Lisa J. Martin

A comprehensive linkage analysis for myocardial infarction and its related risk factors

Coronary artery disease and myocardial infarction (MI) are leading causes of death in the western world. Numerous studies have shown that risk factors such as diabetes mellitus, arterial hypertension and hypercholesterolemia contribute to the development of the disease. Although each risk factor by itself is partly under genetic control, a positive family history is an independent predictor, which suggests that there are additional susceptibility genes. We have scanned the whole genome in 513 families to identify chromosomal regions linked to myocardial infarction and related risk factors that are known to be under genetic control. Here we show, by using variance component analysis and incorporating risk factors, that risk of myocardial infarction maps to a single region on chromosome 14 with a significant lod score of 3.9 (pointwise P=0.00015, genome-wide P<0.05), providing evidence of a principal MI locus. To characterize this locus we analyzed each risk factor by itself. Serum concentrations of lipoprotein (a) show linkage to both the apolipoprotein (a) locus (lod score 26.99) and a new locus on chromosome 1 (lod score 3.8). There is suggestive linkage for diabetes mellitus on chromosome 6 (lod score 2.96), for hypertension on chromosomes 1 and 6, for high-density and low-density lipoprotein cholesterol on chromosomes 1 and 17, and for triglyceride concentrations on chromosome 9. Although some of these risk factors overlap with previously identified loci, none overlaps with the newly identified susceptibility locus for myocardial infarction and coronary artery disease.

Common variants at 5q22 associate with pediatric eosinophilic esophagitis

Eosinophilic esophagitis (EoE) is an allergic disorder characterized by the accumulation of eosinophils in the esophagus. We report association of EoE with variants at chromosome 5q22 encompassing TSLP and WDR36 (rs3806932, combined P = 3.19 × 10−9). TSLP is overexpressed in esophageal biopsies from individuals with EoE compared with unaffected individuals, whereas WDR36 expression is unaltered between the two groups. These data implicate the 5q22 locus in the pathogenesis of EoE and identify TSLP as the most likely candidate gene in the region.

Dietary fat and breast cancer risk revisited: a meta-analysis of the published literature.

Animal experiments and human ecological studies suggest that dietary fat intake is associated with a risk of breast cancer, but individual-based studies have given contradictory results. We have carried out a meta-analysis of this association to include all papers published up to July 2003. Case–control and cohort studies that examined the association of dietary fat, or fat-containing foods, with risk of breast cancer were identified. A total of 45 risk estimates for total fat intake were obtained. Descriptive data from each study were extracted with an estimate of relative risk and its associated 95% confidence interval (CI), and were analysed using the random effects model of DerSimonian and Laird. The summary relative risk, comparing the highest and lowest levels of intake of total fat, was 1.13 (95% CI: 1.03–1.25). Cohort studies (N=14) had a summary relative risk of 1.11 (95% CI: 0.99–1.25) and case–control studies (N=31) had a relative risk of 1.14 (95% CI 0.99–1.32). Significant summary relative risks were also found for saturated fat (RR, 1.19; 95% CI: 1.06–1.35) and meat intake (RR, 1.17; 95% CI 1.06–1.29). Combined estimates of risk for total and saturated fat intake, and for meat intake, all indicate an association between higher intakes and an increased risk of breast cancer. Case–control and cohort studies gave similar results.

Breast Tissue Composition and Susceptibility to Breast Cancer

Breast density, as assessed by mammography, reflects breast tissue composition. Breast epithelium and stroma attenuate x-rays more than fat and thus appear light on mammograms while fat appears dark. In this review, we provide an overview of selected areas of current knowledge about the relationship between breast density and susceptibility to breast cancer. We review the evidence that breast density is a risk factor for breast cancer, the histological and other risk factors that are associated with variations in breast density, and the biological plausibility of the associations with risk of breast cancer. We also discuss the potential for improved risk prediction that might be achieved by using alternative breast imaging methods, such as magnetic resonance or ultrasound. After adjustment for other risk factors, breast density is consistently associated with breast cancer risk, more strongly than most other risk factors for this disease, and extensive breast density may account for a substantial fraction of breast cancer. Breast density is associated with risk of all of the proliferative lesions that are thought to be precursors of breast cancer. Studies of twins have shown that breast density is a highly heritable quantitative trait. Associations between breast density and variations in breast histology, risk of proliferative breast lesions, and risk of breast cancer may be the result of exposures of breast tissue to both mitogens and mutagens. Characterization of breast density by mammography has several limitations, and the uses of breast density in risk prediction and breast cancer prevention may be improved by other methods of imaging, such as magnetic resonance or ultrasound tomography.

The association of breast mitogens with mammographic densities

Radiologically dense breast tissue (mammographic density) is strongly associated with risk of breast cancer, but the biological basis for this association is unknown. In this study we have examined the association of circulating levels of hormones and growth factors with mammographic density. A total of 382 subjects, 193 premenopausal and 189 postmenopausal, without previous breast cancer or current hormone use, were selected in each of five categories of breast density from mammography units. Risk factor information, anthropometric measures, and blood samples were obtained, and oestradiol, progesterone, sex hormone binding globulin, growth hormone, insulin-like growth factor-I and its principal binding protein, and prolactin measured. Mammograms were digitised and measured using a computer-assisted method. After adjustment for other risk factors, we found in premenopausal women that serum insulin-like growth factor-I levels, and in postmenopausal women, serum levels of prolactin, were both significantly and positively associated with per cent density. Total oestradiol and progesterone levels were unrelated to per cent density in both groups. In postmenopausal women, free oestradiol (negatively), and sex hormone binding globulin (positively), were significantly related to per cent density. These data show an association between blood levels of breast mitogens and mammographic density, and suggest a biological basis for the associated risk of breast cancer.

The Association of Measured Breast Tissue Characteristics with Mammographic Density and Other Risk Factors for Breast Cancer

Background: We have examined the relationships between the measured properties of breast tissue and mammographic density and other risk factors for breast cancer, using breast tissue obtained at forensic autopsy and not selected for the presence of abnormalities. Methods: We used randomly selected tissue blocks taken from breast tissue slices obtained by s.c. mastectomy at the time of forensic autopsy to measure histologic features using quantitative microscopy. The proportions of the biopsy occupied by cells (estimated by nuclear area), glandular structures, and collagen were determined. These measurements were examined in relation to the percent density in the faxitron image of the tissue slice from which the biopsy was taken and other risk factors for breast cancer. Results: The percent mammographic density was associated with the proportion of the area of the biopsy occupied by nuclei, both epithelial and nonepithelial, and by collagen and the area of glandular structures. Several other risk factors for breast cancer, notably body weight, parity, and number of births, and menopausal status, that are associated with variations in mammographic density, were also associated with differences in one or more of these tissue features. Conclusion: All risk factors for breast cancer must ultimately exert their influence by an effect on the breast, and these findings suggest that, for some risk factors, this influence includes an effect on the number of cells and the quantity of collagen.

Coordinate Interaction between IL-13 and Epithelial Differentiation Cluster Genes in Eosinophilic Esophagitis

We have previously proposed that the pathogenesis of eosinophilic esophagitis (EE) is mediated by an IL-13–driven epithelial cell response associated with marked gene dysregulation including eotaxin-3 overproduction. In this study, we compared epithelial responses between healthy patients and those with EE, aiming to uncover molecular explanations for EE pathogenesis. Esophageal epithelial cells could be maintained for up to five passages, with 67% and 62% of cell lines reaching confluence in healthy controls and EE cases, respectively. Both sets of epithelial cells avidly responded to IL-13 at similar levels as assessed by eotaxin-3 production. Acidic pH increased cellular release of eotaxin-3 (4.6 ± 1.98 ng/ml versus 12.46 ± 2.90 ng/ml at pH 7.4 and 4, respectively; p < 0.05). Numerous epidermal differentiation complex (EDC) genes, such as filaggrin and SPRR3, were downregulated both in IL-13–stimulated esophageal epithelial cells and in EE biopsies specimens compared with healthy controls. Whereas the filaggrin loss of function mutation 2282del4 was overrepresented in EE compared with control individuals (6.1% versus 1.3% respectively; p = 0.0172), the decreased filaggrin expression was uniformly seen in all EE cases in vivo. Indeed, expression of the EDC genes filaggrin and involucrin was strongly decreased directly by IL-13. These results establish that the epithelial response in EE involves a cooperative interaction between IL-13 and expression of EDC genes.

Variants of thymic stromal lymphopoietin and its receptor associate with eosinophilic esophagitis

BACKGROUND The genetic cause of eosinophilic esophagitis (EE) has been largely unexplored until a recent genome-wide association study identified a disease susceptibility locus on 5q22, a region that harbors the thymic stromal lymphopoietin (TSLP) gene. However, it is unclear whether the observed genetic associations with EE are disease-specific or confounded by the high rate of allergy in patients with EE. In addition, the genetic contributions of other allergy-associated genes to EE risk have not been explored. OBJECTIVE We aimed to delineate single nucleotide polymorphisms (SNPs) that associated with EE apart from allergy. METHODS We used a custom array containing 738 SNPs in 53 genes implicated in allergic responses, immune responses, or both to genotype 220 allergic or 246 nonallergic control subjects and a discovery cohort of 170 patients with EE. We replicated a statistically significant SNP association in an independent case-control cohort and examined the induction of the candidate gene in primary esophageal epithelial cells. RESULTS A single SNP residing in the TSLP gene reached Bonferroni linkage disequilibrium-adjusted significance but only when patients with EE were compared with allergic control subjects (rs10062929; P = 4.11 x 10(-5); odds ratio, 0.35). A nonsynonymous polymorphism in the thymic stromal lymphopoietin receptor (TSLPR) gene on Xp22.3 and Yp11.3 was significantly associated with disease only in male patients with EE. Primary esophageal epithelial cells expressed TSLP mRNA after Toll-like receptor 3 stimulation. CONCLUSION These data collectively identify TSLP as a candidate gene critically involved in EE susceptibility beyond its role in promoting T(H)2 responses.

Gallstones: Genetics Versus Environment

ObjectiveThe aim of this study was to determine if a significant genetic component contributes to the pathogenesis of symptomatic gallstones. Summary Background DataGallstones represent a polygenic disorder that affects more than 30,000,000 Americans and results in more than 750,000 cholecystectomies in the United States annually. Risk factors include age, gender, race, parity, obesity, and diabetes. A family history of gallstones also has been identified as a risk factor suggesting that genetics play a role in gallstone formation. However, the role of genetics in the pathogenesis of gallstone formation has not been determined. MethodsA gallbladder disease-specific questionnaire was administered to 904 healthy unrelated adult volunteers (association study). The questionnaire ascertained a history of cholecystectomy and gallstone disease in first-degree relatives, as well as medical history, demographic, and anthropometric data. A logistic regression model was used to identify risk factors for symptomatic gallstone disease in a multivariate analysis. A maximum likelihood based variance decomposition approach was then used in 1,038 individuals from 358 families (family study) to estimate the additive genetic heritability of symptomatic gallstone disease. ResultsIn the association study significant risk factors for symptomatic gallstone disease were female gender (relative risk 8.8, P < .003), obesity (BMI > 30, relative risk 3.7, P < .001), age > 50 (relative risk 2.5, P < .001), and a positive family history of previous cholecystectomy in a first-degree family member (relative risk 2.2, P < .01). In the family study the additive genetic heritability of symptomatic gallstones was 29% (P < .02), age and gender were significant covariates and explained 9.3% of the phenotypic variation in gallbladder disease. ConclusionsThese data suggest that genetic factors are responsible for at least 30% of symptomatic gallstone disease. However, the true role of heredity in gallstone pathogenesis is probably higher because data based on symptomatic gallbladder disease underestimates the true prevalence in the population.

Postconcussive symptoms in children with mild closed head injuries.

OBJECTIVE To examine the incidence and neuropsychological, behavioral, and neuroimaging correlates of postconcussive symptoms (PCS) in children with mild closed head injuries (CHI). DESIGN 26 Children with mild CHI and 8 of their uninjured siblings, from 8 to 15 years old, were recruited prospectively and assessed at baseline (ie, within 7 days of injury) and at 3 months postinjury. Parents rated PCS, motivation and affective lability, and behavioral adjustment. Baseline ratings assessed premorbid functioning retrospectively, and follow-up ratings assessed postinjury status. On both occasions, children completed neuropsychological testing, and those with mild CHI also underwent magnetic resonance imaging (MRI). RESULTS Children with mild CHI did not differ from siblings in baseline ratings of premorbid PCS but displayed higher ratings on several PCS at 3 months postinjury. Thirty-five percent of children with mild CHI showed increases in PCS, compared with baseline premorbid ratings, but none of the siblings did so. Children with mild CHI whose PCS increased from premorbid levels showed poorer neuropsychological functioning at baseline than did children whose PCS did not increase, although the differences had partially resolved by 3 months. They also displayed decreased motivation over time. Their behavioral adjustment was poorer and they had smaller white matter volumes on MRI, but the latter differences were present at baseline and did not change over time, suggesting that they existed prior to the injury. CONCLUSION Postinjury increases in PCS occur in a sizable minority of children with mild CHI and more often than among uninjured siblings. Increases in PCS following mild CHI are associated with premorbid neurological and psychosocial vulnerability, but also with postinjury decrements in neuropsychological and neurobehavioral functioning.