MASLD의 유전체 지형 정의
MASLD의 유전체적 경관 정의 (DEFINING THE GENOMIC LANDSCAPE OF METABOLIC STEATOTIC LIVER DISEASE)
The Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD) is a leading cause of chronic liver disease globally, with a prevalence exceeding 30% in the population. MASLD is strictly associated with insulin resistance and cardiometabolic conditions, and in 20-30% of cases, it can progress to steatohepatitis (MASH), which is characterized by progressive liver damage and inflammation. In patients at higher risk, the disease can lead to the onset of advanced fibrosis, cirrhosis, and hepatocellular carcinoma (HCC). One of the main problems in the clinical management of MASLD is the absence of specific risk biomarkers and the lack of effective treatments, especially for patients with advanced-stage disease.
MASLD has a well-documented and enormous genetic component, with studies having identified several common variants associated with this pathology, such as those in the PNPLA3, TM6SF2, and MBOAT7 genes. However, these variants identified so far only explain a small part of MASLD's heritability, suggesting the contribution of rare loss-of-function (LoF) variants as well. Furthermore, scientific evidence indicates that the accumulation of somatic variants, both in hepatocytes and myeloid cells, could also play a key role in MASLD progression. In particular, clonal hematopoiesis of indeterminate potential (CHIP), which is a condition characterized by the presence of hematopoietic clones with somatic mutations often associated with leukemia and cardiovascular diseases, might favor the onset of hepatocellular carcinoma. However, the evidence available to date is still limited and requires further investigation and studies on larger cohorts.
The current study therefore aims to deepen this aspect through the analysis of the genetic profile using a Whole-Genome Sequencing (WGS) approach. DNA samples from peripheral blood from patients with advanced MASLD and peripheral blood DNA samples from controls presenting various associated metabolic risk factors will be sequenced.
In addition, 80 liver tissue samples from patients with advanced MASLD will also be sequenced to identify specific somatic mutations. The expected results from this study include the identification of new genetic variants associated with MASLD progression, the improvement of risk stratification through the development of polygenic risk scores, and the identification of potential therapeutic targets. This study represents a fundamental step for understanding the biology of MASLD and could have important clinical implications for disease management.
연구 개요
상태
연구 유형
등록 (실제)
단계
- 해당 없음
연락처 및 위치
연구 장소
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Milano
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Milan, Milano, 이탈리아, 20122
- Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico - Istituto di Ricovero e Cura a Carattere Scientifico di natura pubblica
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참여기준
자격 기준
공부할 수 있는 나이
건강한 자원 봉사자를 받아들입니다
연구 대상 성별
설명
Inclusion Criteria:
Specific Inclusion Criteria for Patients with Advanced MASLD:
- Patients with advanced MASLD defined as liver fibrosis ≥2 and/or the development of HCC (Hepatocellular Carcinoma);
- Patients enrolled in the context of the SERENA study and, where applicable, also in the context of the REASON study;
- Liver biopsy for suspected Non-Alcoholic Steatohepatitis (NASH) at the time of diagnosis;
- Cholecystectomies;
- Age [40-70 years];
- Patients who have signed the informed consent form.
Specific Inclusion Criteria for the Control Group:
Blood donors participating in the Liver Bible study aged between 40 and 70 years who are overweight or obese and have at least two of the following risk factors:
- Impaired fasting glucose or Diabetes Mellitus
- Dyslipidemia
- Arterial hypertension.
Exclusion Criteria:
Specific exclusion Criteria for Patients with Advanced MASLD:
- Positivity for chronic viral hepatitis (HCV-RNA and/or HBsAg);
- Positivity for other liver diseases such as autoimmune and viral hepatitis (Hepatitis B and C), hereditary hemochromatosis, alpha-1-antitrypsin deficiency, or Wilson's disease.
Specific Exclusion Criteria for the Control Group:
Subjects with chronic degenerative diseases will be excluded, with the exception of well-controlled hypertension and Type 2 Diabetes Mellitus that does not require pharmacological therapy (as is already standard practice for blood donation eligibility). Also excluded are donors aged > 65 and < 40 years.
공부 계획
연구는 어떻게 설계됩니까?
디자인 세부사항
- 주 목적: 방지
- 할당: 해당 없음
- 중재 모델: 단일 그룹 할당
- 마스킹: 없음(오픈 라벨)
무기와 개입
참가자 그룹 / 팔 |
개입 / 치료 |
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실험적: Advanced MASLD Patients and Metabolic Controls
This study aims to identify inherited genetic variants and somatic mutations associated with the progression of advanced Metabolic Dysfunction-Associated Steatotic Liver Disease MASLD.The research utilizes two distinct and extensively characterized cohorts for Whole-Genome Sequencing WGS analysis:
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The focusing is the attention on the genetic and somatic variants involved in its progression toward advanced fibrosis and hepatocellular carcinoma. Through Whole-Genome Sequencing WGS of 800 patients with advanced MASLD, 80 liver tissue samples, and 2000 controls, the study aims to:
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연구는 무엇을 측정합니까?
주요 결과 측정
결과 측정 |
측정값 설명 |
기간 |
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Identifying Genetic Risk for Advanced MASLD
기간: 11 months
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The study's outcome measures are defined by two distinct, primary endpoints. The first is the Number of Genetic Variants Associated with Advanced MASLD, reported as the total count of genetic variants (germline and/o somatic) exhibiting a statistically significant association with the risk of developing advanced Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD), defined as fibrosis ≥ 2 and/or hepatocellular carcinoma. The unit of measure for this outcome is Count (Number of variants). The second measure is the Odds Ratio (OR) for Association Between Germline Variants and Advanced MASLD, calculated by comparing the presence of specific germline variants in cases versus controls to determine the strength of their association with advanced MASLD. |
11 months
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2차 결과 측정
결과 측정 |
측정값 설명 |
기간 |
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Mechanisms, Risk Stratification, and Therapy
기간: 11 months
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This study aims to identify inherited genetic variants and somatic mutations associated with the progression of Advanced Metabolic Dysfunction-Associated Steatotic Liver Disease MASLD), utilizing two distinct and extensively characterized cohorts for Whole-Genome Sequencing (WGS) analysis:
The study's goals are to:
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11 months
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공동 작업자 및 조사자
연구 기록 날짜
연구 주요 날짜
연구 시작 (실제)
기본 완료 (실제)
연구 완료 (실제)
연구 등록 날짜
최초 제출
QC 기준을 충족하는 최초 제출
처음 게시됨 (실제)
연구 기록 업데이트
마지막 업데이트 게시됨 (실제)
QC 기준을 충족하는 마지막 업데이트 제출
마지막으로 확인됨
추가 정보
이 연구와 관련된 용어
추가 관련 MeSH 약관
기타 연구 ID 번호
- DETECTIVE
약물 및 장치 정보, 연구 문서
미국 FDA 규제 의약품 연구
미국 FDA 규제 기기 제품 연구
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