Background: Type 2 diabetes mellitus (T2DM) has been shown to increase the risks of cognitive decline and dementia. Paired box gene 4 (PAX4), a transcription factor for beta cell development and function, has recently been implicated in pathways intersecting Alzheimer's disease and T2DM.
Objective: In this report, we evaluated the association of the ethnic-specific PAX4 R192H variant, a T2DM risk factor for East Asians which contributes to earlier diabetes onset, and cognitive function of Chinese T2DM patients.
Methods: 590 Chinese patients aged 45-86 from the SMART2D study were genotyped for PAX4 R192H variation using Illumina OmniExpress-24 Array. The Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) which had been validated in the Singapore population was administered to assess five cognitive domains: immediate memory, visuospatial/constructional, language, attention, and delayed memory. Multiple linear regression was used to assess the association of the R192H risk allele and cognitive domains.
Results: Patients with two PAX4 R192H risk alleles showed significantly lower attention index score (β= -8.46, 95% CI [-13.71, -3.21], p = 0.002) than patients with wild-type alleles after adjusting for age, gender, diabetes onset age, HbA1c, body-mass index, renal function, lipid profiles, systolic blood pressure, metformin usage, smoking history, education level, Geriatric Depression Scale score, and presence of APOEɛ4 allele.
Conclusion: Ethnic-specific R192H variation in PAX4 is associated with attention-specific cognitive impairment in Chinese with T2DM. Pending further validation studies, determining PAX4 R192H genotype may be helpful for early risk assessment of early-onset T2DM and cognitive impairment to improve diabetes care.
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The effects of transcription factor 7-like 2 rs7903146 and paired box 4 rs2233580 variants associated with type 2 diabetes on the therapeutic efficacy of hypoglycemic agents.
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Siriraj Center of Research Excellence for Diabetes and Obesity (SiCORE-DO), Research Department, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand.
Article Synopsis
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Ethnic-Specific Type 2 Diabetes Risk Factor PAX4 R192H Is Associated with Attention-Specific Cognitive Impairment in Chinese with Type 2 Diabetes.
J Alzheimers Dis
July 2022
Clinical Research Unit, Khoo Teck Puat Hospital (KTPH), Singapore.
Background: Type 2 diabetes mellitus (T2DM) has been shown to increase the risks of cognitive decline and dementia. Paired box gene 4 (PAX4), a transcription factor for beta cell development and function, has recently been implicated in pathways intersecting Alzheimer's disease and T2DM.
Objective: In this report, we evaluated the association of the ethnic-specific PAX4 R192H variant, a T2DM risk factor for East Asians which contributes to earlier diabetes onset, and cognitive function of Chinese T2DM patients.
Missense Variants in PAX4 Are Associated with Early-Onset Diabetes in Chinese.
Diabetes Ther
January 2021
Department of Endocrinology and Metabolism, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine (SJTUSM), Shanghai, 200025, China.
Introduction: East Asians are more susceptible to early-onset diabetes than Europeans and exhibit reduced insulin secretion at earlier stages. PAX4 plays a critical role in the development of β-cells. The dysfunction-missense variants PAX4 R192H and PAX4 R192S are common in East Asians but rare in Europeans.
View Article and Find Full Text PDFPAX4 R192H is associated with younger onset of Type 2 diabetes in East Asians in Singapore.
J Diabetes Complications
January 2019
Clinical Research Unit, Khoo Teck Puat Hospital (KTPH), Singapore; Diabetes Center, Khoo Teck Puat Hospital (KTPH), Singapore; Saw Swee Hock School of Public Health, National University of Singapore, Singapore. Electronic address:
Aims: Young-onset T2D (YT2D) is associated with a more fulminant course and greater propensity for diabetic complications. The association of PAX4 R192H (rs2233580) variation with YT2D was inconsistent partly because of its Asian-specificity and under-representation of Asians in international consortiums. Interestingly, in our preliminary YT2D (mean = 25 years old) cohort, the prevalence of PAX4 R192H variant was remarkably higher (21.
View Article and Find Full Text PDFPAX4 R192H and P321H polymorphisms in type 2 diabetes and their functional defects.
J Hum Genet
November 2016
Division of Endocrinology and Metabolism, Department of Medicine, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand.
We have previously identified PAX4 mutations causing MODY9 and a recent genome-wide association study reported a susceptibility locus of type 2 diabetes (T2D) near PAX4. In this study, we aim to investigate the association between PAX4 polymorphisms and T2D in Thai patients and examine functions of PAX4 variant proteins. PAX4 rs2233580 (R192H) and rs712701 (P321H) were genotyped in 746 patients with T2D and 562 healthy normal control subjects by PCR and restriction-fragment length polymorphism method.
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