Epidemiology and risk factors for gallstone disease: Has the paradigm changed in the 21st century?

Gallstone disease is common and costly, creating over 700,000 cholecystectomies annually. Its complications consume approximately $6.5 billion in the United States. Surveys using noninvasive ultrasonography have identified its true prevalence and the associated risk factors. In developed countries, at least 10% of white adults harbor cholesterol gallstones; women have twice the risk, and age further increases the prevalence in both sexes. Gallstones reach epidemic proportions in the North and South American Indian populations, accompanied by an increased risk for gallbladder cancer. In contrast, the rate in sub-Saharan Africa and Asia is quite low. Obesity, a major risk factor, likely relates to insulin resistance (the metabolic syndrome). Evolution and circumstance in American Indians may have ironically selected those with "thrifty" genes that conserve energy. Our abundant access to food places us at the increased risk of obesity and cholelithiasis. The general rise in obesity in many countries raises the specter of heightened disease, best identified by epidemiologic studies.     

Genetic predisposition to gallbladder stones

Geographic and ethnic differences in gallstone prevalence rates and familial clustering of cholelithiasis imply that genetic factors influence the risk of gallstone formation. Recently, twin, family, and linkage studies confirmed a genetic predisposition to the development of symptomatic gallstones. In rare instances, mutations in single genes confer a substantial risk for the formation of gallstones. However, in the majority of cases gallstones might develop as a result of lithogenic polymorphisms in several genes and their interactions with multiple environmental factors, rendering gallstones generally a complex genetic disorder. Some of the rare monogenic forms of cholelithiasis were unraveled but the lithogenic genes that increase the susceptibility to cholelithiasis in the majority of gallstone carriers remain elusive. Identification of these lithogenic genes will provide novel means of risk assessment, strategies for prevention, and targets for nonsurgical management of cholelithiasis, which currently is one of the most expensive digestive disorders.     

Activation of liver X receptor sensitizes mice to gallbladder cholesterol crystallization

Gallstone disease is a hepatobiliary disorder due to biochemical imbalances in the gallbladder bile. In this report, we show that activation of nuclear receptor liver X receptor (LXR) sensitized mice to lithogenic diet-induced gallbladder cholesterol crystallization, which was associated with dysregulation of several hepatic transporters that efflux cholesterol, phospholipids, and bile salts. The combined effect of increased biliary concentrations of cholesterol and phospholipids and decreased biliary concentrations of bile salts in LXR-activated mice led to an increased cholesterol saturation index and the formation of cholesterol crystals. Interestingly, the lithogenic effect of LXR was completely abolished in the low-density lipoprotein receptor (Ldlr) null background or when the mice were treated with Ezetimibe, a cholesterol-lowering drug that blocks intestinal dietary cholesterol absorption. These results suggest that LDLR-mediated hepatic cholesterol uptake and intestinal cholesterol absorption play an essential role in LXR-promoted lithogenesis. Conclusion: The current study has revealed a novel lithogenic role of LXR as well as a functional interplay between LXR and LDLR in gallbladder cholesterol crystallization and possibly cholesterol gallstone disease (CGD). We propose that LXR is a lithogenic factor and that the LXR transgenic mice may offer a convenient CGD model to develop therapeutic interventions for this disease.     

Gallstones: environment, lifestyle and genes

Gallstone disease represents one of the most common and costly gastroenterological disorders. In Germany, 0.25% of the population undergo cholecystectomy per year, and cholelithiasis incurs annual medical expenses of more than USD 6.5 billion in the United States. The paradigm of environmental risk factors for gallstones has lately been challenged by genetic studies in experimental models and humans. The analysis of more than 40,000 Swedish twin pairs with gallstones demonstrated that genetic factors account for 25% of the phenotypic variance. Since then, studies employing genome-wide association analysis, case-control cohorts and analysis of sib-pairs in families with gallstones have expanded our knowledge of 'gallstone genes'. Indeed, gallstone disease phenotypes are likely to result from the complex interaction of genetic factors, chronic overnutrition with carbohydrates, depletion of dietary fibre and other not fully defined environmental factors including physical inactivity and infections. This hypothesis is supported by the profound increases of cholesterol gallstone prevalence rates in Native Americans, post-war European countries and current urban centres in East Asia, all of which were associated with 'westernized' nutrition. Herein, we summarise the spectrum of environmental and genetic risk factors which should pave the way to 'personalised' strategies for the prevention and therapy of gallstones.     

Genetic susceptibility to atopic dermatitis

Atopic dermatitis (AD) is a chronic inflammatory skin disorder with an increasing prevalence in industrialized countries. AD belongs to the group of allergic disorders that includes food allergy, allergic rhinitis, and asthma. A multifactorial background for AD has been suggested, with genetic as well as environmental factors influencing disease development. Recent breakthroughs in genetic methodology have greatly augmented our understanding of the contribution of genetics to susceptibility to AD. A candidate gene association study is a general approach to identify susceptibility genes. Fifty three candidate gene studies (50 genes) have identified 19 genes associated with AD risk in at least one study. Significant associations between single nucleotide polymorphisms (SNPs) in chemokines (chymase 1-1903A > G), cytokines (interleukin13 Arg144Gln), cytokine receptors (interleukin 4 receptor 1727G > A) and SPINK 1258G > A have been replicated in more than one studies. These SNPs may be promising for identifying at-risk individuals. SNPs, even those not strongly associated with AD, should be considered potentially important because AD is a common disease. Even a small increase in risk can translate to a large number of AD cases. Consortia and international collaborative studies, which may maximize study efficacy and overcome the limitations of individual studies, are needed to help further illuminate the complex landscape of AD risk and genetic variations.     

Epidemiology of sarcoidosis: recent advances and future prospects

Sarcoidosis is by definition a disease of "unknown causes," but recent epidemiologic advances suggest that the long-standing definition of sarcoidosis may soon need to be amended. The recently completed ACCESS (A Case-Control Etiologic Study of Sarcoidosis) study was not able to definitively identify the "cause" of sarcoidosis, but yielded important findings regarding familial and environmental risks that have advanced our understanding of this disease. The HLA-DRB1 associations reported in ACCESS along with the results of two recently completed genome scans of sarcoidosis in German Caucasians and African-Americans, respectively, have further defined the genetics of sarcoidosis. These studies suggest genetic heterogeneity of sarcoidosis risk between Caucasians and African-Americans and multiple susceptibility genes that interact together and with environmental factors in the disease pathogenesis. Genes that influence sarcoidosis clinical phenotypes may also be largely separate from sarcoidosis susceptibility genes. Although genetic studies of sarcoidosis in African-American populations are confounded by Caucasian admixture, this same admixture may be useful in identifying sarcoidosis genes linked with African ancestry. Case-only methods may be useful in identifying recent acute exposures linked to disease, genetic variants of risk, and gene-environment interactions. In summary, the epidemiology of sarcoidosis has a promising future that should eventually provide the answers to the etiologic origins of this complex disease.     

Gallstone disease

Gallstone disease is one of the most prevalent gastrointestinal diseases with a substantial burden to health care systems that is supposed to increase in ageing populations at risk. Aetiology and pathogenesis of cholesterol gallstones still are not well defined, and strategies for prevention and efficient nonsurgical therapies are missing. This review summarizes current concepts on the pathogenesis of cholesterol gallstones with focus on the uptake and secretion of biliary lipids and special emphasis on recent studies into the genetic background.     

Coinheritance of Gilbert syndrome-associated UGT1A1 mutation increases gallstone risk in cystic fibrosis

The prevalence of "black" pigment gallstones is increased in patients with cystic fibrosis (CF). Bile acid malabsorption with augmented bilirubin uptake from the intestine and the development of "hyperbilirubinbilia" have been proposed as key factors in gallstone formation in CF patients. We have now tested the hypothesis that the coinheritance of the common UGT1A1 promoter mutation associated with Gilbert syndrome is an additional lithogenic risk factor for gallstone formation in CF. Our results show that patients with CF and gallstones are significantly more likely to carry at least one Gilbert UGT1A1 allele compared with stone-free patients (OR 7.3; P = .042) and that these carriers display significantly higher serum levels of unconjugated bilirubin (P = .002). In conclusion, the Gilbert UGT1A1 allele increases the risk of gallstone formation in CF. This genetic association supports the current concept for gallstone formation in CF and suggests that genetic and exogenous sources contributing to hyperbilirubinbilia might be lithogenic in CF patients.     

Mechanisms of disease: the genetic epidemiology of gallbladder stones

Cholelithiasis is one of the most prevalent and most expensive gastroenterologic diseases. It belongs to the group of complex metabolic disorders that affect humans, and its critical pathogenic mechanisms are not well defined. As a result, primary or secondary prevention strategies are sparse, and the only effective treatment is cholecystectomy. Here we provide an update on the molecular pathogenesis of gallbladder stones, evidence supporting the hypothesis that genetic factors are key elements predisposing to gallstones, and progress in human genetic studies of cholesterol stones. Data from recent identical twin, family and linkage studies provide conclusive evidence for a strong genetic component to gallstone disease. Furthermore, epidemiologic studies in at-risk populations indicate that gallstone formation is caused by multiple environmental influences and common genetic factors and their interactions. By contrast, monogenic subtypes of cholelithiasis, such as ATP-binding-cassette transporter deficiencies, appear to be rare. The summary of human association studies illustrates that distinct common gene variants might contribute to gallstone formation in different ethnic groups. The characterization of lithogenic genes in knockout and transgenic mice and the identification of many gallstone-susceptibility loci in inbred mice provide the basis for studies of the corresponding genes in patients with gallstones. The transfer of findings from mouse genetics to the bedside might lead to new strategies for individual risk assessment and reveal novel molecular targets for prevention and medical therapies.     

Role of genetic polymorphisms in myocardial infarction at young age

Acute myocardial infarction (AMI) in young adult presents a typical pattern of risk factors, clinical, angiographic and prognostic characteristics. In the last years we demonstrated that hemorheological profile is altered in these patients in a persistent way and independently of the number of risk factors and of the extent of coronary lesions. Thus, the hyperviscosity syndrome following AMI could be considered an intrinsic characteristic of these patients. Consequently it is possible to hypothesise the presence of a genetic background at the origin of this predisposition. If this background is able to influence the risk of ischemic heart disease, this should be particularly evident in young subjects. Since inflammatory mechanisms play a central role in mediating all phases of atherosclerosis, genes encoding for inflammatory or anti-inflammatory molecules are candidates for the risk of developing atherosclerosis. As atherosclerosis is the first cause of mortality in Western countries and if pro-inflammatory genotypes contribute to risk of coronary heart disease, alleles associated to disease susceptibility should not be included in the genetic background favouring longevity: People genetically predisposed to a weak inflammatory activity have fewer chances to develop cardiovascular disease and, therefore, have better chance for a long-life. According to this hypothesis, we studied in our population of young patients with AMI, the distribution of some polymorphisms influencing a inflammation and found an higher prevalence of pro-inflammatory polymorphisms (SNP A2080G of pyrin gene, SNP Gly670Arg of PECAM gene, C1019T of Cx 37 gene, SNP G1059C of PCR gene) and a lower prevalence of anti-inflammatory polymorphisms (Asp299Gly of TLR4 gene, SNP -1082 G/A of IL10 gene, CCR5Δ32). Results of these studies show that early myocardial infarction could be associated with a genetic predisposition to an intense inflammatory response, associated also to an hyperviscosity syndrome.     

Gallstone disease. Pathogenesis of gallstones: A genetic perspective

Cholelithiasis is one of the most prevalent gastroenterological diseases, imposing a huge economic burden on health-care systems. Gallbladder stones form when the concentration of cholesterol or bilirubin exceeds the solubility in the bile salt and phospholipid-rich bile. The physiology of biliary lipid secretion by a number of specialized transport proteins has recently been elucidated, and underlying genetic defects in these proteins have been identified as susceptibility factors for gallstone disease. Recent studies of identical twins and family strongly support the idea of a genetic component to gallstone disease. Epidemiological studies in high-risk populations indicate that gallstone formation is caused by multiple environmental influences and common genetic factors and their interactions. Monogenic subtypes of cholelithiasis, such as biliary lipid transporter deficiencies, appear to be rare. The characterization of lithogenic genes in knockout and transgenic mice, and the identification of many gallstone susceptibility loci in inbred mice, provide the basis for studies of the corresponding genes in patients with gallstones. The transfer of findings from mouse genetics to the bedside might lead to new strategies for individual risk assessment and reveal molecular targets for the development of new treatment strategies.     

Genetic determinants of cardiovascular disease in Hispanics

Cardiovascular disease (CVD) affects many people in the United States. Compared with other population groups in the United States, epidemiologic data suggest that Hispanic Americans are at a disproportionate risk for CVD. The etiology of this disparity is complex, with genetic, behavioral, cultural, and other environmental factors acting in an independent, interactive, and/or synergistic fashion. Because many complex conditions mediate risk of CVD, including diabetes, obesity, and hyperlipidemia, genes associated with these conditions have been considered as possible contributors to CVD in Hispanics. In addition, the diversity of background and heritage within this population creates a plethora of environmental determinants that interact with behaviors, cultural practices, and genetic makeup to influence disease risk. In this review, we explore the recent literature on genetic determinants of CVD and explain that effective efforts to reduce CVD disparities in Hispanics in the United States will require an understanding of the interactions of genes, the environment, and health-related practices.     

Genome-wide association studies in type 1 diabetes

Type 1 diabetes (T1D) is a chronic disease that typically manifests itself in childhood through the autoimmune destruction of pancreatic β cells, resulting in a lack of production of insulin. T1D is a multifactorial disease with a strong genetic component that is thought to interact with specific environmental triggers. Several genetic determinants of T1D were already established before the era of genome-wide association studies, primarily with the HLA class II genes, encoding highly polymorphic antigen-presenting proteins that account for almost 50% of the genetic risk for T1D. The recent development of high-throughput single nucleotide polymorphism genotyping array technologies has enabled investigators to perform high-density genomewide association studies in search of the remaining T1D loci. Combined with the well-established genes known for many years, 16 loci have now been uncovered to date as being robustly associated with the pathogenesis of this phenotype.     

Nonconventional genetic risk factors for cardiovascular disease

Despite numerous advances made in identifying the genes for rare mendelian forms of cardiovascular disease (CVD), relatively little is known about the common, complex forms at the genetic level. Moreover, most genes that have been associated with CVD, whether they are single gene forms or more common forms of the disease, have primarily been involved in biochemical pathways related to what are considered “conventional” risk factors. However, recent genetic studies have begun to identify genes and pathways associated with CVD that would not be considered to underlie conventional risk factors. In this review, we discuss the evidence for this latter notion based on recent linkage and association studies in humans. As an example, we also illustrate how a combination of mouse and human genetics led to identification of the 5-lipoxygenase pathway for CVD, with potentially important implications for its treatment and diagnosis. We conclude with a discussion of the prospects for identifying CVD genes in the future and for potentially developing more effective therapeutic strategies.     

Genetic effects on susceptibility,clinical expression,and treatment outcome of type 1 autoimmune hepatitis

Currently, three genetic factors have been short-listed as possible modulators of susceptibility and severity in type 1 AIH. They are female sex, HLA DRB alleles encoding lysine at position DR beta 71, and the CTLA4*G allele. The fourth association (i.e., TNFRSF6) remains to be confirmed. There are many other candidates to investigate. Current hypotheses suggest that the autoimmune genotype will include multiple (some linked, others discrete) loci which make a permissive background. Not all "at risk" individuals will develop clinical disease, and selection will depend on the interaction of this "permissive gene pool" (i.e., the host) with the environment. The resulting autoimmune phenotype will depend on gene dose and gene interaction. The human genome project has presented medical science with the challenge to identify the genes that determine common human diseases, including autoimmunity [1]. Although type 1 AIH is considerably less common than diabetes or RA, it may serve as a useful model for other autoimmune diseases. Diagnosis depends on histologic findings, and liver biopsy examinations are part of the usual assessment strategy in type 1 AIH. The availability of these tissue specimens provides a clear basis for monitoring disease progression and may permit investigators to study the impact of genetic polymorphism on disease activity. The emergence of high throughput technologies will significantly enhance our ability to study the interactions between constellations of polymorphic genes and both disease expression and behavior. An abundance of polymorphism is found in the genome. In many diseases, functional studies and genome scanning have helped revise and reduce the list of candidates. Affected families are rare in type 1 AIH, and patients are at risk if corticosteroid treatment is withheld. Under these circumstances, genetic studies may be the most practical, low risk means to investigate the pathogenesis of type 1 AIH and many other autoimmune diseases.     

Genetic determinants of osteoporosis

PURPOSE OF REVIEW: Osteoporosis is a common disease with a strong genetic component characterised by reduced bone mass and an increased risk of fragility fractures. Several advances have been made over recent years in understanding the genetic basis of susceptibility to osteoporosis. This paper will review recent developments in this area. RECENT FINDINGS: Twin studies have shown that genetic factors contribute to osteoporosis by influencing bone mineral density and other determinants of fracture risk such as ultrasound properties of bone, skeletal geometry, and bone turnover. In the normal population, many different genes contribute to the regulation of these phenotypes by interacting with environmental factors such as diet and exercise. Whereas the effect size of individual genes is small, meta-analysis has been successfully used in many cases to define the role of individual polymorphisms in predisposing to osteoporosis. Linkage studies in humans and experimental animals have identified several quantitative trait loci that regulate osteoporosis-related phenotypes, and many genes that cause monogenic bone diseases have been identified by use of this approach. It has been found that subtle polymorphisms in some of these genes also contribute to regulation of bone mass in the normal population. SUMMARY: Research has recently begun to clarify the genes and genetic variants that predispose to osteoporosis and regulation of bone mass. Clinical applications of this research include the identification of genetic markers for assessment of fracture risk and the identification of novel molecular targets for the design of drugs that can be used to treat bone disease.     

Genetics and essential hypertension: candidate genes or screening of the whole genome?

Essential hypertension is a major cardiovascular risk factor in the industrialised countries. Its hereditary nature has been well established in many familial studies: about 30% of blood pressure variance is thought to be genetically determined. However, the identification of the culprit genes has met with many difficulties: the multitude of genes, the effect of which is difficult to appreciate, the many possible genetic polymorphisms of each gene studied, the very important role of environmental factors (diet, physical activity, etc...) on the blood pressure itself or on the effect of the genes which control the blood pressure. With the exception of some rare caricatural forms of mendelian transmitted hypertension, the search for genes has focused on large case control studies and/or studies of siblings with hypertension. Two main approaches are used with these collections of subjects. The first consists of analysing so-called "candidate" genes which code for proteins whose function is known and which may influence the blood pressure. In the last ten years, many candidate genes have been assessed with often controversial results. The second approach is to carry out, with no a priori, a complete screen of the genome. These more recent studies have also provided contradictory results. To date, the results illustrate the difficulty of genetic analysis of a complex trait and the necessity of more integrated approaches: analysis of combination of polymorphisms, analysis of a phenotype under standardised environmental conditions, analysis of gene-environment interactions.     

Pharmacogenetics of response to statins: Where do we stand?

Cardiovascular disease is one of the leading causes of death, especially in developed countries. Blood cholesterol lowering by way of statin therapy is a common risk-lowering therapy. The risk reduction for coronary artery disease for patients using statins is 27%. These reductions, however, are average effects for all patients included in the trials. There is notable interindividual variation in response to statins, and the origins of this variation are poorly understood. Pharmacogenetics seeks to determine the role of genetic factors in variation of drug response. In patients with primary hypercholesterolemia, 23 studies have examined the effects of genetic polymorphisms at 20 different loci on the lipid response to statin treatment, and 18 studies examined genetic polymorphisms involved in the benefits of statin therapy in the prevention of cardiovascular disease. Even though many studies have been performed, few results have been replicated. It is our contention that larger sample sizes and consideration of multiple genes are needed in the field of pharmacogenetics of statin response.     

Genetic risk factors for chronic obstructive pulmonary disease

Cigarette smoking is clearly the major risk factor for chronic obstructive pulmonary disease. However, only a minority of cigarette smokers develops chronic obstructive pulmonary disease, indicating that other factors are involved. Family and twin studies suggest that at least some of those factors are genetic. This article reviews the genes investigated as potential risk factors for this disease, focusing on the recent literature. The only established genetic risk factor for chronic obstructive pulmonary disease is homozygosity for the Z allele of the alpha1 -antitrypsin gene. There is increasing evidence that heterozygotes for the Z allele may also be at increased risk. Variants in genes involved in xenobiotic metabolism, antioxidation, and the inflammatory response have also been associated with chronic obstructive pulmonary disease. Thus, the genetic basis for chronic obstructive pulmonary disease has begun to be elucidated, and it is likely that several genes will be implicated in the pathogenesis of this disease.     

Vascular Genetics: Presentations,Testing, and Prognostics

Purpose of review

Numerous studies have begun to unravel the genetic basis of not only aortic disease but also other forms of commonly encountered vascular diseases. The goal of this review is to provide clinicians a reference to help identify and diagnose different types of vascular disease with a genetic underpinning.

Recent findings

Ongoing studies have identified numerous genes involved in the TGF-β signaling pathway that are also associated with thoracic aortic aneurysm and dissection, and it is possible to test for pathogenic variants in these genes in the clinical setting using commercially available genetic testing panels. Additional studies have begun to identify genetic variants associated with an increased risk of bicuspid aortic valve, abdominal aortic aneurysm, and fibromuscular dysplasia.

Summary

With increased availability of low-cost genetic testing, clinicians are now able to not only definitively diagnose some vascular syndromes but also provide information on the risk of disease in other family members, as well as provide guidance in terms of family planning. As the cost of genetic testing continues to drop with the benefit of increasing insurance coverage, genetic data will increasingly become part of clinical care for many patients with vascular disease.