Ulf Lindblad

Common Single Nucleotide Polymorphisms in TCF7L2 Are Reproducibly Associated With Type 2 Diabetes and Reduce the Insulin Response to Glucose in Nondiabetic Individuals

Recently, common noncoding variants in the TCF7L2 gene were strongly associated with increased risk of type 2 diabetes in samples from Iceland, Denmark, and the U.S. We genotyped 13 single nucleotide polymorphisms (SNPs) across TCF7L2 in 8,310 individuals in family-based and case-control designs from Scandinavia, Poland, and the U.S. We convincingly confirmed the previous association of TCF7L2 SNPs with the risk of type 2 diabetes (rs7903146T odds ratio 1.40 [95% CI 1.30–1.50], P = 6.74 × 10−20). In nondiabetic individuals, the risk genotypes were associated with a substantial reduction in the insulinogenic index derived from an oral glucose tolerance test (risk allele homozygotes have half the insulin response to glucose of noncarriers, P = 0.003) but not with increased insulin resistance. These results suggest that TCF7L2 variants may act through insulin secretion to increase the risk of type 2 diabetes.

The validity of obesity based on self-reported weight and height: implications for population studies.

Objective: To validate self‐reported information on weight and height in an adult population and to find a useful algorithm to assess the prevalence of obesity based on self‐reported information.

Polymorphism in the beta(1)-adrenergic receptor gene and hypertension

Background—The Arg389 variant of the &bgr;1-adrenergic receptor gene mediates a higher isoproterenol-stimulated adenylate cyclase activity than the Gly389 variant in vitro. We investigated whether the Arg389Gly or the Ser49Gly polymorphism is associated with hypertension in Scandinavians. Methods and Results—A total of 292 unrelated, nondiabetic, hypertensive patients and 265 unrelated healthy control subjects were included in a case-control association study. From 118 families, 102 nondiabetic sibling pairs without antihypertensive medication who were discordant for the Arg389Gly polymorphism were selected for a sibling study. Allele and genotype frequencies of the Arg389Gly and Ser49Gly polymorphisms were compared between hypertensive patients and normotensive control subjects. Blood pressure and heart rate were compared between carriers of the different genotypes. In the case-control study, the age- and body mass index-adjusted odds ratio for hypertension in subjects homozygous for the Arg389 allele was 1.9 (95% confidence interval, 1.3 to 2.7;P =0.0005) when compared with carriers of 1 or 2 copies of the Gly389 allele. The genotype-discordant sibling pair analysis revealed that siblings homozygous for the Arg389 allele had significantly higher diastolic blood pressures (79.4±9.9 versus 76.0±10.1 mm Hg;P =0.003) and higher heart rates (68.3±11.0 versus 65.1±9.4 bpm;P =0.02) than siblings carrying 1 or 2 copies of the Gly389 allele. The Ser49Gly polymorphism was not associated with hypertension. Conclusion—Our data suggest that individuals homozygous for the Arg389 allele of the &bgr;1-adrenergic receptor gene are at increased risk to develop hypertension.

Validity of register data on acute myocardial infarction and acute stroke: The Skaraborg Hypertension Project

In the evaluation of a hypertension treatment program, the end-point surveillance included incidence of acute myocardial infarction and acute stroke identified from hospital in-patient registers and the national mortality register. To ascertain the validity, in-patient records containing the ICD-codes 410–411 and 430–438 were validated. First event of acute myocardial infarction and acute stroke suggested in the in-patient register could be confirmed in 96% and 94%, respectively. In-patient diagnoses of suspected acute myocardial infarction or other acute or subacute ischemic heart diseases, transient ischemic attack and unspecified cerebrovascular disease revealed high proportions of what in fact turned out to be definite events (11%, 24% and 53% respectively). It is concluded that disease ascertainment for this cohort study claims validation of register data with hospital records.

GENDER DIFFERENCES IN KNOWLEDGE, ATTITUDE, BEHAVIOR AND PERCEIVED ORAL HEALTH AMONG ADOLESCENTS

A cross-sectional dental questionnaire census survey was conducted in classrooms of 17,280 students aged 13-18 years in Skaraborg County, Sweden. The overall response rate, based on school attendance on the test day, was 91% with no gender differences at the senior level, and 86% (boys 87%, girls 85%) at the upper secondary level. The aim was to examine gender differences in knowledge, attitude, behavior and perceived oral health. A retest study showed good agreement. Thirty-one percent of the girls and 21% of the boys flossed regularly. Eleven percent reported daily candy consumption, with no significant gender difference. Girls, however, more often than boys considered their own consumption to be too high. This gender difference in attitude was most pronounced among older daily consumers (odds ratio (OR) = 5.8 [3.7-9.2]). Oral health was regarded as important by a majority of the students (95%). Girls considered sound teeth to be more important than did boys, both among the younger (OR = 1.7 [1.4-2.1]) and the older (OR = 2.4 [1.9-3.1]) adolescents. It is concluded that most adolescents had a positive dental attitude and perceived their own oral health to be good. Poorer knowledge and behaviors concerning oral health were demonstrated. Gender differences existed in most issues. Girls scored more favorably on behavioral measures, showed more interest in oral health, and perceived their own oral health to be good to a higher degree than did boys.

Quality of Care of People With Type 2 Diabetes in Eight European Countries: Findings from the Guideline Adherence to Enhance Care (GUIDANCE) study

OBJECTIVE We sought to determine levels of adherence in eight European countries to recommendations for the management of type 2 diabetes and to investigate factors associated with key intermediate outcomes. RESEARCH DESIGN AND METHODS GUIDANCE was a cross-sectional study including retrospective data extraction from the medical records of people with type 2 diabetes recruited, using a shared protocol, from primary and specialist care sites in the following eight European countries: Belgium, France, Germany, Italy, Ireland, Sweden, the Netherlands, and the United Kingdom. The dataset for analysis comprised 7,597 cases. Proportions meeting process and outcome criteria were determined, including between-country variations. Logistic regression was used to investigate potential predictors of meeting targets for HbA1c, blood pressure, and LDL cholesterol. RESULTS In the total sample, adherence to process recommendations was high for some measures, for example, HbA1c recorded in past 12 months in 97.6% of cases. Target achievement for intermediate outcome measures was lower, with only 53.6% having HbA1c <7%. Considerable between-country variation was identified for both processes and outcomes. The following characteristics were associated with an increased likelihood of meeting targets for all three measures considered (HbA1c, blood pressure, LDL cholesterol): shorter diagnosis of diabetes; having one or more macrovascular complications; lower BMI; being prescribed lipid-lowering medication; and no current antihypertensive prescribing. CONCLUSIONS Compared with earlier reports, we have suggested some encouraging positive trends in Europe in relation to meeting targets for the management of people with type 2 diabetes, but there is still scope for further improvement and greater between-country consistency.

Salivary cortisol differs with age and sex and shows inverse associations with WHR in Swedish women: a cross-sectional study

BackgroundMost studies on cortisol have focused on smaller, selected samples. We therefore aimed to sex-specifically study the diurnal cortisol pattern and explore its association with abdominal obesity in a large unselected population.MethodsIn 2001–2004, 1811 men and women (30–75 years) were randomly selected from the Vara population, south-western Sweden (81% participation rate). Of these, 1671 subjects with full information on basal morning and evening salivary cortisol and anthropometric measurements were included in this cross-sectional study. Differences between groups were examined by general linear model and by logistic and linear regression analyses.ResultsMorning and Δ-cortisol (morning – evening cortisol) were significantly higher in women than men. In both genders older age was significantly associated with higher levels of all cortisol measures, however, most consistently with evening cortisol. In women only, age-adjusted means of WHR were significantly lower in the highest compared to the lowest quartile of morning cortisol (p = 0.036) and Δ-cortisol (p < 0.001), respectively. Furthermore, when comparing WHR above and below the mean, the age-adjusted OR in women for the lowest quartile of cortisol compared to the highest was 1.5 (1.0–2.2, p = 0.058) for morning cortisol and 1.9 (1.3–2.8) for Δ-cortisol. All findings for Δ-cortisol remained after adjustments for multiple covariates and were also seen in a linear regression analysis (p = 0.003).ConclusionIn summary, our findings of generally higher cortisol levels in women than men of all ages are novel and the stronger results seen for Δ-cortisol as opposed to morning cortisol in the association with WHR emphasise the need of studying cortisol variation intra-individually. To our knowledge, the associations in this study have never before been investigated in such a large population sample of both men and women. Our results therefore offer important knowledge on the descriptive characteristics of cortisol in relation to age and gender, and on the impact that associations previously seen between cortisol and abdominal obesity in smaller, selected samples have on a population level.

Prescriptions with potential drug interactions dispensed at Swedish pharmacies in January 1999: cross sectional study

The growing use of pharmacological agents means that drug interactions are of increasing interest for public health.1 Monitoring of potential drug interactions may improve the quality of drug prescribing and dispensing, and it might form a basis for education focused on appropriate prescribing.

Common Variants in the ENPP1 Gene Are Not Reproducibly Associated With Diabetes or Obesity

The common missense single nucleotide polymorphism (SNP) K121Q in the ectoenzyme nucleotide pyrophosphate phosphodiesterase (ENPP1) gene has recently been associated with type 2 diabetes in Italian, U.S., and South-Asian populations. A three-SNP haplotype, including K121Q, has also been associated with obesity and type 2 diabetes in French and Austrian populations. We set out to confirm these findings in several large samples. We genotyped the haplotype K121Q (rs1044498), rs1799774, and rs7754561 in 8,676 individuals of European ancestry with and without type 2 diabetes, in 1,900 obese and 930 lean individuals of European ancestry from the U.S. and Poland, and in 1,101 African-American individuals. Neither the K121Q missense polymorphism nor the putative risk haplotype were significantly associated with type 2 diabetes or BMI. Two SNPs showed suggestive evidence of association in a meta-analysis of our European ancestry samples. These SNPs were rs7754561 with type 2 diabetes (odds ratio for the G-allele, 0.85 [95% CI 0.78–0.92], P = 0.00003) and rs1799774 with BMI (homozygotes of the delT-allele, 0.6 [0.42–0.88], P = 0.007). However, these findings are not supported by other studies. We did not observe a reproducible association between these three ENPP1 variants and BMI or type 2 diabetes.

Polymorphisms in the adiponutrin gene are associated with increased insulin secretion and obesity

OBJECTIVE The insulin responsive adiponutrin or patatin-like phospholipase 3 (PNPLA3, previously ADPN) gene shows association with obesity and in vitro adipocyte lipolysis. This study aimed to replicate the association between PNPLA3 variants and obesity, and to investigate their effect on insulin resistance and beta-cell function. METHODS rs738409 (Met148Ile) and rs2072907 (C to G) were genotyped using TaqMan allelic discrimination assay in a Swedish population-based sample (n=1811). Oral glucose tolerance test (OGTT) with data from three time points (0, 30, and 120 min) were available from individuals under the age of 50 years (n=973). RESULTS Both variant alleles were associated with decreased prevalence of obesity (P<0.05); odds ratio 0.75 (0.61-0.93) per carried Ile-allele for rs738409 and 0.80 (0.64-1.00) per carried G-allele for rs2072907. For obesity as a quantitative trait, there was no association in the whole population, but in obese subjects body mass index (BMI; P=0.023) and waist (P=0.0098) were higher in carriers of the Ile-allele. The Ile-carriers also displayed decreased insulin secretion in response to OGTT (30 min insulin; P=0.007, insulinogenic index; P=0.0051) with no significant differences in fasting plasma glucose (P=0.31), beta-cell function (disposition index; P=0.17) or homeostasis model of assessment insulin resistance (HOMA-IR; P=0.063). The correlation between BMI and HOMA-IR differed (Met/X versus Ile/Ile, P=0.028), Met-allele carriers were seemingly more insulin resistant at a lower BMI. The rs2072907 variant shows similar results for insulin secretion. The significance of this finding remained after adjusting for age, gender, and level of self-reported leisure-time physical activity. CONCLUSION We confirm the association between PNPLA3 and obesity. In addition, the rs738409 variant was associated with insulin secretion. There seems to be a differential effect of the Ile-allele depending on the degree of obesity, possibly as a consequence of insulin resistance.