Role of treatment-modifying MTHFR677C>T and 1298A>C polymorphisms in metformin-treated Puerto Rican patients with type-2 diabetes mellitus and peripheral neuropathy

Abstract

Background The study was conducted to investigate potential association between MTHFR genotypes and diabetic peripheral neuropathy (DPN) in Puerto Ricans with type-2 diabetes mellitus (T2DM) treated with metformin. The prevalence of major MTHFR polymorphisms in this cohort was also ascertained. Methods DNAs from 89 metformin-treated patients with T2DM and DPN were genotyped using the PCR-based RFLP assay for MTHFR677C > T and 1298A > C polymorphisms. Frequency distributions of these variants in the study cohort were compared to those reported for three reference populations (HapMap project) and controls (400 newborn specimens). Chi-square (or Fischer’s exact) tests and odds ratios (OR) were used to assess association with DPN susceptibility risk (patients vs. controls) and biochemical markers (wild types vs. carriers). Results Sixty-seven percent (67%) of participants carry at least one of these MTHFR polymorphisms. No deviations from Hardy-Weinberg equilibrium were detected. The genotype and allele frequencies showed statistically significant differences between participants and controls (p < 0.0001 and p = 0.03, respectively). Results suggest that 1298A > C but not 677C > T is associated with DPN susceptibility in this cohort (p = 0.018). Different patterns of allelic dissimilarities are observed when comparing our cohort vs. the three parental ancestries. After sorting individuals by their carrier status, no significant associations were observed between these genetic variants (independently or combined) and any of the biochemical markers (HbA1c, folate, vitamin B12, homocysteine). Conclusions Prevalence of major MTHFR variants in Puerto Rican patients with T2DM is first time ever reported. The study provides further evidence on the use of this genetic marker as an independent risk factor for DPN.

Ethnogeographic Prevalence and Implications of the 677C>T and 1298A>C MTHFR Polymorphisms in Us Primary Care Populations

“…According to early reports, there seems to be a genetic component that may play a role in the development of diabetic peripheral neuropathy (DPN) [37,38]. Jimenez et al found an association between the MTHFR 1298A>C variant and susceptibility to DPN in Puerto Ricans with Type 2 diabetes mellitus treated with metformin [39]. Results suggest that 1298A>C but not 677C>T was associated with DPN susceptibility in this cohort.…”

“…Results suggest that 1298A>C but not 677C>T was associated with DPN susceptibility in this cohort. The authors suggested that a differential haplotype structure and LD pattern in the study cohort might explain the observed association of 1298A>C, but not of 677C>T, with DPN susceptibility in these patients [39]. It has also been found by others that individuals with MTHFR 1298A>C, but not 677C>T, have been associated with metabolic syndrome [40].…”

Association of MTHFR C677T polymorphism and type 2 diabetes mellitus (T2DM) susceptibility

“…After titles and abstracts screening, 81 nonrelevant records were excluded. The remaining 60 articles and eight additional articles identified from retrieved studies were included in the final meta‐analysis (Al‐Harbi et al, ; Al‐Salihi, Ajeena, Al‐Kashwan, & Al‐Lebban, ; Zidan, El Mougy, Moustafa, El attar, & Mohamed, ; Benrahma et al, ; Bluthner et al, ; Cao, Huang, Mao, & Gao, ; Chang et al, ; Chen, Ning, Zhu, Li, & Shi, ; Chen et al, ; P. Chen, Pan, Sun, Bai, & Fu, ; Dai & Yu, ; El Hajj Chehadeh et al, ; Eroglu et al, ; Errera et al, ; Fekih‐Mrissa et al, ; Fujita et al, ; Guo, Pan, Chu, Guo, & Sun, ; Guo et al, ; Hu, Zhang, Fang, Qin, & Liu, ; Hu, Gan, Li, & Bi, ; Jimenez‐Ramirez et al, ; Ksiazek, Bednarek‐Skublewska, & Buraczynska, ; Lin, Wang, & Liu, ; Liu et al, ; Luo, Yan, Li, Cheng, & Song, ; Luo, Yan, Ma, Cheng, & Song, ; Mao, Gao, Qin, & Shi, ; Mehri et al, ; Mei, Chen, & Zheng, ; Mtiraoui et al, ; Neugebauer, Baba, & Watanabe, ; Nithya et al, ; Odawara & Yamashita, ; Pirozzi et al, ; Qiu, ; Rahimi et al, ; Ramanathan, Harichandana, Kannan, Elumalai, & Sfd, ; Raza, Abbas, Siddiqi, & Mahdi, ; Settin, El‐Baz, Ismaeel, Tolba, & Allah, ; Shang, Wang, & Liu, ; Shi, He, Cheng, Wang, & Liu, ; J. Shi, Li, Yu, Chen, & Tao, ; Shpichinetsky et al, ; Soares et al, ; J. Sun, Xu, Xue, Zhu, & Lu, ; Sun, Xu, & Zhu, ; Sun, Xu, Zhu, & Lu, ; Sun, Xu, Lu, & Zhu, ; Sun, Chen, et al, ; Sun, Wang, Shi, & Yang, ; Wang et al, ; Wang, Hu, Xiao, & Wan, ; Wang, Wang, & Li, ; Wang, Wang, Xue, Chen, & Zou,…”

“…The remaining 60 articles and eight additional articles identified from retrieved studies were included in the final meta-analysis (Al-Harbi et al, 2015;Al-Salihi, Ajeena, Al-Kashwan, & Al-Lebban, 2016;Zidan, El Mougy, Moustafa, El attar, & Mohamed, 2019;Benrahma et al, 2012;Bluthner et al, 1999;Cao, Huang, Mao, & Gao, 2005;Chang et al, 2011;Chen, Ning, Zhu, Li, & Shi, 2004;Chen et al, 2010;P. Chen, Pan, Sun, Bai, & Fu, 2008;Dai & Yu, 2012;El Hajj Chehadeh et al, 2016;Eroglu et al, 2007;Errera et al, 2006;Fekih-Mrissa et al, 2017;Fujita et al, 1999;Guo, Pan, Chu, Guo, & Sun, 2005;Guo et al, 2002;Hu, Zhang, Fang, Qin, & Liu, 2009;Hu, Gan, Li, & Bi, 2001;Jimenez-Ramirez et al, 2017;Ksiazek, Bednarek-Skublewska, & Buraczynska, 2004;Lin, Wang, & Liu, 2009;Liu et al, 2014;Luo, Yan, Li, Cheng, & Song, 2007;Luo, Yan, Ma, Cheng, & Song, 2008;Mao, Gao, Qin, & Shi, 2004;Mehri et al, 2010;Mei, Chen, & Zheng, 2012;Mtiraoui et al, 2007;Neugebauer, Baba, & Watanabe, 1998;Nithya et al, 2017;Odawara & Yamashita, 1999;Pirozzi et al, 2018;Qiu, 2009;…”

Obesity, Diabetes mellitus and Methylenetetrahydrofolate reductase mutations: Deadly combinations? How to approach them?

“…The relationships of MTHFR 677 C>T and ACE I/D polymorphisms with DPN patients presented in this meta-analysis support the view that the MTHFR and ACE genes might play an important role in the development of DPN. Meanwhile, Jiménez-Ramírez, et al carried out a study and sixty-seven percent (67%) of participants carry at least one of these MTHFR polymorphisms [17]. No deviations from Hardy-Weinberg equilibrium were detected.…”