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

Abstract

Aims:To investigate the genetic factors contributing to early-onset type 2 diabetes (EOD) in the Chinese Hans populations. Materials and methods: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.Results: 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 ]. Conclusion: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.

Impact of Genetic Factors on the Age of Onset for Type 2 Diabetes Mellitus in Addition to the Conventional Risk Factors

“…Iwata M. et al [43] constructed GRS using 14 SNPs and evaluated its association with the early onset of T2DM in the Japanese population. The same result was observed by Kong X. et al [31] based on 24 SNPs in the Chinese. A study from pooled data of the Framingham Offspring Study which examined GRS constructed from 40 SNPs on individuals below or above 50 years of age witnessed that the risk per risk allele was higher (more than double) in individuals below 50 years than in people above 50 years of age [60].…”

“…Over the last two decades, several single nucleotide polymorphisms (SNPs) have been shown to be associated with the development of EOT2DM [21][22][23][24][25][26][27][28][29][30]. The majority of these SNPs exert their effect on disease risk through deficient insulin secretion [31].…”

“…By identifying these genetically highrisk individuals, it is possible to develop a cost-effective targeted prevention program for EOT2DM. So far only a limited number of studies have examined the effect of genetic factors (such as SNPs) on the age of development of T2DM, and most of these have been studied in Asian, as Chinese Han, Japanese and Taiwanese populations [31,[43][44][45]. Although in a genome-wide search for type 2 diabetes-related traits in a group of people with French ancestry evidence for a susceptibility locus for diabetes and impaired glucose tolerance with early onset (at age < 46 years) on chromosome 3q27-qter was provided [46], we have little knowledge (restricted to diabetics in Tayside, Scotland) on European populations [47].…”

Association of the JAZF1 Variant in Adults With a Parental History of Type 2 Diabetes Mellitus In Pakistan

“…The role of pancreatic beta-cell function has not been demonstrated yet. However, one must hypothesize that the JAZF1 variant (rs864745) also affects betacell mass and function [24][25][26]. Kobiita et al conducted a study regarding the role of JAZF1 in the homeostatic control of ribosome biogenesis and function in metabolic stress.…”

<p>Type 2 Diabetes-Associated Genetic Polymorphisms as Potential Disease Predictors</p>

“…[6][7][8] The development of genetic risk scores using combined analysis of loci has significantly contributed to predicting the incidence of T2DM. [9][10][11] Therefore, it is possible to facilitate early diagnosis and determine preventative strategies to reduce the incidence of the disease. [12][13][14][15] T2DM has a strong genetic basis, and individuals with a first-degree family history are at increased risk of developing the disease, and this risk is increased twofold if both parents have diabetes.…”