Diabetes & Metabolism Journal

Original Article

Genetics
SLC30A8 Rare Variant Modify Contribution of Common Genetic and Lifestyle Factors toward Type 2 Diabetes Mellitus: Hye-Mi Jang, Mi Yeong Hwang, Yi Seul Park, Bong-Jo Kim, Young Jin Kim; Diabetes Metab J. 2026;50(2):385-395. Published online August 13, 2025; DOI: https://doi.org/10.4093/dmj.2024.0830

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Background
This study aimed to investigate the modifying effects of rare genetic variants on the risk of type 2 diabetes mellitus (T2DM) in the context of common genetic and lifestyle factors.
Methods
We conducted a comprehensive analysis of genetic and lifestyle factors associated with T2DM in a cohort of 146,284 Korean individuals. Among them, 4,603 individuals developed T2DM during the follow-up period of up to 17 years. We calculated a polygenic risk score (PRS) for T2DM and identified carriers of the rare allele I349F at SLC30A8. A Healthy Lifestyle Score (HLS) was also derived from physical activity, obesity, smoking, diet, and sodium intake levels. Using Cox proportional hazards models, we analyzed how PRS, HLS, and I349F influenced T2DM incidence.
Results
Results showed that high PRS and poor lifestyle were associated with increased risk. Remarkably, I349F carriers exhibited a lower T2DM prevalence (5.7% compared to 11.7% in non-carriers) and reduced the impact of high PRS from 23.18% to 12.70%. This trend was consistent across different HLS categories, with I349F carriers displaying a lower risk of T2DM.
Conclusion
The integration of common and rare genetic variants with lifestyle factors enhanced T2DM predictability in the Korean population. Our findings highlight the critical role of rare genetic variants in risk assessments and suggest that standard PRS and HLS metrics alone may be inadequate for predicting T2DM risk among carriers of such variants.

Citations

Citations to this article as recorded by

Personalised Nutrition in Obesity and Prediabetes: Do Genotypes Matter?
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Da-eun Lee, Yi Seul Park, Hye-Mi Jang, Bong-Jo Kim, Young Jin Kim, Sung-il Cho, Kyeezu Kim
BMC Medicine.2025;[Epub] CrossRef

Response

Response: Genome-Wide Association Study Identifies Two Novel Loci with Sex-Specific Effects for Type 2 Diabetes Mellitus and Glycemic Traits in a Korean Population (Diabetes Metab J 2014;38:375-87): Min Jin Go, Bong-Jo Kim; Diabetes Metab J. 2014;38(6):487-488. Published online December 15, 2014; DOI: https://doi.org/10.4093/dmj.2014.38.6.487

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Original Article

Genome-Wide Association Study Identifies Two Novel Loci with Sex-Specific Effects for Type 2 Diabetes Mellitus and Glycemic Traits in a Korean Population: Min Jin Go, Joo-Yeon Hwang, Tae-Joon Park, Young Jin Kim, Ji Hee Oh, Yeon-Jung Kim, Bok-Ghee Han, Bong-Jo Kim; Diabetes Metab J. 2014;38(5):375-387. Published online October 17, 2014; DOI: https://doi.org/10.4093/dmj.2014.38.5.375

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29 Web of Science
26 Crossref

Abstract PDF PubReader ePub

Background

Until recently, genome-wide association study (GWAS)-based findings have provided a substantial genetic contribution to type 2 diabetes mellitus (T2DM) or related glycemic traits. However, identification of allelic heterogeneity and population-specific genetic variants under consideration of potential confounding factors will be very valuable for clinical applicability. To identify novel susceptibility loci for T2DM and glycemic traits, we performed a two-stage genetic association study in a Korean population.

Methods

We performed a logistic analysis for T2DM, and the first discovery GWAS was analyzed for 1,042 cases and 2,943 controls recruited from a population-based cohort (KARE, n=8,842). The second stage, de novo replication analysis, was performed in 1,216 cases and 1,352 controls selected from an independent population-based cohort (Health 2, n=8,500). A multiple linear regression analysis for glycemic traits was further performed in a total of 14,232 nondiabetic individuals consisting of 7,696 GWAS and 6,536 replication study participants. A meta-analysis was performed on the combined results using effect size and standard errors estimated for stage 1 and 2, respectively.

Results

A combined meta-analysis for T2DM identified two new (rs11065756 and rs2074356) loci reaching genome-wide significance in CCDC63 and C12orf51 on the 12q24 region. In addition, these variants were significantly associated with fasting plasma glucose and homeostasis model assessment of β-cell function. Interestingly, two independent single nucleotide polymorphisms were associated with sex-specific stratification in this study.

Conclusion

Our study showed a strong association between T2DM and glycemic traits. We further observed that two novel loci with multiple diverse effects were highly specific to males. Taken together, these findings may provide additional insights into the clinical assessment or subclassification of disease risk in a Korean population.

Citations

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Letter: Genome-Wide Association Study Identifies Two Novel Loci with Sex-Specific Effects for Type 2 Diabetes Mellitus and Glycemic Traits in a Korean Population (Diabetes Metab J2014;38:375-87)
Soo Heon Kwak
Diabetes & Metabolism Journal.2014; 38(6): 484. CrossRef
Response: Genome-Wide Association Study Identifies Two Novel Loci with Sex-Specific Effects for Type 2 Diabetes Mellitus and Glycemic Traits in a Korean Population (Diabetes Metab J2014;38:375-87)
Min Jin Go, Bong-Jo Kim
Diabetes & Metabolism Journal.2014; 38(6): 487. CrossRef

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