Association of gene variants with susceptibility to type 2 diabetes among Omanis

Al-Sinani, Siham; Woodhouse, Nicolas; Al-Mamari, Ali; Al-Shafie, Omaima; Al-Shafaee, Mohammed; Al‐Yahyaee, Said; Hassan, Musaab; Jaju, Deepali; Al-Hashmi, Khamis; Abri, Mohammed Al; Al-Rassadi, Khalid; Rizvi, Syed; Yengo, Loic; Froguel, Philippe; Bayoumi, Riad

doi:10.4239/wjd.v6.i2.358

Cited by 44 publications

(28 citation statements)

References 58 publications

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“…A recent study by Kamura et al [25] suggested that the association between FTO variants and T2D is mediated through the lifetime maximum BMI at the time of or before diagnosis of T2D. Nevertheless, our lack of association with the T2D risk has also been reported in populations of similar genetic background to the Kuwaiti population [26, 27]. It is apparent that ethnicity plays a role in FTO rs9939609 and T2D risk among different populations, possibly under the influence of other T2D susceptibility factors of stronger effect.…”

Section: Discussioncontrasting

confidence: 49%

Association of FTO rs9939609 with Obesity in the Kuwaiti Population: A Public Health Concern?

et al. 2018

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Objective: To investigate the effect of the common fat mass and obesity-associated (FTO) gene polymorphism rs9939609 on body mass index (BMI) in one of the most obese populations worldwide. Subjects and Methods: Genotypic data for FTO rs9939609 were available for 1,034 unrelated Kuwaiti adults obtained from Kuwait’s Dasman Diabetes Institute and Kuwait University. The association between the FTO polymorphism with BMI as continuous and categorical (normal BMI [< 25] vs. overweight/obese [> 25]) variables was analyzed using both linear and logistic regression models, respectively, with the assumption of both dominant and additive genetic models performed using the SNPassoc package from R statistics. Results: The A allele was associated with increased BMI (β = 1.21; 95% CI = 0.16–2.26; p = 0.023). In concordance, the categorical BMI (normal vs. overweight/obese) also showed a significant association between the A allele and overweight/obesity (OR = 1.47; 95% CI = 1.01–2.12; p = 0.041). However, no association between the FTO variant was observed with cardiometabolic traits. Conclusion: We observed an association between the common FTO rs9939609 polymorphism and increased BMI (overweight/obesity) in Kuwaiti adults, which is consistent with previous research in other populations. Our findings encourage further investigation of genetic variants to elucidate the mechanisms involved in the development of obesity in such an obesogenic population.

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Section: Discussioncontrasting

confidence: 49%

Association of FTO rs9939609 with Obesity in the Kuwaiti Population: A Public Health Concern?

et al. 2018

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“…However, the association between FTO variants and T2DM was controversial. Consistent with two previous case-control studies [25,26], we found no significant association of FTO variants with T2DM. Also, we did not observe any possible haplotype associated with T2DM in the strong linkage disequilibrium region (block 1).…”

Section: Discussionsupporting

confidence: 92%

Association of FTO methylation level with incident type 2 diabetes mellitus: a nested case–control study within the Rural Chinese Cohort Study

Huang

Chen²,

Zhang

et al. 2020

Preprint

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Objectives This study aimed to investigate the association of FTO methylation level with type 2 diabetes mellitus (T2DM). Methods We conducted a nested case – control study for DNA methylation of FTO in Chinese pople identified from the Rural Chinese Cohort Study with a 6-year follow-up. Controls were matched to the cases on a 1:1 basis by age, sex, ethnicity, marital status, and residence. Unconditional multivariate logistic regression models were used to calculate odds ratios (ORs) and 95% confidence intervals (CIs) for association with Tag-single nucleotide polymorphisms (SNPs) and cytosine guanine (CpG) locus. Haploview was used to analyze the association of possible haplotypes with T2DM. Generalized Multifactor Dimensionality Reduction was used to explore the potential interaction. Results We found a significant association for the CpG9 locus located in the promoter region of FTO with T2DM. With CpG9, the risk of T2DM was 1.84 (1.21–2.80) after adjusting for potential confounders. The Tag-SNPs (rs72803657, rs1558902, rs17817449, rs11076023) nor were possible haplotypes associated with T2DM in the strong linkage disequilibrium region. We found no significant interaction between obesity indexes, serum lipid levels and methylation levels. Conclusions Our study identified a CpG locus located in the promoter region of FTO that altered the T2DM risk independent of body mass index, but the variants of FTO were not significantly associated with T2DM. Our study might provide new insights into the pathways of FTO with T2DM and offer new opportunities for risk stratification and prevention of T2DM among rural Chinese population.

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“…It was the first T2D susceptibility gene identified in linkage studies (HORIKAWA et al 2000), with multiple subsequent GWAS or candidate gene studies having also identified an association between variants near CAPN10 and T2D risk and other diabetes-related phenotypes (BAIER et al 2000;EVANS et al 2001;OROZCO et al 2014;IBRAHIM et al 2015;CUI et al 2016;ZHAO et al 2016;BAYRAMCI et al 2017;HOU et al 2017;CASTRO-MARTINEZ et al 2018). However, many other studies failed to replicate these findings (HEGELE et al 2001;TSAI et al 2001;KHAN et al 2014;AL-SINANI et al 2015;PLENGVIDHYA et al 2015;ZHANG et al 2019). It is tempting to speculate that one potential reason for the inconsistent results could be an incomplete understanding of epistatic interactions between CAPN10 and other loci.…”

Section: Among the Most Significant Genes Whose Expression Is Regulatmentioning

confidence: 99%

A novel mapping strategy utilizing mouse chromosome substitution strains identifies multiple epistatic interactions that regulate complex traits

Miller

Chen

Bartlett

et al. 2020

Preprint

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The genetic contribution of additive versus non-additive (epistasis) effects in the regulation of hematologic and other complex traits is unclear. While genome-wide association studies typically ignore gene-gene interactions, in part because of the lack of statistical power for detecting them, mouse chromosome substitution strains (CSSs) represent an alternate and powerful model for detecting epistasis given their limited allelic variation. Therefore, we utilized CSSs to identify and map both additive and epistatic loci that regulate a range of hematologic-and metabolism-related traits, as well as hepatic gene expression. Quantitative trait loci (QTLs) were identified using a modified backcross strategy involving the segregation of variants on the A/J-derived substituted chromosomes 4 and 6 on an otherwise C57BL/6J genetic background. By analyzing the transcriptomes of offspring from this cross, we identified and mapped additive QTLs regulating the expression of 768 genes, and epistatic QTL pairs for 519 genes. Similarly, we identified additive QTLs for fat pad weight, platelets, and the percentage of granulocytes in blood, as well as epistatic QTL pairs controlling the percentage of lymphocytes in blood and red cell distribution width. The variance attributed to the epistatic QTLs was approximately equal to that of the additive QTLs, demonstrating the importance of identifying genetic interactions to understand the genetic architecture of complex traits. Of particular note, even the epistatic QTLs that accounted for the largest variances were undetected in our single loci GWAS-like association analyses, highlighting the need to account for epistasis in association studies.

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Association of gene variants with susceptibility to type 2 diabetes among Omanis

Abstract: Results confirmed the association of KCNJ11 (rs5219), TCF7L2 (rs7903146), CDKAL1 (rs10946398) and CDKN2A/B (rs10811661) gene variants with susceptibility to T2D among Omani Arabs.

Cited by 44 publications

References 58 publications

Association of <b><i>FTO</i></b> rs9939609 with Obesity in the Kuwaiti Population: A Public Health Concern?

Association of <b><i>FTO</i></b> rs9939609 with Obesity in the Kuwaiti Population: A Public Health Concern?

Association of FTO methylation level with incident type 2 diabetes mellitus: a nested case–control study within the Rural Chinese Cohort Study

A novel mapping strategy utilizing mouse chromosome substitution strains identifies multiple epistatic interactions that regulate complex traits

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