Genotype-by-sex interaction on fasting insulin concentration: the HyperGEN study

Recent studies have demonstrated the importance of sex effects on the underlying genetic architecture of insulin-related traits. To explore sex-specific genetic effects on fasting insulin, we tested for genotype-by-sex interaction and conducted linkage analysis of fasting insulin in Hypertension Genetic Epidemiology Network families. Hypertensive siblings and their first-degree relatives were recruited from five field centers. We performed a genome scan for quantitative trait loci influencing fasting insulin among 1,505 European Americans and 1,616 African Americans without diabetes. Sex-stratified linear regression models, adjusted for race, center, and age, were explored. The Mammalian Genotyping Service typed 391 microsatellite markers, spaced roughly 9 cM. Variance component linkage analysis was performed in SOLAR using ethnic-specific marker allele frequencies and multipoint IBDs calculated in MERLIN. We detected a quantitative trait locus influencing fasting insulin in female subjects (logarithm of odds [LOD] = 3.4) on chromosome 2 at 95 cM (between GATA69E12 and GATA71G04) but not in male subjects (LOD = 0.0, P for interaction = 0.007). This sex-specific signal at 2p13.2 was detected in both European-American (LOD = 2.1) and African-American (LOD = 1.2) female subjects. Our findings overlap with several other linkage reports of insulin-related traits and demonstrate the importance of considering complex context-dependent interactions in the search for insulin-related genes.     

Erythrocyte fatty acid composition and the metabolic syndrome: a National Heart, Lung, and Blood Institute GOLDN study

BACKGROUND: Different fatty acids may vary in their effect on the metabolic syndrome (MetS). We tested whether fatty acid classes measured in erythrocytes are associated with the MetS or its components. METHODS: Included were men [n = 497; mean (SD) age, 49 (16) years] and women [n = 539; age, 48 (16) years] from 187 families in a National Heart, Lung, and Blood Institute (NHLBI) family study of the Genetics of Lipid-Lowering Drugs and Diet Network (GOLDN) conducted in Utah and Minnesota. We used gas chromatography to measure erythrocyte fatty acids and obtained data on potential confounding variables from interviewer-administered questionnaires. RESULTS: The prevalence of the MetS as defined by the updated Adult Treatment Panel III criteria was 36.8% in Utah and 39.6% in Minnesota (P >0.05). In a multivariate model that included 4 fatty acid classes, covariates, and pedigree as a random effect, the odds ratios (95% confidence interval) for the MetS in the 1st, 2nd, 3rd, and 4th quartile of polyunsaturated fatty acids were 1.00, 0.72 (0.47-1.10), 0.67 (0.43-1.05), and 0.39 (0.24-0.64), respectively (P for trend = 0.0002). For the corresponding quartiles of saturated fatty acids, the odds ratios were 1.00, 1.19 (0.77-1.84), 1.48 (0.94-2.34), and 1.63 (1.01-2.63), respectively (P for trend = 0.03). Unlike n6 fatty acids, which showed an inverse association (P <0.05) with MetS, n3, trans, and monounsaturated fatty acids were not associated with the MetS (P >0.05). We observed significant correlations (P <0.05) between fatty acid classes, insulin, and components of the MetS. CONCLUSIONS: Polyunsaturated fats are inversely associated with the MetS, whereas saturated fatty acids are positively associated with the MetS, probably through their effect on lipids, adiposity, insulin, and blood pressure.     

Tonsillar ectopia and headaches

Tonsillar ectopia, encompassing slight descent of the cerebellar tonsils and Chiari I malformations, are disorders observed routinely in older children and adults and are believed to be an acquired form of the Chiari malformations. This entity is different from the other Chiari malformations in that hydrocephalus plays no role in its evolution. More likely it is a disorder of para-axial mesoderm, characterized by posterior fossa hypoplasia and content overcrowding, and not an embryologic anomaly of neuroectoderm.The prevalence of tonsillar ectopia to my knowledge has not been studied. The incidence of Chiari I malformations ranges from less than 1%to 3% at various tertiary centers. The occipital and exertional headache associated with this malformation can be observed in subjects who have new-onset tonsillar ectopia resulting from repeated lumbar puncture,idiopathic intracranial hypotension, lumboperitoneal shunting, or spontaneous development [34-36]. This new-onset headache can remit with return to normal tonsil positioning. These findings support the proposal that pressure dissociation gradients and perhaps traction of pain-sensitive tissues play a role in generation of the headache observed in this malformation. In accordance with this idea, the extent of tonsillar descent is irrelevant alone,and the degree of posterior fossa hypoplasia and decrement of CSF flow velocity are better defining factors for determining the clinical significance of tonsillar ectopia.     

Influence of pH on osteoclasts treated with zoledronate and alendronate

Objectives

The objectives of this study were to analyze the effect of pH on the growth and activity of osteoclasts treated with different doses of two nitrogen-containing BPs, zoledronate and alendronate.

Materials and Methods

Murine osteoclasts cultured on dentine disks were treated with zoledronate (50 or 500 nM) or alendronate (500 or 5 μM) at two different pH values (7.4 or 7.0). Osteoclasts were counted with transmitted light microscopy, apoptosis/necrosis was studied with flow cytometry and confocal microscopy, and resorption pit number and depth were calculated using reflected light and scanning electron microscopy.

Results

The osteoclast count on dentine disks was significantly (p < 0.001) reduced by zoledronate or alendronate treatment at pH 7.0 in comparison to treatment with the same doses at pH 7.4 and untreated disks (controls). The percentage of apoptotic cells was significantly increased by treatment with 500 nM zoledronate or 5 μM alendronate at pH 7.0 in comparison to the same doses at pH 7.4. The number and depth of resorption pits were significantly lower in disks treated at each BP dose studied than in untreated controls at pH 7.0.

Conclusions

Zoledronate and alendronate at therapeutic doses have an adverse effect on the viability and resorptive activity of osteoclasts when the local medium pH is reduced.

Clinical relevance

These findings suggest that periodontal or peri-implant oral cavity infection may be a key trigger of the cascade of events that lead to BRONJ.

     

The ratio of Matriptase/HAI-1 mRNA is higher in colorectal cancer adenomas and carcinomas than corresponding tissue from control individuals

Background  

It has recently been shown that overexpression of the serine protease, matriptase, in transgenic mice causes a dramatically increased frequency of carcinoma formation. Overexpression of HAI-1 and matriptase together changed the frequency of carcinoma formation to normal. This suggests that the ratio of matriptase to HAI-1 influences the malignant progression. The aim of this study has been to determine the ratio of matriptase to HAI-1 mRNA expression in affected and normal tissue from individuals with colorectal cancer adenomas and carcinomas as well as in healthy individuals, in order to determine at which stages a dysregulated ratio of matriptase/HAI-1 mRNA is present during carcinogenesis.     

Dietary linolenic acid and adjusted QT and JT intervals in the National Heart, Lung, and Blood Institute Family Heart study

OBJECTIVES: The goal of this study was to examine whether higher consumption of total linolenic acid was associated with rate-adjusted QT and JT intervals (QTrr and JTrr, respectively). BACKGROUND: Higher intake of fish omega-3 fatty acids and plant omega-3 such as alpha-linolenic acid is associated with lower risk of myocardial infarction. While long-chain omega-3 can inhibit ventricular arrhythmia, it is not known whether alpha-linolenic acid influences ventricular repolarization. METHODS: We studied 3,642 subjects from the National Heart, Lung, and Blood Institute Family Heart study who were free of myocardial infarction, left ventricular hypertrophy, pacemaker, and with QRS <120 ms. We used the 95th percentile of the gender-specific distribution of QTrr and JTrr to define abnormally prolonged repolarization. Within each gender, we created age- and energy-adjusted tertiles of linolenic acid and used regression models for analyses. RESULTS: Mean age was 50 years, and average intake of total linolenic acid was 0.74 g/day. There was an inverse association between consumption of linolenic acid and QTrr and JTrr (p for trend 0.001 and 0.0005, respectively). From the lowest (reference) to the highest gender-, age-, and energy-adjusted tertile of linolenic acid, multivariable adjusted odds ratios for prolonged QTrr were 1.0, 0.74 (95% confidence interval [CI] 0.57 to 0.96), and 0.59 (95% CI 0.44 to 0.77), respectively (p for trend 0.0003). Corresponding values for JTrr were 1.0, 0.73 (95% CI 0.52 to 1.03), and 0.59 (95% CI 0.40 to 0.87), respectively (p for trend 0.009). Exclusion of subjects taking drugs known to influence QT did not influence this association. CONCLUSIONS: Higher intake of dietary linolenic acid might be associated with a reduced risk of abnormally prolonged repolarization in men and women.     

Differences in left ventricular structure between black and white hypertensive adults: the Hypertension Genetic Epidemiology Network study

The degree to which ethnic differences in left ventricular structure among hypertensive adults are independent of clinical and hemodynamic factors remains uncertain. We assessed whether left ventricular mass and geometry differ between black and white hypertensives after accounting for differences in such factors. Our study group comprised 1060 black and 580 white hypertensive participants free of valvular or coronary disease in a population-based cohort. Blood pressure was measured during a clinic visit and echocardiography was performed using standardized protocols. After controlling for clinical and hemodynamic parameters (cardiac index, peripheral resistance index, and pulse pressure/stroke index), both left ventricular mass and relative wall thickness were higher in blacks than whites (173.9+/-30.9 versus 168.3+/-24.3 grams, P=0.006, and 0.355+/-0.055 versus 0.340+/-0.055 grams, P<0.001). Similarly, the adjusted risk of having left ventricular hypertrophy, whether indexed by height(2.7) or by body surface area, was greater for blacks than for whites (odds ratio: 1.80; 95% CI: 1.29 to 2.51; and odds ratio: 2.50; 95% CI: 1.58 to 3.96, respectively), and this was also true for concentric geometry (odds ratio: 2.28; 95% CI: 1.22 to 4.25). Further adjustment for relatedness in this genetic epidemiological study did not attenuate these differences. Our findings confirm the strong association between black ethnicity and increased left ventricular mass and relative wall thickness in hypertensive adults and demonstrate that these differences are independent of standard clinical and hemodynamic parameters. Whether such differences relate to distinct ambulatory pressure profiles or an ethnic propensity to cardiac hypertrophy requires further investigation.