The association of a SNP upstream of INSIG2 with body mass index is reproduced in several but not all cohorts.

A SNP upstream of the INSIG2 gene, rs7566605, was recently found to be associated with obesity as measured by body mass index (BMI) by Herbert and colleagues. The association between increased BMI and homozygosity for the minor allele was first observed in data from a genome-wide association scan of 86,604 SNPs in 923 related individuals from the Framingham Heart Study offspring cohort. The association was reproduced in four additional cohorts, but was not seen in a fifth cohort. To further assess the general reproducibility of this association, we genotyped rs7566605 in nine large cohorts from eight populations across multiple ethnicities (total n = 16,969). We tested this variant for association with BMI in each sample under a recessive model using family-based, population-based, and case-control designs. We observed a significant (p < 0.05) association in five cohorts but saw no association in three other cohorts. There was variability in the strength of association evidence across examination cycles in longitudinal data from unrelated individuals in the Framingham Heart Study Offspring cohort. A combined analysis revealed significant independent validation of this association in both unrelated (p = 0.046) and family-based (p = 0.004) samples. The estimated risk conferred by this allele is small, and could easily be masked by small sample size, population stratification, or other confounders. These validation studies suggest that the original association is less likely to be spurious, but the failure to observe an association in every data set suggests that the effect of SNP rs7566605 on BMI may be heterogeneous across population samples.

Diagnosis of patients with raised serum calcium level in primary care, Sweden.

OBJECTIVE: To study the diagnosis of hypercalcaemic patients and to evaluate whether frequent analyses of serum calcium can detect more patients with hypercalcaemia. DESIGN: Retrospective study of serum calcium analyses performed during the time period 1992-2000 and of the medical records of patients with elevated serum calcium levels between 1995 and 2000. SETTING: Primary care in Tibro, Sweden. SUBJECTS: Patients from the local community attending the primary healthcare centre. MAIN OUTCOME MEASURES: Frequency of serum calcium analyses, hypercalcaemic patients, and their diagnosis. RESULTS: Doubling the number of serum calcium analyses did not increase the detected number of raised calcium levels. On the other hand, more frequent parathyroid hormone (PTH) analyses resulted in a corresponding increase in detected high PTH levels. In Tibro, 15% (n = 22) of the patients with hypercalcaemia were diagnosed with primary hyperparathyroidism, giving a rate of 0.22%. This is comparable to the prevalence in other population studies. Over 40% (n = 9) of patients with primary hyperparathyroidism in the study had only slightly raised serum calcium levels (2.55-2.60 mmol/l). In 70% (n = 99) of the cases, the cause of hypercalcaemia was unknown. The second most common diagnosis was skeletal disorders followed by kidney disease. CONCLUSION: An increase in the number of serum calcium analyses did not result in increased detection of raised calcium levels. In contrast, an increase in the number of PTH analyses resulted in increased detection of primary hyperparathyroidism. Therefore, PTH analyses should be used more frequently.

Functional variant in the (alpha)2B adrenoceptor gene, a positional candidate on chromosome 2, associates with hypertension.

In a genome-wide scan in Scandinavians, we found suggestive linkage between early-onset primary hypertension and a region on chromosome 2. The alpha(2B)-adrenoceptor gene, a candidate gene within this region, harbors a functional insertion/deletion (I/D) polymorphism of three glutamate residues. The aim of this study was to investigate if the DD genotype is associated with hypertension in Swedes. We performed an association study between the I/D polymorphism of the alpha(2B)-adrenoceptor and hypertension in the Skaraborg population. The material consists of all known patients with primary hypertension in Skara (n=772 nondiabetic subjects; n=171 normoalbuminuric type 2 diabetic subjects) and 817 population control subjects. We first compared genotype frequencies between patients with early-onset hypertension (aged 50 years or younger at onset) and subjects with normotension (blood pressure <120/80 mm Hg). Thereafter, the polymorphism was tested for association with hypertension at the population level. When comparing patients with early-onset hypertension and normotensive subjects, the DD versus II genotype was associated with early-onset hypertension when diabetic subjects were excluded from the analysis (OR=2.0; 95% CI=1.2 to 3.5) or when they were not excluded (OR=1.8; 95% CI=1.0 to 3.1). At the population level, the DD versus II genotype was weakly associated with nondiabetic hypertension (OR=1.4; 95% CI=1.0 to 1.8). Our data suggest that carriers of the DD versus II genotype of the alpha(2B)-adrenoceptor are at increased risk for hypertension. The genotypic effect is most evident when comparing groups corresponding to the upper and lower tails of the blood pressure distribution in the population; however, in nondiabetic hypertensive subjects it is weakly detectable even at the population level.

A genome wide scan for early onset primary hypertension in Scandinavians.

With the aim of identifying hypertension susceptibility loci, we performed a genome wide scan in Scandinavian sib-pairs with early onset primary hypertension. To be classified as affected, a diagnosis of primary hypertension at age /= 1.0) were fine mapped with additional markers. Multipoint non-parametric linkage analysis was performed using GENEHUNTER v 2.0. Using simulations, a nominal P