We appreciate the commentary by Hasebe and Su (1) related to our recent publication in Diabetes Care (2).
We agree that maternal glycemia in pregnancy partly reflects the mother’s type 2 diabetes (T2D) genetic risk and that offspring genetic risk of T2D is related to maternal T2D genetic risk. We believe this makes our observation that both maternal glycemia and offspring genetic risk score for T2D (T2D-GRS) are associated with risk of dysglycemia in 11- to 14-year-old children even more striking. We also agree that P = 0.06 for interaction between gestational diabetes mellitus (GDM) and high T2D-GRS (≥75th percentile) suggests more than additive associations for risk of dysglycemia in youth, but we preferred to remain prudent in our interpretation. Moreover, power was potentially limited to detect an interaction in this cohort. However, we believe that adjusting for maternal T2D-GRS would not be appropriate in the context of our main research question, as it would eliminate ∼50% of the variance of the child’s T2D-GRS and part of the “indirect maternal genetic effect” mediated via in utero exposure to hyperglycemia. Structural equation modeling can be used to untangle indirect maternal genetic from fetal genetic effects (3), but that was not our aim. Our goal was to provide a potential future clinical framework in which knowing a child’s genetic risk and in utero GDM exposure status would have valuable predictive ability early in life and allow early implementation of preventative interventions.
Hasebe and Su’s point about using family history of diabetes as a simpler clinical risk factor is interesting. In the same HAPO (Hyperglycemia and Adverse Pregnancy Outcome study) cohort of our original publication (2), 15% of offspring who were exposed to GDM and had a family history of diabetes (self-reported mother’s first-degree relatives) had impaired glucose tolerance or T2D compared with ∼6% of offspring who had neither risk factor. Thus, the overall proportions were similar to our estimates based on high genetic risk (≥75th percentile for T2D-GRS) and GDM exposure. However, many prior publications evaluating T2D-GRS (mostly in adults) have shown that GRS predict risk of T2D beyond family history (4). A recent multiancestry study found that T2D-GRS offers stronger prediction in younger individuals (supporting our rationale for our analyses in youth) and in people with a positive history of diabetes in particular ancestries (5). Future studies should integrate both T2D-GRS and family history into clinical prediction models of T2D, especially in younger populations.
Hasebe and Su suggested that our analyses be adjusted for pubertal status as a precision variable given the potential influence of puberty on insulin resistance and glucose regulation. In previous work within the HAPO Follow-Up Study (HAPO-FUS), there was no appreciable difference in model parameters when adjusting for both age and Tanner stage versus adjusting for age alone (6). Moreover, Tanner stage was missing for a substantial number of HAPO offspring, with systematic differences in missingness patterns across field centers (nonrandom missingness) given variable settings and acceptability across centers.
Article Information
Acknowledgments. The authors thank all the HAPO and HAPO-FUS participants for their time and involvement in research.
The study funder was not involved in the design of the study or the collection, analysis, and interpretation of data or writing the report and did not impose any restrictions regarding publication of the report.
Duality of Interest. No potential conflicts of interest relevant to this article were reported.
Handling Editors. The journal editor responsible for overseeing the review of the manuscript was Steven E. Kahn.
Funding Statement
This study was funded by National Institutes of Health grants DK095963, DK117491, HD34242, HD34243, HG-004415, and R03CA211318. A.C.D. was supported by Ruth L. Kirschstein National Research Service Award T32 DK007169 from the National Institute of Diabetes and Digestive and Kidney Diseases.
References
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