Genetics of Gallstone Disease and Their Clinical Significance: A Narrative Review

There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

Abstract

Gallstone (GS) disease is common and arises from a combination of genetic and environmental factors. Although genetic abnormalities specifically leading to cholesterol GSs are rare, there are clinically significant gene variants associated with cholesterol GSs. In contrast, most bilirubin GSs can be attributed to genetic defects. The pathogenesis of cholesterol and bilirubin GSs differs greatly. Cholesterol GSs are notably influenced by genetic variants within the ABC protein superfamily, including ABCG8, ABCG5, ABCB4, and ABCB11, as well as genes from the apolipoprotein family such as ApoB100 and ApoE (especially the E3/E3 and E3/E4 variants), and members of the MUC family. Conversely, bilirubin GSs are associated with genetic variants in highly expressed hepatic genes, notably UGT1A1, ABCC2 (MRP2), ABCC3 (MRP3), CFTR, and MUC, alongside genetic defects linked to hemolytic anemias and conditions impacting erythropoiesis. While genetic cases constitute a small portion of GS disease, recognizing genetic predisposition is essential for proper diagnosis, treatment, and genetic counseling.

Graphical abstract

Related collections

Most cited references 77

Record: found
Abstract: found
Article: not found

CRISPR-Cas9 Gene Editing for Sickle Cell Disease and β-Thalassemia

Haydar Frangoul, David Altshuler, M Cappellini … (2020)

Transfusion-dependent β-thalassemia (TDT) and sickle cell disease (SCD) are severe monogenic diseases with severe and potentially life-threatening manifestations. BCL11A is a transcription factor that represses γ-globin expression and fetal hemoglobin in erythroid cells. We performed electroporation of CD34+ hematopoietic stem and progenitor cells obtained from healthy donors, with CRISPR-Cas9 targeting the BCL11A erythroid-specific enhancer. Approximately 80% of the alleles at this locus were modified, with no evidence of off-target editing. After undergoing myeloablation, two patients - one with TDT and the other with SCD - received autologous CD34+ cells edited with CRISPR-Cas9 targeting the same BCL11A enhancer. More than a year later, both patients had high levels of allelic editing in bone marrow and blood, increases in fetal hemoglobin that were distributed pancellularly, transfusion independence, and (in the patient with SCD) elimination of vaso-occlusive episodes. (Funded by CRISPR Therapeutics and Vertex Pharmaceuticals; ClinicalTrials.gov numbers, NCT03655678 for CLIMB THAL-111 and NCT03745287 for CLIMB SCD-121.).

0 comments Cited 445 times – based on 0 reviews      Review now

Bookmark

Record: found
Abstract: found
Article: not found

Effects of age, sex, and ethnicity on the association between apolipoprotein E genotype and Alzheimer disease. A meta-analysis. APOE and Alzheimer Disease Meta Analysis Consortium.

B C Hyman, L Farrer, L A Cupples … (1997)

To examine more closely the association between apolipoprotein E (APOE) genotype and Alzheimer disease (AD) by age and sex in populations of various ethnic and racial denominations. Forty research teams contributed data on APOE genotype, sex, age at disease onset, and ethnic background for 5930 patients who met criteria for probable or definite AD and 8607 controls without dementia who were recruited from clinical, community, and brain bank sources. Odds ratios (ORs) and 95% confidence intervals (CIs) for AD, adjusted for age and study and stratified by major ethnic group (Caucasian, African American, Hispanic, and Japanese) and source, were computed for APOE genotypes epsilon2/epsilon2, epsilon2/epsilon3, epsilon2/epsilon4, epsilon3/epsilon4, and epsilon4/epsilon4 relative to the epsilon3/epsilon3 group. The influence of age and sex on the OR for each genotype was assessed using logistic regression procedures. Among Caucasian subjects from clinic- or autopsy-based studies, the risk of AD was significantly increased for people with genotypes epsilon2/epsilon4 (OR=2.6, 95% CI=1.6-4.0), epsilon3/epsilon4 (OR=3.2, 95% CI=2.8-3.8), and epsilon4/epsilon4 (OR=14.9, 95% CI= 10.8-20.6); whereas, the ORs were decreased for people with genotypes epsilon2/epsilon2 (OR=0.6, 95% CI=0.2-2.0) and epsilon2/epsilon3 (OR=0.6, 95% CI=0.5-0.8). The APOE epsilon4-AD association was weaker among African Americans and Hispanics, but there was significant heterogeneity in ORs among studies of African Americans (P<.03). The APOE epsilon4-AD association in Japanese subjects was stronger than in Caucasian subjects (epsilon3/epsilon4: OR=5.6, 95% CI=3.9-8.0; epsilon4/epsilon4: OR=33.1, 95% CI=13.6-80.5). The epsilon2/epsilon3 genotype appears equally protective across ethnic groups. We also found that among Caucasians, APOE genotype distributions are similar in groups of patients with AD whose diagnoses were determined clinically or by autopsy. In addition, we found that the APOE epsilon4 effect is evident at all ages between 40 and 90 years but diminishes after age 70 years and that the risk of AD associated with a given genotype varies with sex. The APOE epsilon4 allele represents a major risk factor for AD in all ethnic groups studied, across all ages between 40 and 90 years, and in both men and women. The association between APOE epsilon4 and AD in African Americans requires clarification, and the attenuated effect of APOE epsilon4 in Hispanics should be investigated further.

0 comments Cited 294 times – based on 0 reviews      Review now

Bookmark

Record: found
Abstract: found
Article: not found

Gallstones.

Frank Lammert, Kurinchi S. Gurusamy, Cynthia W. Ko … (2016)

Gallstones grow inside the gallbladder or biliary tract. These stones can be asymptomatic or symptomatic; only gallstones with symptoms or complications are defined as gallstone disease. Based on their composition, gallstones are classified into cholesterol gallstones, which represent the predominant entity, and bilirubin ('pigment') stones. Black pigment stones can be caused by chronic haemolysis; brown pigment stones typically develop in obstructed and infected bile ducts. For treatment, localization of the gallstones in the biliary tract is more relevant than composition. Overall, up to 20% of adults develop gallstones and >20% of those develop symptoms or complications. Risk factors for gallstones are female sex, age, pregnancy, physical inactivity, obesity and overnutrition. Factors involved in metabolic syndrome increase the risk of developing gallstones and form the basis of primary prevention by lifestyle changes. Common mutations in the hepatic cholesterol transporter ABCG8 confer most of the genetic risk of developing gallstones, which accounts for ∼25% of the total risk. Diagnosis is mainly based on clinical symptoms, abdominal ultrasonography and liver biochemistry tests. Symptoms often precede the onset of the three common and potentially life-threatening complications of gallstones (acute cholecystitis, acute cholangitis and biliary pancreatitis). Although our knowledge on the genetics and pathophysiology of gallstones has expanded recently, current treatment algorithms remain predominantly invasive and are based on surgery. Hence, our future efforts should focus on novel preventive strategies to overcome the onset of gallstones in at-risk patients in particular, but also in the population in general.

0 comments Cited 119 times – based on 0 reviews      Review now

Bookmark

All references

Author and article information

Journal

Journal ID (nlm-ta): J Clin Transl Hepatol

Journal ID (iso-abbrev): J Clin Transl Hepatol

Journal ID (publisher-id): JCTH

Title: Journal of Clinical and Translational Hepatology

Publisher: XIA & HE Publishing Inc.

ISSN (Print): 2225-0719

ISSN (Electronic): 2310-8819

Publication date (Print): 28 March 2024

Publication date (Electronic): 8 February 2024

Volume: 12

Issue: 3

Pages: 316-326

Affiliations

[1 ]Department of Medicine, University of Connecticut Health Center, Farmington, CT, USA

[2 ]Division of Gastroenterology and Hepatology, University of Connecticut Health Center, Farmington, CT, USA

Author notes

[* ] Correspondence to: Christopher J. Costa, Department of Medicine, University of Connecticut Health Center, 263 Farmington Ave, Farmington, CT 06030, USA. ORCID: https://orcid.org/0000-0002-2648-0757. Tel: +1-941-250-4330, Fax: +1-860-679-6582, E-mail: chrcosta@ 123456uchc.edu

None to declare.

GYW has been an Editor-in-Chief of Journal of Clinical and Translational Hepatology since 2013. The other authors have no conflict of interests related to this publication.

CJC conducted extensive literature searches, drafted the manuscript, and created all figures and the table. GYW conceptualized, and edited the review. MTN and HV provided edits. All authors provided revisions and approved the final version.

Author information

Christopher J. Costa https://orcid.org/0000-0002-2648-0757

Article

Publisher ID: JCTH.2023.00563

DOI: 10.14218/JCTH.2023.00563

PMC ID: 10899874

PubMed ID: 38426197

SO-VID: 4008fc79-d0ed-48b2-9070-dcd19c01561e

License:

This is an Open Access article distributed under the terms of the Creative Commons Attribution-Noncommercial 4.0 International License (CC BY-NC 4.0), permitting all non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

History

Date received : 14 December 2023

Date revision received : 16 January 2024

Date accepted : 29 January 2024

Genetics of Gallstone Disease and Their Clinical Significance: A Narrative Review

Read this article at

Abstract

Graphical abstract

Related collections

Anthropocenes – Human, Inhuman, Posthuman

Most cited references 77

CRISPR-Cas9 Gene Editing for Sickle Cell Disease and β-Thalassemia

Effects of age, sex, and ethnicity on the association between apolipoprotein E genotype and Alzheimer disease. A meta-analysis. APOE and Alzheimer Disease Meta Analysis Consortium.

Gallstones.

Author and article information

Journal

Affiliations

Author notes

Author information

Article

History

Categories

Comments

Comment on this article

Similar content 272

Most referenced authors 992