Identification of Metabolic Modifiers That Underlie Phenotypic Variations in Energy-Balance Regulation

Chang, Chia‐Lin; Cai, James J.; Cheng, Po Jen; Chueh, Ho Yen; Hsu, Sze-Bi

doi:10.2337/db10-1331

Cited by 14 publications

(13 citation statements)

References 50 publications

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“…Likewise, we found a similar pattern in two target sites at CYB5R4, a gene associated to geneenvironment interactions [25,26]. In particular, CYB5R4 has been associated to the risk of diabetes, and variants at its 5' region have been found to be specific of African populations [25].…”

Section: Resultssupporting

confidence: 72%

The impact of population variation in the analysis of microRNA target sites

Helmy

Hatlen

Marco

2019

Preprint

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The impact of population variation in the analysis of regulatory interactions is an underdeveloped area. MicroRNA target recognition occurs via pairwise complementarity. Consequently, a number of computational prediction tools have been developed to identify potential target sites, that can be further validated experimentally. However, as microRNA target predictions are done mostly considering a reference genome sequence, target sites showing variation among populations are neglected. Here we study variation at microRNA target sites in human populations and quantify their impact in microRNA target prediction. We found that African populations carry a significant number of potential microRNA target sites that are not detectable in the current human reference genome sequence. Some of these targets are conserved in primates and only lost in Out-of-Africa populations. Indeed, we identified experimentally validated microRNA/transcript interactions that are not detected in standard microRNA target prediction programs, yet they have segregating target alleles abundant in non-European populations. In conclusion, here we show that ignoring population diversity may leave out regulatory elements essential to understand disease and gene expression, particularly neglecting populations of African origin.

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Section: Resultssupporting

confidence: 72%

The impact of population variation in the analysis of microRNA target sites

Helmy

Hatlen

Marco

2019

Preprint

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“…In a recent investigation, we documented the strong selection of a cluster of GIP variants in East Asians ∼8,100 (11,800 to 2,000) years ago [5], [6]. It is surprising to find that the selection of rs7754840 in CDKAL1 occurred in the same population at approximately the same time period (i.e., ∼6,900 years ago).…”

Section: Discussionmentioning

confidence: 94%

Adaptive Human CDKAL1 Variants Underlie Hormonal Response Variations at the Enteroinsular Axis

et al. 2014

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Recent analyses have identified positively selected loci that explain differences in immune responses, body forms, and adaptations to extreme climates, but variants that describe adaptations in energy-balance regulation remain underexplored. To identify variants that confer adaptations in energy-balance regulation, we explored the evolutionary history and functional associations of candidate variants in 207 genes. We screened single nucleotide polymorphisms in genes that had been associated with energy-balance regulation for unusual genetic patterns in human populations, followed by studying associations among selected variants and serum levels of GIP, insulin, and C-peptide in pregnant women after an oral glucose tolerance test. Our analysis indicated that 5′ variants in CDKAL1, CYB5R4, GAD2, and PPARG are marked with statistically significant signals of gene–environment interactions. Importantly, studies of serum hormone levels showed that variants in CDKAL1 are associated with glucose-induced GIP and insulin responses (p<0.05). On the other hand, a GAD2 variant exhibited a significant association with glucose-induced C-peptide response. In addition, simulation analysis indicated that a type 2 diabetes risk variant in CDKAL1 (rs7754840) was selected in East Asians ∼6,900 years ago. Taken together, these data indicated that variants in CDKAL1 and GAD2 were targets of prior environmental selection. Because the selection of the CDKAL1 variant overlapped with the selection of a cluster of GIP variants in the same population ∼11,800 to 2,000 years ago, we speculate that these regulatory genes at the human enteroinsular axis could be highly responsive to environmental selection in recent human history.

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“…We selected 27 protein-coding genes in the mTOR pathway (Supplementary Table 1) and additionally, 4 insulin and obesity related-genes ( CDKAL1 , CYB5R4 , GIP , and IRS1 ) known to have upstream influences on energy-balance regulation [19]. We selected a set of representative single nucleotide polymorphisms (tagSNPs) that had high correlation (r 2 ≥0.8) with other variants within a given linkage disequilibrium (LD) bin, were present at a minor allele frequency (MAF) of ≥0.05 in at least one reference population and were within 10 kb upstream of the 5′-untranslated region (UTR) and 10 kb downstream of the 3′-UTR of the gene using SNPinfo [20].…”

Section: Methodsmentioning

confidence: 99%

Genetic variants in the mTOR pathway and interaction with body size and weight gain on breast cancer risk in African-American and European American women

Cheng

Shankar

Zirpoli

et al. 2016

Cancer Causes Control

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Purpose Positive energy imbalance and growth factors linked to obesity promote the phosphatidylinositol 3-kinase/AKT/mammalian target of rapamycin (mTOR) pathway. As the obesity-breast cancer associations differ between European-American (EA) and African-American (AA) women, we investigated genetic variants in the mTOR pathway and breast cancer risk in these two racial groups. Methods We examined 400 single nucleotide polymorphisms (SNPs) in 31 mTOR pathway genes in the Women’s Circle of Health Study with 1263 incident breast cancers (645 EA, 618 AA) and 1382 controls (641 EA, 741 AA). Multivariable logistic regression was performed separately within racial groups. Effect modification was assessed for measured body size and weight gain since age 20. Results In EA women, variants in FRAP1 rs12125777 (intron), PRR5L rs3740958 (synonymous-coding), and CDKAL1 rs9368197 (intron) were associated with increased breast cancer risk, while variants in RPTOR rs9900506 (intron) were associated with decreased risk (nominal P-trend for functional and FRAP1 SNPs or P adjusted for correlated test [PACT] <0.05). For AA women, variants in RPTOR rs3817293 (intron), PIK3R1 rs7713645 (intron), and CDKAL1 rs9368197 were associated with decreased breast cancer risk. The significance for FRAP1 rs12125777 and RPTOR rs9900506 in EA women did not hold after correction for multiple comparisons. The risk associated with FRAP1 rs12125777 was higher among EAs who had body mass index ≥30 kg/m2 (odds ratio=7.69, 95% CI=2.11–28.0; P-interaction=0.007) and gained weight ≥35 lb. since age 20 (odds ratio=3.34, 95% CI=1.42–7.85; P-interaction=0.021), compared to their counterparts. Conclusions The mTOR pathway may be involved in breast cancer carcinogenesis differently for EA and AA women.

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Identification of Metabolic Modifiers That Underlie Phenotypic Variations in Energy-Balance Regulation

Cited by 14 publications

References 50 publications

The impact of population variation in the analysis of microRNA target sites

The impact of population variation in the analysis of microRNA target sites

Adaptive Human CDKAL1 Variants Underlie Hormonal Response Variations at the Enteroinsular Axis

Genetic variants in the mTOR pathway and interaction with body size and weight gain on breast cancer risk in African-American and European American women

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