-
[show abstract]
[hide abstract]
ABSTRACT: The expansion of lower-body adipose tissue (AT) is paradoxically associated with reduced cardiovascular disease and diabetes risk. We examined whether the beneficial metabolic properties of lower-body AT are related to the production and release of the insulin-sensitizing lipokine palmitoleate (16:1n-7). Using venoarterial difference sampling, we investigated the relative release of 16:1n-7 from lower-body (gluteofemoral) and upper-body (abdominal subcutaneous) AT depots. Paired gluteofemoral and abdominal subcutaneous AT samples were analyzed for triglyceride fatty acid composition and mRNA expression. Finally, the triglyceride fatty acid composition of isolated human preadipocytes was determined. Relative release of 16:1n-7 was markedly higher from gluteofemoral AT compared with abdominal subcutaneous AT. Stearoyl-CoA desaturase 1 (SCD1), the key enzyme involved in endogenous 16:1n-7 production, was more highly expressed in gluteofemoral AT and was associated with greater enrichment of 16:1n-7. Furthermore, isolated human preadipocytes from gluteofemoral AT displayed a higher content of SCD1-derived fatty acids. We demonstrate that human gluteofemoral AT plays a major role in determining systemic concentrations of the lipokine palmitoleate. Moreover, this appears to be an inherent feature of gluteofemoral AT. We propose that the beneficial metabolic properties of lower-body AT may be partly explained by the intrinsically greater production and release of palmitoleate.
Diabetes 04/2012; 61(6):1399-403. · 8.29 Impact Factor
-
Josine L Min,
George Nicholson,
Ingileif Halgrimsdottir,
Kristian Almstrup,
Andreas Petri,
Amy Barrett,
Mary Travers,
Nigel W Rayner,
Reedik Mägi,
Fredrik H Pettersson, [......],
Quin F Wills,
Jane Cheeseman,
Maxine Allen,
Chris C Holmes,
Tim D Spector,
Jan Fleckner,
Mark I McCarthy,
Fredrik Karpe,
Cecilia M Lindgren,
Krina T Zondervan
[show abstract]
[hide abstract]
ABSTRACT: Metabolic Syndrome (MetS) is highly prevalent and has considerable public health impact, but its underlying genetic factors remain elusive. To identify gene networks involved in MetS, we conducted whole-genome expression and genotype profiling on abdominal (ABD) and gluteal (GLU) adipose tissue, and whole blood (WB), from 29 MetS cases and 44 controls. Co-expression network analysis for each tissue independently identified nine, six, and zero MetS-associated modules of coexpressed genes in ABD, GLU, and WB, respectively. Of 8,992 probesets expressed in ABD or GLU, 685 (7.6%) were expressed in ABD and 51 (0.6%) in GLU only. Differential eigengene network analysis of 8,256 shared probesets detected 22 shared modules with high preservation across adipose depots (D(ABD-GLU) = 0.89), seven of which were associated with MetS (FDR P<0.01). The strongest associated module, significantly enriched for immune response-related processes, contained 94/620 (15%) genes with inter-depot differences. In an independent cohort of 145/141 twins with ABD and WB longitudinal expression data, median variability in ABD due to familiality was greater for MetS-associated versus un-associated modules (ABD: 0.48 versus 0.18, P = 0.08; GLU: 0.54 versus 0.20, P = 7.8×10(-4)). Cis-eQTL analysis of probesets associated with MetS (FDR P<0.01) and/or inter-depot differences (FDR P<0.01) provided evidence for 32 eQTLs. Corresponding eSNPs were tested for association with MetS-related phenotypes in two GWAS of >100,000 individuals; rs10282458, affecting expression of RARRES2 (encoding chemerin), was associated with body mass index (BMI) (P = 6.0×10(-4)); and rs2395185, affecting inter-depot differences of HLA-DRB1 expression, was associated with high-density lipoprotein (P = 8.7×10(-4)) and BMI-adjusted waist-to-hip ratio (P = 2.4×10(-4)). Since many genes and their interactions influence complex traits such as MetS, integrated analysis of genotypes and coexpression networks across multiple tissues relevant to clinical traits is an efficient strategy to identify novel associations.
PLoS Genetics 02/2012; 8(2):e1002505. · 8.69 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: The primary products of de novo lipogenesis (DNL) are saturated fatty acids, which confer adverse cellular effects. Human adipocytes differentiated with no exogenous fat accumulated triacylglycerol (TG) in lipid droplets and differentiated normally. TG composition showed the products of DNL (saturated fatty acids from 12:0 to 18:0) together with unsaturated fatty acids (particularly 16:1n-7 and 18:1n-9) produced by elongation/desaturation. There was parallel upregulation of expression of genes involved in DNL and in fatty acid elongation and desaturation, suggesting coordinated control of expression. Enzyme products (desaturation ratios, elongation ratios, and total pathway flux) were also correlated with mRNA levels. We used (13)C-labeled substrates to study the pathway of DNL. Glucose (5 mM or 17.5 mM in the medium) provided less than half the carbon used for DNL (42% and 47%, respectively). Glutamine (2 mM) provided 9-10%, depending upon glucose concentration. In contrast, glucose provided most (72%) of the carbon of TG-glycerol. Pathway analysis using mass isotopomer distribution analysis (MIDA) revealed that the pathway for conversion of glucose to palmitate is complex. DNL in human fat cells is tightly coupled with further modification of fatty acids to produce a range of saturated and unsaturated fatty acids consistent with normal maturation.
The Journal of Lipid Research 06/2011; 52(9):1683-92. · 5.56 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: The accurate quantification of cellular and tissue mRNA and microRNA content is reliant upon the selection of stable endogenous control transcripts for normalizing quantitative real-time-PCR (qRT-PCR) data. Using the combination of unbiased and informed approaches and a wide range of human adipose tissues and cells, we sought to identify invariant control transcripts for mRNA and microRNA. A total of 26 mRNA transcript candidates were selected from the literature. MicroRNA candidates were selected from a microRNA-microarray (Agilent, n = 22 tissues), and together with candidates from the literature resulted in 14 different microRNAs. The variability of these mRNA and microRNA transcripts were then tested in a large (n = 180) collection of a variety of human adipose tissues and cell samples. Phosphoglycerate kinase-1 (PGK1) and peptidylprolyl isomerase A (PPIA) were identified as the most stable mRNAs across all tissues and panels. MiR-103 was overall the most stable microRNA transcript across all biological backgrounds. Several proposed and commonly used normalization transcripts were found to be highly variable. We then tested the effect on expression of two established adipocyte-related transcripts (fatty acid binding protein 4 (FABP4) and microRNA-145 (miR-145)), either normalized to the optimal or a commonly used controls transcript. This test clearly indicated that spurious results could arise from using less stable control transcripts for mRNA and microRNA qRT-PCR.
Obesity 04/2011; 19(4):888-92. · 4.28 Impact Factor
-
Iris M Heid,
Anne U Jackson,
Joshua C Randall,
Thomas W Winkler,
Lu Qi,
Valgerdur Steinthorsdottir,
Gudmar Thorleifsson,
M Carola Zillikens,
Elizabeth K Speliotes,
Reedik Mägi, [......],
Unnur Thorsteinsdottir,
Cornelia M van Duijn,
Kari Stefansson,
L Adrienne Cupples,
Ruth J F Loos,
Inês Barroso,
Mark I McCarthy,
Caroline S Fox,
Karen L Mohlke,
Cecilia M Lindgren
Nature Genetics 01/2011; 43(11):1164. · 35.53 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: A feature of the Asian Indian phenotype is low birth weight with increased adult type 2 diabetes risk. Most populations show consistent associations between low birth weight and adult type 2 diabetes. Recently, two birth weight-lowering loci on chromosome 3 (near CCNL1 and ADCY5) were identified in a genome-wide association study, the latter of which is also a type 2 diabetes locus. We therefore tested the impact of these genetic variants on birth weight and adult glucose/insulin homeostasis in a large Indian birth cohort.
Adults (n = 2,151) enrolled in a birth cohort (established 1969-73) were genotyped for rs900400 (near CCNL1) and rs9883204 (ADCY5). Associations were tested for birth weight, anthropometry from infancy to adulthood, and type 2 diabetes related glycemic traits. The average birth weight in this population was 2.79±0.47 kg and was not associated with genetic variation in CCNL1 (p = 0.87) or ADCY5 (p = 0.54). Allele frequencies for the 'birth weight-lowering' variants were similar compared with Western populations. There were no significant associations with growth or adult weight. However, the 'birth weight-lowering' variant of ADCY5 was associated with modest increase in fasting glucose (β 0.041, p = 0.027), 2-hours glucose (β 0.127, p = 0.019), and reduced insulinogenic index (β -0.106, p = 0.050) and 2-hour insulin (β -0.058, p = 0.010).
The low birth weight in Asian Indians is not even partly explained by genetic variants near CCNL1 and ADCY5 which implies that non-genetic factors may predominate. However, the 'birth-weight-lowering' variant of ADCY5 was associated with elevated glucose and decreased insulin response in early adulthood which argues for a common genetic cause of low birth weight and risk of type 2 diabetes.
PLoS ONE 01/2011; 6(6):e21331. · 4.09 Impact Factor
-
Mattias Rantalainen,
Blanca M Herrera,
George Nicholson,
Rory Bowden,
Quin F Wills,
Josine L Min, Matt J Neville,
Amy Barrett,
Maxine Allen,
Nigel W Rayner,
Jan Fleckner,
Mark I McCarthy,
Krina T Zondervan,
Fredrik Karpe,
Chris C Holmes,
Cecilia M Lindgren
[show abstract]
[hide abstract]
ABSTRACT: To understand how miRNAs contribute to the molecular phenotype of adipose tissues and related traits, we performed global miRNA expression profiling in subcutaneous abdominal and gluteal adipose tissue of 70 human subjects and characterised which miRNAs were differentially expressed between these tissues. We found that 12% of the miRNAs were significantly differentially expressed between abdominal and gluteal adipose tissue (FDR adjusted p<0.05) in the primary study, of which 59 replicated in a follow-up study of 40 additional subjects. Further, 14 miRNAs were found to be associated with metabolic syndrome case-control status in abdominal tissue and three of these replicated (primary study: FDR adjusted p<0.05, replication: p<0.05 and directionally consistent effect). Genome-wide genotyping was performed in the 70 subjects to enable miRNA expression quantitative trait loci (eQTL) analysis. Candidate miRNA eQTLs were followed-up in the additional 40 subjects and six significant, independent cis-located miRNA eQTLs (primary study: p<0.001; replication: p<0.05 and directionally consistent effect) were identified. Finally, global mRNA expression profiling was performed in both tissues to enable association analysis between miRNA and target mRNA expression levels. We find 22% miRNAs in abdominal and 9% miRNAs in gluteal adipose tissue with expression levels significantly associated with the expression of corresponding target mRNAs (FDR adjusted p<0.05). Taken together, our results indicate a clear difference in the miRNA molecular phenotypic profile of abdominal and gluteal adipose tissue, that the expressions of some miRNAs are influenced by cis-located genetic variants and that miRNAs are associated with expression levels of their predicted mRNA targets.
PLoS ONE 01/2011; 6(11):e27338. · 4.09 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Possession of the APOE-ε4 allele is the best established genetic risk factor for sporadic Alzheimer's disease (AD), while the ε2 allele may confer protection against the disease. Previous functional magnetic resonance imaging (fMRI) studies have shown an effect of APOE genotype on brain function, typically by comparing only ε4 carriers with noncarriers. Here we included a wide range of genotype groups to determine how closely the effects of APOE on brain function are related to differences in relative risk for AD. We used functional magnetic resonance imaging (fMRI) to compare the pattern of activation during an episodic encoding task and during a counting Stroop task in 76 adults, aged 32 to 55, with different APOE genotypes (23 ε2/ε3, 20 ε3/ε3, 26 ε3/ε4, and 7 ε4/ε4). Strikingly, participants with an increased risk (ε4 carriers) and with a decreased risk (ε2 carriers) for AD both showed increased activation, relative to ε3 homozygotes, during both tasks. The increased activation was due to decreased deactivation or paradoxical activation of nontask-related regions of the brain, which suggests an intrinsic effect of APOE on the differentiation of functional cortical networks. These results question the often assumed link between APOE, the blood oxygenation level dependent (BOLD) response, and AD risk.
Neurobiology of aging 01/2011; 33(3):618.e1-618.e13. · 5.94 Impact Factor
-
Iris M Heid,
Anne U Jackson,
Joshua C Randall,
Thomas W Winkler,
Lu Qi,
Valgerdur Steinthorsdottir,
Gudmar Thorleifsson,
M Carola Zillikens,
Elizabeth K Speliotes,
Reedik Mägi, [......],
Unnur Thorsteinsdottir,
Cornelia M van Duijn,
Kari Stefansson,
L Adrienne Cupples,
Ruth J F Loos,
Inês Barroso,
Mark I McCarthy,
Caroline S Fox,
Karen L Mohlke,
Cecilia M Lindgren
[show abstract]
[hide abstract]
ABSTRACT: Waist-hip ratio (WHR) is a measure of body fat distribution and a predictor of metabolic consequences independent of overall adiposity. WHR is heritable, but few genetic variants influencing this trait have been identified. We conducted a meta-analysis of 32 genome-wide association studies for WHR adjusted for body mass index (comprising up to 77,167 participants), following up 16 loci in an additional 29 studies (comprising up to 113,636 subjects). We identified 13 new loci in or near RSPO3, VEGFA, TBX15-WARS2, NFE2L3, GRB14, DNM3-PIGC, ITPR2-SSPN, LY86, HOXC13, ADAMTS9, ZNRF3-KREMEN1, NISCH-STAB1 and CPEB4 (P = 1.9 × 10⁻⁹ to P = 1.8 × 10⁻⁴⁰) and the known signal at LYPLAL1. Seven of these loci exhibited marked sexual dimorphism, all with a stronger effect on WHR in women than men (P for sex difference = 1.9 × 10⁻³ to P = 1.2 × 10⁻¹³). These findings provide evidence for multiple loci that modulate body fat distribution independent of overall adiposity and reveal strong gene-by-sex interactions.
Nature Genetics 10/2010; 42(11):949-60. · 35.53 Impact Factor
-
Elizabeth K Speliotes,
Cristen J Willer,
Sonja I Berndt,
Keri L Monda,
Gudmar Thorleifsson,
Anne U Jackson,
Hana Lango Allen,
Cecilia M Lindgren,
Jian'an Luan,
Reedik Mägi, [......],
Unnur Thorsteinsdottir,
Gonçalo R Abecasis,
Inês Barroso,
Michael Boehnke,
Kari Stefansson,
Kari E North,
Mark I McCarthy,
Joel N Hirschhorn,
Erik Ingelsson,
Ruth J F Loos
[show abstract]
[hide abstract]
ABSTRACT: Obesity is globally prevalent and highly heritable, but its underlying genetic factors remain largely elusive. To identify genetic loci for obesity susceptibility, we examined associations between body mass index and ∼ 2.8 million SNPs in up to 123,865 individuals with targeted follow up of 42 SNPs in up to 125,931 additional individuals. We confirmed 14 known obesity susceptibility loci and identified 18 new loci associated with body mass index (P < 5 × 10⁻⁸), one of which includes a copy number variant near GPRC5B. Some loci (at MC4R, POMC, SH2B1 and BDNF) map near key hypothalamic regulators of energy balance, and one of these loci is near GIPR, an incretin receptor. Furthermore, genes in other newly associated loci may provide new insights into human body weight regulation.
Nature Genetics 10/2010; 42(11):937-48. · 35.53 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: De novo lipogenesis (DNL) is paradoxically up-regulated by its end product, saturated fatty acids (SAFAs). We tested the hypothesis that SAFA-induced up-regulation of DNL reflects coordinate up-regulation of elongation and desaturation pathways for disposal of SAFAs and production of monounsaturated fatty acids to protect cells from SAFA toxicity. Human preadipocytes were differentiated in vitro for 14 days with [U-(13)C]palmitate (0-200 microM) to distinguish exogenous fatty acids from those synthesized by DNL. Exogenous palmitate up-regulated DNL (p < 0.001) concomitantly with SCD and elongation (each p < 0.001). Adipocytes from some donors were intolerant to high palmitate concentrations (400 microM). Palmitate-intolerant cells showed lower TG accumulation. They had lower expression of SCD mRNA and less monounsaturated fatty acids in TG, emphasizing the importance of desaturation for dealing with exogenous SAFAs. There was greater [U-(13)C]palmitate incorporation in phospholipids. SCD knockdown with small interfering RNA caused down-regulation of DNL and of expression of DNL-related genes, with reduced membrane fluidity (p < 0.02) and insulin sensitivity (p < 0.01), compared with scrambled small interfering RNA controls. There was preferential channeling of DNL-derived versus exogenous palmitate into elongation and of DNL-derived versus exogenous stearate into desaturation. DNL may not act primarily to increase fat stores but may serve as a key regulator, in tandem with elongation and desaturation, to maintain cell membrane fluidity and insulin sensitivity within the human adipocyte.
Journal of Biological Chemistry 02/2010; 285(9):6044-52. · 4.77 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: The aim of this study was to identify potential protein targets for insulin sensitization in human adipose tissue using unbiased proteomic approaches. Ten moderately obese, but otherwise healthy, subjects were treated with rosiglitazone 4 mg b.i.d. for 14 days and global protein and gene expression changes were monitored. Proteomic analysis revealed distinct up- or downregulation (greater than twofold) in 187 protein spots on the two-dimensional (2-D) gel images between day 0 and day 1 adipose tissue samples. When comparing the protein spots on the gels from day 0 with that of 14-day-treated samples, 122 spots showed differential expression. There was a striking increase in the expression of proteins involved in glucose transporter-4 (GLUT4) granule transport and fusion (actin, myosin-9, tubulin, vimentin, annexins, moesin, LIM, and SH3 domain protein-1), signaling (calmodulin, guanine nucleotide-binding proteins), redox regulation (superoxide dismutase, catalase, ferritin, transferrin, heat shock proteins), and adipogenesis (collagens, galectin-1, nidogen-1, laminin, lamin A/C). However, there was an intriguing absence of correlated changes in mRNA expression, suggesting adaptation at a post-transcriptional level in response to rosiglitazone. Thus, the major changes observed were among proteins involved in cytoskeletal rearrangement, insulin and calcium signaling, and inflammatory and redox signals that decisively upregulate GLUT4 granule trafficking in human adipose tissue. Such orchestrated changes in expression of multiple proteins provide insights into the mechanism underlying the increased efficiency in glucose uptake and improvement of insulin sensitivity in response to rosiglitazone treatment.
Obesity 07/2009; 18(1):27-34. · 4.28 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Polymorphisms for the microsomal triglyceride transfer protein (MTTP) gene have been associated with longevity and with lower risk for cardiovascular mortality. However, the association of MTTP with longevity has been contested in a large German collection of nonagenarians and centenarians.
We made a detailed characterization of MTTP haplotype carrier status in a cohort of 1398 old men and women (mean age 78 years) and a population-based cohort (n = 777) of younger controls (mean age 40 years) in Oxford, England.
There were no significant differences in haplotypes for MTTP gene between the younger and older age groups.
This study, which adopted a more detailed genetic analysis of the MTTP gene in a large case-control study of older people provides reliable evidence against any significant association of the MTTP gene with longevity.
The Journals of Gerontology Series A Biological Sciences and Medical Sciences 03/2007; 62(2):202-5. · 4.60 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Fatty acid desaturases such as steaoryl-CoA desaturase (SCD) convert saturated to unsaturated fatty acids and are involved in lipogenesis. Observational and animal data suggest that SCD-1 activity is related to insulin sensitivity. However, the effects of insulin-sensitizing drugs on SCD gene expression and desaturase activities are unknown in humans. In a randomized, placebo-controlled, double-blind, crossover study, 24 subjects with type 2 diabetes and one subject with partial lipodystrophy and diabetes due to dominant-negative mutation in the peroxisome proliferator-activated receptor-gamma (PPARgamma) gene (P467L) received placebo and rosiglitazone for 3 months. SCD gene expression in adipose tissue was determined in 23 subjects, and in a representative subgroup (n = 10) we assessed fatty acid composition in fasting plasma triglycerides to estimate SCD and delta6- and delta5-desaturase activity, using product-to-precursor indexes. SCD mRNA expression increased by 48% after rosiglitazone (P < 0.01). SCD and delta5-desaturase but not delta6-desaturase activity indexes were increased after rosiglitazone versus placebo (P < 0.01 and P < 0.05, respectively). The change in activity index but not the expression of SCD was associated with improved insulin sensitivity (r = 0.73, P < 0.05). In the P467L PPARgamma carrier, SCD and delta5-desaturase activity indexes were exceptionally low but were restored (52- and 15-fold increases, respectively) after rosiglitazone treatment. This study shows for the first time that rosiglitazone increases SCD activity indexes and gene expression in humans. An increased SCD activity index may reflect increased lipogenesis and might contribute to insulin sensitization by rosiglitazone. The restored SCD activity index after rosiglitazone in PPARgamma mutation supports a pivotal role of PPARgamma function in SCD regulation.
Diabetes 06/2005; 54(5):1379-84. · 8.29 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Cytochrome P450 2B6 (CYP2B6) has a role in the metabolism of many clinically important substances, but the variation within the CYP2B6 gene has not been fully characterized. The aim of the present study was to develop a reliable and robust assay for determining genotypic variants.
We used a two-stage procedure. An initial multiplex PCR reaction amplified the relevant gene fragments in exonic and regulatory regions to ensure isolation of CYP2B6 from its similar pseudogene (CYP2B7). This product was then genotyped by allele-specific PCR.
The assay detected the following published single-nucleotide polymorphisms: C64T (Arg22Cys), C78T, G216C, G516T (Gln172His), C777A (Ser259Arg), A785G (Lys262Arg), and C1459T (Arg487Cys), as well as additional loci found within the single-nucleotide polymorphism (SNP) databases: A1190G, C1268A, C1330T, A1382G, A1402T, and an A/T SNP in intron 2 (A12917T). This approach detected all common, previously reported alleles and identified a new allele (CYP2B6*4C) present in 2.2% of a Caucasian population. Genotypic frequencies obtained were consistent with previously published results.
This method is simple, reliable, rapid, and amenable to automation and could facilitate the large-scale genotypic analysis of CYP2B6.
Clinical Chemistry 09/2004; 50(8):1372-7. · 7.91 Impact Factor
-
Jin Hong Low,
Fiona A Williams,
Xuesong Yang,
Sue Cullen,
James Colley,
Khoon Lin Ling,
Alessandro Armuzzi,
Tariq Ahmad, Matt J Neville,
Bryan M Dechairo,
Robert Walton,
Nick J Lench,
Derek P Jewell
[show abstract]
[hide abstract]
ABSTRACT: Genome-wide scans have implicated several susceptibility loci, but linkage of 19p13 (IBD6) to Crohn's disease (CD) has not been fully replicated. We report a replication study of IBD6 in a UK Caucasian population. Two hundred eighty-four affected sibling pairs from 234 families were used for the linkage study. Linkage between IBD6 linkage and CD was replicated (LOD score = 1.59). Two candidate genes (DDXL and ICAM-1) within the IBD6 locus were examined in a case/control study with a total of 228 CD and 243 ulcerative colitis (UC) patients and 407 healthy controls. No association to either UC or CD was found in three novel intronic single nucleotide polymorphisms (SNPs) in DDXL. For ICAM-1, a significant association was found between K469 homozygosity and CD overall (39.9% vs 29.4%; Pc = 0.0096) and between E469 and fistulating disease (21.8% vs 10.0%, Pc = 0.030). In the UC group, limited disease extent was associated with homozygosity of the G241 allele (82.7% vs 64.7%, Pc = 0.0040). These data support linkage for CD at 19p13 and suggest that the amino acid polymorphisms in ICAM-1 may be associated with IBD.
Inflammatory Bowel Diseases 06/2004; 10(3):173-81. · 4.86 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: The dopamine D2 receptor has been extensively studied in relation to alcoholism, substance abuse, and nicotine dependence. The most frequently examined polymorphism linked to this gene is the Taq1A restriction fragment length polymorphism (RFLP) (dbSNP rs1800497; g.32806C>T in GenBank AF050737.1), which has been associated with a reduction in D2 receptor density, although this is not universally accepted. The Taq1A RFLP lies 10 kB downstream of DRD2 and may therefore fall within a different coding region than the DRD2 gene or within a regulatory region. Within this downstream region, we have identified a novel kinase gene, named ankyrin repeat and kinase domain containing 1 (ANKK1), which contains a single serine/threonine kinase domain and is expressed at low levels in placenta and whole spinal cord RNA. This gene is a member of an extensive family of proteins involved in signal transduction pathways. The DRD2 Taq1A RFLP is a single nucleotide polymorphism (SNP) that causes an amino acid substitution within the 11th ankyrin repeat of ANKK1 (p.Glu713Lys), which, while unlikely to affect structural integrity, may affect substrate-binding specificity. If this is the case, then changes in ANKK1 activity may provide an alternative explanation for previously described associations between the DRD2 Taq1A RFLP and neuropsychiatric disorders such as addiction.
Human Mutation 06/2004; 23(6):540-5. · 5.69 Impact Factor
-
Iris M Heid,
Anne U Jackson,
Joshua C Randall,
Thomas W Winkler,
Lu Qi,
Valgerdur Steinthorsdottir,
Gudmar Thorleifsson,
M Carola Zillikens,
Elizabeth K Speliotes,
Reedik Mägi, [......],
Unnur Thorsteinsdottir,
Cornelia M van Duijn,
Kari Stefansson,
L Adrienne Cupples,
Ruth J F Loos,
Inês Barroso,
Mark I McCarthy,
Caroline S Fox,
Karen L Mohlke,
Cecilia M Lindgren
-
Elizabeth K Speliotes,
Cristen J Willer,
Sonja I Berndt,
Keri L Monda,
Gudmar Thorleifsson,
Anne U Jackson,
Hana Lango Allen,
Cecilia M Lindgren,
Jian'an Luan,
Reedik Mägi, [......],
Unnur Thorsteinsdottir,
Gonçalo R Abecasis,
Inês Barroso,
Michael Boehnke,
Kari Stefansson,
Kari E North,
Mark I McCarthy,
Joel N Hirschhorn,
Erik Ingelsson,
Ruth J F Loos
