Epigenetic associations of type 2 diabetes and BMI in an Arab population

Abstract

BackgroundThe prevalence of type 2 diabetes (T2D) and obesity has dramatically increased within a few generations, reaching epidemic levels. In addition to genetic risk factors, epigenetic mechanisms triggered by changing environment are investigated for their role in the pathogenesis of these complex diseases. Epigenome-wide association studies (EWASs) have revealed significant associations of T2D, obesity, and BMI with DNA methylation. However, populations from the Middle East, where T2D and obesity rates are highest worldwide, have not been investigated so far.MethodsWe performed the first EWAS in an Arab population with T2D and BMI and attempted to replicate 47 EWAS associations previously reported in Caucasians. We used the Illumina Infinium HumanMethylation450 BeadChip to quantify DNA methylation in whole blood DNA from 123 subjects of 15 multigenerational families from Qatar. To investigate the effect of differing genetic background and environment on the epigenetic associations, we further assessed the effect of replicated loci in 810 twins from UK.ResultsOur EWAS suggested a novel association between T2D and cg06721411 (DQX1; p value = 1.18 × 10−9). We replicated in the Qatari population seven CpG associations with BMI (SOCS3, p value = 3.99 × 10−6; SREBF1, p value = 4.33 × 10−5; SBNO2, p value = 5.87 × 10−5; CPT1A, p value = 7.99 × 10−5; PRR5L, p value = 1.85 × 10−4; cg03078551, intergenic region on chromosome 17; p value = 1.00 × 10−3; LY6G6E, p value = 1.10 × 10−3) and one with T2D (TXNIP, p value = 2.46 × 10−5). All the associations were further confirmed in the UK cohort for both BMI and T2D. Meta-analysis increased the significance of the observed associations and revealed strong heterogeneity of the effect sizes (apart from CPT1A), although associations at these loci showed concordant direction in the two populations.ConclusionsOur study replicated eight known CpG associations with T2D or BMI in an Arab population. Heterogeneity of the effects at all loci except CPT1A between the Qatari and UK studies suggests that the underlying mechanisms might depend on genetic background and environmental pressure. Our EWAS results provide a basis for comparison with other ethnicities.Electronic supplementary materialThe online version of this article (doi:10.1186/s13148-016-0177-6) contains supplementary material, which is available to authorized users.

An epigenome-wide study of body mass index and DNA methylation in blood using participants from the Sister Study cohort

“…A second study utilizing the Atherosclerosis Risk in Communities cohort and multiple replication cohorts identified 76 CpGs that were differentially associated with body mass index and replicated 37 sites(10). 18 of these associations were recently replicated in an Arab population (19) and we found that 27 of these associations replicated in our dataset, including the site cg06500161 in ABCG1 identified in our discovery set. We provide the first replication for associations with BMI at the CpG sites cg09554443 in CD247 , cg04986899 in XYLT1 , cg05242915 on chromosome 19, and cg03562528 in ASB2 .…”

DNA methylation signatures in peripheral blood strongly predict all-cause mortality

“…Of note, associations with prevalent T2D and mortality were also observed in the current study for cg23190089 in SLC22A18AS (on 11p15.4), a locus located ∼198 kb downstream of cg26963277 in KCNQ1OT1 . The chromosome region 11p15.5/4, along with SLC1A5 , SQLE and SOCS3 methylation that were suggested to be involved in T2D in both the current and previous studies525404142, therefore appear to be attractive targets for diabetes investigation, and even for CVD given the biological functions of these genes and their methylation in CVD4043 and also the well-known causal relationship between diabetes and CVD. Similar to SQLE , KCNQ1OT1 and SOCS3 , which are involved in diabetes, CVD and various cancers5264043444546, most identified genes are characterized by their relevance to multiple diseases, making them the most robust signals on an epigenome-wide scale, which may explain the extremely strong association of the risk score based on identified DNAm markers with all-cause mortality.…”

Association of Body Mass Index with DNA Methylation and Gene Expression in Blood Cells and Relations to Cardiometabolic Disease: A Mendelian Randomization Approach

“…Similarly, many of the BMI-related differentially methylated CpGs identified in this study were also reported in relation to BMI in people of Arabic ancestry [34]. In GWASs, failure to replicate across racial/ethnic groups may be due to differences in allele frequencies and linkage disequilibrium patterns.…”

“…The majority of BMI-related CpGs (65%-85% of CpGs depending on the cohort) had mean sample CpG methylation levels between 20% and 80% (S4 Table). Fifty of the 83 replicated differentially methylated CpGs have not been previously reported in microarraybased EWASs of BMI [28][29][30][31][32][33][34][35][36] (Table 3). Age and sex interactions among the BMI EWAS findings.…”