Diabetes Metab J.  2022 Nov;46(6):879-889. 10.4093/dmj.2021.0265.

Sex Differences in the Effects of CDKAL1 Variants on Glycemic Control in Diabetic Patients: Findings from the Korean Genome and Epidemiology Study

• Lee HA
• Park H
• Hong YS

• KMID: 2536146
• DOI: http://doi.org/10.4093/dmj.2021.0265

Abstract

Background
Using long-term data from the Korean Genome and Epidemiology Study, we defined poor glycemic control and investigated possible risk factors, including variants related to type 2 diabetes mellitus (T2DM). In addition, we evaluated interaction effects among risk factors for poor glycemic control.
Methods
Among 436 subjects with newly diagnosed diabetes, poor glycemic control was defined based on glycosylated hemoglobin trajectory patterns by group-based trajectory modeling. For the variants related to T2DM, genetic risk scores (GRSs) were calculated and divided into quartiles. Risk factors for poor glycemic control were assessed using a logistic regression model.
Results
Of the subjects, 43% were in the poor-glycemic-control group. Body mass index (BMI) and triglyceride (TG) were associated with poor glycemic control. The risk for poor glycemic control increased by 11.0% per 1 kg/m² increase in BMI and by 3.0% per 10 mg/dL increase in TG. The risk for GRS with poor glycemic control was sex-dependent (P_interaction=0.07), and a relationship by GRS quartiles was found in females but not in males. Moreover, the interaction effect was found to be significant on both additive and multiplicative scales. The interaction effect was evident in the variants of cyclin-dependent kinase 5 regulatory subunit-associated protein 1-like (CDKAL1).
Conclusion
Females with risk alleles of variants in CDKAL1 associated with T2DM had a higher risk for poor glycemic control than males.

Keyword

Diabetes mellitus; Gene-environment interaction; Glycemic control; Sex characteristics

Figure

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  Fig. 1. Trajectories of glycosylated hemoglobin (HbA1c, %) after diabetes diagnosis. Trajectory patterns were identified using group-based trajectory modeling. Solid lines represent estimates and bars represent 95% confidence intervals. Dashed red line indicates that the target HbA1c level was 6.5%.

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  Fig. 2. Changes in average glycosylated hemoglobin (HbA1c, %) after diabetes diagnosis according to single nucleotide polymorphisms in CDKAL1 by sex. (A) rs7754840 of CDKAL1 in male. (B) rs7754840 of CDKAL1 in female. (C) rs10440833 of CDKAL1 in male. (D) rs10440833 of CDKAL1 in female. Values are least-squared means and 95% confidence intervals. Estimates were obtained using a mixed model assuming a random intercept with a compound symmetric structure. The model included genotypes, follow-up time, and interaction between genotypes and follow-up time, age at diagnosis of diabetes, and body mass index and triglycerides as time-varying covariates. In linkage disequilibrium, r2 of rs7754840 with the other four variants (rs4712523, rs4712524, rs9295474, and rs10946398) was 1.0, while the r2 value with rs10440833 was 0.8 (data not shown). Therefore, only the results for rs7754840 and rs10440833 are presented. MM, major-allele homozygotes; Mm, heterozygotes; mm, minor-allele homozygotes.

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