22q11.2 microdeletion and increased risk for type 2 diabetes

Abstract

Background: The 22q11.2 microdeletion is the pathogenic copy number variation (CNV) associated with 22q11.2 deletion syndrome (22q11.2DS, formerly known as DiGeorge syndrome). Familiar endocrinological manifestations include hypoparathyroidism and hypothyroidism, with recent elucidation of elevated risk for obesity in adults. In this study, we aimed to determine whether adults with 22q11.2DS have an increased risk of developing type 2 diabetes (T2D).

Methods: We studied the effect of the 22q11.2 microdeletion on risk for T2D, defined by history and glycosylated hemoglobin (HbA1c), using weighted survey data from the adult Canadian population (based on n = 11,874) and from a clinical cohort of adults with 22q11.2DS (n = 314), aged 17-69 years. Binomial logistic regression models accounted for age, sex, non-European ethnicity, family history of T2D, obesity, and antipsychotic medication use.

Findings: The 22q11.2 microdeletion was a significant independent risk factor for T2D (OR 2·44, 95% CI 1·39-4·31), accounting for other factors (p < 0·0001). All factors except sex were also significant within 22q11.2DS. The median age at diagnosis of T2D was significantly younger in 22q11.2DS than in the Canadian population sample (32 vs 50 years, p < 0·0001). In adults without T2D, HbA1c was significantly higher in 22q11.2DS than the population (p = 0·042), after accounting for younger age of the 22q11.2DS group.

Interpretation: The results support the 22q11.2 microdeletion as a novel independent risk factor and potential model for early onset T2D. The findings complement emerging evidence that rare CNVs may contribute to risk for T2D. The results have implications for precision medicine and research into the underlying pathogenesis of T2D.

Keywords: Diabetes; Early diagnosis; Genetics; Genotype; Molecular diagnostics; Risk; Structural variant.

Fig. 1

Age at diagnosis of type 2 diabetes in adults with 22q11.2 deletion syndrome compared to the Canadian population. Plotted are prevalence ratios (PR, as %, bar graphs: red, 22q11.2DS; blue, Canadian population) and 95% confidence intervals (CI, vertical lines) per age group for age at diagnosis of type 2 diabetes (T2D). Asterisks (*) indicate a statistically significant difference between the two groups. The proportion of those diagnosed with type 2 diabetes for the 22q11.2DS group was significantly greater in the 25–44 year age group (PR=2·38, 95% CI=1·39–4·08), and significantly lower in the 45–64 year age group (PR=0·54, 95% CI=0·31–0·97), than in the population. Of the two individuals in the 22q11.2DS group in the 65–69 year age range, neither had T2D diagnosed. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)

Fig. 2

HbA1c values by age in adults without type 2 diabetes, comparing results for 22q11.2 microdeletion and population-based samples. The regressions of HbA1c values by age for individuals without type 2 diabetes aged 17–69 years are represented by solid lines: for those in the 22q11.2DS sample (red), and in the Canadian population-based sample (blue); the respective 95% confidence intervals (CIs) are represented by lighter coloured shaded areas around these solid lines (F_{(1, 11,478)} = 4·15, p = 0·042). The 95% CIs for each of the two samples (shaded areas) appear to diverge at about age 35 years. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)

Fig. 3

Proposed model of increased risk for type 2 diabetes in individuals with a 22q11.2 microdeletion. Diagram illustrating the proposed relationships between the 22q11.2 deletion and risk of type 2 diabetes, including clinical variables with known enrichment in individuals with 22q11.2DS. The direction of proposed relationships is indicated by arrows. Orange arrows (solid, significant findings) indicate evidence derived from the current study. Green dashed arrows indicate relationships suggested by previous studies of 22q11.2DS; blue dashed arrows indicate evidence from previous studies of T2D risk factors in the general population [5,6,11,21]. The green and blue dashed lines unaccompanied by orange lines indicate possible mediation effects that the current study did not investigate. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)