MicroRNA expression in abdominal and gluteal adipose tissue is associated with mRNA expression levels and partly genetically driven.

paper Cited Public

Authors: Rantalainen, Mattias; Herrera, Blanca M; Nicholson, George; Bowden, Rory; Wills, Quin F; Min, Josine L; Neville, Matt J; Barrett, Amy; Allen, Maxine; Rayner, Nigel W; Fleckner, Jan; McCarthy, Mark I; Zondervan, Krina T; Karpe, Fredrik; Holmes, Chris C; Lindgren, Cecilia M
Year: 2011
Journal: PloS one
PMID: 22102887
DOI: 10.1371/journal.pone.0027338
PMCID: PMC3216936

Figure 1

Tissue differential expression (the tissue-related fixed-effects coefficients (β)), of the 59 miRNA that were replicated (p-value<0.05) in the replication study.The coefficients (β) are sorted on effect-size, a positive value indicating higher expression in gluteal adipose tissue relative abdominal adipose tissue. Error-bars show the standard-error of β for each miRNA.

Figure 2

Locus plots for miRNA eQTLs that replicated.P-values from the primary study are shown in figure (criteria for replication: p-value<0.001 in the primary study and p-value<0.05 in the replication study with a directionally consistent effect). A) Abdominal adipose tissue hsa-miR-1255a:rs1822168 (p-value = 1.83E-05 in primary study and p-value = 9.91E-03 in replication study) B) Abdominal adipose tissue hsa-miR-618: rs1716543 (p-value = 5.34E-04 in primary study and p-value = 5.80E-03 in replication study) C) Abdominal adipose tissue hsa-miR-146a*:rs2961920 (p-value = 5.87E-04e in primary study and p-value = 6.45E-06 in replication study) D) Gluteal adipose tissue hsa-miR-1255a:rs1822168 (p-value = 1.56E-05 in primary study and p-value = 1.65E-04 in replication study), E) Gluteal adipose tissue hsa-miR-1307:rs11191666 (p-value = 1.27E-04 in primary study and p-value = 3.55E-04 in replication study), F) Gluteal adipose tissue hsa-miR-330-3p:rs7252175 (p-value = 3.85E-04 in primary study and p-value = 4.04E-02 in replication study).

Figure 3

Genetic effects in replicated miRNA eQTLs in abdominal adipose tissue (see Materials and Methods section for criteria).The violin-plot represents the density of miRNA expression relating to the SNP effect for each genotype (variability relating to the other fixed effects was regressed out); the line represents the fixed-effect coefficient (β) relating to the SNP effect. A) Primary study hsa-miR-1255a:rs1822168 B) Primary study hsa-miR-618:rs1716543 C) Primary study hsa-miR-146a*:rs2961920 D) Replication study hsa-miR-1255a:rs1822168 E) Replication study hsa-miR-618:rs1716543. F) Replication study hsa-miR-146a*:rs2961920.

Figure 4

Genetic effects in replicated miRNA eQTLs in gluteal adipose tissue (see Materials and Methods section for criteria).The violin-plot represents the density of miRNA expression relating to the SNP effect for each genotype (variability relating to other fixed effects was regressed out); the line represents the fixed-effect coefficient (β) relating to the SNP effect. A) Primary study hsa-miR-1255a:rs1822168 B) Primary study hsa-miR-1307:rs11191666. C) Primary study hsa-miR-330-3p:rs7252175 D) Replication study hsa-miR-1255a:rs1822168. E) Follow up study hsa-miR-1307:rs11191666. F) Replication study hsa-miR-330-3p:rs7252175.

Figure 5

(A) Venn diagram showing the number of common and unique miRNAs with significant association to their target mRNAs in each adipose tissue type.(B) Venn diagram showing the number of common and unique KEGG terms in each adipose tissue type.

#	Section	Preview
20	Discussion	Genetic variants affecting miRNA expression suggest a possible mechanism through which genetic…
21	Discussion	reported to be under genetic control [23]. We note that the relatively high FDR adjusted p-values…
22	Discussion	Since our miRNA analyses revealed differential miRNA expression associated with adipose tissue…
23	Discussion	Few of the miRNAs found significant in at least one of the four analyses (i.e. association with…
24	Discussion	case-control status and cis- located genetic variants (eQTLs). Another potential reason for finding…
25	Discussion	Despite limitations in respect to sample sizes and statistical power, the current results have…
26	Discussion	Our results indicate that there is a clear difference in the miRNA molecular phenotypic profile of…
27	Materials and Methods — Ethics statement	The study has received ethical approval from National Health Service (NHS), National Research Ethics…
28	Materials and Methods — Study design and experimental material and methods — Sample and subject information – primary study	Tissue samples from 70 human subjects (40 male and 30 female) belonging to either a healthy control…
29	Materials and Methods — Study design and experimental material and methods — Sample and subject information – replication study	To validate results from the primary study, gluteal and abdominal adipose tissue samples from 40…
30	Materials and Methods — Study design and experimental material and methods — Single Nucleotide Polymorphism (SNP) genotyping – primary study	DNA was extracted from each subject using GeneCatcher™ (Invitrogen Life Technologies, Carlsbad,…
31	Materials and Methods — Study design and experimental material and methods — Single Nucleotide Polymorphism (SNP) genotyping – replication study	Genotyping was performed using the Sequenom iPLEX™ assays with the mass spectrometry based…
32	Materials and Methods — Study design and experimental material and methods — miRNA expression profiling – primary study	Total RNA was extracted from homogenized adipose tissue samples from each subject using TRI Reagent…
33	Materials and Methods — Study design and experimental material and methods — miRNA expression profiling – primary study	technical duplicates (with a few in triplicates). Due to a small number of failed assays, data are…
34	Materials and Methods — Study design and experimental material and methods — miRNA expression profiling – replication study	In total, data were collected from 40 subjects and both abdominal and gluteal adipose tissue, 13 of…
35	Materials and Methods — Study design and experimental material and methods — mRNA expression profiling	Total RNA was extracted with TRIreagent (SIGMA-ALDRICH) from fat biopsies. RNA expression was…
36	Materials and Methods — Data preprocessing	All data analysis was carried out using R version 2.9.0 [53] unless otherwise stated.
37	Materials and Methods — Data preprocessing — miRNA expression data preprocessing	Data was imported into R using the beadarray package [54]. Data was background corrected by…
38	Materials and Methods — Data preprocessing — miRNA expression data preprocessing	confidence interval in the score space. One array was defined as an outlier by PCA, two additional…
39	Materials and Methods — Data preprocessing — mRNA expression data preprocessing	mRNA expression data was collected on the Affymetrix human GeneChip HGU133 Plus 2.0 array and…

Name	Type
40 subjects local	cohort
70 human subjects local	cohort
abdominal adipose local	cohort
Abdominal adipose local	cohort
abdominal adipose cohort local	cohort
abdominal adipose tissue local	cohort
abdominal adipose tissue local	drug
abdominal adipose tissue	phenotype
abdominal tissue local	anatomy
Abdominal tissue local	drug
ACVR2B local	gene
adipocyte differentiation	phenotype
Adipocytokine signalling pathway local	drug
adipose tissue	phenotype
adipose tissue depots local	phenotype
adipose tissue development local	phenotype
adipose tissue distribution local	phenotype
adiposity	phenotype
adverse metabolic outcomes local	phenotype
adverse metabolic risk local	phenotype
Affymetrix GeneChip HGU133 Plus 2.0 array local	drug
Affymetrix human GeneChip HGU133 Plus 2.0 array local	drug
age	phenotype
android fat distribution local	phenotype
Batch (96-well plate) local	drug
blood pressure	phenotype
BMI	phenotype
body mass index	phenotype
case-control status local	cohort
case group	cohort
cis-located genetic variants local	variant
cis miRNA eQTL local	variant
cis-SNPs local	variant
common variants	cohort
control group	cohort
custom chip-definition files (CDFs) local	drug
dyslipidaemia local	phenotype
Ensembl-annotated gene local	gene
Fasting glucose level local	phenotype
fat distribution	phenotype
GeneCatcher™ local	drug
general metabolic deregulation local	phenotype
genetic variants	cohort
GenomeStudio version 1.6.0 local	drug
Genotype detection local	phenotype
GIANT consortium	cohort
gluteal adipose local	cohort
Gluteal adipose local	cohort
gluteal adipose cohort local	cohort
gluteal adipose tissue local	cohort
gluteal adipose tissue local	drug
gluteal adipose tissue local	phenotype
gluteal tissue local	anatomy
Gluteal tissue local	drug
gynoid fat distribution local	phenotype
HC	cohort
healthy controls	cohort
High-density lipoprotein level local	phenotype
hsa-miR-10a local	drug
hsa-miR-10b local	drug
hsa-miR-1179 local	drug
hsa-miR-1255a local	drug
hsa-miR-128 local	gene
hsa-miR-141 local	gene
hsa-miR-181a local	gene
hsa-miR-183 local	gene
hsa-miR-186 local	gene
hsa-miR-195 local	drug
hsa-miR-196b local	gene
hsa-miR-199a-5p local	drug
hsa-miR-204 local	drug
hsa-miR-211 local	drug
hsa-miR-27b local	drug
hsa-miR-27b local	gene
hsa-miR-28-5p local	drug
hsa-miR-28-5p local	gene
hsa-miR-30a local	gene
hsa-miR-30d local	gene
hsa-miR-326 local	drug
hsa-miR-326 local	gene
hsa-miR-331-3p local	drug
hsa-miR-335* local	drug
hsa-miR-340 local	gene
hsa-miR-34a local	drug
hsa-miR-365 local	drug
hsa-miR-503 local	drug
hsa-miR-519d local	drug
hsa-miR-519d local	gene
hsa-miR-520c-3p local	gene
hsa-miR-520f local	gene
hsa-miR-590-3p local	gene
hsa-miR-652 local	drug
hsa-miR-7-2* local	drug
hsa-miR-7-2* local	gene
human fibroblasts	cohort
human fibroblasts local	drug
hypertension	phenotype
IDF criteria local	phenotype
Illumina 317 k Beadchip platform local	drug
Illumina 317k Beadchip platform local	drug
Illumina BeadArray scanner local	drug
Illumina miRNA BeadArray platform local	drug
increased morbidity local	phenotype
INS	gene
Insulin signaling pathway local	drug
International Diabetes Foundation criteria local	phenotype
Isl1	gene
KEGG terms local	drug
KEGG terms local	phenotype
MAPK signaling pathway	drug
MassARRAY platform local	drug
metabolic disorders	phenotype
metabolic dysregulation local	phenotype
metabolic syndrome	phenotype
Metabolic syndrome case local	phenotype
Metabolic syndrome case-control cohort local	cohort
metabolic syndrome case group local	cohort
metabolic syndrome cases local	cohort
Metabolic syndrome control local	phenotype
metabolic syndrome group local	cohort
metabolism	phenotype
miRNA	drug
miRNA local	gene
miRNA eQTL local	variant
miRNA eQTL SNP local	variant
miRNA expression local	drug
miRNA expression	phenotype
MolOBB study local	cohort
mRNA	drug
obesity	phenotype
obesity-related phenotype	phenotype
Oxford Biobank local	cohort
primary study local	cohort
Primary study local	cohort
Primary Study local	cohort
PSKH1 local	gene
RMA method local	drug
RNA	drug
rodent models of T2D local	cohort
Sequenom iPLEX assay local	drug
severe disease local	phenotype
sex	phenotype
SNP	cohort
SNP variant local	variant
study cohort	cohort
Study samples local	cohort
target mRNA local	gene
tissue	anatomy
tissue development local	phenotype
triglyceride levels	phenotype
TRIreagent local	drug
TRI Reagent local	drug
type 2 diabetes	phenotype
Type II diabetes mellitus local	phenotype
Universal-12 Illumina BeadChip local	drug
waist circumference	phenotype
waist hip ratio corrected for BMI local	phenotype

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