| 1. |
- Lindgren, Cecilia M, et al.
(författare)
-
Genome-wide association scan meta-analysis identifies three Loci influencing adiposity and fat distribution.
- 2009
-
Ingår i: PLoS genetics. - : Public Library of Science (PLoS). - 1553-7404. ; 5:6, s. e1000508-
-
Tidskriftsartikel (refereegranskat)abstract
- To identify genetic loci influencing central obesity and fat distribution, we performed a meta-analysis of 16 genome-wide association studies (GWAS, N = 38,580) informative for adult waist circumference (WC) and waist-hip ratio (WHR). We selected 26 SNPs for follow-up, for which the evidence of association with measures of central adiposity (WC and/or WHR) was strong and disproportionate to that for overall adiposity or height. Follow-up studies in a maximum of 70,689 individuals identified two loci strongly associated with measures of central adiposity; these map near TFAP2B (WC, P = 1.9x10(-11)) and MSRA (WC, P = 8.9x10(-9)). A third locus, near LYPLAL1, was associated with WHR in women only (P = 2.6x10(-8)). The variants near TFAP2B appear to influence central adiposity through an effect on overall obesity/fat-mass, whereas LYPLAL1 displays a strong female-only association with fat distribution. By focusing on anthropometric measures of central obesity and fat distribution, we have identified three loci implicated in the regulation of human adiposity.
|
|
| 2. |
- Willer, Cristen J., et al.
(författare)
-
Six new loci associated with body mass index highlight a neuronal influence on body weight regulation
- 2009
-
Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 41:1, s. 25-34
-
Tidskriftsartikel (refereegranskat)abstract
- Common variants at only two loci, FTO and MC4R, have been reproducibly associated with body mass index (BMI) in humans. To identify additional loci, we conducted meta-analysis of 15 genome-wide association studies for BMI (n > 32,000) and followed up top signals in 14 additional cohorts (n > 59,000). We strongly confirm FTO and MC4R and identify six additional loci (P < 5 x 10(-8)): TMEM18, KCTD15, GNPDA2, SH2B1, MTCH2 and NEGR1 (where a 45-kb deletion polymorphism is a candidate causal variant). Several of the likely causal genes are highly expressed or known to act in the central nervous system (CNS), emphasizing, as in rare monogenic forms of obesity, the role of the CNS in predisposition to obesity.
|
|
| 3. |
- Zeggini, Eleftheria, et al.
(författare)
-
Meta-analysis of genome-wide association data and large-scale replication identifies additional susceptibility loci for type 2 diabetes
- 2008
-
Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 40:5, s. 638-645
-
Tidskriftsartikel (refereegranskat)abstract
- Genome-wide association (GWA) studies have identified multiple loci at which common variants modestly but reproducibly influence risk of type 2 diabetes (T2D)(1-11). Established associations to common and rare variants explain only a small proportion of the heritability of T2D. As previously published analyses had limited power to identify variants with modest effects, we carried out meta-analysis of three T2D GWA scans comprising 10,128 individuals of European descent and similar to 2.2 million SNPs (directly genotyped and imputed), followed by replication testing in an independent sample with an effective sample size of up to 53,975. We detected at least six previously unknown loci with robust evidence for association, including the JAZF1 (P=5.0 x 10(-14)), CDC123-CAMK1D (P=1.2 x 10(-10)), TSPAN8-LGR5 (P=1.1 x 10(-9)), THADA (P=1.1 x 10(-9)), ADAMTS9 (P=1.2 x 10(-8)) and NOTCH2 (P=4.1 x 10(-8)) gene regions. Our results illustrate the value of large discovery and follow-up samples for gaining further insights into the inherited basis of T2D.
|
|
| 4. |
- Holmkvist, Johan, et al.
(författare)
-
Common variants in maturity-onset diabetes of the young genes and future risk of type 2 diabetes
- 2008
-
Ingår i: Diabetes. - : American Diabetes Association. - 1939-327X .- 0012-1797. ; 57:6, s. 1738-1744
-
Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE-Mutations in the hepatocyte nuclear factor (HNF)-1 alpha, HNF-4 alpha, glucokinase (GCK), and HNF-1 beta genes cause maturity-onset diabetes of the young (MODY), but it is not known whether common variants in these genes predict future type 2 diabetes. RESEARCH DESIGN AND METHODS-We tested 14 previously associated polymorphisms in HNF-1 alpha, HNF-4 alpha, GCK, and HNF-1 beta for association with type 2 diabetes-related traits and future risk of type 2 diabetes in 2,293 individuals from the Botnia study (Finland) and in 15,538 individuals from the Malmo Preventive Project (Sweden) with a total follow-up >360,000 years. RESULTS-The polymorphism rs1169288 in HNF-1 alpha strongly predicted future type 2 diabetes (hazard ratio [HR] 1.2, P = 0.0002). Also, SNPs rs4810424 and rs3212198 in HNF-4a nominally predicted future type 2 diabetes (HR 1.3 [95% CI 1.0-1.6], P = 0.03; and 1.1 [1.0-1.2], P = 0.04). The rs2144908 polymorphism in HNF-4 alpha was associated with elevated rate of hepatic glucose production during a hyperinsulinemic-euglycemic clamp (P = 0.03) but not with deterioration of insulin secretion over time. The SNP rs1799884 in the GCK promoter was associated with elevated fasting plasma glucose (fPG) concentrations that remained unchanged during the follow-up period (P = 0.4; SE 0.004 [-0.003-0.007]) but did not predict future type 2 diabetes (HR 0.9 [0.8 -1.0], P = 0.1). Polymorphisms in HNF-1 beta (transcription factor 2 [TCF2]) did not significantly influence insulin or glucose values nor did they predict future type 2 diabetes. CONCLUSIONS-In conclusion, genetic variation in both HNF-1 alpha and HNF-4 alpha predict future type 2 diabetes, whereas variation in the GCK promoter results in a sustained but subtle elevation of fPG that is not sufficient to increase risk for future type 2 diabetes.
|
|
| 5. |
- Ling, Charlotte, et al.
(författare)
-
Genetic and epigenetic factors are associated with expression of respiratory chain component NDUFB6 in human skeletal muscle.
- 2007
-
Ingår i: The Journal of clinical investigation. - 0021-9738. ; 117:11, s. 3427-35
-
Tidskriftsartikel (refereegranskat)abstract
- Insulin resistance and type 2 diabetes are associated with decreased expression of genes that regulate oxidative phosphorylation in skeletal muscle. To determine whether this defect might be inherited or acquired, we investigated the association of genetic, epigenetic, and nongenetic factors with expression of NDUFB6, a component of the respiratory chain that is decreased in muscle from diabetic patients. Expression of NDUFB6 was influenced by age, with lower gene expression in muscle of elderly subjects. Heritability of NDUFB6 expression in muscle was estimated to be approximately 60% in twins. A polymorphism in the NDUFB6 promoter region that creates a possible DNA methylation site (rs629566, A/G) was associated with a decline in muscle NDUFB6 expression with age. Although young subjects with the rs629566 G/G genotype exhibited higher muscle NDUFB6 expression, this genotype was associated with reduced expression in elderly subjects. This was subsequently explained by the finding of increased DNA methylation in the promoter of elderly, but not young, subjects carrying the rs629566 G/G genotype. Furthermore, the degree of DNA methylation correlated negatively with muscle NDUFB6 expression, which in turn was associated with insulin sensitivity. Our results demonstrate that genetic, epigenetic, and nongenetic factors associate with NDUFB6 expression in human muscle and suggest that genetic and epigenetic factors may interact to increase age-dependent susceptibility to insulin resistance.
|
|
| 6. |
- Lyssenko, Valeriya, et al.
(författare)
-
Clinical risk factors, DNA variants, and the development of type 2 diabetes.
- 2008
-
Ingår i: New England Journal of Medicine. - 0028-4793. ; 359:21, s. 2220-2232
-
Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Type 2 diabetes mellitus is thought to develop from an interaction between environmental and genetic factors. We examined whether clinical or genetic factors or both could predict progression to diabetes in two prospective cohorts. METHODS: We genotyped 16 single-nucleotide polymorphisms (SNPs) and examined clinical factors in 16,061 Swedish and 2770 Finnish subjects. Type 2 diabetes developed in 2201 (11.7%) of these subjects during a median follow-up period of 23.5 years. We also studied the effect of genetic variants on changes in insulin secretion and action over time. RESULTS: Strong predictors of diabetes were a family history of the disease, an increased body-mass index, elevated liver-enzyme levels, current smoking status, and reduced measures of insulin secretion and action. Variants in 11 genes (TCF7L2, PPARG, FTO, KCNJ11, NOTCH2, WFS1, CDKAL1, IGF2BP2, SLC30A8, JAZF1, and HHEX) were significantly associated with the risk of type 2 diabetes independently of clinical risk factors; variants in 8 of these genes were associated with impaired beta-cell function. The addition of specific genetic information to clinical factors slightly improved the prediction of future diabetes, with a slight increase in the area under the receiver-operating-characteristic curve from 0.74 to 0.75; however, the magnitude of the increase was significant (P=1.0x10(-4)). The discriminative power of genetic risk factors improved with an increasing duration of follow-up, whereas that of clinical risk factors decreased. CONCLUSIONS: As compared with clinical risk factors alone, common genetic variants associated with the risk of diabetes had a small effect on the ability to predict the future development of type 2 diabetes. The value of genetic factors increased with an increasing duration of follow-up.
|
|
| 7. |
- Lyssenko, Valeriya, et al.
(författare)
-
Mechanisms by which common variants in the TCF7L2 gene increase risk of type 2 diabetes.
- 2007
-
Ingår i: Journal of Clinical Investigation. - 0021-9738. ; 117:8, s. 2155-2163
-
Tidskriftsartikel (refereegranskat)abstract
- Genetic variants in the gene encoding for transcription factor-7-like 2 (TCF7L2) have been associated with type 2 diabetes (T2D) and impaired beta cell function, but the mechanisms have remained unknown. We therefore studied prospectively the ability of common variants in TCF7L2 to predict future T2D and explored the mechanisms by which they would do this. Scandinavian subjects followed for up to 22 years were genotyped for 3 SNPs (rs7903146, rs12255372, and rs10885406) in TCF7L2, and a subset of them underwent extensive metabolic studies. Expression of TCF7L2 was related to genotype and metabolic parameters in human islets. The CT/TT genotypes of SNP rs7903146 strongly predicted future T2D in 2 independent cohorts (Swedish and Finnish). The risk T allele was associated with impaired insulin secretion, incretin effects, and enhanced rate of hepatic glucose production. TCF7L2 expression in human islets was increased 5-fold in T2D, particularly in carriers of the TT genotype. Overexpression of TCF7L2 in human islets reduced glucose-stimulated insulin secretion. In conclusion, the increased risk of T2D conferred by variants in TCF7L2 involves the enteroinsular axis, enhanced expression of the gene in islets, and impaired insulin secretion.
|
|
| 8. |
- Saxena, Richa, et al.
(författare)
-
Genome-wide association analysis identifies loci for type 2 diabetes and triglyceride levels
- 2007
-
Ingår i: Science. - : American Association for the Advancement of Science (AAAS). - 1095-9203 .- 0036-8075. ; 316:5829, s. 1331-1336
-
Tidskriftsartikel (refereegranskat)abstract
- New strategies for prevention and treatment of type 2 diabetes (T2D) require improved insight into disease etiology. We analyzed 386,731 common single-nucleotide polymorphisms (SNPs) in 1464 patients with T2D and 1467 matched controls, each characterized for measures of glucose metabolism, lipids, obesity, and blood pressure. With collaborators (FUSION and WTCCC/UKT2D), we identified and confirmed three loci associated with T2D - in a noncoding region near CDKN2A and CDKN2B, in an intron of IGF2BP2, and an intron of CDKAL1 - and replicated associations near HHEX and in SLC30A8 found by a recent whole-genome association study. We identified and confirmed association of a SNP in an intron of glucokinase regulatory protein (GCKR) with serum triglycerides. The discovery of associated variants in unsuspected genes and outside coding regions illustrates the ability of genome-wide association studies to provide potentially important clues to the pathogenesis of common diseases.
|
|
| 9. |
- Toenjes, Anke, et al.
(författare)
-
Genetic variation in GPR133 is associated with height: genome wide association study in the self-contained population of Sorbs
- 2009
-
Ingår i: Human Molecular Genetics. - : Oxford University Press (OUP). - 0964-6906 .- 1460-2083. ; 18:23, s. 4662-4668
-
Tidskriftsartikel (refereegranskat)abstract
- Recently, associations of several common genetic variants with height have been reported in different populations. We attempted to identify further variants associated with adult height in a self-contained population (the Sorbs in Eastern Germany) as discovery set. We performed a genome wide association study (GWAS) (similar to 390 000 genetic polymorphisms, Affymetrix gene arrays) on adult height in 929 Sorbian individuals. Subsequently, the best SNPs (P < 0.001) were taken forward to a meta-analysis together with two independent cohorts [Diabetes Genetics Initiative, British 1958 Birth Cohort, (58BC, publicly available)]. Furthermore, we genotyped our best signal for replication in two additional German cohorts (Leipzig, n = 1044 and Berlin, n = 1728). In the primary Sorbian GWAS, we identified 5 loci with a P-value < 10(-5) and 455 SNPs with P-value < 0.001. In the meta-analysis on those 455 SNPs, only two variants in GPR133 (rs1569019 and rs1976930; in LD with each other) retained a P-value at or below 10(-6) and were associated with height in the three cohorts individually. Upon replication, the SNP rs1569019 showed significant effects on height in the Leipzig cohort (P = 0.004, beta = 1.166) and in 577 men of the Berlin cohort (P = 0.049, beta = 1.127) though not in women. The combined analysis of all five cohorts (n = 6,687) resulted in a P-value of 4.7 x 10(-8) (beta = 0.949). In conclusion, our GWAS suggests novel loci influencing height. In view of the robust replication in five different cohorts, we propose GPR133 to be a novel gene associated with adult height.
|
|
| 10. |
- Arnfalk, Peter, et al.
(författare)
-
Miljöarbete inom Svensk Tillverkningsindustri. En färd från myt till verklighet
- 2008
-
Rapport (övrigt vetenskapligt/konstnärligt)abstract
- Föreliggande undersökning genomfördes under hösten och vintern 2007 av forskare vid Internatio-nella Institutet för Industriell Miljöekonomi (IIIEE) vid Lunds Universitet på uppdrag av Miljömålsrå-det. Syftet med undersökningen var att belysa dagens miljöarbete inom tillverkningsindustrin och göra jämförelser med resultat från tidigare motsvarande studier som genomfördes 1991 och 1998. Syftet var också att belysa hur och i vilken omfattning de nationella miljökvalitetsmålen påverkar företagens miljöarbete. Rapporten bidrog därmed till den samlade utvärderingen av arbetet med de nationella miljökvalitetsmålen som presenterades under våren 2008. Undersökningen baserades på telefonintervjuer med miljöansvariga/personer som konkret utför miljöarbete i 272 slumpvis valda tillverkande företag fördelade över landet i olika branscher och storleksklasser. Bortfallsfrekvensen var 16 procent. Miljöarbetet undersöktes genom vilka konkreta åtgärder som genomförts inom olika områden, hur dessa åtgärder speglas i den övergripande bil-den av företagets miljöaspekter, hur miljöarbetet organiserats och personalen involverats. En sam-lad bedömning av företagens miljöarbete gjordes genom att indela dem i olika kategorier. Katego-rierna motsvarar en femgradig ”betygsskala” från miljöpassiva till miljöanpassade strategier för mil-jöarbetet. Företagens drivkrafter, policies och motiv för miljöarbete undersöktes också. Under tidsperioden 1991- 2007 har tillverknings¬industrins miljöarbete suc¬cessivt förbättrats. Kategorimedelvärdet (”medel¬betyget”) har höjts mellan varje undersökningstillfälle, såväl totalt sett som inom varje storleksklass, vilket framgår av diagrammet. Kategorimedel¬värdet för hela till-verkningsindustrin var år 2007 1,9 jämförelse med 1,4 år 1991. Kategorimedelvärdet för anställda inom tillverkningsindustrin har ökat från 2,1 år 1991 till 2,7 år 2007. Ett mönster som går igen från de tidigare undersökningarna är att de större företagen i allmänhet har mer utvecklat miljöarbete och tydligare miljöstrategi än de mindre företagen. De största företagen (>500 anställda) införde mycket av sitt miljöarbete under 1990-talet och har fortsatt att utveckla sitt miljöarbete. Det är dock bland de medelstora (50 – 499 anställda) företagen de tydligaste förbättringarna kan konstateras. Kategorimedelvärdet har även ökat inom storleksklassen småföretag (1- 49 anställda), men i väsentligt lägre utsträckning. Fortfarande är miljömedvetenheten relativt låg bland de minsta före-tagen. Miljökravställarna har skiftat från att domineras av miljömyndigheterna till i allt högre grad utgöras av kunder och konsumenter. Klassiska ”end-of-pipe”-lösningar på miljöproblemen har under perio-den 1991-2007 kompletterats en blandning av tekniska och organisatoriska åtgärder. Miljöanpass-ning av transporterna har seglat upp som en miljöaspekt som anses som allt viktigare och underle-verantörernas roll i miljöarbetet har fått större betydelse. Miljöarbetet integreras i styrningen och uppföljningen i företagen och ifrågasätts alltmer sällan. Företag med miljöledningssystem (ISO 14001) har generellt ett mer utvecklat och systematiskt miljöarbete. De flesta tillverkningsföretag (78 procent) känner inte till Sveriges 16 miljökvalitetsmål. Omkring var femte företag (21 procent) känner till målen, men endast 1 procent av företagen vet vilka de olika målen är. Dessa siffror präglas dock av småföretagens stora dominans i antal. Mer än hälften av de företag som har femtio eller fler anställda känner till miljökvalitetsmålen. Det är endast 5 procent av det totala antalet tillverkande företag som anser sig påverkade av miljömålen. Eftersom dessa i huvudsak är större företag sysselsätter de emellertid ca 30 procent av arbetskraften inom tillverk-ningsindustrin.
|
|
