Genome-wide gene-ferritin interaction and pathway analysis for incidence risk of type 2 diabetes in adults aged 40 years or older: The Multi-Rural Communities Cohort (MRCohort)_Yangpyeong and Namwon

Abstract

Abstract Genome-wide gene-ferritin interaction and pathway analysis for incidence risk of type 2 diabetes in adults aged 40 years or older: The Multi-Rural Communities Cohort (MRCohort)The Korean Genome and Epidemiology Study (KoGES)_Yangpyeong and Namwon

[Background] Genetic factors, environmental factors, and their interactions contribute to the development of Type 2 diabetes (T2D). Iron is a vital nutrient for humans, but it is a strong pro-oxidant that may play a role in the pathogenesis of T2D. Elevated serum ferritin is associated with incident Type 2 diabetes (T2D), but the interactions between serum ferritin and genetic factors are still unclear. Thus, to enhance our understanding of the development of T2D, it may be important to find new genetic factors interacted with ferritin and their related pathway in the development of T2D. In addition, if ferritin is an important factor in the development of T2D, regardless of the influence of ferritin itself or through the interaction with genetic factors, it may be also important to understand modifiable determinants of blood ferritin level for the public health.

[Objectives] Therefore, this study was performed to achieve the aims as follows: 1) to determine the contribution of gene-ferritin interactions to the development of T2D by genome-wide gene-ferritin interaction analysis; 2) to explore genetic factors interacted with ferritin on the risk of T2D in gene and pathway levels; and 3) to examine the association of dietary and non-dietary factors with serum ferritin levels regardless of genetic risks.

[Method]

The process of selecting participants in Chapters 2 and 3 was identical. Data from the Yangpyeong and Namwon cohort, a part of multi-rural communities cohort (MRCohort) which three rural communities, Yangpyeong (located in 45 km east of Seoul, the capital of South Korea), Namwon (located in southwestern and southeastern areas of South Korea), were used. The baseline study was conducted between January 2005 and August 2011 and follow-up examinations were conducted every 2-4 years. A total of 3,405 participants from two communities were included, and the median follow up time was 3.99 years. Unlike Chapters 2 and 3, we try to eliminate an influence of inflammation on serum ferritin by excluding participants with CRP values > 3 mg/L (n =534), resulting in the inclusion of a total of 3,309 participants in Chapter 4, a cross-sectional study. In Chapter 2, genome-wide gene-ferritin interactions were analyzed using the joint test with two degrees of freedom as a screening step, and then we conducted 1 degree of freedom interaction analysis for SNPs selected in the first screening step. In Chapter 3, genome-wide gene-ferritin interactions (1 degree of freedom) at levels of single nucleotide polymorphisms, genes, and pathways were conducted. General linear model and multivariable logistic regression models were used to assess the association between serum ferritin levels and their determinants in Chapter 4. [Results]

In Chapter 2, there was a positive association between serum ferritin level and incidence risk of T2D (IRR 1.90, 95% CI 1.22, 2.99 in the highest tertile (T3) vs. the lowest tertile (T1) of ferritin level; IRR 3.15, 95% CI 2.04, 4.87 in the raised ferritin status (> 300 ng/ml for men and > 200 ng/ml for women) vs. the normal ferritin level). Four independent variants (rs355140, rs4075576, rs1332202, and rs713157) showed interactions with serum ferritin level in the two steps interaction analysis. Joint test was used as the screening step and 1 df interaction analysis for SNPs selected in the first screening step. In the association analyses between serum ferritin levels (tertiles of ferritin and ferritin status) and the incidence of T2D according to genotype, the incidence rate ratios in the highest tertile of ferritin or raised ferritin status were significantly greater and linearly increasing compared with those in the lowest tertile or normal ferritin status for mutant heterozygotes of all four SNPs. Particularly, the positive associations of ferritin overload (raised ferritin) with incidence of T2D were more clear in those with mutant homozygotes, although there was no significant association in T3 for mutant homozygotes. In Chapter 3, we identified significant and independent 33 SNPs in SNP level genome wide-ferritin interaction for the incidence of T2D. Using a versatile gene-based test approach, we found significant nine genes (DNAH6, LINC00312, SVIL-AS1, HAVCR2, PLCB2, C9orf72, IFNK, GPR26, and TPRX1) interacted with serum ferritin level. However, there were no pathways reached the statistical significance in pathway level analysis. In Chapter 4, non-dietary factors (WC and regular exercise in men and age, and menopausal status, WC in women) and dietary factors (alcohol consumption and total meat intake in men and red meat intake in women) were associated serum ferritin level regardless of genetic factors.

[Conclusion]

In conclusion, serum ferritin level interacted with genetic variants (rs355140, rs4075576, rs1332202, and rs713157) in the development of T2D. In addition, by gene-based analysis, nine genes that may interact with serum ferritin levels were found in this study. However, there was a known specific pathway in relation to gene-ferritin interaction. Nevertheless, there was a positive association between serum ferritin and T2D. maintaining a healthy waist circumference, doing regular exercise, and reducing alcohol and meat consumption may help to prevent the development of T2D regardless of genetic factors.