Numerous linkage studies have indicated chromosome 18q21-22 as a locus of importance for blood pressure regulation. This locus harbors the neural precursor cell expressed developmentally downregulated 4-like (NEDD4L) gene, which is instrumental for the regulation of the amiloride-sensitive epithelial sodium channel (ENaC). In a linkage study of 16 markers (including two single nucleotide polymorphism markers located within the NEDD4L gene) on chromosome 18 between 70-104 cM and ambulatory blood pressure (ABP), in 118 families, the strongest evidence of linkage was found for 24 h and day-time systolic ABP at the NEDD4L locus (82.25 cM) (P=0.0014). In a large population sample (n=4001), we subsequently showed that a NEDD4L gene variant (rs4149601), which by alternative splicing leads to varying expression of a functionally crucial C2 domain, was associated with diastolic blood pressure (DBP) (P=0.03) and DBP progression over time (P=0.04). A genotype combination of the rs4149601 and an intronic NEDD4L marker (rs2288774) was associated with systolic blood pressure (SBP) (P=0.01), DBP (P=0.04), and progression of both SBP (P=0.03) and DBP (P=0.05) over time. A quantitative transmission disequilibrium test in the family material of the rs4149601 supported this NEDD4L variant as being at least partially causative of the linkage result. In conclusion, our findings suggest that the chromosome 18 linkage peak at 82.25 cM is explained by genetic NEDD4L variation affecting cross-sectional and longitudinal blood pressure, possibly as a consequence of altered NEDD4L interaction with ENaC.
AIMS/HYPOTHESIS: Recent reports have suggested that genotypes at the FTO locus interact with physical activity to modify levels of obesity-related traits. We tested this hypothesis in two non-diabetic population-based cohorts, the first from southern Sweden and the second from the Botnia region of western Finland. METHODS: In total 2,511 Finnish and 15,925 Swedish non-diabetic middle-aged adults were genotyped for the FTO rs9939609 variant. Physical activity was assessed by questionnaires and standard clinical procedures were conducted, including measures of height and weight and glucose regulation. Tests of gene x physical activity interaction were performed using linear interaction effects to determine whether the effect of this variant on BMI is modified by physical activity. RESULTS: The minor A allele at rs9939609 was associated with higher BMI in both cohorts, with the per allele difference in BMI being about 0.13 and 0.43 kg/m(2) in the Swedish and Finnish cohorts, respectively (p
Hypertension has been associated with raised plasma levels of complement factor 3 and 4 (C3 and C4). The nature of this association is unclear. This population-based longitudinal study explored whether C3 or C4 is associated with development of hypertension. Blood pressure and plasma levels of C3 and C4 were determined in 2178 healthy men, aged 35-50 years, initially without treatment for hypertension. Incidence of hypertension and blood pressure increase over 15.7 (+/-2.2) years follow-up was studied in relation to C3 and C4 at baseline. Among men with initially normal blood pressure (or=160/95 mm Hg or treatment) was 32, 42, 37 and 47%, respectively, for men with C3 in the first, second, third and fourth quartile (trend: P=0.001). This relationship remained significant after adjustment for confounding factors. Among men without blood pressure treatment, systolic BP increase (mean+standard error, adjusted for age, initial blood pressure and follow-up time) was 17.5+0.8, 19.6+0.9, 19.8+0.8 and 20.8+0.8 mm Hg, respectively, in the C3 quartiles (trend: P=0.004). C3 was not associated diastolic blood pressure at follow-up. Although C4 was associated with blood pressure at the baseline examination, there was no relationship between C4 and development of hypertension or future blood pressure increase. It is concluded that C3 in plasma is associated with future blood pressure increase and development of hypertension.
AIMS/HYPOTHESIS: Glucose-stimulated insulin secretion is dependent on the electrical activity of beta cells; hence, genes encoding beta cell ion channels are potential candidate genes for type 2 diabetes. The gene encoding the voltage-dependent Ca(2+) channel Ca(V)2.3 (CACNA1E), telomeric to a region that has shown suggestive linkage to type 2 diabetes (1q21-q25), has been ascribed a role for second-phase insulin secretion. METHODS: Based upon the genotyping of 52 haplotype tagging single nucleotide polymorphisms (SNPs) in a type 2 diabetes case-control sample (n = 1,467), we selected five SNPs that were nominally associated with type 2 diabetes and genotyped them in the following groups (1) a new case-control sample of 6,570 individuals from Sweden; (2) 2,293 individuals from the Botnia prospective cohort; and (3) 935 individuals with insulin secretion data from an IVGTT. RESULTS: The rs679931 TT genotype was associated with (1) an increased risk of type 2 diabetes in the Botnia case-control sample [odds ratio (OR) 1.4, 95% CI 1.0-2.0, p = 0.06] and in the replication sample (OR 1.2, 95% CI 1.0-1.5, p = 0.01 one-tailed), with a combined OR of 1.3 (95% CI 1.1-1.5, p = 0.004 two-tailed); (2) reduced insulin secretion [insulinogenic index at 30 min p = 0.02, disposition index (D (I)) p = 0.03] in control participants during an OGTT; (3) reduced second-phase insulin secretion at 30 min (p = 0.04) and 60 min (p = 0.02) during an IVGTT; and (4) reduced D (I) over time in the Botnia prospective cohort (p = 0.05). CONCLUSIONS/INTERPRETATION: We conclude that genetic variation in the CACNA1E gene contributes to an increased risk of the development of type 2 diabetes by reducing insulin secretion.
AIMS: To calculate the population-attributable risk (PAR) of coronary events (CE) from 10 risk factors, during long-term follow-up. METHODS: We used both case-cohort and case-control analyses for calculation of PAR in relation to 10 baseline risk factors. First CE (fatal or nonfatal, n=3072) in 22,444 males and 10,902 females was recorded during a mean follow-up of 20 years by use of national registers. RESULTS: Using a Cox regression analysis in a case-cohort design, smoking (prevalence in men 49%, women 37%) was the strongest risk factor, RR 2.29 (95% CI 2.09-2.52; PAR 39%), followed by hypercholesterolaemia, RR 1.70 (95% CI 1.56-1.86; PAR 18%), and diabetes, RR 1.67 (95% CI 1.41-1.99; PAR 3%). For women the strongest risk factors were smoking, RR 3.16 (95% CI 2.50-3.98; PAR 44%), diabetes, RR 2.59 (95% CI 1.78-3.76; PAR 6%), and hypertension, RR 2.47 (95% CI 1.94-3.14; PAR 23%). In men, smoking was the strongest predictor both after 10 years [RR 2.69 (95% CI 2.23-3.24)] and 20 years [RR 2.45 (95% CI 2.15-2.79)], followed by hypercholesterolaemia (RR 2.16-1.63), hypertension (RR 2.04-1.51), and diabetes (RR 1.85 -1.47). The case-control design gave very similar results. Total PAR varied from 74% (fully adjusted Cox regression, case-control, in men) to 116% in women (case-cohort). CONCLUSION: Smoking is the most important long-term risk factor for CE in both genders, based on data from a population with a high proportion of smokers. Ten measured variables explained almost all variation in risk and could be used as a basis for intervention programmes.
BACKGROUND: To determine if the common Pro12Ala polymorphism (rs1801282) of the peroxisome proliferator-activated receptor (PPARG) gene is associated with the metabolic syndrome (MetS) or with its individual components in middle-aged Swedish individuals. METHODS: MetS was defined according to the National Cholesterol Education Program/Adult Panel III (NCEP/ATP III), the International Diabetes Federation (IDF) and the European Group for the Study of Insulin Resistance (EGIR) criteria in a population-based sample of nearly 5000 subjects participating in the Malmö Diet and Cancer-cardiovascular arm. RESULTS: Of the subjects included in the analysis, 21.8, 29.4 and 20.4% had MetS according to the NCEP/ATP III, IDF and EGIR (only in subjects without diabetes) definitions, respectively. The Pro12Ala was not associated with MetS or with its individual components. These results were similar when patients with diabetes were excluded. Hypertensive and obese ala-carriers had lower fasting glucose and hypertensive ala-carriers also had lower level triglycerides (P
BACKGROUND: The role of inflammation as part of the explanation of socioeconomic differences in carotid atherosclerosis has not been specifically investigated. METHODS AND RESULTS: The associations between socioeconomic position (SEP), C-reactive protein (CRP), and preclinical carotid atherosclerosis were investigated in a general population sample of 3921 middle-aged Swedish men and women. Common carotid intima-media thickness (IMT) and presence of carotid plaque (focal IMT > 1.2 mm) were determined by B-mode ultrasound. The results showed that low SEP was associated with increased levels of CRP, independently of established risk factors. Furthermore, common carotid IMT increased with increasing CRP-levels. Presence of carotid plaque increased with increasing CRP-levels in men, but not in women. While the socioeconomic differences in carotid IMT were weak, there were associations between low educational level and carotid plaque prevalence with an age- and sex-adjusted odds ratio (OR) of 1.39 (95% CI: 1.21, 1.59). A similar association was seen for having a manual occupation, OR = 1.23 (95% CI: 1.07, 1.42). The age- and sex-adjusted absolute differences in carotid plaque prevalence were 9% with regard to educational level and 7% with regard to occupational status. Adjustment for CRP caused only a minor attenuation of the association between SEP and carotid atherosclerosis. CONCLUSIONS: The association between SEP and carotid atherosclerosis as measured by carotid IMT and carotid plaque could only to a minor extent be referred to differences in low grade inflammation as measured by CRP.
OBJECTIVE: Insulin resistance is associated with progression of atherosclerosis. We assessed the effect of 12 months of treatment with rosiglitazone (RSG) on the progression of carotid intima-media thickness (IMT) in people with type 2 diabetes mellitus (T2DM) or the insulin resistance syndrome (IRS). DESIGN: Randomized, double-blind, placebo-controlled trial. SETTING: Malmö University Hospital, Malmö, Sweden. SUBJECTS: 555 subjects (200 with T2DM and 355 nondiabetics with IRS according to EGIR criteria), aged 35-80 years. 447 subjects (165 T2DM and 282 IRS) completed the study. INTERVENTION: Participants were allocated to placebo or RSG 4 mg for 2 months and then 8 mg daily. MAIN OUTCOME MEASURE: Change in composite IMT [mean IMT in the common carotid artery (CCA) and maximal IMT in the bulb] was the primary and various other IMT measures were secondary outcome variables. RESULTS: There was no effect of RSG treatment in the mixed population. In T2DM patients there was a reduced progression of the composite IMT (mean change: 0.041 vs. 0.070 mm, P = 0.07), and of the mean IMT CCA (mean change: -0.005 mm vs. 0.021 mm, P = 0.007). RSG treatment led to significant reductions of HOMA-IR, fasting plasma glucose, HbA1c, PAI-1 activity, fibrinogen, C-reactive protein and matrix metalloproteinase-9. CONCLUSIONS: In a mixed study population of patients with T2DM and IRS RSG treatment was not associated with a statistically significant reduction of carotid IMT progression rate. Separate analyses of these two patient groups indicated, however, a significant beneficial effect on CCA IMT in T2DM patients but no similar effect in subjects with IRS.