143 results on '"Hattersley, Andrew T."'
Search Results
2. YIPF5 mutations cause neonatal diabetes and microcephaly through endoplasmic reticulum stress
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De Franco, Elisa, Lytrivi, Maria, Ibrahim, Hazem, Montaser, Hossam, Wakeling, Matthew N., Fantuzzi, Federica, Patel, Kashyap, Demarez, Celine, Cai, Ying, Igoillo-Esteve, Mariana, Cosentino, Cristina, Lithovius, Vaino, Vihinen, Helena, Jokitalo, Eija, Laver, Thomas W., Johnson, Matthew B., Sawatani, Toshiaki, Shakeri, Hadis, Pachera, Nathalie, Haliloglu, Belma, Ozbek, Mehmet Nuri, Unal, Edip, Yildirim, Ruken, Godbole, Tushar, Yildiz, Melek, Aydin, Banu, Bilheu, Angeline, Suzuki, Ikuo, Flanagan, Sarah E., Vanderhaeghen, Pierre, Senee, Valerie, Julier, Cecile, Marchetti, Piero, Eizirik, Decio L., Ellard, Sian, Saarimaki-Vire, Jonna, Otonkoski, Timo, Cnop, Miriam, and Hattersley, Andrew T.
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Pediatric research ,Diabetes mellitus -- Genetic aspects -- Causes of -- Development and progression ,Microcephaly -- Genetic aspects -- Causes of -- Development and progression ,Stress (Physiology) -- Genetic aspects -- Health aspects ,Neonatal diseases -- Genetic aspects -- Causes of -- Development and progression ,Endoplasmic reticulum -- Physiological aspects -- Health aspects ,Health care industry - Abstract
Neonatal diabetes is caused by single gene mutations reducing pancreatic [beta] cell number or impairing [beta] cell function. Understanding the genetic basis of rare diabetes subtypes highlights fundamental biological processes in [beta] cells. We identified 6 patients from 5 families with homozygous mutations in the YIPF5 gene, which is involved in trafficking between the endoplasmic reticulum (ER) and the Golgi. All patients had neonatal/early-onset diabetes, severe microcephaly, and epilepsy. YIPF5 is expressed during human brain development, in adult brain and pancreatic islets. We used 3 human [beta] cell models (YIPF5 silencing in EndoC-[beta]H1 cells, YIPF5 knockout and mutation knockin in embryonic stem cells, and patient-derived induced pluripotent stem cells) to investigate the mechanism through which YIPF5 loss of function affects [beta] cells. Loss of YIPF5 function in stem cell-derived islet cells resulted in proinsulin retention in the ER, marked ER stress, and p cell failure. Partial YIPF5 silencing in EndoC-[beta]H1 cells and a patient mutation in stem cells increased the [beta] cell sensitivity to ER stress-induced apoptosis. We report recessive YIPF5 mutations as the genetic cause of a congenital syndrome of microcephaly, epilepsy, and neonatal/early-onset diabetes, highlighting a critical role of YIPF5 in [beta] cells and neurons. We believe this is the first report of mutations disrupting the ER-to-Golgi trafficking, resulting in diabetes., Introduction Neonatal diabetes mellitus develops before 6 months of age and is caused by reduced pancreatic [beta] cell number (reduced formation/increased destruction) or impaired [beta] cell function. Previous studies have [...]
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- 2020
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3. Prediction algorithms: pitfalls in interpreting genetic variants of autosomal dominant monogenic diabetes
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Ellard, Sian, Colclough, Kevin, Patel, Kashyap A., and Hattersley, Andrew T.
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Algorithms ,Evidence-based medicine ,DNA ,DNA sequencing ,Base sequence ,Computational biology ,Diseases ,Algorithm ,Health care industry - Abstract
The increasing availability of DNA sequence data and access to sophisticated bioinformatic algorithms mean that an unbiased bioinformatics-based assessment of the predicted impact of a genomic variant is rapidly available. [...]
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- 2020
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4. Association of maternal circulating 25(OH)D and calcium with birth weight: A mendelian randomisation analysis
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Thompson, William D., Tyrrell, Jessica, Borges, Maria-Carolina, Beaumont, Robin N., Knight, Bridget A., Wood, Andrew R., Ring, Susan M., Hattersley, Andrew T., Freathy, Rachel M., and Lawlor, Debbie A.
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Calcium (Nutrient) -- Health aspects -- Influence ,Birth weight -- Evaluation ,Pregnant women -- Health aspects ,Vitamin D -- Health aspects -- Influence ,Genetic research ,Genomes ,Genetics ,Vitamins ,Genomics ,Type 2 diabetes ,Newborn infants ,Biological sciences - Abstract
Background Systematic reviews of randomised controlled trials (RCTs) have suggested that maternal vitamin D (25[OH]D) and calcium supplementation increase birth weight. However, limitations of many trials were highlighted in the reviews. Our aim was to combine genetic and RCT data to estimate causal effects of these two maternal traits on offspring birth weight. Methods and findings We performed two-sample mendelian randomisation (MR) using genetic instrumental variables associated with 25(OH)D and calcium that had been identified in genome-wide association studies (GWAS; sample 1; N = 122,123 for 25[OH]D and N = 61,275 for calcium). Associations between these maternal genetic variants and offspring birth weight were calculated in the UK Biobank (UKB) (sample 2; N = 190,406). We used data on mother-child pairs from two United Kingdom birth cohorts (combined N = 5,223) in sensitivity analyses to check whether results were influenced by fetal genotype, which is correlated with the maternal genotype (r [almost equal to] 0.5). Further sensitivity analyses to test the reliability of the results included MR-Egger, weighted-median estimator, 'leave-one-out', and multivariable MR analyses. We triangulated MR results with those from RCTs, in which we used randomisation to supplementation with vitamin D (24 RCTs, combined N = 5,276) and calcium (6 RCTs, combined N = 543) as an instrumental variable to determine the effects of 25(OH)D and calcium on birth weight. In the main MR analysis, there was no strong evidence of an effect of maternal 25(OH)D on birth weight (difference in mean birth weight -0.03 g [95% CI -2.48 to 2.42 g, p = 0.981] per 10% higher maternal 25[OH]D). The effect estimate was consistent across our MR sensitivity analyses. Instrumental variable analyses applied to RCTs suggested a weak positive causal effect (5.94 g [95% CI 2.15-9.73, p = 0.002] per 10% higher maternal 25[OH]D), but this result may be exaggerated because of risk of bias in the included RCTs. The main MR analysis for maternal calcium also suggested no strong evidence of an effect on birth weight (-20 g [95% CI -44 to 5 g, p = 0.116] per 1 SD higher maternal calcium level). Some sensitivity analyses suggested that the genetic instrument for calcium was associated with birth weight via exposures that are independent of calcium levels (horizontal pleiotropy). Application of instrumental variable analyses to RCTs suggested that calcium has a substantial effect on birth weight (178 g [95% CI 121-236 g, p = 1.43 x 10.sup.-9 ] per 1 SD higher maternal calcium level) that was not consistent with any of the MR results. However, the RCT instrumental variable estimate may have been exaggerated because of risk of bias in the included RCTs. Other study limitations include the low response rate of UK Biobank, which may bias MR estimates, and the lack of suitable data to test whether the effects of genetic instruments on maternal calcium levels during pregnancy were the same as those outside of pregnancy. Conclusions Our results suggest that maternal circulating 25(OH)D does not influence birth weight in otherwise healthy newborns. However, the effect of maternal circulating calcium on birth weight is unclear and requires further exploration with more research including RCT and/or MR analyses with more valid instruments., Author(s): William D. Thompson 1,2, Jessica Tyrrell 1, Maria-Carolina Borges 2,3, Robin N. Beaumont 1, Bridget A. Knight 1, Andrew R. Wood 1, Susan M. Ring 2,3,4, Andrew T. Hattersley [...]
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- 2019
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5. Genetic scores to stratify risk of developing multiple islet autoantibodies and type 1 diabetes: A prospective study in children
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Bonifacio, Ezio, Beyerlein, Andreas, Hippich, Markus, Winkler, Christiane, Vehik, Kendra, Weedon, Michael N., Laimighofer, Michael, Hattersley, Andrew T., Krumsiek, Jan, Frohnert, Brigitte I., Steck, Andrea K., Hagopian, William A., Krischer, Jeffrey P., Lernmark, Åke, Rewers, Marian J., She, Jin-Xiong, Toppari, Jorma, Akolkar, Beena, Oram, Richard A., Rich, Stephen S., and Ziegler, Anette-G.
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Pancreatic beta cells -- Genetic aspects -- Health aspects ,Genotypes -- Identification and classification ,Autoantibodies -- Genetic aspects -- Health aspects ,Type 1 diabetes -- Genetic aspects -- Risk factors ,Biological sciences - Abstract
Background Around 0.3% of newborns will develop autoimmunity to pancreatic beta cells in childhood and subsequently develop type 1 diabetes before adulthood. Primary prevention of type 1 diabetes will require early intervention in genetically at-risk infants. The objective of this study was to determine to what extent genetic scores (two previous genetic scores and a merged genetic score) can improve the prediction of type 1 diabetes. Methods and findings The Environmental Determinants of Diabetes in the Young (TEDDY) study followed genetically at-risk children at 3- to 6-monthly intervals from birth for the development of islet autoantibodies and type 1 diabetes. Infants were enrolled between 1 September 2004 and 28 February 2010 and monitored until 31 May 2016. The risk (positive predictive value) for developing multiple islet autoantibodies (pre-symptomatic type 1 diabetes) and type 1 diabetes was determined in 4,543 children who had no first-degree relatives with type 1 diabetes and either a heterozygous HLA DR3 and DR4-DQ8 risk genotype or a homozygous DR4-DQ8 genotype, and in 3,498 of these children in whom genetic scores were calculated from 41 single nucleotide polymorphisms. In the children with the HLA risk genotypes, risk for developing multiple islet autoantibodies was 5.8% (95% CI 5.0%-6.6%) by age 6 years, and risk for diabetes by age 10 years was 3.7% (95% CI 3.0%-4.4%). Risk for developing multiple islet autoantibodies was 11.0% (95% CI 8.7%-13.3%) in children with a merged genetic score of >14.4 (upper quartile; n = 907) compared to 4.1% (95% CI 3.3%-4.9%, P 14.4 compared with 2.7% (95% CI 1.9%-3.6%) in children with a score of [less than or equal to]14.4 (P 14.4. Scores were higher in European versus US children (P = 0.003). In children with a merged score of >14.4, risk for multiple islet autoantibodies was similar and consistently >10% in Europe and in the US; risk was greater in males than in females (P = 0.01). Limitations of the study include that the genetic scores were originally developed from case-control studies of clinical diabetes in individuals of mainly European decent. It is, therefore, possible that it may not be suitable to all populations. Conclusions A type 1 diabetes genetic score identified infants without family history of type 1 diabetes who had a greater than 10% risk for pre-symptomatic type 1 diabetes, and a nearly 2-fold higher risk than children identified by high-risk HLA genotypes alone. This finding extends the possibilities for enrolling children into type 1 diabetes primary prevention trials., Author(s): Ezio Bonifacio 1, Andreas Beyerlein 2,3,4, Markus Hippich 2,3,4, Christiane Winkler 2,3,4, Kendra Vehik 5, Michael N. Weedon 6, Michael Laimighofer 7, Andrew T. Hattersley 6, Jan Krumsiek 7, [...]
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- 2018
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6. Rfx6 directs islet formation and insulin production in mice and humans
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Smith, Stuart B., Qu, Hui-Qi, Taleb, Nadine, Kishimoto, Nina Y., Scheel, David W., Lu, Yang, Patch, Ann-Marie, Grabs, Rosemary, Wang, Juehu, Lynn, Francis C., Miyatsuka, Takeshi, Mitchell, John, Seerke, Rina, Desir, Julie, Eijnden, Serge Vanden, Abramowicz, Marc, Kacet, Nadine, Weill, Jacques, Renard, Marie-Eve, Gentile, Mattia, Hansen, Inger, Dewar, Ken, Hattersley, Andrew T., Wang, Rennian, Wilson, Maria E., Johnson, Jeffrey D., Polychronakos, Constantin, and German, Michael S.
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Binding proteins -- Genetic aspects ,Embryonic development ,Diabetes -- Care and treatment -- Causes of ,Environmental issues ,Science and technology ,Zoology and wildlife conservation - Abstract
Insulin from the β-cells of the pancreatic islets of Langerhans controls energy homeostasis in vertebrates, and its deficiency causes diabetes mellitus. During embryonic development, the transcription factor neurogenin 3 (Neurog3) initiates the differentiation of the β-cells and other islet cell types from pancreatic endoderm, but the genetic program that subsequently completes this differentiation remains incompletely understood. Here we show that the transcription factor Rfx6 directs islet cell differentiation downstream of Neurog3. Mice lacking Rfx6 failed to generate any of the normal islet cell types except for pancreatic-polypeptide-producing cells. In human infants with a similar autosomal recessive syndrome of neonatal diabetes, genetic mapping and subsequent sequencing identified mutations in the human RFX6 gene. These studies demonstrate a unique position for Rfx6 in the hierarchy of factors that coordinate pancreatic islet development in both mice and humans. Rfx6 could prove useful in efforts to generate β-cells for patients with diabetes., During embryonic development, the pancreas first appears as clusters of cells on the dorsal and ventral aspects of the gut endoderm. The exocrine and endocrine cells that form the adult [...]
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- 2010
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7. Regulation of Fto/Ftm gene expression in mice and humans
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Stratigopoulos, George, Padilla, Stephanie L., LeDuc, Charles A., Watson, Elizabeth, Hattersley, Andrew T., McCarthy, Mark I., Zeltser, Lori M., Chung, Wendy K., and Leibel, Rudolph L.
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Gene expression -- Analysis ,Rodents as pets -- Genetic aspects ,Rodents as pets -- Health aspects ,Hypothalamus -- Research ,Obesity -- Causes of ,Obesity -- Research ,Biological sciences - Abstract
Two recent, large whole-genome association studies (GWAS) in European populations have associated a ~47-kb region that contains part of the FTO gene with high body mass index (BMI). The functions of FTO and adjacent FTM in human biology are not clear. We examined expression of these genes in organs of mice segregating for monogenic obesity mutations, exposed to underfeeding/overfeeding, and to 4[degrees]C. Fto/Ftm expression was reduced in mesenteric adipose tissue of mice segregating for the [A.sup.y], [Lep.sup.ob], [Lepr.sup.db], [Cpe.sup.fat], or tub mutations, and there was a similar trend in other tissues. These effects were not due to adiposity per se. Hypothalamic Fto and Ftm expression were decreased by fasting in lean and obese animals and by cold exposure in lean mice. The fact that responses of Fto and Ftm expression to these manipulations were almost indistinguishable suggested that the genes might be coregulated. The putative overlapping regulatory region contains at least two canonical CUTL1 binding sites. One of these nominal CUTL1 sites includes rs8050136, a SNP associated with high body mass. The A allele of rs8050136 associated with lower body mass than the C allele preferentially bound CUTL1 in human fibroblast DNA. 70% knockdown of CUTL1 expression in human fibroblasts decreased FTO and FTM expression by 90 and 65%, respectively. Animals and humans with various genetic interruptions of FTO or FTM have phenotypes reminiscent of aspects of the Bardet-Biedl obesity syndrome, a confirmed 'ciliopathy.' FTM has recently been shown to be a ciliary basal body protein. obesity; hypothalamus; adipose tissue; CUTL1
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- 2008
8. Exploring the developmental overnutrition hypothesis using parental-offspring associations and FTO as an instrumental variable
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Lawlor, Debbie A., Timpson, Nicholas J., Harbord, Roger M., Leary, Sam, Ness, Andy, McCarthy, Mark I., Frayling, Timothy M., Hattersley, Andrew T., and Smith, George Davey
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Biological sciences - Abstract
Background The developmental overnutrition hypothesis suggests that greater maternal obesity during pregnancy results in increased offspring adiposity in later life. If true, this would result in the obesity epidemic progressing across generations irrespective of environmental or genetic changes. It is therefore important to robustly test this hypothesis. Methods and Findings We explored this hypothesis by comparing the associations of maternal and paternal prepregnancy body mass index (BMI) with offspring dual energy X-ray absorptiometry (DXA)-determined fat mass measured at 9 to 11 y (4,091 parent-offspring trios) and by using maternal FTO genotype, controlling for offspring FTO genotype, as an instrument for maternal adiposity. Both maternal and paternal BMI were positively associated with offspring fat mass, but the maternal association effect size was larger than that in the paternal association in all models: mean difference in offspring sex- and age-standardised fat mass z-score per 1 standard deviation BMI 0.24 (95% confidence interval [CI]: 0.22 to 0.26) for maternal BMI versus 0.13 (95% CI: 0.11, 0.15) for paternal BMI; p-value for difference in effect < 0.001. The stronger maternal association was robust to sensitivity analyses assuming levels of non-paternity up to 20%. When maternal FTO, controlling for offspring FTO, was used as an instrument for the effect of maternal adiposity, the mean difference in offspring fat mass z-score per 1 standard deviation maternal BMI was -0.08 (95% CI: -0.56 to 0.41), with no strong statistical evidence that this differed from the observational ordinary least squares analyses (p = 0.17). Conclusions Neither our parental comparisons nor the use of FTO genotype as an instrumental variable, suggest that greater maternal BMI during offspring development has a marked effect on offspring fat mass at age 9-11 y. Developmental overnutrition related to greater maternal BMI is unlikely to have driven the recent obesity epidemic. doi:10.1371/journal.pmed.0050033, Introduction According to the developmental overnutrition hypothesis, high maternal glucose and high free fatty acid and amino acid plasma concentrations result in permanent changes in appetite control, neuroendocrine functioning, or [...]
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- 2008
9. Rare and low-frequency coding variants alter human adult height
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Marouli, Eirini, Graff, Mariaelisa, Medina-Gomez, Carolina, Lo, Ken Sin, Wood, Andrew R., Kjaer, Troels R., Fine, Rebecca S., Lu, Yingchang, Schurmann, Claudia, Highland, Heather M., Reger, Sina, Thorleifsson, Gudmar, Justice, Anne E., Lamparter, David, Stirrups, Kathleen E., Turcot, Valrie, Young, Kristin L., Winkler, Thomas W., Esko, Tnu, Karaderi, Tugce, Locke, Adam E., Masca, Nicholas G. D., Ng, Maggie C. Y., Mudgal, Poorva, Rivas, Manuel A., Vedantam, Sailaja, Mahajan, Anubha, Guo, Xiuqing, Abecasis, Goncalo, Aben, Katja K., Adair, Linda S., Alam, Dewan S., Albrecht, Eva, Allin, Kristine H., Allison, Matthew, Amouyel, Philippe, Appel, Emil V., Arveiler, Dominique, Asselbergs, Folkert W., Auer, Paul L., Balkau, Beverley, Banas, Bernhard, Bang, Lia E., Benn, Marianne, Bergmann, Sven, Bielak, Lawrence F., Blher, Matthias, Boeing, Heiner, Boerwinkle, Eric, Bger, Carsten A., Bonnycastle, Lori L., Bork-Jensen, Jette, Bots, Michiel L., Bottinger, Erwin P., Bowden, Donald W., Brandslund, Ivan, Breen, Gerome, Brilliant, Murray H., Broer, Linda, Burt, Amber A., Butterworth, Adam S., Carey, David J., Caulfield, Mark J., Chambers, John C., Chasman, Daniel I., Chen, Yii-Der Ida, Chowdhury, Rajiv, Christensen, Cramer, Chu, Audrey Y., Cocca, Massimiliano, Collins, Francis S., Cook, James P., Corley, Janie, Galbany, Jordi Corominas, Cox, Amanda J., Cuellar-Partida, Gabriel, Danesh, John, Davies, Gail, de Bakker, Paul I. W., de Borst, Gert J., de Denus, Simon, de Groot, Mark C. H., de Mutsert, Rene, Deary, Ian J., Dedoussis, George, Demerath, Ellen W., den Hollander, Anneke I., Dennis, Joe G., Di Angelantonio, Emanuele, Drenos, Fotios, Du, Mengmeng, Dunning, Alison M., Easton, Douglas F., Ebeling, Tapani, Edwards, Todd L., Ellinor, Patrick T., Elliott, Paul, Evangelou, Evangelos, Farmaki, Aliki-Eleni, Faul, Jessica D., Feitosa, Mary F., Feng, Shuang, Ferrannini, Ele, Ferrario, Marco M., Ferrieres, Jean, Florez, Jose C., Ford, Ian, Fornage, Myriam, Franks, Paul W., Frikke-Schmidt, Ruth, Galesloot, Tessel E., Gan, Wei, Gandin, Ilaria, Gasparini, Paolo, Giedraitis, Vilmantas, Giri, Ayush, Girotto, Giorgia, Gordon, Scott D., Gordon-Larsen, Penny, Gorski, Mathias, Grarup, Niels, Grove, Megan L., Gudnason, Vilmundur, Gustafsson, Stefan, Hansen, Torben, Harris, Kathleen Mullan, Harris, Tamara B., Hattersley, Andrew T., Hayward, Caroline, He, Liang, Heid, Iris M., Heikkil, Kauko, Helgeland, yvind, Hernesniemi, Jussi, Hewitt, Alex W., Hocking, Lynne J., Hollensted, Mette, Holmen, Oddgeir L., Hovingh, G. Kees, Howson, Joanna M. M., Hoyng, Carel B., Huang, Paul L., Hveem, Kristian, Ikram, M. Arfan, Ingelsson, Erik, Jackson, Anne U., Jansson, Jan-Hkan, Jarvik, Gail P., Jensen, Gorm B., Jhun, Min A., Jia, Yucheng, Jiang, Xuejuan, Johansson, Stefan, Jrgensen, Marit E., Jrgensen, Torben, Jousilahti, Pekka, Jukema, J. Wouter, Kahali, Bratati, Kahn, Ren S., Khnen, Mika, Kamstrup, Pia R., Kanoni, Stavroula, Kaprio, Jaakko, Karaleftheri, Maria, Kardia, Sharon L. R., Karpe, Fredrik, Kee, Frank, Keeman, Renske, Kiemeney, Lambertus A., Kitajima, Hidetoshi, Kluivers, Kirsten B., Kocher, Thomas, Komulainen, Pirjo, Kontto, Jukka, Kooner, Jaspal S., Kooperberg, Charles, Kovacs, Peter, Kriebel, Jennifer, Kuivaniemi, Helena, Kry, Sbastien, Kuusisto, Johanna, La Bianca, Martina, Laakso, Markku, Lakka, Timo A., Lange, Ethan M., Lange, Leslie A., Langefeld, Carl D., Langenberg, Claudia, Larson, Eric B., Lee, I-Te, Lehtimki, Terho, Lewis, Cora E., Li, Huaixing, Li, Jin, Li-Gao, Ruifang, Lin, Honghuang, Lin, Li-An, Lin, Xu, Lind, Lars, Lindstrm, Jaana, Linneberg, Allan, Liu, Yeheng, Liu, Yongmei, Lophatananon, Artitaya, Luan, Jianan, Lubitz, Steven A., Lyytikinen, Leo-Pekka, Mackey, David A., Madden, Pamela A. F., Manning, Alisa K., Mnnist, Satu, Marenne, Galle, Marten, Jonathan, Martin, Nicholas G., Mazul, Angela L., Meidtner, Karina, Metspalu, Andres, Mitchell, Paul, Mohlke, Karen L., Mook-Kanamori, Dennis O., Morgan, Anna, Morris, Andrew D., Morris, Andrew P., Mller-Nurasyid, Martina, Munroe, Patricia B., Nalls, Mike A., Nauck, Matthias, Nelson, Christopher P., Neville, Matt, Nielsen, Sune F., Nikus, Kjell, Njlstad, Pl R., Nordestgaard, Brge G., Ntalla, Ioanna, OConnel, Jeffrey R., Oksa, Heikki, Loohuis, Loes M. Olde, Ophoff, Roel A., Owen, Katharine R., Packard, Chris J., Padmanabhan, Sandosh, Palmer, Colin N. A., Pasterkamp, Gerard, Patel, Aniruddh P., Pattie, Alison, Pedersen, Oluf, Peissig, Peggy L., Peloso, Gina M., Pennell, Craig E., Perola, Markus, Perry, James A., Perry, John R. B., Person, Thomas N., Pirie, Ailith, Polasek, Ozren, Posthuma, Danielle, Raitakari, Olli T., Rasheed, Asif, Rauramaa, Rainer, Reilly, Dermot F., Reiner, Alex P., Renstrm, Frida, Ridker, Paul M., Rioux, John D., Robertson, Neil, Robino, Antonietta, Rolandsson, Olov, Rudan, Igor, Ruth, Katherine S., Saleheen, Danish, Salomaa, Veikko, Samani, Nilesh J., Sandow, Kevin, Sapkota, Yadav, Sattar, Naveed, Schmidt, Marjanka K., Schreiner, Pamela J., Schulze, Matthias B., Scott, Robert A., Segura-Lepe, Marcelo P., Shah, Svati, Sim, Xueling, Sivapalaratnam, Suthesh, Small, Kerrin S., Smith, Albert Vernon, Smith, Jennifer A., Southam, Lorraine, Spector, Timothy D., Speliotes, Elizabeth K., Starr, John M., Steinthorsdottir, Valgerdur, Stringham, Heather M., Stumvoll, Michael, Surendran, Praveen, t Hart, Leen M., Tansey, Katherine E., Tardif, Jean-Claude, Taylor, Kent D., Teumer, Alexander, Thompson, Deborah J., Thorsteinsdottir, Unnur, Thuesen, Betina H., Tnjes, Anke, Tromp, Gerard, Trompet, Stella, Tsafantakis, Emmanouil, Tuomilehto, Jaakko, Tybjaerg-Hansen, Anne, Tyrer, Jonathan P., Uher, Rudolf, Uitterlinden, Andr G., Ulivi, Sheila, van der Laan, Sander W., Van Der Leij, Andries R., van Duijn, Cornelia M., van Schoor, Natasja M., van Setten, Jessica, Varbo, Anette, Varga, Tibor V., Varma, Rohit, Edwards, Digna R. Velez, Vermeulen, Sita H., Vestergaard, Henrik, Vitart, Veronique, Vogt, Thomas F., Vozzi, Diego, Walker, Mark, Wang, Feijie, Wang, Carol A., Wang, Shuai, Wang, Yiqin, Wareham, Nicholas J., Warren, Helen R., Wessel, Jennifer, Willems, Sara M., Wilson, James G., Witte, Daniel R., Woods, Michael O., Wu, Ying, Yaghootkar, Hanieh, Yao, Jie, Yao, Pang, Yerges-Armstrong, Laura M., Young, Robin, Zeggini, Eleftheria, Zhan, Xiaowei, Zhang, Weihua, Zhao, Jing Hua, Zhao, Wei, Zheng, He, Zhou, Wei, Rotter, Jerome I, Boehnke, Michael, Kathiresan, Sekar, McCarthy, Mark I., Willer, Cristen J., Stefansson, Kari, Borecki, Ingrid B., Liu, Dajiang J., North, Kari E., Heard-Costa, Nancy L., Pers, Tune H., Lindgren, Cecilia M., Oxvig, Claus, Kutalik, Zoltn, Rivadeneira, Fernando, Loos, Ruth J. F., Frayling, Timothy M., Hirschhorn, Joel N., Deloukas, Panos, and Lettre, Guillaume
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Body height -- Genetic aspects ,Genetic variation -- Observations ,Environmental issues ,Science and technology ,Zoology and wildlife conservation - Abstract
Height is a highly heritable, classic polygenic trait with approximately 700 common associated variants identified through genome-wide association studies so far. Here, we report 83 height-associated coding variants with lower minor-allele frequencies (in the range of 0.14.8%) and effects of up to 2centimetres per allele (such as those in IHH, STC2, AR and CRISPLD2), greater than ten times the average effect of common variants. In functional follow-up studies, rare height-increasing alleles of STC2 (giving an increase of 12centimetres per allele) compromised proteolytic inhibition of PAPP-A and increased cleavage of IGFBP-4 in vitro, resulting in higher bioavailability of insulin-like growth factors. These 83 height-associated variants overlap genes that are mutated in monogenic growth disorders and highlight new biological candidates (such as ADAMTS3, IL11RA and NOX4) and pathways (such as proteoglycan and glycosaminoglycan synthesis) involved in growth. Our results demonstrate that sufficiently large sample sizes can uncover rare and low-frequency variants of moderate-to-large effect associated with polygenic human phenotypes, and that these variants implicate relevant genes and pathways., Author(s): Eirini Marouli [1]; Mariaelisa Graff [2]; Carolina Medina-Gomez [3, 4]; Ken Sin Lo [5]; Andrew R. Wood [6]; Troels R. Kjaer [7]; Rebecca S. Fine [8, 9, 10]; Yingchang [...]
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- 2017
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10. Increased ATPase activity produced by mutations at arginine-1380 in nucleotide-binding domain 2 of ABCC8 causes neonatal diabetes
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de Wet, Heidi, Rees, Mathew G., Shimomura, Kenju, Aittoniemi, Jussi, Patch, Ann-Marie, Flanagan, Sarah E., Ellard, Sian, Hattersley, Andrew T., Sansom, Mark S.P., and Ashcroft, Frances M.
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Adenosine triphosphatase -- Properties ,Arginine -- Properties ,Arginine -- Influence ,Diabetes -- Research ,Potassium channels -- Genetic aspects ,Infants (Newborn) -- Diseases ,Infants (Newborn) -- Research ,Science and technology - Abstract
Gain-of-function mutations in the genes encoding the ATPsensitive potassium ([K.sub.ATP]) channel subunits Kir6.2 (KCNJ11) and SUR1 (ABCC8) are a common cause of neonatal diabetes mellitus. Here we investigate the molecular mechanism by which two heterozygous mutations in the second nucleotide-binding domain (NBD2) of SUR1 (R1380L and R1380C) separately cause neonatal diabetes. SUR1 is a channel regulator that modulates the gating of the pore formed by Kir6.2. KATP channel activity is inhibited by ATP binding to Kir6.2 but is stimulated by MgADP binding, or by MgATP binding and hydrolysis, at the NBDs of SUR1. Functional analysis of purified NBD2 showed that each mutation enhances MgATP hydrolysis by purified isolated fusion proteins of maltose-binding protein and NBD2. Inhibition of ATP hydrolysis by MgADP was unaffected by mutation of R1380, but inhibition by beryllium fluoride (which traps the ATPase cycle in the prehydrolytic state) was reduced. MgADP-dependent activation of KATP channel activity was unaffected. These data suggest that the R1380L and R1380C mutations enhance the off-rate of [P.sub.i], thereby enhancing the hydrolytic rate. Molecular modeling studies supported this idea. Because mutant channels were inhibited less strongly by MgATP, this would increase KATP currents in pancreatic beta cells, thus reducing insulin secretion and producing diabetes. SUR1 | KATP channel | ATP hydrolysis | sulfonylurea receptor
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- 2007
11. Insulin gene mutations as a cause of permanent neonatal diabetes
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Stoy, Julie, Edghill, Emma L., Flanagan, Sarah E., Ye, Honggang, Paz, Veronica P., Pluzhnikov, Anna, Below, Jennifer E., Hayes, M. Geoffrey, Cox, Nancy J., Lipkind, Gregory M., Lipton, Rebecca B., Greeley, Siri Atma W., Patch, Ann-Marie, Ellard, Sian, Steiner, Donald F., Hattersley, Andrew T., Philipson, Louis H., and Bell, Graeme I.
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Insulin -- Genetic aspects ,Diabetes -- Diagnosis ,Diabetes -- Genetic aspects ,Gene mutations -- Health aspects ,Gene mutations -- Evaluation ,Infants (Newborn) -- Diseases ,Infants (Newborn) -- Genetic aspects ,Infants (Newborn) -- Diagnosis ,Science and technology - Abstract
We report 10 heterozygous mutations in the human insulin gene in 16 probands with neonatal diabetes. A combination of linkage and a candidate gene approach in a family with four diabetic members led to the identification of the initial INS gene mutation. The mutations are inherited in an autosomal dominant manner in this and two other small families whereas the mutations in the other 13 patients are de novo. Diabetes presented in probands at a median age of 9 weeks, usually with diabetic ketoacidosis or marked hyperglycemia, was not associated with [beta] cell autoantibodies, and was treated from diagnosis with insulin. The mutations are in critical regions of the preproinsulin molecule, and we predict that they prevent normal folding and progression of proinsulin in the insulin secretory pathway. The abnormally folded proinsulin molecule may induce the unfolded protein response and undergo degradation in the endoplasmic reticulum, leading to severe endoplasmic reticulum stress and potentially [beta] cell death by apoptosis. This process has been described in both the Akita and Munich mouse models that have dominant-acting missense mutations in the Ins2 gene, leading to loss of [beta] cell function and mass. One of the human mutations we report here is identical to that in the Akita mouse. The identification of insulin mutations as a cause of neonatal diabetes will facilitate the diagnosis and possibly, in time, treatment of this disorder. endoplasmic reticulum stress | insulin biosynthesis | disulfide bonds | unfolded protein response
- Published
- 2007
12. Permanent neonatal diabetes caused by dominant, recessive, or compound heterozygous SUR1 mutations with opposite functional effects
- Author
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Ellard, Sian, Parrish, Andrew, Edghill, Emma L., Girard, Christophe A., Flanagan, Sarah E., Patch, Ann-Marie, Harries, Lorna W., Mackey, Deborah J.G., Proks, Peter, Shimomura, Kenju, Haberland, Holger, Shield, Julian P.H., Hattersley, Andrew T., Ashcroft, Frances M., and Carson, Dennis J.
- Subjects
Gene mutations -- Research ,Genetic code -- Research ,Diabetes in children -- Causes of ,Pancreatic beta cells -- Research ,Biological sciences - Abstract
The article describes about the active mutations that are heterozygous in the KCNJ11 gene encodes pore-forming Kir6.2 subunits of the pancreatic beta cell [K.sub.ATP] channel are the most common cause of permanent neonatal diabetes (PNDM).
- Published
- 2007
13. Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls
- Author
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Burton, Paul R., Clayton, David G., Cardon, Lon R., Craddock, Nick, Deloukas, Panos, Duncanson, Audrey, Kwiatkowski, Dominic P., McCarthy, Mark I., Ouwehand, Willem H., Samani, Nilesh J., Todd, John A., Donnelly, Peter, Barrett, Jeffrey C., Davison, Dan, Easton, Doug, Evans, David, Leung, Hin-Tak, Marchini, Jonathan L., Morris, Andrew P., Spencer, Chris C. A., Tobin, Martin D., Attwood, Antony P., Boorman, James P., Cant, Barbara, Everson, Ursula, Hussey, Judith M., Jolley, Jennifer D., Knight, Alexandra S., Koch, Kerstin, Meech, Elizabeth, Nutland, Sarah, Prowse, Christopher V., Stevens, Helen E., Taylor, Niall C., Walters, Graham R., Walker, Neil M., Watkins, Nicholas A., Winzer, Thilo, Jones, Richard W., McArdle, Wendy L., Ring, Susan M., Strachan, David P., Pembrey, Marcus, Breen, Gerome, St Clair, David, Caesar, Sian, Gordon-Smith, Katherine, Jones, Lisa, Fraser, Christine, Green, Elaine K., Grozeva, Detelina, Hamshere, Marian L., Holmans, Peter A., Jones, Ian R., Kirov, George, Moskvina, Valentina, Nikolov, Ivan, O'Donovan, Michael C., Owen, Michael J., Collier, David A., Elkin, Amanda, Farmer, Anne, Williamson, Richard, McGuffin, Peter, Young, Allan H., Ferrier, I. Nicol, Ball, Stephen G., Balmforth, Anthony J., Barrett, Jennifer H., Bishop, D. Timothy, Iles, Mark M., Maqbool, Azhar, Yuldasheva, Nadira, Hall, Alistair S., Braund, Peter S., Dixon, Richard J., Mangino, Massimo, Stevens, Suzanne, Thompson, John R., Bredin, Francesca, Tremelling, Mark, Parkes, Miles, Drummond, Hazel, Lees, Charles W., Nimmo, Elaine R., Satsangi, Jack, Fisher, Sheila A., Forbes, Alastair, Lewis, Cathryn M., Onnie, Clive M., Prescott, Natalie J., Sanderson, Jeremy, Mathew, Christopher G., Barbour, Jamie, Mohiuddin, M. Khalid, Todhunter, Catherine E., Mansfield, John C., Ahmad, Tariq, Cummings, Fraser R., Jewell, Derek P., Webster, John, Brown, Morris J., Lathrop, G. Mark, Connell, John, Dominiczak, Anna, Marcano, Carolina A. Braga, Burke, Beverley, Dobson, Richard, Gungadoo, Johannie, Lee, Kate L., Munroe, Patricia B., Newhouse, Stephen J., Onipinla, Abiodun, Wallace, Chris, Xue, Mingzhan, Caulfield, Mark, Farrall, Martin, Barton, Anne, Bruce, Ian N., Donovan, Hannah, Eyre, Steve, Gilbert, Paul D., Hider, Samantha L., Hinks, Anne M., John, Sally L., Potter, Catherine, Silman, Alan J., Symmons, Deborah P. M., Thomson, Wendy, Worthington, Jane, Dunger, David B., Widmer, Barry, Frayling, Timothy M., Freathy, Rachel M., Lango, Hana, Perry, John R. B., Shields, Beverley M., Weedon, Michael N., Hattersley, Andrew T., Hitman, Graham A., Walker, Mark, Elliott, Kate S., Groves, Christopher J., Lindgren, Cecilia M., Rayner, Nigel W., Timpson, Nicholas J., Zeggini, Eleftheria, Newport, Melanie, Sirugo, Giorgio, Lyons, Emily, Vannberg, Fredrik, Hill, Adrian V. S., Bradbury, Linda A., Farrar, Claire, Pointon, Jennifer J., Wordsworth, Paul, Brown, Matthew A., Franklyn, Jayne A., Heward, Joanne M., Simmonds, Matthew J., Gough, Stephen C. L., Seal, Sheila, Stratton, Michael R., Rahman, Nazneen, Ban, Maria, Goris, An, Sawcer, Stephen J., Compston, Alastair, Conway, David, Jallow, Muminatou, Rockett, Kirk A., Bumpstead, Suzannah J., Chaney, Amy, Downes, Kate, Ghori, Mohammed J. R., Gwilliam, Rhian, Hunt, Sarah E., Inouye, Michael, Keniry, Andrew, King, Emma, McGinnis, Ralph, Potter, Simon, Ravindrarajah, Rathi, Whittaker, Pamela, Widden, Claire, Withers, David, Cardin, Niall J., Ferreira, Teresa, Pereira-Gale, Joanne, Hallgrimsdottir, Ingileif B., Howie, Bryan N., Su, Zhan, Teo, Yik Ying, Vukcevic, Damjan, Bentley, David, and Compston, Alistair
- Subjects
Environmental issues ,Science and technology ,Zoology and wildlife conservation - Abstract
Author(s): The Wellcome Trust Case Control Consortium; Management Committee; Paul R. Burton [1]; David G. Clayton [2]; Lon R. Cardon [3]; Nick Craddock [4]; Panos Deloukas [5]; Audrey Duncanson [6]; [...]
- Published
- 2007
- Full Text
- View/download PDF
14. Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls
- Author
-
Burton, Paul R., Clayton, David G., Cardon, Lon R., Craddock, Nick, Deloukas, Panos, Duncanson, Audrey, Kwiatkowski, Dominic P., McCarthy, Mark I., Ouwehand, Willem H., Samani, Nilesh J., Todd, John A., Barrett, Jeffrey C., Davison, Dan, Donnelly, Peter, Easton, Doug, Evans, David, Leung, Hin-Tak, Marchini, Jonathan L., Morris, Andrew P., Spencer, Chris C. A., Tobin, Martin D., Attwood, Antony P., Boorman, James P., Cant, Barbara, Everson, Ursula, Hussey, Judith M., Jolley, Jennifer D., Knight, Alexandra S., Koch, Kerstin, Meech, Elizabeth, Nutland, Sarah, Prowse, Christopher V., Stevens, Helen E., Taylor, Niall C., Walters, Graham R., Walker, Neil M., Watkins, Nicholas A., Winzer, Thilo, Jones, Richard W., McArdle, Wendy L., Ring, Susan M., Strachan, David P., Pembrey, Marcus, Breen, Gerome, Caesar, Sian, Gordon-Smith, Katherine, Fraser, Christine, Green, Elaine K., Grozeva, Detelina, Hamshere, Marian L., Holmans, Peter A., Jones, Ian R., Kirov, George, Moskvina, Valentina, Nikolov, Ivan, O'Donovan, Michael C., Owen, Michael J., Collier, David A., Elkin, Amanda, Farmer, Anne, Williamson, Richard, Young, Allan H., Ball, Stephen G., Balmforth, Anthony J., Barrett, Jennifer H., Bishop, D. Timothy, Iles, Mark M., Maqbool, Azhar, Yuldasheva, Nadira, Braund, Peter S., Dixon, Richard J., Mangino, Massimo, Stevens, Suzanne, Thompson, John R., Bredin, Francesca, Tremelling, Mark, Drummond, Hazel, Lees, Charles W., Nimmo, Elaine R., Fisher, Sheila A., Forbes, Alastair, Lewis, Cathryn M., Onnie, Clive M., Prescott, Natalie J., Sanderson, Jeremy, Barbour, Jamie, Mohiuddin, M. Khalid, Mansfield, John C., Ahmad, Tariq, Cummings, Fraser R., Brown, Morris J., Connell, John, Marcano, Carolina A. Braga, Burke, Beverley, Dobson, Richard, Gungadoo, Johannie, Lee, Kate L., Munroe, Patricia B., Newhouse, Stephen J., Onipinla, Abiodun, Wallace, Chris, Xue, Mingzhan, Barton, Anne, Bruce, Ian N., Donovan, Hannah, Eyre, Steve, Gilbert, Paul D., Hider, Samantha L., Hinks, Anne M., John, Sally L., Potter, Catherine, Silman, Alan J., Symmons, Deborah P. M., Thomson, Wendy, Worthington, Jane, Dunger, David B., Widmer, Barry, Frayling, Timothy M., Freathy, Rachel M., Lango, Hana, Perry, John R. B., Shields, Beverley M., Weedon, Michael N., Elliott, Kate S., Groves, Christopher J., Lindgren, Cecilia M., Rayner, Nigel W., Timpson, Nicholas J., Zeggini, Eleftheria, Newport, Melanie, Lyons, Emily, Vannberg, Fredrik, Bradbury, Linda A., Farrar, Claire, Pointon, Jennifer J., Wordsworth, Paul, Brown, Matthew A., Franklyn, Jayne A., Heward, Joanne M., Simmonds, Matthew J., Gough, Stephen C. L., Seal, Sheila, Stratton, Michael R., Rahman, Nazneen, Ban, Maria, Goris, An, Sawcer, Stephen J., Compston, Alastair, Conway, David, Jallow, Muminatou, Rockett, Kirk A., Bumpstead, Suzannah J., Chaney, Amy, Downes, Kate, Ghori, Mohammed J. R., Gwilliam, Rhian, Hunt, Sarah E., Inouye, Michael, Keniry, Andrew, King, Emma, McGinnis, Ralph, Potter, Simon, Ravindrarajah, Rathi, Whittaker, Pamela, Widden, Claire, Withers, David, Cardin, Niall J., Ferreira, Teresa, Pereira-Gale, Joanne, Hallgrimsdottir, Ingileif B., Howie, Bryan N., Su, Zhan, Teo, Yik Ying, Vukcevic, Damjan, Bentley, David, Caulfield, Mark, Compston, Alistair, Farrall, Martin, Hall, Alistair S., Hattersley, Andrew T., Hill, Adrian V. S., Mathew, Christopher G., and Parkes, Miles
- Subjects
Environmental issues ,Science and technology ,Zoology and wildlife conservation - Abstract
Author(s): The Wellcome Trust Case Control Consortium; Management Committee; Paul R. Burton [1]; David G. Clayton [2]; Lon R. Cardon [3]; Nick Craddock [4]; Panos Deloukas [5]; Audrey Duncanson [6]; [...]
- Published
- 2007
- Full Text
- View/download PDF
15. Type 2 diabetes TCF7L2 risk genotypes alter birth weight: A study of 24, 053 individuals
- Author
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Freathy, Rachel M., Weedon, Micahel N., Bennett, Amanda, Hypponen, Elina, Ben-Shlomo, Yoav, Strachan, David P., Power, Chris, Jarvelin, Marjo-Riitta, McCarthy, Mark I., Smith, George Davey, Hattersley, Andrew T., Frayling, Timothy M., Relton, Caroline L., Knight, Beatrice, Shields, Beverley, Parnell, Kirstie S., Groves, Christopher J., Ring, Susan M., and Pembrey, Marcus E.
- Subjects
Type 2 diabetes -- Genetic aspects ,Type 2 diabetes -- Research ,Genotype -- Research ,Birth size -- Research ,Birth weight -- Research ,Biological sciences - Abstract
A hypothesis that fetal TCF7L2 type-2 diabetes predisposing genotypes at rs7903146 and rs12255372 would be associated with reduced birth weight was investigated in individuals from six population-based studies. The first type-2 diabetes susceptibility allele was identified and found to be reproducibly associated with birth weight and common gene variants were found to substantially influence normal birth weight variation.
- Published
- 2007
16. Replication of genome-wide association signals in UK samples reveals risk loci for type 2 diabetes
- Author
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Zeggini, Eleftheria, Weedon, Michael N., Lindgren, Cecilia M., Frayling, Timothy M., Elliott, Katherine S., Lango, Hana, Timpson, Nicholas J., Perry, John R.B., Rayner, Nigel W., Freathy, Rachel M., Barrett, Jeffrey C., Shields, Beverley, Morris, Andrew P., Ellard, Sian, Groves, Christopher J., Harries, Lorna W., Marchini, Jonathan L., Owen, Katharine R., Knight, Beatrice, Cardon, Lon R., Walker, Mark, Hitman, Graham A., Morris, Andrew D., Doney, Alex S.F., McCarthy, Mark I., and Hattersley, Andrew T.
- Subjects
Type 2 diabetes -- Research ,Type 2 diabetes -- Risk factors ,Type 2 diabetes -- Genetic aspects - Published
- 2007
17. A common variant in the FTO gene is associated with body mass index and predisposes to childhood and adult obesity
- Author
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Frayling, Timothy M., Timpson, Nicholas J., Weedon, Michael N., Zeggini, Eleftheria, Freathy, Rachel M., Lindgren, Cecilia M., Perry, John R.B., Elliott, Katherine S., Lango, Hana, Rayner, Nigel W., Shields, Beverley, Harries, Lorna W., Barrett, Jeffrey C., Ellard, Sian, Groves, Christopher J., Knight, Bridget, Patch, Ann-Marie, Ness, Andrew R., Ebrahim, Shah, Lawlor, Debbie A., Ring, Susan M., Ben-Shlomo, Yoav, Jarvelin, Marjo-Riitta, Sovio, Ulla, Bennett, Amanda J., Melzer, David, Ferrucci, Luigi, Loos, Ruth J.F., Barroso, Ines, Wareham, Nicholas J., Karpe, Fredrik, Owen, Katharine R., Cardon, Lon R., Walker, Mark, Hitman, Graham A., Palmer, Colin N.A., Doney, Alex S.F., Morris, Andrew D., Smith, George Davey, Hattersley, Andrew T., and McCarthy, Mark I.
- Subjects
Obesity gene -- Research ,Body mass index -- Research - Published
- 2007
18. Macrosomia and hyperinsulinaemic hypoglycaemia in patients with heterozygous mutations in the HNF4A gene
- Author
-
Pearson, Ewan R., Boj, Sylvia F., Steele, Anna M., Barrett, Timothy, Stals, Karen, Shield, Julian P., Ellard, Sian, Ferrer, Jorge, and Hattersley, Andrew T.
- Subjects
Metabolic diseases -- Research ,Metabolic diseases -- Genetic aspects ,Morbidity -- Research ,Mutation (Biology) -- Research - Abstract
ABSTRACT Background Macrosomia is associated with considerable neonatal and maternal morbidity. Factors that predict macrosomia are poorly understood. The increased rate of macrosomia in the offspring of pregnant women with [...]
- Published
- 2007
19. Genome-wide associations for birth weight and correlations with adult disease
- Author
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Horikoshi, Momoko, Beaumont, Robin N., Day, Felix R., Warrington, Nicole M., Kooijman, Marjolein N., Fernandez-Tajes, Juan, Feenstra, Bjarke, van Zuydam, Natalie R., Gaulton, Kyle J., Grarup, Niels, Bradfield, Jonathan P., Strachan, David P., Li-Gao, Ruifang, Ahluwalia, Tarunveer S., Kreiner, Eskil, Rueedi, Rico, Lyytikinen, Leo-Pekka, Cousminer, Diana L., Wu, Ying, Thiering, Elisabeth, Wang, Carol A., Have, Christian T., Hottenga, Jouke-Jan, Vilor-Tejedor, Natalia, Joshi, Peter K., Boh, Eileen Tai Hui, Ntalla, Ioanna, Pitknen, Niina, Mahajan, Anubha, van Leeuwen, Elisabeth M., Joro, Raimo, Lagou, Vasiliki, Nodzenski, Michael, Diver, Louise A., Zondervan, Krina T., Bustamante, Mariona, Marques-Vidal, Pedro, Mercader, Josep M., Bennett, Amanda J., Rahmioglu, Nilufer, Nyholt, Dale R., Ma, Ronald C. W., Tam, Claudia H. T., Tam, Wing Hung, Ganesh, Santhi K., van Rooij, Frank J. A., Jones, Samuel E., Loh, Po-Ru, Ruth, Katherine S., Tuke, Marcus A., Tyrrell, Jessica, Wood, Andrew R., Yaghootkar, Hanieh, Scholtens, Denise M., Paternoster, Lavinia, Prokopenko, Inga, Kovacs, Peter, Atalay, Mustafa, Willems, Sara M., Panoutsopoulou, Kalliope, Wang, Xu, Carstensen, Lisbeth, Geller, Frank, Schraut, Katharina E., Murcia, Mario, van Beijsterveldt, Catharina E. M., Willemsen, Gonneke, Appel, Emil V. R., Fonvig, Cilius E., Trier, Caecilie, Tiesler, Carla M. T., Standl, Marie, Kutalik, Zoltn, Bons-Guarch, Slvia, Hougaard, David M., Snchez, Friman, Torrents, David, Waage, Johannes, Hollegaard, Mads V., de Haan, Hugoline G., Rosendaal, Frits R., Medina-Gomez, Carolina, Ring, Susan M., Hemani, Gibran, McMahon, George, Robertson, Neil R., Groves, Christopher J., Langenberg, Claudia, Luan, Jianan, Scott, Robert A., Zhao, Jing Hua, Mentch, Frank D., MacKenzie, Scott M., Reynolds, Rebecca M., Lowe, William L., Tnjes, Anke, Stumvoll, Michael, Lindi, Virpi, Lakka, Timo A., van Duijn, Cornelia M., Kiess, Wieland, Krner, Antje, Srensen, Thorkild I. A., Niinikoski, Harri, Pahkala, Katja, Raitakari, Olli T., Zeggini, Eleftheria, Dedoussis, George V., Teo, Yik-Ying, Saw, Seang-Mei, Melbye, Mads, Campbell, Harry, Wilson, James F., Vrijheid, Martine, de Geus, Eco J. C. N., Boomsma, Dorret I., Kadarmideen, Haja N., Holm, Jens-Christian, Hansen, Torben, Sebert, Sylvain, Hattersley, Andrew T., Beilin, Lawrence J., Newnham, John P., Pennell, Craig E., Heinrich, Joachim, Adair, Linda S., Borja, Judith B., Mohlke, Karen L., Eriksson, Johan G., Widn, Elisabeth, Khnen, Mika, Viikari, Jorma S., Lehtimki, Terho, Vollenweider, Peter, Bnnelykke, Klaus, Bisgaard, Hans, Mook-Kanamori, Dennis O., Hofman, Albert, Rivadeneira, Fernando, Uitterlinden, Andr G., Pisinger, Charlotta, Pedersen, Oluf, Power, Christine, Hyppnen, Elina, Wareham, Nicholas J., Hakonarson, Hakon, Davies, Eleanor, Walker, Brian R., Jaddoe, Vincent W. V., Jrvelin, Marjo-Riitta, Grant, Struan F. A., Vaag, Allan A., Lawlor, Debbie A., Frayling, Timothy M., Smith, George Davey, Morris, Andrew P., Ong, Ken K., Felix, Janine F., Timpson, Nicholas J., Perry, John R. B., Evans, David M., McCarthy, Mark I., and Freathy, Rachel M.
- Subjects
Genome-wide association studies ,Birth weight -- Genetic aspects -- Health aspects ,Metabolic diseases -- Risk factors -- Genetic aspects ,Cardiovascular diseases -- Risk factors -- Genetic aspects ,Environmental issues ,Science and technology ,Zoology and wildlife conservation - Abstract
Author(s): Momoko Horikoshi [1, 2]; Robin N. Beaumont [3]; Felix R. Day [4]; Nicole M. Warrington [5, 6]; Marjolein N. Kooijman [7, 8, 9]; Juan Fernandez-Tajes [1]; Bjarke Feenstra [10]; [...]
- Published
- 2016
- Full Text
- View/download PDF
20. A common haplotype of the glucokinase gene alters fasting glucose and birth weight: Association in six studies and population-genetics analyses
- Author
-
Weedon, Michael N., Clark, Vanessa J., Yudong Qian, Ben-Shlomo, Yoav, Timpson, Nicholas, Ebrahim, Shah, Lawlor, Debbie A., Pembrey, Marcus E., Ring, Susan, Wilkin, Terry J., Voss, Linda D., Jeffrey, Alison N., Metcalf, Brad, Ferrucci, Luigi, Corsi, Anna Maria, Murray, Anna, Melzer, David, Knight, Bridget, Shields, Bev, Smith, George Davey, Hattersley, Andrew T., Di Rienzo, Anna, and Frayling, Tim M.
- Subjects
Glucokinase -- Research ,Human population genetics -- Research ,Fasting -- Research ,Birth size -- Research ,Birth weight -- Research ,Biological sciences - Abstract
The role of variation of glucokinase (GCK) in the determination of fasting glucose and birth weight is examined using a tagging single-nucleotide polymorphism (tSNP) approach. A comprehensive analysis of common variation of the glucokinase gene has indicated that this is the first gene to be reproducibly associated with fasting glucose and fetal growth.
- Published
- 2006
21. Switching from insulin to oral sulfonylureas in patients with diabetes due to Kir6.2 mutations
- Author
-
Pearson, Eawn R., Flechter, Isabelle, Njolstad, Pal R., Malecki, Maciej T., Flanagan, Sarah E., Larkin, Brian, Ashcroft, Frances M., Klimes, Iwar, Shield, Julian, Codner, Ethel, Iotova, Violeta; Slingerland, Annabelle S., Robert, Jean-Jacques; Holst, Jens J., Clark, Penny M.; Ellard, Sian, and Sovik, Oddmund; Polak, Michel; Hattersley, Andrew T.
- Subjects
Hypoglycemic sulfonylureas -- Care and treatment ,Sulfonylurea compounds -- Care and treatment ,Insulin -- Health aspects ,Blood sugar -- Control - Abstract
The glycemic control in patients with Kir6.2 mutations who received appropriate doses of sulfonylureas are assessed and the mechanism of insulin dependence in patients who are able to switch from insulin to oral sulfonylurea therapy are examined. The results have shown that sulfonylurea therapy is safe in the short term for patients with diabetes caused by KCNJ11 mutations and is probably more effective than insulin therapy.
- Published
- 2006
22. C-reactive protein and its role in metabolic syndrome: mendelian randomisation study
- Author
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Timpson, Nicholas J., Lawlor, Debbie A., Harbord, Roger M., Gaunt, Tom R., Day, Ian N.M., Palmer, Lyle J., Hattersley, Andrew T., Ebrahim, Shah, Lowe, Gordon, D.O., Rumley, Ann, and Smith, George Davey
- Subjects
C-reactive protein -- Genetic aspects ,Metabolic syndrome X -- Causes of ,Metabolic syndrome X -- Genetic aspects ,Genetic research - Published
- 2005
23. Genetic epidemiology 5: what makes a good genetic association study?
- Author
-
Hattersley, Andrew T. and McCarthy, Mark I.
- Subjects
Epidemiology -- Genetic aspects ,Epidemiologic methods -- Analysis - Published
- 2005
24. What makes a good genetic association study?
- Author
-
Hattersley, Andrew T. and McCarthy, Mark I.
- Subjects
Genetic susceptibility -- Health aspects ,Genetic susceptibility -- Research ,Genetic variation -- Research - Published
- 2005
25. Molecular basis of Kir6.2 mutations associated with neonatal diabetes or neonatal diabetes plus neurological features
- Author
-
Proks, Peter, Antcliff, Jennifer F., Lippiat, Jon, Gloyn, Anna L., Hattersley, Andrew T., and Ashcroft, Frances M.
- Subjects
Potassium channels -- Research ,Molecules -- Research ,Science and technology - Abstract
Inwardly rectifying potassium channels (Kir channels) control cell membrane [K.sup.+] fluxes and electrical signaling in diverse cell types. Heterozygous mutations in the human Kir6.2 gene (KCNJ11), the pore-forming subunit of the ATP-sensitive ([K.sub.ATP]) channel, cause permanent neonatal diabetes mellitus (PNDM). For some mutations, PNDM is accompanied by marked developmental delay, muscle weakness, and epilepsy (severe disease). To determine the molecular basis of these different phenotypes, we expressed wild-type or mutant (R201C, Q52R, or V59G) Kir6.2/sulfonylurea receptor 1 channels in Xenopus oocytes. All mutations increased resting whole-cell [K.sub.ATP] currents by reducing channel inhibition by ATP, but, in the simulated heterozygous state, mutations causing PNDM alone (R201C) produced smaller [K.sub.ATP] currents and less change in ATP sensitivity than mutations associated with severe disease (Q52R and V59G). This finding suggests that increased [K.sub.ATP] currents hyperpolarize pancreatic beta cells and impair insulin secretion, whereas larger [K.sub.ATP] currents are required to influence extrapancreatic cell function. We found that mutations causing PNDM alone impair ATP sensitivity directly (at the binding site), whereas those associated with severe disease act indirectly by biasing the channel conformation toward the open state. The effect of the mutation on ATP sensitivity in the heterozygous state reflects the different contributions of a single subunit in the Kir6.2 tetramer to ATP inhibition and to the energy of the open state. Our results also show that mutations in the slide helix of Kir6.2 (V59G) influence the channel kinetics, providing evidence that this domain is involved in Kir channel gating, and suggest that the efficacy of sulfonylurea therapy in PNDM may vary with genotype. potassium channel | [K.sub.ATP] channel | KCNJ11 | ATP-binding site
- Published
- 2004
26. GATA6 mutations cause a broad phenotypic spectrum of diabetes from pancreatic agenesis to adult-onset diabetes without exocrine insufficiency
- Author
-
De Franco, Elisa, Shaw-Smith, Charles, Flanagan, Sarah E., Shepherd, Maggie H., Hattersley, Andrew T., and Ellard, Sian
- Subjects
Gene mutations -- Research -- Analysis ,Diabetes -- Research -- Genetic aspects -- Analysis ,Health - Abstract
We recently reported de novo GATA6 mutations as the most common cause of pancreatic agenesis, accounting for 15 of 27 (56%) patients with insulin-treated neonatal diabetes and exocrine pancreatic insufficiency requiring enzyme replacement therapy. We investigated the role of GATA6 mutations in 171 subjects with neonatal diabetes of unknown genetic etiology from a cohort of 795 patients with neonatal diabetes. Mutations in known genes had been confirmed in 624 patients (including 15 GATA6 mutations). Sequencing of the remaining 171 patients identified nine new case subjects (24 of 795, 3%). Pancreatic agenesis was present in 21 case subjects (six new); two patients had permanent neonatal diabetes with no enzyme supplementation and one had transient neonatal diabetes. Four parents with heterozygous GATA6 mutations were diagnosed with diabetes outside the neonatal period (12-46 years). Subclinical exocrine insufficiency was demonstrated by low fecal elastase in three of four diabetic patients who did not receive enzyme supplementation. One parent with a mosaic mutation was not diabetic but had a heart malformation. Extrapancreatic features were observed in all 24 probands and three parents, with congenital heart defects most frequent (83%). Heterozygous GATA6 mutations cause a wide spectrum of diabetes manifestations, ranging from pancreatic agenesis to adult-onset diabetes with subclinical or no exocrine insufficiency., Exome sequencing recently led to the discovery that heterozygous GATA6 mutations are the most common cause of pancreatic agenesis, accounting for 15 of 27 patients with neonatal diabetes (NDM) requiring [...]
- Published
- 2013
- Full Text
- View/download PDF
27. Lessons from the mixed-meal tolerance test: use of 90-minute and fasting C-peptide in pediatric diabetes
- Author
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Besser, Rachel E.J., Shields, Beverley M., Casas, Rosaura, Hattersley, Andrew T., and Ludvigsson, Johnny
- Subjects
Type 1 diabetes -- Diagnosis -- Care and treatment -- Patient outcomes -- Research ,C-reactive protein -- Health aspects -- Measurement -- Research ,Fasting -- Health aspects -- Research ,Health - Abstract
OBJECTIVE--Mixed-meal tolerance test (MMTT) area under the curve C-peptide (AUC CP) is the gold-standard measure of endogenous insulin secretion in type 1 diabetes but is intensive and invasive to perform. [...]
- Published
- 2013
- Full Text
- View/download PDF
28. Genetic cause of hyperglycaemia and response to treatment in diabetes
- Author
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Pearson, Ewan R., Starkey, Bryan J., Powell, Roy J., Gribble, Fiona M., Clark, Penny M., and Hattersley, Andrew T.
- Published
- 2003
29. Integrating genetics into diabetes care: a new role for DSNs
- Author
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Shepherd, Maggie, Stride, Amanda, Ellard, Sian, and Hattersley, Andrew T.
- Subjects
Diabetes -- Care and treatment -- Research ,Nurses -- Practice -- Research ,Health ,Health care industry ,Practice ,Care and treatment ,Research - Abstract
Introduction The importance of molecular genetic testing in diagnosing genetic subtypes of diabetes is well recognised as it can guide optimal treatment, help genetic counselling and explain the co-inheritance of [...]
- Published
- 2003
30. Evidence for linkage of stature to chromosome 3p26 in a large U.K. family data set ascertained for type 2 diabetes. (Report)
- Author
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Wiltshire, Steven, Frayling, Timothy M., Hattersley, Andrew T., Hitman, Graham A., Walker, Mark, Levy, Jonathan C., O'Rahilly, Stephen, Groves, Christopher J., Menzel, Stephan, Cardon, Lon R., and McCarthy, Mark I.
- Subjects
United Kingdom -- Research ,Stature -- Genetic aspects ,Linkage (Genetics) -- Research ,Biological sciences - Published
- 2002
31. Hypoglycaemic counter-regulation at normal blood glucose concentrations in patients with well controlled type-2 diabetes
- Author
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Spyer, Gill, Hattersley, Andrew T., MacDonald, IA, Amiel, Stephanie, and MacLeod, Kenneth M.
- Published
- 2000
32. Mutations of the same conserved glutamate residue in NBD2 of the sulfonylurea receptor 1 subunit of the [K.sub.ATP] channel can result in either hyperinsulinism or neonatal diabetes
- Author
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Mannikko, Roope, Flanagan, Sarah E., Sim, Xiuli, Segal, David, Hussain, Khalid, Ellard, Sian, Hattersley, Andrew T., and Ashcroft, Frances M.
- Subjects
Gene mutations -- Physiological aspects -- Research ,Potassium channels -- Physiological aspects -- Genetic aspects -- Research ,Diabetes in children -- Risk factors -- Genetic aspects -- Research ,Health - Abstract
OBJECTIVE--Two novel mutations (E1506D, E1506G) in the nucleotide-binding domain 2 (NBD2) of the ATP-sensitive K+ channel ([K.sub.ATP] channel) sulfonylurea receptor 1 (SUR1) subunit were detected heterozygously in patients with neonatal diabetes. A mutation at the same residue (E1506K) was previously shown to cause congenital hyperinsulinemia. We sought to understand why mutations at the same residue can cause either neonatal diabetes or hyperinsulinemia. RESEARCH DESIGN AND METHODS--Neonatal diabetic patients were sequenced for mutations in ABCC8 (SUR1) and KCNJ11 (Kir6.2). Wild-type and mutant [K.sub.ATP] channels were expressed in Xenopus laevis oocytes and studied with electrophysiological methods. RESULTS--Oocytes expressing neonatal diabetes mutant channels had larger resting whole-cell [K.sub.ATP] currents than wild-type, consistent with the patients' diabetes. Conversely, no E1506K currents were recorded at rest or after metabolic inhibition, as expected for a mutation causing hyperinsulinemia. [K.sub.ATP] channels are activated by Mg-nucleotides (via SUR1) and blocked by ATP (via Kir6.2). All mutations decreased channel activation by MgADP but had little effect on MgATP activation, as assessed using an ATP-insensitive Kir6.2 subtmit. Importantly, using wild-type Kir6.2, a 30-s preconditioning exposure to physiological MgATP concentrations (>300 µmol/L) caused a marked reduction in the ATP sensitivity of neonatal diabetic channels, a small decrease in that of wild-type channels, and no change for E1506K channels. This difference in MgATP inhibition may explain the difference in resting whole-cell currents found for the neonatal diabetes and hyperinsulinemia mutations. CONCLUSIONS--Mutations in the same residue can cause either hyperinsulinemia or neonatal diabetes. Differentially altered nucleotide regulation by NBD2 of SUR1 can explain the respective clinical phenotypes. Diabetes 60:1813-1822, 2011, The ATP-sensitive [K.sup.+] ([K.sub.ATP]) channel plays a central role in glucose-stimulated insulin secretion from the pancreatic β-cell by linking the metabolic state of the cell to its electrical excitability (1-3). [...]
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- 2011
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33. Permanent neonatal diabetes and enteric anendocrinosis associated with biallelic mutations in NEUROG3
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Rubio-Cabezas, Oscar, Jensen, Jan N., Hodgson, Maria I., Codner, Ethel, Ellard, Sian, Serup, Palle, and Hattersley, Andrew T.
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Gene mutations -- Health aspects -- Research ,Diabetes in children -- Risk factors -- Development and progression -- Genetic aspects -- Research ,Transcription factors -- Physiological aspects -- Research ,Health - Abstract
OBJECTIVE--NEUROG3 plays a central role in the development of both pancreatic islets and enteroendocrine cells. Homozygons hypomorphic missense mutations in NEUROG3 have been recently associated with a rare form of congenital malabsorptive diarrhea secondary to enteroendocrine cell dysgenesis. Interestingly, the patients did not develop neonatal diabetes but childhood-onset diabetes. We hypothesized that null mutations in NEUROG3 might be responsible for the disease in a patient with permanent neonatal diabetes and severe congenital malabsorptive diarrhea. RESEARCH DESIGN AND METHODS--The single coding exon of NEUROG3 was amplified and sequenced from genomic DNA. The mutant protein isoforms were functionally characterized by measuring their ability to bind to an E-box element in the NEUROD1 promoter in vitro and to induce ectopic endocrine cell formation and cell delamination after in ovo chicken endoderm electroporation. RESULTS--Two different heterozygous point mutations in NEUROG3 were identified in the proband [c.82G>T (p.E28X) and c.404T>C (p.L135P)], each being inherited from an unaffected parent. Both in vitro and in vivo functional studies indicated that the mutant isoforms are biologically inactive. In keeping with this, no enteroendocrine cells were detected in intestinal biopsy samples from the patient. CONCLUSIONS--Severe deficiency of neurogenin 3 causes a rare novel subtype of permanent neonatal diabetes. This finding confirms the essential role of NEUROG3 in islet development and function in humans., Permanent neonatal diabetes (PNDM), defined as diabetes diagnosed within the first 6 months of life, is a rare condition with an estimated incidence of 1 in 260,000 live births (1). [...]
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- 2011
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34. Mendelian randomization studies do not support a role for raised circulating triglyceride levels influencing type 2 diabetes, glucose levels, or insulin resistance
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De Silva, N. Maneka G., Freathy, Rachel M., Palmer, Tom M., Donnelly, Louise A., Luan, Jian'an, Gaunt, Tom, Langenberg, Claudia, Weedon, Michael N., Shields, Beverley, Knight, Beatrice A., Ward, Kirsten J., Sandhu, Manjinder S., Harbord, Roger M., McCarthy, Mark I., Smith, George Davey, Ebrahim, Shah, Hattersley, Andrew T., Wareham, Nicholas, Lawlor, Debbie A., Morris, Andrew D., Palmer, Colin N.A., and Frayling, Timothy M.
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Genes -- Physiological aspects -- Research ,Insulin resistance -- Genetic aspects -- Risk factors -- Research ,Triglycerides -- Physiological aspects -- Research ,Type 2 diabetes -- Genetic aspects -- Risk factors -- Research ,Health - Abstract
OBJECTIVE--The causal nature of associations between circulating triglycerides, insulin resistance, and type 2 diabetes is unclear. We aimed to use Mendelian randomization to test the hypothesis that raised circulating triglyceride levels causally influence the risk of type 2 diabetes and raise normal fasting glucose levels and hepatic insulin resistance. RESEARCH DESIGN AND METHODS--We tested 10 common genetic variants robustly associated with circulating triglyceride levels against the type 2 diabetes status in 5,637 case and 6,860 control subjects and four continuous outcomes (reflecting glycemia and hepatic insulin resistance) in 8,271 nondiabetic individuals from four studies. RESULTS--Individuals carrying greater numbers of triglyceride-raising alleles had increased circulating triglyceride levels (SD 0.59 [95% CI 0.52-0.65] difference between the 20% of individuals with the most alleles and the 20% with the fewest alleles). There was no evidence that the carriers of greater numbers of triglyceride-raising alleles were at increased risk of type 2 diabetes (per weighted allele odds ratio [OR] 0.99 [95% CI 0.97-1.01]; P = 0.26). In nondiabetic individuals, there was no evidence that carriers of greater numbers of triglyceride-raising alleles had increased fasting insulin levels (SD 0.00 per weighted allele [95% CI -0.01 to 0.02]; P = 0.72) or increased fasting glucose levels (0.00 [-0.01 to 0.01]; P = 0.88). Instrumental variable analyses confirmed that genetically raised circulating triglyceride levels were not associated with increased diabetes risk, fasting glucose, or fasting insulin and, for diabetes, showed a trend toward a protective association (OR per 1-SD increase in [log.sub.10] triglycerides: 0.61 [95% CI 0.45-0.83]; P = 0.002). CONCLUSIONS--Genetically raised circulating triglyceride levels do not increase the risk of type 2 diabetes or raise fasting glucose or fasting insulin levels in nondiabetic individuals. One explanation for our results is that raised circulating triglycerides are predominantly secondary to the diabetes disease process rather than causal., Raised circulating triglyceride levels are strongly correlated with insulin resistance, raised glucose levels, and type 2 diabetes (1-8), but the causal nature of these associations is unclear because of the [...]
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- 2011
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35. Urinary C-peptide creatinine ratio is a practical outpatient tool for identifying hepatocyte nuclear factor 1-α/ hepatocyte nuclear factor 4-α maturity-onset diabetes of the young from long-duration type 1 diabetes
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Besser, Rachel E.J., Shepherd, Maggie H., McDonald, Timothy J., Shields, Beverley M., Knight, Bridget A., Ellard, Sian, and Hattersley, Andrew T.
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Diabetes -- Research ,Diabetics -- Care and treatment ,Type 2 diabetes -- Research -- Care and treatment ,Health - Abstract
OBJECTIVE--Hepat0cyte nuclear factor 1-α (HNF1A)/hepatocyte nuclear factor 4-(α (HNF4A) maturity-onset diabetes of the young (MODY) is frequently misdiagnosed as type 1 diabetes, and patients are inappropriately treated with insulin. Blood [...]
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- 2011
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36. A gene for autosomal recessive spondylocostal dysostosis maps to 19q13.1-q13.3
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Turnpenny, Peter D., Bulman, Michael P., Frayling, Timothy M., Abu-Nastra, Tewfiq K., Garrett, Christine, Hattersley, Andrew T., and Ellard, Sian
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Genetic disorders -- Research ,Chromosome mapping -- Usage ,Ribs -- Abnormalities ,Spine -- Abnormalities ,Bones -- Genetic aspects ,Dysostosis -- Genetic aspects ,Biological sciences - Abstract
A gene for autosomal recessive spondylocostal dysostosis (SD), a disorder in which vertebral-segmentation defects and rib anomalies are associated, maps to 19q13.1-q13.3. Short trunk and stature result as do other problems. The disorder can be familial and has been reported with both autosomal and dominant and autosomal recessive (AR) inheritance. Genomewide scanning was carried out in a large consanguineous ARSD Arab Israeli family which has six definitely affected members, and confirmation involved a second family, one of Pakistani descent, with three affected members.
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- 1999
37. Hyperglyceima and adverse pregnancy outcome (HAPO) study: common genetic variants in GCK and TCF7L2 are associated with fasting and postchallenge glucose levels in pregnancy and with the new consensus definition of gestational diabetes mellitus from the international association of diabetes and pregnancy study groups
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Freathy, Rachel M., Hayes, M. Geoffrey, Urbanek, Margrit, Lowe, Lynn P., Lee, Hoon, Ackerman, Christine, Frayling, Timothy M., Cox, Nancy J., Dunger, David B., Dyer, Alan R., Hattersley, Andrew T., Metzger, Boyd E., and Lowe, William L., Jr.
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Glucose tolerance tests -- Health aspects -- Physiological aspects ,Diabetes in pregnancy -- Patient outcomes -- Diagnosis -- Risk factors -- Genetic aspects -- Care and treatment ,Pregnancy, Complications of -- Risk factors -- Care and treatment -- Genetic aspects -- Diagnosis -- Patient outcomes ,Hyperglycemia -- Genetic aspects -- Physiological aspects -- Care and treatment -- Risk factors -- Diagnosis -- Patient outcomes ,Health - Abstract
OBJECTIVE--Common genetic variants in GCK and TCF7L2 are associated with higher fasting glucose and type 2 diabetes in nonpregnant populations. However, their associations with glucose levels from oral glucose tolerance tests (OGTTs) in pregnancy have not been assessed in a large sample. We hypothesized that these variants are associated with quantitative measures of glycemia in pregnancy. RESEARCH DESIGN AND METHODS--We analyzed the associations between variants rs1799884 (GCK) and rs7903146 (TCF7L2) and OGTT outcomes at 24-32 weeks' gestation in 3,811 mothers of European (U.K. and Australia) and 1,706 mothers of Asian (Thailand) ancestry from the HAPO cohort. We also tested associations with offspring birth anthropometrics. RESULTS--The maternal GCK variant was associated with higher fasting glucose in Europeans (P = 0.001) and Thais (P < 0.0001), 1-h glucose in Europeans (P = 0.001), and 2-h glucose in Thais (P = 0.005). It was also associated with higher European offspring birth weight, fat mass, and skinfold thicknesses (P < 0.05). The TCFTL2 variant was associated with all three maternal glucose outcomes (P = 0.03, P < 0.0001, and P < 0.0001 for fasting and 1-h and 2-h glucose, respectively) in the Europeans but not in the Thais (P > 0.05). In both populations, both variants were associated with higher odds of gestational diabetes mellitus according to the new International Association of Diabetes and Pregnancy Study Groups recommendations (P = 0.001-0.08). CONCLUSIONS--Maternal GCK and TCF7L2 variants are associated with glucose levels known to carry an increased risk of adverse pregnancy outcome in women without overt diabetes. Further studies will be important to determine the variance in maternal glucose explained by all known genetic variants. Diabetes 59:2682-2689, 2010, Maternal glycemia in pregnancy is associated with adverse pregnancy outcomes including birth weight >90th percentile, delivery by cesarean section, neonatal hypoglycemia, and fetal hyperinsulinemia (1). These associations occur across the [...]
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- 2010
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38. Homozygous mutations in NEUROD1 are responsible for a novel syndrome of permanent neonatal diabetes and neurological abnormalities
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Rubio-Cabezas, Oscar, Minton, Jayne A.L., Kantor, Iren, Williams, Denise, Ellard, Sian, and Hattersley, Andrew T.
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Nervous system diseases -- Genetic aspects -- Development and progression -- Research ,Diabetes -- Genetic aspects -- Development and progression -- Research ,Pancreatic beta cells -- Research -- Health aspects ,Infants (Newborn) -- Health aspects -- Research ,Deafness -- Genetic aspects -- Development and progression -- Research ,Health - Abstract
OBJECTIVE--NEUROD1 is expressed in both developing and mature p-cells. Studies in mice suggest that this basic helix-loophelix transcription factor is critical in the development of endocrine cell lineage. Heterozygous mutations have previously been identified as a rare cause of maturity-onset diabetes of the young (MODY). We aimed to explore the potential contribution of NEUROD1 mutations in patients with permanent neonatal diabetes. RESEARCH DESIGN AND METHODS--We sequenced the NEUROD1 gene in 44 unrelated patients with permanent neonatal diabetes of unknown genetic etiology. RESULTS--Two homozygous mutations in NEUROD1 (c.427_ 428del and c.364dupG) were identified in two patients. Both mutations introduced a frameshift that would be predicted to generate a truncated protein completely lacking the activating domain. Both patients had permanent diabetes diagnosed in the first 2 months of life with no evidence of exocrine pancreatic dysfunction and a morphologically normal pancreas on abdominal imaging. In addition to diabetes, they had learning difficulties, severe cerebellar hypoplasia, profound sensorineural deafness, and visual impairment due to severe myopia and retinal dystrophy. CONCLUSIONS--We describe a novel clinical syndrome that results from homozygous loss of function mutations in NEUROD1. It is characterized by permanent neonatal diabetes and a consistent pattern of neurological abnormalities including cerebellar hypoplasia, learning difficulties, sensorineural deafness, and visual impairment. This syndrome highlights the critical role of NEUROD1 in both the development of the endocrine pancreas and the central nervous system in humans. Diabetes 59:2326-2331, 2010, Monogenic permanent neonatal diabetes (PNDM) is typically diagnosed within the first 6 months of birth in contrast to polygenic autoimmune type 1 diabetes, which is usually diagnosed later in childhood [...]
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- 2010
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39. Detailed investigation of the role of common and low-frequency WFS1 variants in type 2 diabetes risk
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Fawcett, Katherine A., Wheeler, Eleanor, Morris, Andrew P., Ricketts, Sally L., Hallmans, Goran, Rolandsson, Olov, Daly, Allan, Wasson, Jon, Permutt, Alan, Hattersley, Andrew T., Glaser, Benjamin, Franks, Paul W., McCarthy, Mark I., Wareham, Nicholas J., Sandhu, Manjinder S., and Barroso, Ines
- Subjects
Nucleotide sequencing -- Usage -- Research -- Genetic aspects ,DNA sequencing -- Usage -- Research -- Genetic aspects ,Single nucleotide polymorphisms -- Research -- Usage -- Genetic aspects ,Type 2 diabetes -- Risk factors -- Genetic aspects -- Research - Abstract
OBJECTIVE--Wolfram syndrome 1 (WFS1) single nucleotide polymorphisms (SNPs) are associated with risk of type 2 diabetes. In this study we aimed to refine this association and investigate the role of low-frequency WFS1 variants in type 2 diabetes risk. RESEARCH DESIGN AND METHODS--For fine-mapping, we sequenced WFS1 exons, splice junctions, and conserved noncoding sequences in samples from 24 type 2 diabetic case and 68 control subjects, selected tagging SNPs, and genotyped these in 959 U.K. type 2 diabetic case and 1,386 control subjects. The same genomic regions were sequenced in samples from 1,235 type 2 diabetic case and 1,668 control subjects to compare the frequency of rarer variants between ease and control subjects. RESULTS--Of 31 tagging SNPs, the strongest associated was the previously untested 3' untranslated region rs1046320 (P = 0.008); odds ratio 0.84 and P = 6.59 x [10.sup.-7] on further replication in 3,753 case and 4,198 control subjects. High correlation between rs1046320 and the original strongest SNP (rs10010131) ([r.sup.2] = 0.92) meant that we could not differentiate between their effects in our samples. There was no difference in the cumulative frequency of 82 rare (minor allele frequency [MAF] CONCLUSIONS--We identified six highly correlated SNPs that show strong and comparable associations with risk of type 2 diabetes, but further refinement of these associations will require large sample sizes (>100,000) or studies in ethnically diverse populations. Low frequency variants in WFS1 are unlikely to have a large impact on type 2 diabetes risk in white U.K. populations, highlighting the complexities of undertaking association studies with low-frequency variants identified by resequencing. Diabetes 59:741-746, 2010, The post genome-wide association study era presents several challenges. These include fine-mapping association signals to genes and/or variants within the genomic regions of interest, assessing the impact of low frequency [...]
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- 2010
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40. Polygenic risk variants for type 2 diabetes susceptibility modify age at diagnosis in monogenic HNF1A diabetes
- Author
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Allen, Hana Lango, Johansson, Stefan, Ellard, Sian, Shields, Beverley, Hertel, Jens K., Raeder, Helge, Colclough, Kevin, Molven, Anders, Frayling, Timothy M., Njolstad, Pal R., Hattersley, Andrew T., and Weedon, Michael N.
- Subjects
Liver cells -- Physiological aspects -- Research ,Type 2 diabetes -- Diagnosis -- Genetic aspects ,Hyperglycemia -- Diagnosis -- Genetic aspects ,Health - Abstract
OBJECTIVE--Mutations in the HNF1A gene are the most common cause of maturity-onset diabetes of the young (MODY). There is a substantial variation in the age at diabetes diagnosis, even within families where diabetes is caused by the same mutation. We investigated the hypothesis that common polygenic variants that predispose to type 2 diabetes might account for the difference in age at diagnosis. RESEARCH DESIGN AND METHODS--Fifteen robustly associated type 2 diabetes variants were successfully genotyped in 410 individuals from 203 HNF1A-MODY families, from two study centers in the U.K. and Norway. We assessed their effect on the age at diagnosis both individually and in a combined genetic score by summing the number of type 2 diabetes risk alleles carried by each patient. RESULTS--We confirmed the effects of environmental and genetic factors known to modify the age at HNF1A-MODY diagnosis, namely intrauterine hyperglycemia (-5.1 years ff present, P = 1.6 x [10.sup.-10]) and HNF1A mutation position (-5.2 years if at least two isoforms affected, P = 1.8 x [10.sup.-2]). Additionally, our data showed strong effects of sex (females diagnosed 3.0 years earlier, P = 6.0 x [10.sup.-4]) and age at study (0.3 years later diagnosis per year increase in age, P = 4.7 x [10.sup.-38]). There were no strong individual single nucleotide polymorphism effects; however, in the combined genetic score model, each additional risk allele was associated with 0.35 years earlier diabetes diagnosis (P = 5.1 x [10.sup.-3]). CONCLUSIONS--We show that type 2 diabetes risk variants of modest effect sizes reduce the age at diagnosis in HNF1A-MODY. This is one of the first studies to demonstrate that clinical characteristics of a monogenic disease can be modified by common polygenic variants., Maturity-onset diabetes of the young (MODY) is a young-onset, dominantly inherited noninsulin-dependent diabetes resulting from β-cell dysfunction (1). There are at least eight genetic subgroups of MODY (1,2), with most [...]
- Published
- 2010
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41. Interrogating type 2 diabetes genome-wide association data using a biological pathway-based approach
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Perry, John R.B., McCarthy, Mark I., Hattersley, Andrew T., Zeggini, Eleftheria, Weedon, Michael N., and Frayling, Timothy M.
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Genetic research -- Genetic aspects ,Diabetes -- Research ,Genetic variation -- Research -- Genetic aspects ,Type 2 diabetes -- Genetic aspects -- Research ,Health ,Research ,Genetic aspects - Abstract
OBJECTIVE--Recent genome-wide association studies have resulted in a dramatic increase in our knowledge of the genetic loci involved in type 2 diabetes. In a complementary approach to these single-marker studies, we attempted to identify biological pathways associated with type 2 diabetes. This approach could allow us to identify additional risk loci. RESEARCH DESIGN AND METHODS--We used individual level genotype data generated from the Wellcome Trust Case Control Consortium (WTCCC) type 2 diabetes study, consisting of 393,143 autosomal SNPs, genotyped across 1,924 case subjects and 2,938 control subjects. We sought additional evidence from summary level data available from the Diabetes Genetics Initiative (DGI) and the Finland-United States Investigation of NIDDM Genetics (FUSION) studies. Statistical analysis of pathways was performed using a modification of the Gene Set Enrichment Algorithm (GSEA). A total of 439 pathways were analyzed from the Kyoto Encyclopedia of Genes and Genomes, Gene Ontology, and BioCarta databases. RESULTS---After correcting for the number of pathways tested, we found no strong evidence for any pathway showing association with type 2 diabetes (top [P.sub.adj] = 0.31). The candidate WNT-signaling pathway ranked top (nominal P = 0.0007, excluding TCF7L2; P = 0.002), containing a number of promising single gene associations. These include CCND2 (rs11833537; P = 0.003), SMAD3 (rs7178347; P = 0.0006), and PRICKLE1 (rs1796390; P = 0.001), all expressed in the pancreas. CONCLUSIONS--Common variants involved in type 2 diabetes risk are likely to occur in or near genes in multiple pathways. Pathway-based approaches to genome-wide association data may be more successful for some complex traits than others, depending on the nature of the underlying disease physiology., Recent genome-wide association (GWA) studies have resulted in a dramatic increase in our knowledge of the genetic loci involved in type 2 diabetes. There are now 18 common variants with [...]
- Published
- 2009
42. Reduced-function SLC22A1 polymorphisms encoding organic cation transporter 1 and glycemic response to metformin: a GoDARTS study
- Author
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Zhou, Kaixin, Donnelly, Louise A., Kimber, Charlotte H., Donnan, Peter T., Doney, Alex S.F., Leese, Graham, Hattersley, Andrew T., McCarthy, Mark I., Morris, Andrew D., Palmer, Colin N.A., and Pearson, Ewan R.
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Medical research -- Health aspects ,Medicine, Experimental -- Health aspects ,Glucose tolerance tests -- Research -- Health aspects ,Human genetics -- Research -- Health aspects ,Metformin -- Health aspects -- Research ,Hypoglycemic agents -- Health aspects -- Research ,Health - Abstract
OBJECTIVE--Metformin is actively transported into the liver by the organic cation transporter (OCT)1 (encoded by SLC22A1). In 12 normoglycemic individuals, reduced-function variants in SLC22A1 were shown to decrease the ability of metformin to reduce glucose excursion in response to oral glucose. We assessed the effect of two common loss-of-function polymorphisms in SLC22A1 on metformin response in a large cohort of patients with type 2 diabetes. RESEARCH DESIGN AND METHODS--The Diabetes Audit and Research in Tayside Scotland (DARTS) database includes prescribing and biochemistry information and clinical phenotypes of all patients with diabetes within Tayside, Scotland, from 1992 onwards. R61C and 420del variants of SLC22A1 were genotyped in 3,450 patients with type 2 diabetes who were incident users of metformin. We assessed metformin response by modeling the maximum A1C reduction in 18 months after starting metformin and investigated whether a treatment target of A1C RESULTS--A total of 1,531 patients were identified with a definable metformin response. R61C and 420del variants did not affect the initial A1C reduction (P = 0.47 and P = 0.92, respectively), the chance of achieving a treatment target (P = 0.83 and P = 0.36), the average A1C on monotherapy up to 42 months (P = 0.44 and P = 0.75), or the hazard of monotherapy failure (P = 0.85 and P = 0.56). CONCLUSIONS--The SLC22A1 loss-of-function variants, R61C and 420del, do not attenuate the A1C reduction achieved by metformin in patients with type 2 diabetes., Metformin is recommended as first-line oral treatment in the joint American Diabetes Association (ADA)/European Association for the Study of Diabetes (EASD) guidelines on the treatment of type 2 diabetes (1) [...]
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- 2009
43. Type 2 diabetes risk alleles are associated with reduced size at birth
- Author
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Freathy, Rachel M., Bennett, Amanda J., Ring, Susan M., Shields, Beverley, Groves, Christopher J., Timpson, Nicholas J., Weedon, Michael N., Zeggini, Eleftheria, Lindgren, Cecilia M., Lango, Hana, Perry, John R.B., Pouta, Anneli, Ruokonen, Aimo, Hypponen, Elina, Power, Chris, Elliott, Paul, Strachan, David P., Jarvelin, Marjo-Riitta, Smith, George Davey, McCarthy, Mark I., Frayling, Timothy M., and Hattersley, Andrew T.
- Subjects
Birth weight -- Health aspects -- Physiological aspects ,Birth size -- Health aspects -- Physiological aspects ,Allelomorphism -- Physiological aspects -- Health aspects -- Genetic aspects ,Type 2 diabetes -- Risk factors -- Genetic aspects ,Health - Abstract
OBJECTIVE--Low birth weight is associated with an increased risk of type 2 diabetes. The mechanisms underlying this association are unknown and may represent intrauterine programming or two phenotypes of one genotype. The fetal insulin hypothesis proposes that common genetic variants that reduce insulin secretion or action may predispose to type 2 diabetes and also reduce birth weight, since insulin is a key fetal growth factor. We tested whether common genetic variants that predispose to type 2 diabetes also reduce birth weight. RESEARCH DESIGN AND METHODS--We genotyped single-nucleotide polymorphisms (SNPs) at five recently identified type 2 diabetes loci (CDKAL1, CDKN2A/B, HHEX-IDE, IGF2BP2, and SLC3OA8) in 7,986 mothers and 19,200 offspring from four studies of white Europeans. We tested the association between maternal or fetal genotype at each locus and birth weight of the offspring. RESULTS--We found that type 2 diabetes risk alleles at the CDKAL1 and HHEX-IDE loci were associated with reduced birth weight when inherited by the fetus (21 g [95)A CI 11-31], P = 2 X [10.sup.-5], and 14 g [4-23], P = 0.004, lower birth weight per risk allele, respectively). The 4% of offspring carrying four risk alleles at these two loci were 80 g (95% CI 39-120) lighter at birth than the 8% carrying none ([P.sub.trend] = 5 X 10-7). There were no associations between birth weight and fetal genotypes at the three other loci or maternal genotypes at any locus. CONCLUSIONS--Our results are in keeping with the fetal insulin hypothesis and provide robust evidence that common disease-associated variants can alter size at birth directly through the fetal genotype., Reduced birth weight is associated with late-onset diseases including type 2 diabetes, hypertension, and heart disease (1). The cause of this association is not known. It is often proposed to [...]
- Published
- 2009
44. Adiposity-related heterogeneity in patterns of type 2 diabetes susceptibility observed in genome-wide association data
- Author
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Timpson, Nicholas J., Lindgren, Cecilia M., Weedon, Michael N., Randall, Joshua, Ouwehand, Willem H., Strachan, David P., Rayner, N. William, Walker, Mark, Hitman, Graham A., Doney, Alex S.F., Palmer, Colin N.A., Morris, Andrew D., Hattersley, Andrew T., Zeggini, Eleftheria, Frayling, Timothy M., and McCarthy, Mark I.
- Subjects
Obesity -- Complications and side effects -- Research -- Risk factors -- Genetic aspects ,Disease susceptibility -- Genetic aspects -- Research -- Complications and side effects -- Risk factors ,Type 2 diabetes -- Research -- Genetic aspects -- Risk factors -- Complications and side effects ,Health ,Complications and side effects ,Genetic aspects ,Research ,Risk factors - Abstract
OBJECTIVE--This study examined how differences in the BMI distribution of type 2 diabetic case subjects affected genomewide patterns of type 2 diabetes association and considered the implications for the etiological heterogeneity of type 2 diabetes. RESEARCH DESIGN AND METHODS--We reanalyzed data from the Wellcome Trust Case Control Consortium genome-wide association scan (1,924 case subjects, 2,938 control subjects: 393,453 single-nucleotide polymorphisms [SNPs]) after stratifying case subjects (into 'obese' and 'nonobese') according to median BMI (30.2 kg/[m.sup.2]). Replication of signals in which alternative case-ascertainment strategies generated marked effect size heterogeneity in type 2 diabetes association signal was sought in additional samples. RESULTS--In the 'obese-type 2 diabetes' scan, FTO variants had the strongest type 2 diabetes effect (rs8050136: relative risk [RR] 1.49 [95% CI 1.34-1.66], P = 1.3 x [10.sup.-13]), with only weak evidence for TCF7L2 (rs7901695 RR 1.21 [1.09-1.35], P = 0.001). This situation was reversed in the 'nonobese' scan, with FTO association undetectable (RR 1.07 [0.97-1.19], P = 0.19) and TCF7L2 predominant (RR 1.53 [1.37-1.71], P = 1.3 x [10.sup.-14]). These patterns, confirmed by replication, generated strong combined evidence for between-stratum effect size heterogeneity (FTO: [P.sub.DIFF] = 1.4 x [10.sup.-7]; TCF7L2: [P.sub.DIFF] = 4.0 x [10.sup.-6]). Other signals displaying evidence of effect size heterogeneity in the genome-wide analyses (on chromosomes 3, 12, 15, and 18) did not replicate. Analysis of the current list of type 2 diabetes susceptibility variants revealed nominal evidence for effect size heterogeneity for the SLC30A8 locus alone ([RR.sub.obese] 1.08 [1.01-1.15]; [RR.sub.nonobese] 1.18 [1.10-1.27]: [P.sub.DIFF] = 0.04). CONCLUSIONS--This study demonstrates the impact of differences in case ascertainment on the power to detect and replicate genetic associations in genome-wide association studies. These data reinforce the notion that there is substantial etiological heterogeneity within type 2 diabetes., Over the past year, the capacity to perform large-scale high-density genome-wide association (GWA) analyses has provided the first global view of the genetic etiology of type 2 diabetes, albeit one [...]
- Published
- 2009
45. Clinical heterogeneity in patients with FOXP3 mutations presenting with permanent neonatal diabetes
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Rubio-Cabezas, Oscar, Minton, Jayne A.L., Caswell, Richard, Shield, Julian P., Deiss, Dorothee, Sumnik, Zdenek, Cayssials, Amely, Herr, Mathias, Loew, Anja, Lewis, Vaughan, Ellard, Sian, and Hattersley, Andrew T.
- Subjects
Diabetes -- Genetic aspects -- Research ,Infants (Newborn) -- Genetic aspects ,Health ,Genetic aspects - Abstract
OBJECTIVE--Immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome is caused by FOXP3 mutations. We aimed to determine the prevalence, genetics, and clinical phenotype of FOXP3 mutations in a large cohort with [...]
- Published
- 2009
46. Population-specific risk of type 2 diabetes conferred by HNF4A P2 promoter variants: a lesson for replication studies
- Author
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Barroso, Ines, Luan, Jian'an, Wheeler, Eleanor, Whittaker, Pamela, Wasson, Jon, Zeggini, Eleftheria, Weedon, Michael N., Hunt, Sarah, Venkatesh, Ranganath, Frayling, Timothy M., Delgado, Marcos, Neuman, Rosalind J., Zhao, Jinghua, Sherva, Richard, Glaser, Benjamin, Walker, Mark, Hitman, Graham, McCarthy, Mark I., Hattersley, Andrew T., Permutt, M. Alan, Wareham, Nicholas J., and Deloukas, Panagiotis
- Subjects
Gene mutations -- Research -- Genetic aspects ,Genotype -- Research -- Genetic aspects ,Type 2 diabetes -- Research -- Genetic aspects -- Risk factors ,Health ,Genetic aspects ,Research ,Risk factors - Abstract
OBJECTIVE--Single nucleotide polymorphisms (SNPs) in the P2 promoter region of HNF4A were originally shown to be associated with predisposition for type 2 diabetes in Finnish, Ashkenazi, and, more recently, Scandinavian populations, but they generated conflicting results in additional populations. We aimed to investigate whether data from a large-scale mapping approach would replicate this association in novel Ashkenazi samples and in U.K. populations and whether these data would allow us to refine the association signal. RESEARCH DESIGN AND METHODS--Using a dense linkage disequilibrium map of 20q, we selected SNPs from a 10-Mb interval centered on HNF4A. In a staged approach, we first typed 4,608 SNPs in case-control populations from four U.K. populations and an Ashkenazi population (n = 2,516). In phase 2, a subset of 763 SNPs was genotyped in 2,513 additional samples from the same populations. RESULTS--Combined analysis of both phases demonstrated association between HNF4A P2 SNPs (rs1884613 and rs2144908) and type 2 diabetes in the Ashkenazim (n = 991; P < 1.6 x [10.sup.-6]). Importantly, these associations are significant in a subset of Ashkenazi samples (n = 531) not previously tested for association with P2 SNPs (odds ratio [OR] ~1.7; P < 0.002), thus providing replication within the Ashkenazim. In the U.K. populations, this association was not significant (n = 4,022; P > 0.5), and the estimate for the OR was much smaller (OR 1.04; [95%CI 0.91-1.19]). CONCLUSIONS--These data indicate that the risk conferred by HNF4A P2 is significantly different between U.K. and Ashkenazi populations (P < 0.00007), suggesting that the underlying causal variant remains unidentified. Interactions with other genetic or environmental factors may also contribute to this difference in risk between populations., The presence of type 2 diabetes susceptibility genes on chromosome 20 has been suggested by linkage scans in several populations. The 20q12-q13 region (Online Mendelian Inheritance in Man [OMIM] 603694) [...]
- Published
- 2008
47. Assessing the combined impact of 18 common genetic variants of modest effect sizes on type 2 diabetes risk
- Author
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Lango, Hana, Palmer, Colin N.A, Morris, Andrew D., Zeggini, Eleftheria, Hattersley, Andrew T., McCarthy, Mark I., Frayling, Timothy M., and Weedon, Michael N.
- Subjects
Genotype -- Research -- Genetic aspects ,Type 2 diabetes -- Genetic aspects -- Risk factors -- Research ,Health ,Research ,Genetic aspects ,Risk factors - Abstract
OBJECTIVES--Genome-wide association studies have dramatically increased the number of common genetic variants that are robustly associated with type 2 diabetes. A possible clinical use of this information is to identify individuals at high risk of developing the disease, so that preventative measures may be more effectively targeted. Here, we assess the ability of 18 confirmed type 2 diabetes variants to differentiate between type 2 diabetic case and control subjects. RESEARCH DESIGN AND METHODS--We assessed index single nucleotide polymorphisms (SNPs) for the 18 independent loci in 2,598 control subjects and 2,309 ease subjects from the Genetics of Diabetes Audit and Research Tayside Study. The discriminatory ability of the combined SNP information was assessed by grouping individuals based on number of risk alleles carried and determining relative odds of type 2 diabetes and by calculating the area under the receiver-operator characteristic curve (AUC). RESULTS--Individuals carrying more risk alleles had a higher risk of type 2 diabetes. For example, 1.296 of individuals with >24 risk alleles had an odds ratio of 4.2 (95% CI 2.11-8.56) against the 1.8% with 10-12 risk alleles. The AUC (a measure of discriminative accuracy) for these variants was 0.60. The AUC for age, BMI, and sex was 0.78, and adding the genetic risk variants only marginally increased this to 0.80. CONCLUSIONS--Currently, common risk variants for type 2 diabetes do not provide strong predictive value at a population level. However, the joint effect of risk variants identified subgroups of the population at substantially different risk of disease. Further studies are needed to assess whether individuals with extreme numbers of risk alleles may benefit from genetic testing., Recent genome-wide association (GWA) studies, which assay >300,000 single nucleotide polymorphisms (SNPs) across many thousands of individuals, have led to the discoveries of variants predisposing to many common complex diseases, [...]
- Published
- 2008
48. Learning from molecular genetics: novel insights arising from the definition of genes for monogenic and type 2 diabetes
- Author
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McCarthy, Mark I. and Hattersley, Andrew T.
- Subjects
Molecular genetics -- Health aspects -- Genetic aspects ,Genetic polymorphisms -- Health aspects -- Genetic aspects ,Type 2 diabetes -- Genetic aspects ,Health ,Genetic aspects ,Health aspects - Abstract
Genetic factors for many decades have been known to play a critical role in the etiology of diabetes, but it has been only recently that the specific genes have been [...]
- Published
- 2008
49. The fat mass- and obesity-associated locus and dietary intake in children
- Author
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Timpson, Nicholas J., Emmett, Pauline M., Frayling, Timothy M., Rogers, Imogen, Hattersley, Andrew T., McCarthy, Mark I., and Smith, George Davey
- Subjects
Obesity in children -- Research ,Obesity in children -- Risk factors ,Food habits -- Physiological aspects ,Obesity gene -- Research ,Food/cooking/nutrition ,Health - Abstract
Background: A region of chromosome 16 containing the fat mass-and obesity-associated gene (FTO) is reproducibly associated with fat mass and body mass index (BMI), risk of obesity, and adiposity. Objectives: We aimed to assess the possibility that appetite plays a role in the association between FTO and BMI. Design: Detailed dietary report information from the Avon Longitudinal Study of Parents and Children allowed the exploration of relations between FTO variation and dietary intake. Analyses were performed to investigate possible associations between variation at the FTO locus and the intake of a range of micronutrients and macronutrients, with adjustment for the bias often found within dietary report data when factors related to BMI are assessed. To test the hypothesis that FTO may be influencing appetite directly, rather than indirectly via BMI and altered intake requirements, we also assessed associations between FTO and dietary intake independent of BMI. Results: Relations between a single-nucleotide polymorphism characterizing the FTO signal (rs9939609) and dietary variables were found and can be summarized by the effect of each additional allele (per-allele effects) on total energy and total fat (P < 0.001 for both). These associations were attenuated, but they persisted specifically for fat and energy consumption after adjustment for BMI [total daily fat consumption: [approximately equal to] 1.5 g/d (P = 0.02 for the per-allele difference); total daily energy consumption: [approximately equal to] 25 kJ/d (P = 0.03 for the per-allele difference)]. Conclusion: These associations suggest that persons carrying minor variants at rs9939609 were consuming more fat and total energy than were those not carrying such variants. They also suggest that this difference was not simply dependent on having higher average BMIs among the former group.
- Published
- 2008
50. Diabetes susceptibility in the Canadian Oji-Cree population is moderated by abnormal mRNA processing of HNF1A G319S transcripts
- Author
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Harries, Lorna W., Sloman, Melissa J., Sellers, Elizabeth A.C., Hattersley, Andrew T., and Ellard, Sian
- Subjects
Obesity -- Research -- Physiological aspects ,Diabetes -- Surveys -- Demographic aspects -- Research ,Genetic polymorphisms -- Research -- Physiological aspects -- Surveys ,RNA processing -- Research -- Physiological aspects -- Surveys ,Health ,Physiological aspects ,Research ,Surveys ,Demographic aspects - Abstract
OBJECTIVE--The G319S HNF1A variant is associated with an increased risk of type 2 diabetes in the Canadian Oji-Cree population. We hypothesized that the variant site at the 3' end of exon 4 might influence splicing and characterized mRNA transcripts to investigate the mutational mechanism underlying this susceptibility to diabetes. RESEARCH DESIGN AND METHODS--We established lymphoblastoid cell lines from a G319S homozygote and controls. HNF1A transcripts were characterized in the cell lines and pancreatic tissue by sequence analysis of RT-PCR products and quantification using real-time PCR. Susceptibility to mRNA surveillance was investigated using cycloheximide. RESULTS--Full-length G319S mRNA accounted for 24% of mRNA transcripts in the homozygous G319S cell line. A novel isoform lacking the terminal 12 bases of exon 4 was upregulated (55% of mRNA transcripts) compared with control cell lines (33%) and human pancreatic tissue (17%). Two abnormal transcripts present only in the G319S cell line included premature termination codons as a result of the inclusion of seven nucleotides from intron 4 or the deletion of exon 8. Cycloheximide treatment increased the levels of both transcripts. CONCLUSIONS--The G319S variant results in the production of two abnormal transcripts and an alteration in the relative balance of normal splicing products. This is predicted to lead to a reduction in total HNF1A transcript levels, but residual hepatocyte nuclear factor-1α protein activity in G319S homozygotes may still reach up to 66% of normal levels. A combination of abnormal splicing and reduced activity of the G319S protein may explain the diabetes susceptibility., The Oji-Cree are an isolated population from North Central Canada who are among the most diabetes-prone subpopulations in the world; almost 40% of adults (1) and a high proportion of [...]
- Published
- 2008
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