Lorna W. Harries

Obesity is a serious international health problem that increases the risk of several common diseases. The genetic factors predisposing to obesity are poorly understood. A genome-wide search for type 2 diabetes-susceptibility genes identified a common variant in the FTO (fat mass and obesity associated) gene that predisposes to diabetes through an effect on body mass index (BMI). An additive association of the variant with BMI was replicated in 13 cohorts with 38,759 participants. The 16% of adults who are homozygous for the risk allele weighed about 3 kilograms more and had 1.67-fold increased odds of obesity when compared with those not inheriting a risk allele. This association was observed from age 7 years upward and reflects a specific increase in fat mass.

The molecular mechanisms involved in the development of type 2 diabetes are poorly understood. Starting from genome-wide genotype data for 1924 diabetic cases and 2938 population controls generated by the Wellcome Trust Case Control Consortium, we set out to detect replicated diabetes association signals through analysis of 3757 additional cases and 5346 controls and by integration of our findings with equivalent data from other international consortia. We detected diabetes susceptibility loci in and around the genes CDKAL1, CDKN2A/CDKN2B, and IGF2BP2 and confirmed the recently described associations at HHEX/IDE and SLC30A8. Our findings provide insight into the genetic architecture of type 2 diabetes, emphasizing the contribution of multiple variants of modest effect. The regions identified underscore the importance of pathways influencing pancreatic beta cell development and function in the etiology of type 2 diabetes.

A versus G. This results in a single amino acid difference, EH4 2XU, UK valine versus isoleucine at codon 105 (Figure This residue 4 To whom correspondence should be addressed lies in close proximity to the hydrophobic binding site for electrophilic substrates In order to establish whether these base pair (AG) substitution at nucleotide 313 of the sequences represent alleles at the GSTP1 locus, we designed GSTP1 cDNA. This results in an amino acid substitution a PCR assay to rapidly and simply detect their presence in the which alters the function of the enzyme. In this study, a population. Since GSTP1 is a major enzyme involved in the novel PCR assay has been developed which demonstrates inactivation of cigarette smoke carcinogens such as benzo[a]that these two variant cDNAs represent distinct GSTP1 pyrene diol epoxide and also other toxic cigarette smoke alleles (GSTP1a and GSTP1b). In a study of individuals constituents such as acrolein (1), we were interested to deterwith different forms of cancer, the GSTP1b allele is found mine whether this polymorphism was related to diseases to be strongly associated with bladder cancer and testicular associated with cigarette smoking such as certain types of cancer. In controls 6.5% of individuals were homozygous cancer and chronic obstructive pulmonary disease (COPD*). for the GSTP1b allele. In bladder cancer cases, this rose to 19.7% [n 71, odds ratio 3.6 (1.4-9.2), P 0.006] and in testicular cancer to 18.7% [n 155, odds ratio 3.3 (1.5-Materials and methods 7.7), P 0.002]. In addition, in prostate cancer a highly Patient materials significant decrease in the frequency of the GSTP1a homo-Populations analysed for GSTP1 genotype were 155 control individuals from zygotes was observed [control 51.0% versus 27.8% cancer the Edinburgh area. These random samples were obtained from the Clinical cases, n 36, odds ratio 0.4 (0.02-3.3), P 0.008]. Biochemistry Department at Edinburgh Royal Infirmary; they were all Caucasi-Increases in the frequency of GSTP1b homozygotes was ans. Other samples tested were 79 COPD cases; 155 lung cancer cases [mean age 67.2 years (49-87 years), 97% smokers or ex-smokers, 69% males]; 71 also observed in lung cancer and chronic obstructive bladder cancer cases [mean age 72.2 years (54-91 years), 86% smokers or pulmonary disease. However, these were not statistically ex-smokers, 68% males]; 90 teratoma cases [mean age 40.5 years (22-56 significant. No change in breast or colon cancer allele years), 70% smokers or ex-smokers]; 65 seminoma cases [mean age 45.6 frequencies was observed. years (30-64 years), 50% smokers or ex-smokers]; 36 prostatic cancer cases [mean age 70.4 years (62-88 years), 90% smokers or ex-smokers]; 62 breast cancer cases [mean age 60.3 years (37-82 years), 60% smokers or ex-smokers] and 100 colon cancer cases were studied. All samples from cancer patients

The central dogma of molecular biology states that DNA is transcribed into RNA, which in turn is translated into proteins. We now know, however, that as much as 50% of the transcriptome has no protein-coding potential, but rather represents an important class of regulatory molecules responsible for the fine-tuning of gene expression. Although the role of small regulatory RNAs [microRNAs and siRNAs (small interfering RNA)] is well defined, another much less characterized category of non-coding transcripts exists, namely lncRNAs (long non-coding RNAs). Pervasively expressed by eukaryotic genomes, lncRNAs can be kilobases long and regulate their targets by influencing the epigenetic control, chromatin status, mRNA processing or translation capacity of their targets. In the present review, I outline the potential mechanisms of action of lncRNAs, the cellular processes that have been associated with them, and also explore some of the emerging evidence for their involvement in common human disease.