as having a protective role against myocardial infarction. The FVII R353Q polymorphism, with substitution of arginine (R) by glutamine (Q) in codon 353 of exon 8, and the 5' F7 polymorphism, a decanucleotide insertion at position -323 of the 5' region of the promoter, with two alleles, A1 (without the insertion) and A2 (with the insertion). People who are homozygous for the Q or A2 genotype have plasma levels of activated factor VII which are 70% lower than in R or A1 homozygotes. In one Italian study the Q or A2 allele was associated with a reduction in the risk of myocardial infarction (Iacoviello et al., 1998). Another Italian study replicated these results and showed that these polymorphisms were major determinants of factor VII levels (Girelli etal., 2000). Failure to replicate the association with CAD in other investigations has been ascribed to geographical variation in the frequency of these polymorphisms, implying that these polymorphisms are not themselves the functional variants underlying altered factor VII or CHD susceptibility, although other closely linked polymorphisms might underlie these significant phenotypes (Doggen et al., 1998; Lane et al., 1996).

Three further candidate gene studies merit particular attention. Arising from a very high throughput screen of over 92 000 single nucleotide polymorphisms (SNPs) in a study of over 3000 cases and controls, Ozaki and colleagues showed strong association (P < 10~5) between susceptibility to myocardial infarction and SNPs in the lympho-toxin-a gene (Ozaki et al., 2002). Subsequently the same research group showed association of myocardial infarction with another gene on the same pathway, galectin-2, which plays a part in the regulation of lymphotoxin-a secretion (Ozaki etal., 2004). Most recently Helgadottir et al. (2006) demonstrated strong association between leuko-triene A4 hydrolase and myocardial infarction in African-Americans, and replication in European-Americans, though with less signficance, again implicating inflammatory pathways in the patho-genesis of myocardial infarction, but also suggesting interaction between inflammatory and other pathways.

Insulin resistance has a central role in the development of hypertension, dyslipidemia, and T2DM (Figure 24.2) and, with the current epidemic of obesity and T2DM, it is a contributory factor in an increasing proportion of cases of premature

The Metabolic Syndrome and Cardiovascular Disease

Major Risk Factors For Heart Disease

Figure 24.2 Insulin resistance and the development of major cardiovascular risk factors. Insulin resistance alone has subtle effects that may be detected biochemically, but when combined with pancreatic beta cell failure, renal salt retention or hepatic overproduction of lipoproteins, leads to clinically overt diabetes, hypertension and dyslipidemia. These are amongst the strongest and most prevalent risk factors for coronary heart disease.


Figure 24.2 Insulin resistance and the development of major cardiovascular risk factors. Insulin resistance alone has subtle effects that may be detected biochemically, but when combined with pancreatic beta cell failure, renal salt retention or hepatic overproduction of lipoproteins, leads to clinically overt diabetes, hypertension and dyslipidemia. These are amongst the strongest and most prevalent risk factors for coronary heart disease.

coronary heart disease, estimated to be as high as 60% in some populations (McKeigue et al., 1993; Reaven, 1988). Since the original description of the Metabolic Syndrome, its component features have expanded to include microalbuminuria, central obesity, raised levels of plasminogen activator inhibitor-1 (PAI-1) and uric acid. Genetic associations have been shown in case-control studies, although many of these still require replication and mechanistic explanation. The most consistent of these associations is that of the peroxisome pro-liferator activated receptor (PPAR)-g polymorphism Pro12Ala with type 2 diabetes mellitus and insulin sensitivity. By analyzing over 3000 individuals, the authors found a modest (1.25-fold) but significant (P—0.002) increase in diabetes risk associated with the more common proline allele (~85%o frequency). Because the risk allele occurs at such high frequency, its modest effect translates into a large population attributable risk, influencing as much as 25% of type 2 diabetes in the general population (Altshuler et al., 2000).

The possibility that Cd36 deficiency in humans might be a cause of insulin resistance arose initially from rodent studies (Aitman et al., 1997b; 1999; Pravenec et al., 2001). Cd36 is a multi-functional protein and belongs to the scavenger receptor family typified by SrB1 and mediates the specific uptake of long chain-free fatty acids by adipocytes and muscle cells. Cd36 is also a high affinity receptor for oxidized low density lipoproteins, a role which has been suggested to play a part in macrophage foam cell formation and atherosclerosis (Tontonoz et al., 1998). Varying rates of prevalence of CD36-deficiency in different ethnic groups have been documented but are as high as 1% in black Africans and African-Caribbeans. Japanese subjects with CD36-deficiency have increased levels of triglycerides, increased fasting plasma glucose, hypertension and reduced insulin action (Miyaoka et al., 2001). Importantly, diabetes and insulin resistance are more common in CD36-deficient Japanese than in the wider Japanese population (Furuhashi et al., 2003). Whether heterozygous or homozygous mutations for human Cd36-deficiency predispose or protect against CHD has yet to be determined.

Finally, mention should be made of two novel genetic mechanisms that may play a part in CHD pathogenesis. Samani and colleagues showed evidence for telomere shortening in subjects with atherosclerosis, showing a possible association of accelerated chromosomal ageing with CHD (Samani etal., 2001). Other studies have implicated structural rearrangements in the genome, such as gene duplication and deletion, as a cause of common human diseases such as HIV susceptibility and glomerulonephritis (Gonzalez et al., 2005; Aitman et al., 2006). Although specific studies to test the hypothesis that structural rearrangements predispose to CHD have as yet not been carried out, such studies, if positive, have the potential to elucidate entirely new mechanisms for evolution of CHD risk and pathogenesis of CHD.

Dynamic Six Pack Abs

Dynamic Six Pack Abs

Reasonable care has been taken to ensure that the information presented in this book is accurate. However, the reader should understand that the information provided does not constitute legal, medical or professional advice of any kind.

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