遺伝学と単細胞の表遺伝学による1型糖尿病リスクの解釈

Joshua Chiou^1,2, Ryan J Geusz³, Mei-Lin Okino⁴

¹Biomedical Sciences Graduate Program, University of California San Diego, La Jolla, CA, USA. joshua.chiou@pfizer.com.

Nature

|May 20, 2021

まとめ

1型糖尿病 (T1D) に関する遺伝的変異は,臓細胞で活性な調節要素で発見されています. この研究により臓の外分細胞が

科学分野:

ゲノミクスとエピジェノミクス
免疫学と内分泌学

背景:

全ゲノム関連研究 (GWAS) は,タイプ1糖尿病 (T1D) のような複雑な疾患の多くの非コーディング遺伝的リスク変異を特定します.
これらの変異体の機能的影響を理解するには,疾患に関連する細胞の遺伝子調節の詳細な地図が必要です.

研究の目的:

T1Dの大規模GWASデータを単細胞のエピジェノミックプロファイリングと統合する.
臓と免疫細胞で活動する候補シス調節要素 (cCREs) を特定する.
T1Dの病原性における外分臓の役割を調査する.

主な方法:

T1DのGWASを520,580のサンプルで実施した.
臓および外周血液単核細胞からの131,554の核で,配列化 (snATAC-seq) によるトランポゼーゼアクセシブルクロマチンの単核測定を行った.
強化されたcCREsを特定するために, snATAC-seqデータと統合されたGWAS結果.

主要な成果:

T1Dリスクの変種は,T細胞および外分臓細胞 (アシナおよびダクト細胞) に活性化しているcCREsで濃縮された.
いくつかのT1Dリスク変異は,エクソクリン特異の遺伝子発現に関連したエクソクリン特異のcCREsと重複した.
CFTRロカスでは,T1Dリスク変異体 (rs7795896) が管細胞におけるCFTR発現を調節し,リスクアレルは強化剤の活性とCFTR発現を低下させた.

結論:

外分臓はT1Dの病原性において重要な役割を果たします.
単細胞エピジェノミクスと大規模GWASは複雑な疾患の細胞起源を明らかにする強力なアプローチです
管細胞の特定の調節要素は,CFTR調節を通してT1Dリスクに影響を与えます.

さらに関連する動画

11:34

Single-cell RNA Sequencing and Analysis of Human Pancreatic Islets

Published on: July 18, 2019

16.7K

10:05

Single-cell Transcriptomic Analyses of Mouse Pancreatic Endocrine Cells

Published on: September 30, 2018

11.3K

関連する概念動画

01:22

Diabetes Mellitus: Type 2 and Gestational

3.7K

Type 2 diabetes, characterized by insulin resistance, arises when the insulin receptors on cells lose responsiveness to insulin, diminishing the cell's capacity to take up glucose, resulting in elevated blood glucose levels. To receive a diagnosis of Type 2 diabetes, a series of blood glucose tests are necessary to assess whether the blood glucose falls within normal parameters. If the result is out of the normal range, a patient may be diagnosed as prediabetic or diabetic, depending on the...

3.7K

01:22

Diabetes Mellitus: Overview and Type I Subtype

4.1K

Diabetes mellitus is a chronic metabolic disorder characterized by high blood glucose levels due to inadequate insulin production, insulin resistance, or both. The condition affects millions worldwide and can significantly impact their health and quality of life.
Type 1 diabetes is an autoimmune disease in which the immune system mistakenly attacks and destroys the insulin-producing beta cells in the pancreas. As a result, the body is unable to produce sufficient insulin, and individuals with...

4.1K

01:28

Human Genetics

959

Human genetics provides a profound framework for understanding the interplay between genetic predispositions and human psychology. At the heart of this discipline lies the study of how genes influence physical traits, behaviors, and susceptibility to diseases. Each person carries a unique genetic code that subtly or significantly shapes their psychological and behavioral landscape.
The complex relationship between genetics and psychology is observable through common biological components such...

959

01:36

Carbohydrate Metabolism

12.8K

Carbohydrates are polymers composed of molecules containing atoms of carbon, hydrogen and oxygen. One gram of carbohydrate can provide four kilo-calories of energy, which makes it the most efficient instant energy source.
Starch accounts for approximately 60% of the carbohydrates consumed by humans. Since amylase enzymes cannot function in the stomach's acidic environment, starch can only be digested in the mouth and small intestine. Simple sugars are found naturally in milk and fruits in...

12.8K

01:11

Genome-wide Association Studies-GWAS

14.8K

Genome-wide association studies or GWAS are used to identify whether common SNPs are associated with certain diseases. Suppose specific SNPs are more frequently observed in individuals with a particular disease than those without the disease. In that case, those SNPs are said to be associated with the disease. Chi-square analysis is performed to check the probability of the allele likely to be associated with the disease.
GWAS does not require the identification of the target gene involved in...

14.8K

01:20

Pathophysiology of Diabetes

2.3K

Diabetes mellitus is a chronic metabolic disorder characterized by hyperglycemia. The four categories of diabetes are type 1 diabetes, type 2 diabetes, other specific types of diabetes, and gestational diabetes.
Type 1 diabetes is characterized by autoimmune-mediated destruction of pancreatic β cells, with environmental factors potentially triggering this process in genetically susceptible individuals. Despite many not having a family history, certain genes increase susceptibility,...