DNA methylation in the TXNIP gene is associated with type 2 diabetes in Pacific Peoples living in NZ

Abstract Background Pacific Peoples living in Aotearoa New Zealand (NZ) have higher rates of type 2 diabetes (T2D) and have benefited less from improvements in cardiovascular health outcomes when compared with other populations in NZ. DNA methylation markers of T2D have been identified in non-Pacific populations and could be used to monitor the cumulative effects of T2D on cardiovascular disease risk. However, no study has yet investigated the relationships between T2D and DNA methylation in Pacific Peoples living in NZ. Purpose This study aimed to quantify the relationship between DNA methylation and T2D in two cohorts of Pacific Peoples living in NZ. Methods Whole-blood DNA methylation at over 850,000 loci was measured on Illumina MethylationEPIC arrays in 288 Pacific participants from the Pasifika Heart Study (PHS, n=191), a community cohort, and the Multi-Ethnic NZ Study of Acute Coronary Syndromes (MENZACS, n=97), a cohort of patients with acute coronary syndromes. In the PHS, the median age was 41 years, and 98 (51%) participants were female. In MENZACS, the median age was 53 years, and 18 (19%) participants were female. In both cohorts, T2D cases were defined by either previous diagnosis (n=58) or had an HbA1c measurement >58 mmol/mol (n=7). We compared 65 participants with T2D and 223 participants without T2D of Samoan (n=116), Tongan (n=66), Fijian (n=61), Cook Island Māori (n=22), Niuean (n=9), or of Other/Multiple Pacific (n=14) ethnicity in a meta epigenome-wide association study (EWAS). EWAS comparisons were adjusted for age, sex, and imputed blood cell composition. We compared the difference in means at differentially methylated loci between the European and Pacific MENZACS participants using a two-sample z statistic. For the 525 European participants, 85 had T2D, the median age was 57 years, and 149 (28%) were female. Results One locus cg19693031, in the thioredoxin interacting protein (TXNIP) gene, exhibited differential methylation between those with T2D and those without in the meta EWAS (false discovery rate =6.9x10-9). In the PHS we observed a mean reduction in cg19693031 methylation of 7.0% (95% CI, 5.0, 8.9) between those with T2D and those without. Similarly in the MENZACS Pacific participants we observed a mean reduction in cg19693031 methylation of 10.9% (95% CI, 7.6, 12.4) between those with T2D and those without. The MENZACS European participants with T2D had a mean reduction in cg19693031 methylation of 6.5% (95% CI, 5.3, 7.7, p<0.001) compared to those without T2D. The difference in means in T2D cases and controls between MENZACS Pacific and European participants was non-significant (p =0.08). Conclusion DNA methylation at cg19693031 is associated with T2D in Pacific Peoples living in NZ and may be a sensitive marker of T2D in Pacific Peoples with acute coronary syndromes. DNA methylation at this locus may provide valuable information on the relationship between T2D and cardiovascular disease.Miami plot of Pacific T2D EWAST2D methylation by population in MENZACS