Study calls for monogenic screening in type 1 diabetes

2019 07 04 00 23 3413 Pancreas New 400

Young people with type 1 diabetes should undergo genetic screening for monogenic variants of the disease, according to a Joslin Diabetes Center study of patients who had been dependent on insulin for more than 50 years. Results were published on July 2 in the Journal of Clinical Investigation.

The study of 1,018 people with type 1 diabetes (T1D) and 68 pancreases examined postmortem found that some had monogenic forms of the disease, meaning they had at least one gene mutation that affects insulin secretion. Some of these patients might respond to treatment with oral drugs and therefore be able to do without insulin injections.

Of the total patient population, 27.5% had at least one rare genetic variant in monogenic diabetes genes, Joslin endocrinologist Dr. Marc Gregory Yu and colleagues reported. In addition, 7.9% had variants that met the rare exome variant ensemble learner (REVEL) threshold for pathogenicity. As for the 68 pancreases studied postmortem, 11 had monogenic diabetes variants.

The researchers also found that all participants had insulin-positive beta cells, even though they had been dependent on insulin for decades.

The data suggest that people with type 1 diabetes should be tested for monogenic variants, as this has important implications for treatment; currently, they are screened for human leukocyte antigen (HLA) alleles but do not undergo monogenic screening. Yu et al reported that many who were HLA-positive also had monogenic diabetes variants, which suggests the value of genetic testing for people clinically diagnosed with type 1 diabetes.

In a statement, Joslin Chief Scientific Officer Dr. George King said the center advises monogenic diabetes screening for all people with the disease younger than age 18.

How testing was done

The monogenic analysis was part of a larger study -- the Joslin Medalist Study -- following people with long-term type 1 diabetes over a median of four years and evaluating their beta-cell function. Research was funded by the Dianne Nunnally Hoppes Fund, the Beatson Pledge Fund, and the U.S. National Institute of Diabetes and Digestive and Kidney Diseases, part of the National Institutes of Health.

Investigators observed detectable levels of C-peptide in serum tests and beta cells, which "strongly suggests beta-cell regeneration may be possible," Yu and colleagues wrote.

"These findings from the Medalist Study clearly establish that residual beta cells are present in most, if not all, people with [type 1 diabetes] regardless of disease duration or measurable C-peptide levels," they wrote.

The group noted that this is the first study involving genotyping for monogenic diabetes genes in a large cohort of people who had the disease for a long time. Monogenic genetic analyses were done on genomic DNA using the SureSelect capture assay (Agilent Technologies), and samples were fragmented with the S2 ultrasonicator (Covaris) and prepared with the HiSeq 2500 high-throughput sequencing system (Illumina).

The investigators tested the patients for 29 known genes:

  • 13 maturity-onset diabetes of the young (MODY) genes: HNF4A, GCK, HNF1A, PDX1, HNF1B, NEUROD1, KLF11, CEL, PAX4, INS, BLK, ABCC8, and KCNJ11
  • 16 neonatal diabetes/familial partial lipodystrophy/familial diabetes genes: PTF1A, NEUROG3, RFX6, EIF2AK3, FOXP3, GLIS3, SLC19A2, SLC2A2, IER3IP1, ZFP57, WFS1, GATA6, GATA4, LMNA, PPARG, and APPL1

Next steps include a trial of oral diabetes drugs in older patients with mutated monogenic forms of diabetes, according to the Joslin researchers.

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