Kristina Bengtsson Boström

Genome-Wide Association Analysis Identifies Loci for Type 2 Diabetes and Triglyceride Levels

New strategies for prevention and treatment of type 2 diabetes (T2D) require improved insight into disease etiology. We analyzed 386,731 common single-nucleotide polymorphisms (SNPs) in 1464 patients with T2D and 1467 matched controls, each characterized for measures of glucose metabolism, lipids, obesity, and blood pressure. With collaborators (FUSION and WTCCC/UKT2D), we identified and confirmed three loci associated with T2D—in a noncoding region near CDKN2A and CDKN2B, in an intron of IGF2BP2, and an intron of CDKAL1—and replicated associations near HHEX and in SLC30A8 found by a recent whole-genome association study. We identified and confirmed association of a SNP in an intron of glucokinase regulatory protein (GCKR) with serum triglycerides. The discovery of associated variants in unsuspected genes and outside coding regions illustrates the ability of genome-wide association studies to provide potentially important clues to the pathogenesis of common diseases.

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.

Evaluation of Common Variants in the Six Known Maturity-Onset Diabetes of the Young (MODY) Genes for Association With Type 2 Diabetes

An important question in human genetics is the extent to which genes causing monogenic forms of disease harbor common variants that may contribute to the more typical form of that disease. We aimed to comprehensively evaluate the extent to which common variation in the six known maturity-onset diabetes of the young (MODY) genes, which cause a monogenic form of type 2 diabetes, is associated with type 2 diabetes. Specifically, we determined patterns of common sequence variation in the genes encoding Gck, Ipf1, Tcf2, and NeuroD1 (MODY2 and MODY4–MODY6, respectively), selected a comprehensive set of 107 tag single nucleotide polymorphisms (SNPs) that captured common variation, and genotyped each in 4,206 patients and control subjects from Sweden, Finland, and Canada (including family-based studies and unrelated case-control subjects). All SNPs with a nominal P value <0.1 for association to type 2 diabetes in this initial screen were then genotyped in an additional 4,470 subjects from North America and Poland. Of 30 nominally significant SNPs from the initial sample, 8 achieved consistent results in the replication sample. We found the strongest effect at rs757210 in intron 2 of TCF2, with corrected P values <0.01 for an odds ratio (OR) of 1.13. This association was observed again in an independent sample of 5,891 unrelated case and control subjects and 500 families from the U.K., for an overall OR of 1.12 and a P value <10−6 in >15,000 samples. We combined these results with our previous studies on HNF4α and TCF1 and explicitly tested for gene-gene interactions among these variants and with several known type 2 diabetes susceptibility loci, and we found no genetic interactions between these six genes. We conclude that although rare variants in these six genes explain most cases of MODY, common variants in these same genes contribute very modestly, if at all, to the common form of type 2 diabetes.

Validity of registration of ICD codes and prescriptions in a research database in Swedish primary care: a cross-sectional study in Skaraborg primary care database

BackgroundIn recent years, several primary care databases recording information from computerized medical records have been established and used for quality assessment of medical care and research. However, to be useful for research purposes, the data generated routinely from every day practice require registration of high quality. In this study we aimed to investigate (i) the frequency and validity of ICD code and drug prescription registration in the new Skaraborg primary care database (SPCD) and (ii) to investigate the sources of variation in this registration.MethodsSPCD contains anonymous electronic medical records (ProfDoc III) automatically retrieved from all 24 public health care centres (HCC) in Skaraborg, Sweden. The frequencies of ICD code registration for the selected diagnoses diabetes mellitus, hypertension and chronic cardiovascular disease and the relevant drug prescriptions in the time period between May 2002 and October 2003 were analysed. The validity of data registration in the SPCD was assessed in a random sample of 50 medical records from each HCC (n = 1200 records) using the medical record text as gold standard. The variance of ICD code registration was studied with multi-level logistic regression analysis and expressed as median odds ratio (MOR).ResultsFor diabetes mellitus and hypertension ICD codes were registered in 80-90% of cases, while for congestive heart failure and ischemic heart disease ICD codes were registered more seldom (60-70%). Drug prescription registration was overall high (88%). A correlation between the frequency of ICD coded visits and the sensitivity of the ICD code registration was found for hypertension and congestive heart failure but not for diabetes or ischemic heart disease.The frequency of ICD code registration varied from 42 to 90% between HCCs, and the greatest variation was found at the physician level (MORPHYSICIAN = 4.2 and MORHCC = 2.3).ConclusionsSince the frequency of ICD code registration varies between different diagnoses, each diagnosis must be separately validated. Improved frequency and quality of ICD code registration might be achieved by interventions directed towards the physicians where the greatest amount of variation was found.

Interaction between the angiotensin-converting enzyme gene insertion/deletion polymorphism and obstructive sleep apnoea as a mechanism for hypertension.

Objective Obstructive sleep apnoea (OSA) confers a risk of hypertension and cardiovascular complications. Both the renin–angiotensin–aldosterone system and OSA are important determinants of blood pressure, but it is not fully known how they interact. The aim of this study was to explore the interaction between the angiotensin-converting enzyme (ACE) gene insertion/deletion (I/D) polymorphism and OSA in the association with hypertension. Design A community-based, case–control design with hypertensive patients in primary care (n = 157) and normotensive population controls (n = 181). Methods All subjects underwent ambulatory polysomnography during one night. OSA was defined by a minimum of 10 apnoea/hypopnoea events per hour. Office blood pressure was measured and hypertension status was assessed. The genotypes were determined using polymerase chain reaction. Results An interaction analysis including sex, ACE I/D polymorphism (DD and ID versus II), and OSA identified a significant interaction between OSA and the ACE I/D polymorphism: odds ratio (OR) 6.3, 95% confidence interval (CI) 1.8–22.5, P = 0.004 as well as between OSA and sex: OR 3.3, 95% CI 1.1–9.6, P = 0.033. OSA was significantly associated with hypertension in men but not in women. Conclusion The interaction between the ACE gene I/D polymorphism and OSA appears to be an important mechanism in the development of hypertension, particularly in men.

Gender differences in antihypertensive drug treatment: results from the Swedish Primary Care Cardiovascular Database (SPCCD)

There are gender differences in antihypertensive treatment. This study aimed to investigate if gender differences in treatment could be explained by comorbidities. In addition, we aimed to study whether blood pressure control is different in women and men, and whether women interrupt treatment more often with angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin receptor blockers (ARBs) compared with men.This cohort study within the Swedish Primary Care Cardiovascular Database included 40,825 patients with hypertension attending primary health care from 2007 to 2008. Cardiovascular comorbidities, with the exception of heart failure, were more common in men. Women were more often treated with diuretics, and men with ACEI, as were hypertensive patients with diabetes. Comorbidities could not entirely explain gender differences in antihypertensive treatment in a regression model. Women had higher systolic and lower diastolic blood pressure; this was also true in subgroups with cardiovascular comorbidity. Men more often than women were prescribed ACEIs/ARBs and interrupted treatment. Women and men are treated with different antihypertensive drugs, and this is not fully explained by differences in comorbidities. Women have higher systolic blood pressures, irrespective of comorbidity. Men have interrupted treatment more often with ACEIs/ARBs. These gender differences could affect outcome and warrant further investigation.

The Swedish Primary Care Cardiovascular Database (SPCCD): 74 751 hypertensive primary care patients.

Abstract Objective. To describe the Swedish Primary Care Cardiovascular Database, SPCCD. Design. Longitudinal data from electronic medical records, linked to national registers. Setting. 48 primary healthcare centres in urban (south-western Stockholm) and rural (Skaraborg) regions in Sweden. Subjects. Patients diagnosed with hypertension 2001–2008. Main outcome measures. Blood pressure (BP) and impact of retrieval of data on BP levels, clinical characteristics, co-morbidity and pharmacological treatment. Results. The SPCCD contains 74 751 individuals, 56% women. Completeness of data ranged from > 99% for drug prescriptions to 34% for smoking habits. BP was recorded in 98% of patients during 2001–2008 and in 63% in 2008. Mean BP based on the last recorded value in 2008 was 142 ± 17/80 ± 13 mmHg. Digit preference in BP measurements differed between the two regions, p < 0.001. Antihypertensive drugs were prescribed in primary healthcare to 88% of the patients in 2008; however, when all prescribers were included 96% purchased their drugs. Cardiovascular co-morbidity and diabetes mellitus were present in 28% and 22%, respectively. Conclusion. This large and representative database shows that there is room for improvement of BP control in Sweden. The SPCCD will provide a rich source for further research of hypertension and its complications.

The Krüppel-Like Factor 11 (KLF11) Q62R Polymorphism Is Not Associated With Type 2 Diabetes in 8,676 People

Krüppel-like factor 11 is a pancreatic transcription factor whose activity induces the insulin gene. A common glutamine-to-arginine change at codon 62 (Q62R) in its gene KLF11 has been recently associated with type 2 diabetes in two independent samples. Q62R and two other rare missense variants (A347S and T220M) were also shown to affect the function of KLF11 in vitro, and insulin levels were lower in carriers of the minor allele at Q62R. We therefore examined their impact on common type 2 diabetes in several family-based and case-control samples of northern-European ancestry, totaling 8,676 individuals. We did not detect the rare A347S and T220M variants in our samples. With respect to Q62R, despite >99% power to detect an association of the previously published magnitude, Q62R was not associated with type 2 diabetes (pooled odds ratio 0.97 [95% CI 0.88–1.08], P = 0.63). In a subset of normoglycemic individuals, we did not observe significant differences in various insulin traits according to genotype at KLF11 Q62R. We conclude that the KLF11 A347S and T220M mutations do not contribute to increased risk of diabetes in European-derived populations and that the Q62R polymorphism has, at best, a minor effect on diabetes risk.

Very low calorie diet (VLCD) followed by a randomized trial of corset treatment for obesity in primary care

Abstract Objective. The primary objective was to investigate the feasibility and cost-effectiveness of weight reduction using very low calorie diet (VLCD) in groups. The secondary objective was to investigate whether subsequent corset treatment could maintain the weight reduction long term. Design. Participants, consecutively included in groups of 8–14 subjects, underwent three months of VLCD with lifestyle advice at group meetings. Subjects attaining ≥ 8 kg reduction were randomized to corset (A) or no corset (B) treatment for nine months. Weight was registered at all meetings and after 24 months. Costs were calculated using current salaries and anti-obesity drug prices as at 2008. Settings. Primary care in Skaraborg, Sweden. Subjects. A total of 26 men and 65 women aged 30–60 years with BMI ≥ 30−< 45 kg/m2. Main outcome measures. Weight changes and costs of treatment. Results. VLCD (dropout n = 14) resulted in a mean weight reduction of 20.1±6.6 kg (20 men) and 15.7±4.7 kg (57 women). These 77 subjects were randomized to treatment A (n = 39) or B (n = 38). Compliance with corset was only 20% after three months. After one year (dropout n = 17) weight loss was 11.7±8.1 kg (A) and 9.3±6.9 kg (B), p = 0.23 and after two years (dropout n = 22) 6.1±7.0 kg and 4.4±7.3 kg respectively, p = 0.94. Serum glucose and lipids were altered favourably. The cost per participant of treatments A and B was SEK 4440 and SEK 1940 respectively. Conclusions. VLCD in groups was feasible and reduced weight even after one year. The cost of treatment was lower than drug treatment. Corset treatment suffered from poor compliance and could therefore not be evaluated.

No physician gender difference in prescription of sick-leave certification: A retrospective study of the Skaraborg Primary Care Database

Abstract Objective. The primary objective was to investigate how physicians’ gender and level of experience affects the rate and length of sick-leave certificate prescription. The secondary objective was to study the physicians’ gender and professional experience in relation to the diagnoses on the certificates. Design. Retrospective, cross-sectional study of computerized medical records from 24 health care centres in 2005. Setting. Primary care in Sweden. Subjects. Primary care physicians (n = 589) and patients (n = 88 780) aged 18–64 years. Main outcome measures. Rate and duration of sick leave certified by different categories of physicians and for different diagnoses and gender of patients. Results. Sick leave was certified in 9.0% (musculoskeletal (3%) and psychiatric (2.3%) diagnoses were most common) of all contacts and the mean duration was 32.2 days. Overall there was no difference between male and female physicians in the sick-leave certification prescription rate (9.1% vs. 9.0%) or duration of sick leave (32.1 vs. 32.6 days). The duration of sick leave was associated with the physicians level of professional experience in general practice (GPs (Distriktläkare) 37, GP trainees (ST-läkare) 26, interns (AT-läkare) 20 and locum (vikarier) 19 days, p < 0.001). Conclusion. Contrary to earlier studies we found no difference in sick-leave certification prescription rate and length between male and female physicians.