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Articles by M. N. Weedon
Total Records ( 2 ) for M. N. Weedon
  S. D. Rees , M. Islam , M. Z. I. Hydrie , B. Chaudhary , S. Bellary , S. Hashmi , J. P. O`Hare , S. Kumar , D. K. Sanghera , N. Chaturvedi , A. H. Barnett , A. S. Shera , M. N. Weedon , A. Basit , T. M. Frayling , M. A. Kelly and T. H. Jafar
  Aims  A common variant, rs9939609, in the FTO (fat mass and obesity) gene is associated with adiposity in Europeans, explaining its relationship with diabetes. However, data are inconsistent in South Asians. Our aim was to investigate the association of the FTO rs9939609 variant with obesity, obesity-related traits and Type 2 diabetes in South Asian individuals, and to use meta-analyses to attempt to clarify to what extent BMI influences the association of FTO variants with diabetes in South Asians.

Methods  We analysed rs9939609 in two studies of Pakistani individuals: 1666 adults aged ≥ 40 years from the Karachi population-based Control of Blood Pressure and Risk Attenuation (COBRA) study and 2745 individuals of Punjabi ancestry who were part of a Type 2 diabetes case-control study (UK Asian Diabetes Study/Diabetes Genetics in Pakistan; UKADS/DGP). The main outcomes were BMI, waist circumference and diabetes. Regression analyses were performed to determine associations between FTO alleles and outcomes. Summary estimates were combined in a meta-analysis of 8091 South Asian individuals (3919 patients with Type 2 diabetes and 4172 control subjects), including those from two previous studies.

Results  In the 4411 Pakistani individuals from this study, the age-, sex- and diabetes-adjusted association of FTO variant rs9939609 with BMI was 0.45 (95% CI 0.24-0.67) kg/m2 per A-allele (= 3.0 x 10−5) and with waist circumference was 0.88 (95% CI 0.36-1.41) cm per A-allele (= 0.001). The A-allele (30% frequency) was also significantly associated with Type 2 diabetes [per A-allele odds ratio (95% CI) 1.18 (1.07-1.30); = 0.0009]. A meta-analysis of four South Asian studies with 8091 subjects showed that the FTO A-allele predisposes to Type 2 diabetes [1.22 (95% CI 1.14-1.31); = 1.07 x 10-8] even after adjusting for BMI [1.18 (95% CI 1.10-1.27); = 1.02 x 10-5] or waist circumference [1.18 (95% CI 1.10-1.27); = 3.97 x 10−5].

Conclusions  The strong association between FTO genotype and BMI and waist circumference in South Asians is similar to that observed in Europeans. In contrast, the strong association of FTO genotype with diabetes is only partly accounted for by BMI.

  E. L. Edghill , A. Khamis , M. N. Weedon , M. Walker , G. A. Hitman , M. I. McCarthy , K. R. Owen , S. Ellard , A. T Hattersley and T. M. Frayling
  Aim  Genome-wide association studies have identified > 30 common variants associated with Type 2 diabetes (> 5% minor allele frequency). These variants have small effects on individual risk and do not account for a large proportion of the heritable component of the disease. Monogenic forms of diabetes are caused by mutations that occur in < 1:2000 individuals and follow strict patterns of inheritance. In contrast, the role of low frequency genetic variants (minor allele frequency 0.1-5%) in Type 2 diabetes is not known. The aim of this study was to assess the role of low frequency PDX1 (also called IPF1) variants in Type 2 diabetes.

Methods  We sequenced the coding and flanking intronic regions of PDX1 in 910 patients with Type 2 diabetes and 878 control subjects.

Results  We identified a total of 26 variants that occurred in 5.3% of individuals, 14 of which occurred once. Only D76N occurred in > 1%. We found no difference in carrier frequency between patients (5.7%) and control subjects (5.0%) (P = 0.46). There were also no differences between patients and control subjects when analyses were limited to subsets of variants. The strongest subset were those variants in the DNA binding domain where all five variants identified were only found in patients (P = 0.06).

Conclusion  Approximately 5% of UK individuals carry a PDX1 variant, but there is no evidence that these variants, either individually or cumulatively, predispose to Type 2 diabetes. Further studies will need to consider strategies to assess the role of multiple variants that occur in < 1 in 1000 individuals.

 
 
 
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