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Genetic Modifiers of Cystic Fibrosis-Related Diabetes Have Extensive Overlap With Type 2 Diabetes and Related Traits.

ABSTRACT: CONTEXT:Individuals with cystic fibrosis (CF) develop a distinct form of diabetes characterized by ?-cell dysfunction and islet amyloid accumulation similar to type 2 diabetes (T2D), but generally have normal insulin sensitivity. CF-related diabetes (CFRD) risk is determined by both CFTR, the gene responsible for CF, and other genetic variants. OBJECTIVE:To identify genetic modifiers of CFRD and determine the genetic overlap with other types of diabetes. DESIGN AND PATIENTS:A genome-wide association study was conducted for CFRD onset on 5740 individuals with CF. Weighted polygenic risk scores (PRSs) for type 1 diabetes (T1D), T2D, and diabetes endophenotypes were tested for association with CFRD. RESULTS:Genome-wide significance was obtained for variants at a novel locus (PTMA) and 2 known CFRD genetic modifiers (TCF7L2 and SLC26A9). PTMA and SLC26A9 variants were CF-specific; TCF7L2 variants also associated with T2D. CFRD was strongly associated with PRSs for T2D, insulin secretion, postchallenge glucose concentration, and fasting plasma glucose, and less strongly with T1D PRSs. CFRD was inconsistently associated with PRSs for insulin sensitivity and was not associated with a PRS for islet autoimmunity. A CFRD PRS comprising variants selected from these PRSs (with a false discovery rate < 0.1) and the genome-wide significant variants was associated with CFRD in a replication population. CONCLUSIONS:CFRD and T2D have more etiologic and mechanistic overlap than previously known, aligning along pathways involving ?-cell function rather than insulin sensitivity. Two CFRD risk loci are unrelated to T2D and may affect multiple aspects of CF. An 18-variant PRS stratifies risk of CFRD in an independent population.

SUBMITTER: Aksit MA

PROVIDER: S-EPMC7236628 | biostudies-literature | 2020 May

REPOSITORIES: biostudies-literature

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Genetic Modifiers of Cystic Fibrosis-Related Diabetes Have Extensive Overlap With Type 2 Diabetes and Related Traits.

Aksit Melis A MA Pace Rhonda G RG Vecchio-Pagán Briana B Ling Hua H Rommens Johanna M JM Boelle Pierre-Yves PY Guillot Loic L Raraigh Karen S KS Pugh Elizabeth E Zhang Peng P Strug Lisa J LJ Drumm Mitch L ML Knowles Michael R MR Cutting Garry R GR Corvol Harriet H Blackman Scott M SM

The Journal of clinical endocrinology and metabolism 20200501 5

<h4>Context</h4>Individuals with cystic fibrosis (CF) develop a distinct form of diabetes characterized by β-cell dysfunction and islet amyloid accumulation similar to type 2 diabetes (T2D), but generally have normal insulin sensitivity. CF-related diabetes (CFRD) risk is determined by both CFTR, the gene responsible for CF, and other genetic variants.<h4>Objective</h4>To identify genetic modifiers of CFRD and determine the genetic overlap with other types of diabetes.<h4>Design and patients</h4 ...[more]

PMID: 31697830

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Project description:ContextA subset (approximately 3%-5%) of patients with cystic fibrosis (CF) develops severe liver disease with portal hypertension.ObjectiveTo assess whether any of 9 polymorphisms in 5 candidate genes (alpha(1)-antitrypsin or alpha(1)-antiprotease [SERPINA1], angiotensin-converting enzyme [ACE], glutathione S-transferase [GSTP1], mannose-binding lectin 2 [MBL2], and transforming growth factor beta1 [TGFB1]) are associated with severe liver disease in patients with CF.Design, setting, and participantsTwo-stage case-control study enrolling patients with CF and severe liver disease with portal hypertension (CFLD) from 63 CF centers in the United States as well as 32 in Canada and 18 outside of North America, with the University of North Carolina at Chapel Hill as the coordinating site. In the initial study, 124 patients with CFLD (enrolled January 1999-December 2004) and 843 control patients without CFLD were studied by genotyping 9 polymorphisms in 5 genes previously studied as modifiers of liver disease in CF. In the second stage, the SERPINA1 Z allele and TGFB1 codon 10 genotype were tested in an additional 136 patients with CFLD (enrolled January 2005-February 2007) and 1088 with no CFLD.Main outcome measuresDifferences in distribution of genotypes in patients with CFLD vs patients without CFLD.ResultsThe initial study showed CFLD to be associated with the SERPINA1 Z allele (odds ratio [OR], 4.72; 95% confidence interval [CI], 2.31-9.61; P = 3.3 x 10(-6)) and with TGFB1 codon 10 CC genotype (OR, 1.53; 95% CI, 1.16-2.03; P = 2.8 x 10(-3)). In the replication study, CFLD was associated with the SERPINA1 Z allele (OR, 3.42; 95% CI, 1.54-7.59; P = 1.4 x 10(-3)) but not with TGFB1 codon 10. A combined analysis of the initial and replication studies by logistic regression showed CFLD to be associated with SERPINA1 Z allele (OR, 5.04; 95% CI, 2.88-8.83; P = 1.5 x 10(-8)).ConclusionsThe SERPINA1 Z allele is a risk factor for liver disease in CF. Patients who carry the Z allele are at greater risk (OR, approximately 5) of developing severe liver disease with portal hypertension.

Dataset Information

Genetic Modifiers of Cystic Fibrosis-Related Diabetes Have Extensive Overlap With Type 2 Diabetes and Related Traits.

Publications

Genetic Modifiers of Cystic Fibrosis-Related Diabetes Have Extensive Overlap With Type 2 Diabetes and Related Traits.

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