MetallothioneinMT2AA-5G Polymorphism as a Risk Factor for Chronic Kidney Disease and Diabetes: Cross-Sectional and Cohort Studies

Abstract

Metallothioneins (MTs) are proteins that protect cells from toxic agents such as heavy metal ions or reactive oxygen species. MT2A A-5G is a single nucleotide polymorphism in the promoter region of the MT2A gene, and the minor G allele results in lower transcription efficiency. We aimed to elucidate associations between MT2A A-5G and risks of 2 diseases potentially related to lowered MT expression, chronic kidney disease (CKD), and diabetes mellitus (DM), in a community-dwelling population. Study subjects were Nagoya city residents participating in the Japan Multi-Institutional Collaborative Cohort Study (J-MICC) Daiko Study, comprised 749 men and 2,025 women, aged 39–75 years. CKD (>stage 3) and DM were defined by standard guidelines. Associations were evaluated using logistic regression models with adjustments for age, sex and potential confounders in a cross-sectional study, and verified in a 5-year longitudinal study. Odds ratios (OR [95% confidence interval]) were calculated relative to the AA genotype. Serum MT (I + II), Cd and zinc levels were also determined by genotype. The OR of the GG genotype for CKD risk was 3.98 (1.50, 10.58) in the cross-sectional study and 5.17 (1.39, 19.28) in the longitudinal study. The OR of the GA genotype for DM was 1.86 (1.26, 2.75) in the cross-sectional study and 2.03 (1.19, 3.46) in the longitudinal study. MT2A A-5G may be associated with CKD and DM risks. This polymorphism is a promising target for evaluations of CKD and DM risks with possible involvement of low-dose chronic exposure to environmental pollutants.

Reappraisal of metallothionein: Clinical implications for patients with diabetes mellitus

“…In a following study from the same group, a positive association was demonstrated between an MT1A polymorphism (+647 AA or AC) and T2DM . Consistent with these studies, an association between mutations in the MT‐I and MT‐II genes and a high risk of T2DM was reported in Chinese Han descendents and residents of Nagoya, Japan . Among the Chinese population, there was a significant difference between the control and T2DM groups in the frequency distribution of the MT‐IA rs8052394 alleles, with a positive correlation between the frequency of the G allele and the incidence of T2DM .…”

“…In a recent Japan Multi‐Institutional Collaborative Cohort Study (J‐MICC) of residents of Nagoya (749 men, 2025 women), associations between MT2A polymorphisms and chronic kidney disease (CKD) were evaluated using logistic regression models with adjustments for age, sex, and potential confounders in a cross‐sectional study, and verified in a 5‐year longitudinal study . That study confirmed that subjects with the GG genotype had an approximate four‐ to fivefold greater risk of developing CKD than others in both the cross‐sectional and longitudinal study …”

“…Among the Chinese population, there was a significant difference between the control and T2DM groups in the frequency distribution of the MT‐IA rs8052394 alleles, with a positive correlation between the frequency of the G allele and the incidence of T2DM . Japanese residents with the GG genotype of MT‐II2A gene mutations also had an approximate twofold higher prevalence of T2DM than those without the MT‐II2A gene mutation …”

“…149 Consistent with these studies, an association between mutations in the MT-I and MT-II genes and a high risk of T2DM was reported in Chinese Han descendents 150 and residents of Nagoya, Japan. 151 Among the Chinese population, there was a significant difference between the control and T2DM groups in the frequency distribution of the MT-IA rs8052394 alleles, with a positive correlation between the frequency of the G allele and the incidence of T2DM. 150 Japanese residents with the GG genotype of MT-II2A gene mutations also had an approximate twofold higher prevalence of T2DM than those without the MT-II2A gene mutation.…”

“…150 Japanese residents with the GG genotype of MT-II2A gene mutations also had an approximate twofold higher prevalence of T2DM than those without the MT-II2A gene mutation. 151 Mutations of the MT gene are associated not only with a high risk of diabetes, but also with cardiovascular disease. Giacconi et al 148 reported that among the Italian population both the −209 AA and AG MT2A polymorphisms are associated with high risk of diabetes; however, patients with −209 AA MT2A polymorphisms are related to the high risk of developing diabetes with cardiovascular complications (atherosclerosis and ischemic cardiomyopathy).…”