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Rafn Benediktsson

Publications and source records attributed to Rafn Benediktsson.

9 recordsLinked to original sources
PubMed2007

Refining the impact of TCF7L2 gene variants on type 2 diabetes and adaptive evolution.

We recently described an association between risk of type 2diabetes and variants in the transcription factor 7-like 2 gene (TCF7L2; formerly TCF4), with a population attributable risk (PAR) of 17%-28% in three populations of European ancestry. Here, we refine the definition of the TCF7L2 type 2diabetes risk variant, HapB(T2D), to the ancestral T allele of a SNP, rs7903146, through replication in West African and Danish type 2 diabetes case-control studies and an expanded Icelandic study. We also identify another variant of the same gene, HapA, that shows evidence of positive selection in East Asian, European and West African populations. Notably, HapA shows a suggestive association with body mass index and altered concentrations of the hunger-satiety hormones ghrelin and leptin in males, indicating that the selective advantage of HapA may have been mediated through effects on energy metabolism.

Asian People↗
PubMed2006

Variant of transcription factor 7-like 2 (TCF7L2) gene confers risk of type 2 diabetes.

We have previously reported suggestive linkage of type 2 diabetes mellitus to chromosome 10q. We genotyped 228 microsatellite markers in Icelandic individuals with type 2 diabetes and controls throughout a 10.5-Mb interval on 10q. A microsatellite, DG10S478, within intron 3 of the transcription factor 7-like 2 gene (TCF7L2; formerly TCF4) was associated with type 2 diabetes (P = 2.1 x 10(-9)). This was replicated in a Danish cohort (P = 4.8 x 10(-3)) and in a US cohort (P = 3.3 x 10(-9)). Compared with non-carriers, heterozygous and homozygous carriers of the at-risk alleles (38% and 7% of the population, respectively) have relative risks of 1.45 and 2.41. This corresponds to a population attributable risk of 21%. The TCF7L2 gene product is a high mobility group box-containing transcription factor previously implicated in blood glucose homeostasis. It is thought to act through regulation of proglucagon gene expression in enteroendocrine cells via the Wnt signaling pathway.

Chromosome Mapping↗
PubMed2005

[Latent autoimmune diabetes in adults in Iceland: prevalence, phenotype and relatedness].

INTRODUCTION: Ninety percent of diabetic individuals in Iceland suffer from type 2 diabetes mellitus. Antibodies against ss-cell components characterise type 1 diabetes, but these antibodies are also found in type 2 diabetic individuals, defined as latent autoimmune diabetes in adults or LADA. The purpose of this investigation was to estimate the prevalence of LADA in Iceland and to describe the phenotype and relatedness of these individuals. MATERIAL AND METHODS: A list of individuals diagnosed with type 2 diabetes was generated from outpatient clinic lists and the Reykjavik Study of the Icelandic Heart Association. A genealogy database (Book of Icelanders; deCODE Genetics) was used to identify all individuals related to these index cases within six meioses. This method identified 950 type 2 diabetic individuals during the years 1998-2000. We analyzed their phenotype and measured glutamic acid decarboxylase antibody (GAD). Kinship coefficient was used to compare the relatedness of those with antibodies to GAD to the relatedness of all type 2 diabetic individuals in the study. RESULTS: 10.1% of men and 9.3% women had measurable antibodies against GAD (non-significant difference). The mean age of GAD positive and GAD negative individuals was comparable (67.1 +/- 10.7 and 68.0 +/- 11.3; years +/- SD). Body mass index was significantly lower (p=0,02) for the GAD positive individuals or 28.2 kg/m(2) (27.2-29.2; 95% CI) vs. 29.7 (29.3-30.1). Of the GAD positive individuals, 47% +/- 9% (95% CI) had the metabolic syndrome as defined by WHO compared with 60 +/- 4% of the GAD negative individuals (p=0.02). The kinship coefficient for GAD positive individuals (n=94) was 6.00x10(-4) compared with 3.93x10(-4) +/- 8.3x10(-5) for 500 random samples (each of 94 individuals) of the whole cohort (p=0.008). CONCLUSION: About 10% of Icelandic type 2 diabetic individuals have antibodies against GAD, which is comparable to the results of other investigators. Icelandic GAD positive type 2 diabetic individuals have less frequently the metabolic syndrome than other type 2 diabetic individuals and GAD positive individuals are significantly more related to each other than type 2 diabetic individuals in general.

Adult↗
PubMed2003

Localization of a susceptibility gene for type 2 diabetes to chromosome 5q34-q35.2.

We report a genomewide linkage study of type 2 diabetes (T2D [MIM 125853]) in the Icelandic population. A list of type 2 diabetics was cross-matched with a computerized genealogical database clustering 763 type 2 diabetics into 227 families. The diabetic patients and their relatives were genotyped with 906 microsatellite markers. A nonparametric multipoint linkage analysis yielded linkage to 5q34-q35.2 (LOD = 2.90, P=1.29 x 10(-4)) in all diabetics. Since obesity, here defined as body mass index (BMI) > or =30 kg/m(2), is a key risk factor for the development of T2D, we studied the data either independently of BMI or by stratifying the patient group as obese (BMI > or =30) or nonobese (BMI <30). A nonparametric multipoint linkage analysis yielded linkage to 5q34-q35.2 (LOD = 3.64, P=2.12 x (10)-5) in the nonobese diabetics. No linkage was observed in this region for the obese diabetics. Linkage analysis conditioning on maternal transmission to the nonobese diabetics resulted in a LOD score of 3.48 (P=3.12 x 10(-5)) in the same region, whereas conditioning on paternal transmission led to a substantial drop in the LOD score. Finally, we observed potential interactions between the 5q locus and two T2D susceptibility loci, previously mapped in other populations.

Aged↗
PubMed2003

[Three simple steps for improving diagnostic accuracy in hypertension.].

OBJECTIVE: Most patients have only had three measurements of blood pressure before being labelled as hypertensive. This abbreviated assessment may lead to inaccurate classification, unnecessary treatment and dilution in treatment benefit for the population. We aimed to explore how accurate current methods are in diagnosing mild hypertension, and to explore practical methods of improving targeting of antihypertensive treatment using clinic visits but without lengthy observation. MATERIAL AND METHODS: We applied current diagnostic methods to 3965 individuals with mild hypertension who were followed for a year in the placebo arm of the MRC Mild Hypertension Trial (Medical Research Council). We thus calculated the proportion selected for treatment by current methods and the diagnostic accuracy, using average blood pressure beyond six months as representing "true" long-term blood pressure. We looked at the benefit of averaging blood pressures, prolonging observation modestly and estimating within-person blood pressure variability. RESULTS: Prolonging observation to three months selects a smaller (by about 12%) proportion of the sample for treatment. At three months the proportion of the sample selected is similar to the proportion defined as "truly" hypertensive. The diagnostic accuracy of current methods is poor with up to 69% discrepancy in classification. This discrepancy was improved in absolute terms by up to 18% by prolonging observation to three months and using average blood pressures. Identifying those individuals with low within-person variability allows marked improvement in the prediction of "true" hypertension. CONCLUSION: Although some inaccuracy in the diagnosis of hypertension is inevitable, observation for three months, averaging blood pressures and estimating within-person blood pressure variability can markedly improve upon current methods used for targeting antihypertensive treatment.

English Abstract↗
PubMed2002

Size at birth and glucose intolerance in a relatively genetically homogeneous, high-birth weight population.

BACKGROUND: The results of epidemiologic studies have linked birth size to adult glucose intolerance. OBJECTIVE: We investigated this association in a genetically homogeneous population with higher birth weights and a lower prevalence of type 2 diabetes than previously studied. DESIGN: The subjects were 2362 men and 2286 women aged 33-65 y. Size at birth was obtained from the National Archives of Iceland. Data for adult anthropometry, fasting blood glucose, and blood glucose after an oral glucose load came from the randomized prospective Reykjavík Study. RESULTS: Postchallenge glucose concentrations were inversely related to birth weight and length in men and inversely related to birth weight and ponderal index in women (P < 0.001). This association was mainly found among those within the highest one-third of adult body mass index values. In men, the prevalence of dysglycemia was lower with increasing weight (P = 0.04) and length (P = 0.003) at birth but there was no relation of dysglycemia to ponderal index. For women, there was no linear trend for dysglycemia in relation to size at birth but the relation with birth length was U shaped. CONCLUSIONS: Greater birth weight and length appear to offer a protective effect against glucose intolerance. Adult overweight or obesity enhances the risk associated with low birth weight and length. Because the population studied has higher birth weights and a lower prevalence of type 2 diabetes than are found in neighboring countries, it is possible that decreasing the number of low-birth weight infants might help to stem the increasing prevalence of type 2 diabetes worldwide.

Adult↗
PubMed2002

Size at birth and coronary artery disease in a population with high birth weight.

BACKGROUND: Epidemiologic studies suggest a link between fetal and childhood growth and later coronary artery disease (CAD). The influence of adult body size on the relation between birth size and CAD has not been thoroughly studied. OBJECTIVE: We investigated the association between birth and adult sizes and CAD within a population with higher birth weight and a lower incidence of and mortality rate from CAD than those seen in other Scandinavian populations. DESIGN: Fatal or nonfatal CAD was ascertained in 2399 men and 2376 women born in the Greater Reykjavik area between 1914 and 1935. Birth size was obtained from the National Archives. Anthropometric measurements in adults were obtained from the randomized prospective Reykjavik Study. RESULTS: CAD was inversely related to birth length (P for trend = 0.029) in men but was not significantly related to birth weight or ponderal index (kg/m(3)). In men who were born short (< or = 50.5 cm) and who became tall adults (either 175-180.5 or > 180.5 cm), the odds ratios (95% CI) for CAD were 1.9 (1.1, 3.1) and 2.2 (1.2, 4.0), respectively, when compared with men in the reference group (those born 52.5-54.0 cm long). A U-shaped relation between birth size and CAD was found for women. CONCLUSIONS: Size at birth has an effect on CAD, but the effect is modified by adult body size. This confirms that environmental factors operate in both the prenatal and postnatal periods with regard to the development of CAD. The large birth size seen among Icelanders may explain the lower incidence and mortality rate of CAD in Iceland than are seen in other white populations.

Aged↗
PubMed2002

Relationship between size at birth and hypertension in a genetically homogeneous population of high birth weight.

OBJECTIVE: To investigate the association between birth size and hypertension within a genetically homogeneous population of high birth weight. DESIGN: Cohort-study with retrospectively collected data on size at birth. SUBJECTS AND SETTING: The study included 4601 men and women born 1914-1935 in Reykjavik, Iceland, who participated in the Reykjavik Study of the Icelandic Heart Association. MAIN OUTCOME MEASURES: Birth size measurements, adult blood pressure (BP) and body mass index (BMI), and family history of hypertension. RESULTS: Birth weight was inversely related to hypertension in adulthood in women (P for trend < 0.001). The relationship was of borderline significance in men (P for trend = 0.051). A low ponderal index was significantly associated with high BP in women (P for trend = 0.025) but not men (P > 0.05). For women with an adult BMI > 26 kg/m2, the odds ratio for hypertension for those born weighing < 3.45 kg was 2.1 [95% confidence interval, 1.3-3.3, compared with women born weighing > 3.75 kg. The association was only significant in women without a family history of hypertension. CONCLUSIONS: An inverse association between size at birth and adult hypertension was seen in a population of greater birth size than has previously been investigated. The relation was strongest among women born small who were overweight in adulthood, and for those without a family history of hypertension. The results support the hypothesis that the association between birth weight and hypertension is not of genetic origin only. The large birth size of Icelanders might be protective and partly explain the lower mean systolic blood pressure in Iceland than in related nations.

Adult↗