Epigenome-wide association study of incident type 2 diabetes in Black and White participants from the Atherosclerosis Risk in Communities Study
Authors' conclusion
This study illustrates improved discovery of CpG sites and regions by leveraging both individual CpG site analysis and DMR analyses in an unexplored population. Our findings include genes linked to diabetes in experimental studies (e.g. GPX6, JPH3 and TP63). The JPH3 and GPX6 sites were likely associated with incident type 2 diabetes independently of BMI. All the CpG sites except that at JPH3 were likely consequences of elevated glucose. Replication in African-descent individuals of CpG sites previously discovered mostly in individuals of European descent indicates that some of these methylation-type 2 diabetes associations are robust across racial and ethnic groups. This study is a first step towards understanding the influence of methylation on the incidence of type 2 diabetes and its disparity in two major racial and ethnic groups in the USA. It paves the way for future studies to investigate causal relationships between type 2 diabetes and the CpG sites and potentially elucidate molecular targets for intervention.
Study context
- Population
- Black and White US adults without T2D, Atherosclerosis Risk in Communities study
- Participants
- 2,091 vs 1,029
- Exposure
- Black vs White
- Blackn = 2,091
- Whiten = 1,029
- Outcome
- Association of blood-based DNA methylation (CpG sites) with incident T2D
- Follow-up
- Median 17 years
Methodological detailsepigenome-wide association study, Cox regression, meta-analysis of Black and White participants, All analyses adjusted for batch effects, cell-type proportions and relevant confounders
- Epigenome-wide association study
- Cox regression
- Meta-analysis of Black and White participants
- All analyses adjusted for batch effects, cell-type proportions and relevant confounders
Main finding
As reported in the abstract
- Novel diabetes-associated CpG sites detected
- 7
- MICOS10 (cg05380846), Black adults
- HR 0.89, p=8.4 × 10-12
- ZNF2 (cg01585592), Black adults
- HR 0.88, p=1.6 × 10-9
- JPH3 (cg16696007), Black adults
- HR 0.87, p=7.8 × 10-9
- GPX6 (cg02793507), Black adults
- HR 0.85, p=2.7 × 10-8
- GPX6 (cg00647063), Black adults
- HR 1.20, p=2.5 × 10-8
- chr17q25 (cg16865890), White adults
- HR 0.8, p=6.9 × 10-8
- chr11p15 (cg13738793), meta-analysed group
- HR 1.11, p=7.7 × 10-8
Observational data: associations, not effects.
Further findings
Adjustment for BMI or fasting glucose
- JPH3 and GPX6 sites remained epigenome-wide significant after BMI adjustment; only JPH3 retained significance after fasting glucose adjustment
Replication of known T2D-associated CpG sites
- Replicated in Black adults at epigenome-wide threshold
- 3
- Replicated cg19693031 (TXNIP), cg00574958 (CPT1A), cg16567056 (PLCB2), cg11024682 (SREBF1), cg08857797 (VPS25), cg06500161 (ABCG1); all directionally consistent
T2D variance explained: traditional risk factors and fasting glucose vs plus significant CpG sites
- Black adults
- 26.2% vs 30.5%
- White adults
- 36.9% vs 39.4%
- Modest increase
Differentially methylated region (DMR) analyses (Šidák-corrected threshold 5%)
- DMR with previously discovered CpG site at ADCY7
- pBlack=1.8 × 10-4, pWhite=3.6 × 10-3, pAll=1.6 × 10-9
- DMR of TP63 promoter region
- pBlack=7.4 × 10-4, pWhite=3.9 × 10-3, pAll=1.4 × 10-5
- Differentially methylated across all racial and ethnic groups
Original publication
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