Early-onset type 2 diabetes is associated with genetic variants of β-cell function in the Chinese Han population

To investigate the genetic factors contributing to early-onset type 2 diabetes (EOD) in the Chinese Hans populations.

For 2734 newly diagnosed type 2 diabetes patients and 4041 normal glycemic controls, 25 single nucleotide polymorphisms from 24 genomic loci linked to diabetes were successfully genotyped. Three genetic risk scores (GRSs) were constructed, including the weighted type 2 diabetes-related GRS (wT-GRS), the weighted β-cell function-related GRS (wB-GRS), and the weighted GRS constructed by risk alleles not related to β-cell function (wNB-GRS). For patients with diabetes, EOD, middle-age-onset type 2 diabetes (MOD), and late-onset type 2 diabetes (LOD) were defined by onset ages ≤40, 40 to 60, and ≥60 years, respectively.

From single marker analysis, different gene profiles were identified between EOD and LOD patients. EOD patients had greater wT-GRS and wB-GRS values than LOD patients. After adjustment for sex, elevated wT-GRS and wB-GRS values were significantly associated with an increased risk for EOD by 1.11- and 1.21-fold per allele (P = 1.69 × 10^-7 ; 6.07 × 10^-8 ). The wT-GRS and wNB-GRS were nominally related to an increased risk of LOD by 1.03-fold per allele (P = 1.03 × 10^-2 , 1.78 × 10^-2 ). In patients with diabetes, higher wT-GRS and wB-GRS were associated with younger onset age [wT-GRS: β (SE) = -0.0033(0.0016), P = 3.74 × 10^-2 ; wB-GRS: -0.0076(0.0028), 7.45 × 10^-3 ] and decreased insulinogenic index [wT-GRS: -0.0384(0.0098), 9.39 × 10^-5 ; wB-GRS: -0.0722(0.0176), 4.21 × 10^-5 ].

Our findings indicate a strong genetic predisposition for EOD, which can be mainly attributed to genetic variants linked to β-cell function, suggesting the β-cell dysfunction plays a key role in the pathogenesis of EOD in Chinese Han individuals.