Ethnic-Specific Type 2 Diabetes Risk Factor PAX4 R192H Is Associated with Attention-Specific Cognitive Impairment in Chinese with Type 2 Diabetes

Article type: Research Article

Authors: Ang, Su Fen^a | Low, Serena^a | Ng, Tze Pin^b | Tan, Clara S.H.^a | Ang, Keven^a | Lim, Ziliang^c | Tang, Wern Ee^c | Subramaniam, Tavintharan^d | Sum, Chee Fang^d | Lim, Su Chi^{a; d; e; f; *}

Affiliations: [a] Clinical Research Unit, Khoo Teck Puat Hospital (KTPH), Singapore | [b] Department of Psychological Medicine, Gerontology Research Programme, Yong Loo Lin School of Medicine, National University of Singapore, Singapore | [c] National Healthcare Group Polyclinics (NHGP), Singapore | [d] Diabetes Centre, Admiralty Medical Centre (AdMC) c/o Khoo Teck Puat Hospital, Singapore | [e] Saw Swee Hock School of Public Health, National University of Singapore (NUS), Singapore | [f] Lee Kong Chian School of Medicine, Nanyang Technological University (NTU), Singapore

Correspondence: [*] Correspondence to: Associate Professor Su Chi Lim, Clinical Research Unit, Khoo Teck Puat Hospital, 90 Yishun Central, Singapore 768828, Singapore. Tel.: +65 66022353; Fax: +65 66023772; E-mail: lim.su.chi@ktph.com.sg.

Abstract: 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 APOE ɛ4 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.

Keywords: Cognitive impairment, ethnic-specific, PAX4, type 2 diabetes

DOI: 10.3233/JAD-220036

Journal: Journal of Alzheimer's Disease, vol. 88, no. 1, pp. 241-249, 2022