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Articles by T. M Frayling
Total Records ( 2 ) for T. M Frayling
  C Cluett , M. M McDermott , J Guralnik , L Ferrucci , S Bandinelli , I Miljkovic , J. M Zmuda , R Li , G Tranah , T Harris , N Rice , W Henley , T. M Frayling , A Murray and D. Melzer

Background— A common variant at chromosome 9p21 (tagged by the rs1333049 or rs10757278 single-nucleotide polymorphism) is strongly associated with myocardial infarction and major arterial aneurysms. An association with peripheral arterial disease (PAD) was also reported in a sample younger than 75 years, but this disappeared on removal of respondents with a myocardial infarction history, resulting in an odds ratio of 1.09 for PAD (P=0.075). We aimed at estimating the association of this variant with an Ankle-Brachial Index (ABI) and PAD in 3 older populations.

Methods and Results— We used data from the InCHIANTI, Baltimore Longitudinal Study of Aging, and Health, Aging, and Body Composition studies. In 2630 white individuals (mean age, 76.4 years), the C allele at rs1333049 was associated with lower mean ABI measures and with an increased prevalence of PAD. These associations remained after removal of baseline and incident myocardial infarction cases over a 6-year follow-up for both ABI (–0.017 ABI units; 95% CI, –0.03 to –0.01; P=1.3x10–4) and PAD (per allele odds ratio, 1.29; 95% CI, 1.06 to 1.56; P=0.012). These associations also remained after adjustment for known atherosclerosis risk factors, including diabetes mellitus, smoking, hypercholesterolemia, and hypertension.

Conclusions— The C allele at rs1333049 is associated with an increased prevalence of PAD and lower mean ABI. This association was independent of the presence of diagnosed myocardial infarction and atherosclerotic risk factors in 3 older white populations.

  R. M Freathy , A. J Bennett , S. M Ring , B Shields , C. J Groves , N. J Timpson , M. N Weedon , E Zeggini , C. M Lindgren , H Lango , J. R.B Perry , A Pouta , A Ruokonen , E Hypponen , C Power , P Elliott , D. P Strachan , M. R Jarvelin , G. D Smith , M. I McCarthy , T. M Frayling and A. T. Hattersley

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.


We genotyped single-nucleotide polymorphisms (SNPs) at five recently identified type 2 diabetes loci (CDKAL1, CDKN2A/B, HHEX-IDE, IGF2BP2, and SLC30A8) 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.


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% CI 11–31], P = 2 x 10–5, 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 (Ptrend = 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.


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.

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