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Genetic Modifiers of Cystic Fibrosis-Related Diabetes Have Extensive Overlap With Type 2 Diabetes and Related Traits
- Source :
- J Clin Endocrinol Metab
- Publication Year :
- 2019
- Publisher :
- The Endocrine Society, 2019.
-
Abstract
- Context 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. 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 β-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.
- Subjects :
- Adult
Male
medicine.medical_specialty
endocrine system diseases
Adolescent
Cystic Fibrosis
Endocrinology, Diabetes and Metabolism
Clinical Biochemistry
Population
Cystic fibrosis-related diabetes
030209 endocrinology & metabolism
Genome-wide association study
Type 2 diabetes
Bioinformatics
Biochemistry
Cohort Studies
Young Adult
03 medical and health sciences
Diabetes mellitus genetics
Quantitative Trait, Heritable
0302 clinical medicine
Endocrinology
Risk Factors
Internal medicine
Diabetes mellitus
Diabetes Mellitus
medicine
Humans
Genetic Predisposition to Disease
Child
education
030304 developmental biology
Clinical Research Article
0303 health sciences
Type 1 diabetes
education.field_of_study
Genes, Modifier
business.industry
Biochemistry (medical)
nutritional and metabolic diseases
medicine.disease
Diabetes Mellitus, Type 2
Female
France
business
TCF7L2
Genome-Wide Association Study
Subjects
Details
- ISSN :
- 19457197 and 0021972X
- Volume :
- 105
- Database :
- OpenAIRE
- Journal :
- The Journal of Clinical Endocrinology & Metabolism
- Accession number :
- edsair.doi.dedup.....20fa8ae65685a83c566a25a19414afe8