Kristian Midthjell

Meta-analysis of genome-wide association data and large-scale replication identifies additional susceptibility loci for type 2 diabetes

Genome-wide association (GWA) studies have identified multiple loci at which common variants modestly but reproducibly influence risk of type 2 diabetes (T2D). Established associations to common and rare variants explain only a small proportion of the heritability of T2D. As previously published analyses had limited power to identify variants with modest effects, we carried out meta-analysis of three T2D GWA scans comprising 10,128 individuals of European descent and ∼2.2 million SNPs (directly genotyped and imputed), followed by replication testing in an independent sample with an effective sample size of up to 53,975. We detected at least six previously unknown loci with robust evidence for association, including the JAZF1 (P = 5.0 × 10−14), CDC123-CAMK1D (P = 1.2 × 10−10), TSPAN8-LGR5 (P = 1.1 × 10−9), THADA (P = 1.1 × 10−9), ADAMTS9 (P = 1.2 × 10−8) and NOTCH2 (P = 4.1 × 10−8) gene regions. Our results illustrate the value of large discovery and follow-up samples for gaining further insights into the inherited basis of T2D.

Cohort Profile: The HUNT Study, Norway

The HUNT Study includes large total population-based cohorts from the 1980ies, covering 125 000 Norwegian participants; HUNT1 (1984-86), HUNT2 (1995-97) and HUNT3 (2006-08). The study was primarily set up to address arterial hypertension, diabetes, screening of tuberculosis, and quality of life. However, the scope has expanded over time. In the latest survey a state of the art biobank was established, with availability of biomaterial for decades ahead. The three population based surveys now contribute to important knowledge regarding health related lifestyle, prevalence and incidence of somatic and mental illness and disease, health determinants, and associations between disease phenotypes and genotypes. Every citizen of Nord-Trøndelag County in Norway being 20 years or older, have been invited to all the surveys for adults. Participants may be linked in families and followed up longitudinally between the surveys and in several national health- and other registers covering the total population. The HUNT Study includes data from questionnaires, interviews, clinical measurements and biological samples (blood and urine). The questionnaires included questions on socioeconomic conditions, health related behaviours, symptoms, illnesses and diseases. Data from the HUNT Study are available for researchers who satisfy some basic requirements (www.ntnu.edu/hunt), whether affiliated in Norway or abroad.

Age-specific prevalence of the metabolic syndrome defined by the International Diabetes Federation and the National Cholesterol Education Program: the Norwegian HUNT 2 study

BackgroundThe 2005 International Diabetes Federation (IDF) definition of the metabolic syndrome was designed to be useful worldwide, but to date few prevalence studies have used that definition in European populations. We estimated the age- and sex-stratified prevalence of IDF-defined metabolic syndrome in a county of Norway and compared it with the prevalence estimated using the revised National Cholesterol Education Program-Adult Treatment Panel-III definition (2005 ATP III).MethodsCross-sectional analysis of 10,206 participants aged 20–89 years in the Nord-Trøndelag Health Study 1995–97 (HUNT 2).ResultsPrevalence of IDF-defined metabolic syndrome was 29.6% (95% CI: 28.8 to 30.5), compared to 25.9% (95% CI: 25.0 to 26.7) using the 2005 ATP III criteria. The prevalence of IDF-defined metabolic syndrome increased from 11.0% in the 20–29 years age group to 47.2% in the 80–89 years group in men, and from 9.2% to 64.4% for women in the corresponding age groups. Among men and women aged ≥60 years, the IDF criteria classified 56.7% and 75.0%, respectively, as having central obesity, and 89.3% and 90.9%, respectively, as being hypertensive.ConclusionAccording to both definitions, the prevalence of the metabolic syndrome increased strongly with age. The IDF and the American Heart Association/National Heart, Lung, and Blood Institute guidelines for clinical management of metabolic syndrome would classify a high proportion of elderly Norwegians as in need of overall risk assessment for cardiovascular disease.

Change in body mass index and its impact on blood pressure: a prospective population study

BACKGROUND:Overweight and obesity increase the risk of elevated blood pressure, but the knowledge of the effect of weight change on blood pressure is sparse.OBJECTIVE:To investigate the association between change in body mass index (BMI) and change in diastolic blood pressure (DBP), systolic blood pressure (SBP), and hypertension status.DESIGN:Two population-based cross-sectional studies, one in 1984–86 and the other in 1995–97.SETTING:The Nord-Trøndelag Health Study (HUNT).PARTICIPANTS:We included 15 971 women and 13 846 men who were 20 y or older at the first survey, without blood pressure medication at both surveys and without diabetes, cardiovascular disease or dysfunction in daily life at baseline.MEASUREMENTS:Weight, height and blood pressure were measured standardised. Change in BMI was categorised as stable (initial BMI±0.1 kg/m2 each follow-up year), increased or decreased, and BMI was categorised by using World Health Organisations categorisation (underweight BMI: <18.5 kg/m2, normal weight BMI: 18.5–24.9 kg/m2, overweight BMI: 25.0–29.9 kg/m2, obesity BMI≥30 kg/m2).RESULTS:An increase in BMI and a decrease in BMI were significantly associated with increased and decreased SBP and DBP, respectively, compared to a stable BMI in both genders and all age groups, although the strongest effect was found among those who were 50 y and older. The adjusted odds ratio for having hypertension at HUNT 2 was 1.8 (95% confidence interval (CI): 1.5, 2.2) among women and 1.6 (95% CI: 1.4,1.8) among men aged 20–49 y who increased their BMI compared to those who had stable BMI. A similar, but weaker association was found among women and men aged 50 y or more. The mean change in both SBP and DBP was higher for those who changed BMI category from first to the second survey than for those who were in the same BMI class at both surveys.CONCLUSIONS:Our result supports an independent effect of change in BMI on change in SBP and DBP in both women and men, and that people who increase their BMI are at increased risk for hypertension.

Change in height, weight and body mass index: Longitudinal data from the HUNT Study in Norway

Objective:The aim of this study was to analyse changes in body weight and height, and the changes in the prevalence of overweight and obesity.Design:Prospective population based study with 11-year follow-up.Subjects:Norwegian men (n=21565) and women (n=24337) aged 20 years or more who participated in two health surveys, the first in 1984–1986 and the other in 1995–1997.Measurements:Height and weight were measured by using standardised procedures at both surveys, and we computed body mass index (BMI) as weight in kilo divided by the squared value of height in meters.Results:Participants who were younger than 50 years at the first survey showed a large increase in body weight, and men and women aged 20–29 years increased their weight with an average of 7.9 kg and 7.3 kg, respectively. Contradictory, participants who were 70 years or older had on average a weight loss. The prevalence of overweight (BMI=25.0–29.9 kg/m2) and obesity (BMI⩾30 kg/m2) increased between the surveys, especially in the youngest age groups. Overall, the proportion classified as obese increased from 6.7 to 15.5% among men and from 11.0 to 21.0% among women. Some of this increase was due to a reduction in height, which was most pronounced in the oldest age groups.Conclusion:During approximately 10 years, body weight increased in all age groups below 70 years, and the prevalence of overweight and obese persons was approximately 20% higher at the second survey compared with the first survey.

Reliability and validity of two frequently used self-administered physical activity questionnaires in adolescents

BackgroundTo create and find accurate and reliable instruments for the measurement of physical activity has been a challenge in epidemiological studies. We investigated the reliability and validity of two different physical activity questionnaires in 71 adolescents aged 13–18 years; the WHO, Health Behaviour in Schoolchildren (HBSC) questionnaire, and the International Physical Activity Questionnaire (IPAQ, short version).MethodsThe questionnaires were administered twice (8–12 days apart) to measure reliability. Validity was assessed by comparing answers from the questionnaires with a cardiorespiratory fitness test (VO2peak) and seven days activity monitoring with the ActiReg, an instrument measuring physical activity level (PAL) and total energy expenditure (TEE).ResultsIntraclass correlation coefficients for reliability for the WHO HBSC questionnaire were 0.71 for frequency and 0.73 for duration. For the frequency question, there was a significant difference between genders; 0.87 for girls and 0.59 for boys (p < 0.05). The intraclass correlation coefficients the IPAQ varied between 0.10 and 0.62 for the reliability. Spearman correlation coefficients for validity for both the WHO HBSC questionnaire and the IPAQ (recoded into low, moderate and high activity) measured against VO2peak were fair, ranging between 0.29 – 0.39. The WHO HBSC questionnaire measured against VO2peak for girls were acceptable, ranging between 0.30 – 0.55. Both questionnaires, except the walking question in IPAQ, showed a low correlation with PAL and TEE, ranging between 0.01 and 0.29.ConclusionThese data indicate that the WHO HBSC questionnaire had substantial reliability and were acceptable instrument for measuring cardiorespiratory fitness, especially among girls. None of the questionnaires however seemed to be a valid instrument for measuring physical activity compared to TEE and PAL in adolescents.

History of Foot Ulcer Increases Mortality Among Individuals With Diabetes Ten-year follow-up of the Nord-Trøndelag Health Study, Norway

OBJECTIVE To compare mortality rates for individuals with diabetes with and without a history of foot ulcer (HFU) and with that for the nondiabetic population. RESEARCH DESIGN AND METHODS This population-based study included 155 diabetic individuals with an HFU, 1,339 diabetic individuals without an HFU, and 63,632 nondiabetic individuals who were all followed for 10 years with mortality as the end point. RESULTS During the follow-up period, a total of 49.0% of diabetic individuals with an HFU died, compared with 35.2% of diabetic individuals without an HFU and 10.5% of those without diabetes. In Cox regression analyses adjusted for age, sex, education, current smoking, and waist circumference, having an HFU was associated with more than a twofold (2.29 [95% CI 1.82–2.88]) hazard risk for mortality compared with that of the nondiabetic group. In corresponding analyses comparing diabetic individuals with and without an HFU, an HFU was associated with 47% increased mortality (1.47 [1.14–1.89]). Significant covariates were older age, male sex, and current smoking. After inclusion of A1C, insulin use, microalbuminuria, cardiovascular disease, and depression scores in the model, each was significantly related to life expectancy. CONCLUSIONS AN HFU increased mortality risk among community-dwelling adults and elderly individuals with diabetes. The excess risk persisted after adjustment for comorbidity and depression scores, indicating that close clinical monitoring might be warranted among individuals with an HFU, who may be particularly vulnerable to adverse outcomes.

Secular decline in mortality from coronary heart disease in adults with diabetes mellitus: cohort study

Objective To examine trends in fatal coronary heart disease in adults with and without diabetes. Design Cohort study. Setting Two surveys of the Nord-Trøndelag health study (HUNT), a population based study in Norway. Participants 74 914 men and women from the first survey (1984-6) and 64 829 from the second survey (1995-7). Main outcome measure Age specific mortality from coronary heart disease among adults with and without diabetes during two consecutive nine year follow-up periods. Results A total of 2623 men and 1583 women died from coronary heart disease. Mortality rates were substantially lower during the most recent follow-up period: among men aged 70-79 without diabetes, deaths per 1000 person years declined from 16.38 to 8.79 (reduction 48%, 95% confidence interval 39% to 55%) and among women aged 70-79 from 6.84 to 2.68 (62%, 52% to 70%). Among the same age group with diabetes, deaths per 1000 person years in men declined from 38.97 to 17.89 (54%, 32% to 69%) and in women from 28.15 to 11.83 (59%, 37% to 73%). The reduction was more noticeable in age groups younger than 70 at baseline, and less pronounced among people aged 80 or more. Mortality from coronary heart disease was more than twofold higher in people with than without diabetes, with a slightly stronger association in women. The difference in mortality by diabetes status remained almost unchanged from the first to the second survey. Conclusion The strong general reduction in mortality rates from coronary heart disease from the first to the second follow-up period also benefited people with diabetes, but the more than twofold higher mortality from coronary heart disease associated with diabetes persisted over time.

A History of Foot ulcer increases Mortality among Persons with Diabetes. 10-year Follow-up of the Nord-Trøndelag Health Study, Norway

OBJECTIVE To compare mortality rates for individuals with diabetes with and without a history of foot ulcer (HFU) and with that for the nondiabetic population. RESEARCH DESIGN AND METHODS This population-based study included 155 diabetic individuals with an HFU, 1,339 diabetic individuals without an HFU, and 63,632 nondiabetic individuals who were all followed for 10 years with mortality as the end point. RESULTS During the follow-up period, a total of 49.0% of diabetic individuals with an HFU died, compared with 35.2% of diabetic individuals without an HFU and 10.5% of those without diabetes. In Cox regression analyses adjusted for age, sex, education, current smoking, and waist circumference, having an HFU was associated with more than a twofold (2.29 [95% CI 1.82–2.88]) hazard risk for mortality compared with that of the nondiabetic group. In corresponding analyses comparing diabetic individuals with and without an HFU, an HFU was associated with 47% increased mortality (1.47 [1.14–1.89]). Significant covariates were older age, male sex, and current smoking. After inclusion of A1C, insulin use, microalbuminuria, cardiovascular disease, and depression scores in the model, each was significantly related to life expectancy. CONCLUSIONS AN HFU increased mortality risk among community-dwelling adults and elderly individuals with diabetes. The excess risk persisted after adjustment for comorbidity and depression scores, indicating that close clinical monitoring might be warranted among individuals with an HFU, who may be particularly vulnerable to adverse outcomes.

FTO, Type 2 Diabetes, and Weight Gain Throughout Adult Life: A Meta-Analysis of 41,504 Subjects From the Scandinavian HUNT, MDC, and MPP Studies

OBJECTIVE FTO is the most important polygene identified for obesity. We aimed to investigate whether a variant in FTO affects type 2 diabetes risk entirely through its effect on BMI and how FTO influences BMI across adult life span. RESEARCH DESIGN AND METHODS Through regression models, we assessed the relationship between the FTO single nucleotide polymorphisms rs9939609, type 2 diabetes, and BMI across life span in subjects from the Norwegian population-based HUNT study using cross-sectional and longitudinal perspectives. For replication and meta-analysis, we used data from the Malmö Diet and Cancer (MDC) and Malmö Preventive Project (MPP) cohorts, comprising a total sample of 41,504 Scandinavians. RESULTS The meta-analysis revealed a highly significant association for rs9939609 with both type 2 diabetes (OR 1.13; P = 4.5 × 10−8) and the risk to develop incident type 2 diabetes (OR 1.16; P = 3.2 × 10−8). The associations remained also after correction for BMI and other anthropometric measures. Furthermore, we confirmed the strong effect on BMI (0.28 kg/m2 per risk allele; P = 2.0 × 10−26), with no heterogeneity between different age-groups. We found no differences in change of BMI over time according to rs9939609 risk alleles, neither overall (∆BMI = 0.0 [−0.05, 0.05]) nor in any individual age stratum, indicating no further weight gain attributable to FTO genotype in adults. CONCLUSIONS We have identified that a variant in FTO alters type 2 diabetes risk partly independent of its observed effect on BMI. The additional weight gain as a result of the FTO risk variant seems to occur before adulthood, and the BMI difference remains stable thereafter.