Amanda M. Shearman

The t(7;11)(p15;p15) translocation in acute myeloid leukaemia fuses the genes for nucleoporin NUP98 and class I homeoprotein HOXA9.

The t(7;11)(p15;p15) translocation is a recurrent chromosomal abnormality associated primarily with acute myeloid leukaemia (FAB M2 and M4). We present here the molecular definition of this translocation. On chromosome 7 positional cloning revealed the consistent rearrangement of the HOXA9 gene, which encodes a class I homeodomain protein potentially involved in myeloid differentiation. On chromosome 11 the translocation targets the human homologue of NUPP98, a member of the GLFG nucleoporin family. Chimaeric messages spliced over the breakpoint fuse the GLFG repeat domains of NUP98 in-frame to the HOXA9 homeobox. The predicted NUP98–HOXA9 fusion protein may promote leukaemogenesis through inhibition of HOXA9-mediated terminal differentiation and/or aberrant nucleocytoplasmic transport.

Estrogen Receptor α Gene Variation and the Risk of Stroke

Background and Purpose— Estrogen receptor α (ESR1) gene variation is associated with a range of important estrogen-dependent characteristics, including responses of lipid profile and atherosclerotic severity to hormone replacement therapy, coronary heart disease risk, and migraine. The roles that reproductive steroids play in cerebrovascular pathophysiology and ischemia are an important area of investigation. Given that there is a significantly higher risk of myocardial infarction among men with the CC genotype (PP of PvuII) of c.454-397T>C (rs2234693), we asked whether this genotype is associated with a higher risk of stroke. Methods— Relative risk of stroke by genotype was determined in 2709 participants of the Second Northwick Park Heart Study, white males with a mean baseline age 56 years and follow up 10.5 years. Results— Compared with participants with the ESR1 c.454-397CT or TT genotype, those with the CC genotype had a relative risk of stroke of 1.92 (95% confidence interval, 1.06 to 3.48, P=0.03) after adjustment for age, primary care practice; additional adjustment for body mass index, serum cholesterol and triglyceride levels, hypertension, diabetes, and smoking status. Exclusion of stroke cases with coronary heart disease gave results that were essentially unchanged. Conclusions— In this study, subjects with the common ESR1 c.454-397CC genotype have a substantial increase in risk of stroke. In another publication, other ESR1 variation was associated with migraine. We thus hypothesize that estrogen receptor variation may provide a basis for the established relationship among estrogens, migraine, and stroke.

Estrogen Receptor α Gene Variation Is Associated With Risk of Myocardial Infarction in More Than Seven Thousand Men From Five Cohorts

Understanding the mechanisms by which estrogens affect cardiovascular disease risk, including the role of variation in the gene for estrogen receptor α (ESR1), may be key to new treatment strategies. We investigated whether the CC genotype at ESR1 c.454-397T>C is associated with increased risk among men. Study of more than 7000 whites in 5 cohorts from 4 countries provided evidence that genotype CC, present in roughly 20% of individuals, is a risk factor for nonfatal acute myocardial infarction (odds ratio=1.44; P<0.0001), after adjustment for established cardiovascular risk factors. After exclusion of younger subjects from 2 cohorts, because of age interaction, the odds ratio increased (to 1.63).

Estrogen receptor β polymorphisms are associated with bone mass in women and men: The Framingham study

ESR2 is expressed in bone cells, yet few studies have tested its variation for association with BMD, an important determinant of osteoporotic fractures. This was investigated in 723 men and 795 women from the Framingham study. Results show association of variation in this gene with BMD in both women and men.

Variation in estrogen-related genes and cross-sectional and longitudinal blood pressure in the Framingham Heart Study.

Objective To examine the association between variation in estrogen-related genes and cross-sectional and longitudinal blood pressure in men and women. Design In 1780 unrelated members of the community-based Framingham Heart Study offspring cohort, systolic blood pressure and diastolic blood pressure were measured over a total of six examination cycles encompassing 24 years of follow-up. Multivariate regression analyses were used to assess the relation between untreated cross-sectional and longitudinal blood pressure and polymorphisms at the estrogen receptor-α (ESR1), estrogen receptor-β (ESR2), aromatase (CYP19A1), and nuclear receptor coactivator 1 (NCOA1) genes after adjustment for common risk factors. Results In men, systolic blood pressure and pulse pressure (systolic blood pressure minus diastolic blood pressure) were associated with two polymorphisms in ESR1, while pulse pressure was also associated with variations in NCOA1 and CYP19A1. Polymorphisms in ESR1, CYP19A1, and NCOA1 were associated with diastolic blood pressure in women. Conclusions Although the underlying relations between genes involved in estrogen action and hypertension remain to be completely understood, our findings provide suggestive evidence of gender-specific contributions of estrogen-related genes to blood pressure variation. As no correction for multiple testing was performed in the analyses, we view these results as suggestive and not definitive. Further studies are warranted to confirm these results using a comprehensive set of polymorphisms in order to shed more light on the involvement of estrogen in blood pressure regulation.

Age-Related Changes in Echocardiographic Measurements Association With Variation in the Estrogen Receptor-α Gene

Left ventricular (LV) mass and other LV measures have been shown to be heritable. In this study we hypothesized that functional variation in the gene coding for estrogen receptor-&agr; (ESR1), known for mediating the effect of estrogens on myocardium, is associated with age-related changes in LV structure. Four genetic markers (ESR1 TA repeat; rs2077647, or +30T>C; rs2234693, or PvuII; and rs9340799, or XbaI) were genotyped in 847 unrelated individuals (488 women) from the Framingham Offspring Study, who attended 2 examination cycles 16 years apart (mean ages at first examination: 43±9 years; at follow-up: 59±9 years). ANCOVA was used to assess the association of polymorphisms and their haplotypes with cross-sectional measurements and longitudinal changes in LV mass, wall thickness, end-diastolic and end-systolic internal diameter, and fractional shortening after adjustment for factors known to influence these variables. Changes over time were detected for all of the LV measurements (P ranging from <0.0001 to 0.02), except for fractional shortening in men. The SS genotype of the ESR1 TA repeat polymorphism in the promoter region was associated with longitudinal changes in LV mass and LV wall thickness (P ranging from 0.0006 to 0.01). Moreover, the TA[S]–+30[T]–PvuII[T]–XbaI[A] haplotype (frequency: 47.5%) was associated with greater LV changes as compared with the TA[L]–+30[C]–PvuII[C]–XbaI[G] haplotype (frequency: 31.8%). Our results are consistent with the hypothesis that common ESR1 polymorphisms are significantly associated with age-related changes in LV structure. Understanding the mechanisms predisposing to unfavorable LV remodeling of the heart with advancing age may aid in the discovery of new therapeutic targets for the prevention of heart failure.

The relationship of estrogen receptor-α and -β genes with osteoarthritis of the hand.

Objective. We examined reported associations between radiographic hand osteoarthritis (OA) and single-nucleotide polymorphisms (SNP) in 2 candidate genes associated with OA in other joints: estrogen receptor alpha (ESR1) and beta (ESR2). Methods. In 539 Framingham Offspring Study participants (49% men; mean age 61 ± 9 yrs) joint-specific radiographic hand OA was defined as Kellgren/Lawrence (K/L) scores ≥ 2 in the first carpometacarpal joint (CMC), distal interphalangeal joints (DIP), first-digit interphalangeal joint (IP), or proximal interphalangeal joints (PIP). Four SNP were genotyped for ESR1 (PvuII-rs2234693, XbaI-rs9340799, rs2077647, and rs1801132) and 4 for ESR2 (rs1256031, rs1256034, rs1256059, rs944460). Logistic regression analyses were performed to evaluate the relationships between genotypes and hand OA, adjusting for age, sex, height, and weight. Results. Radiographic hand OA was identified in at least one investigated joint of DIP (39%), PIP (33%), and first CMC (40%). There was no evidence of association between OA and genotype at any polymorphism. We found no significant association between our OA phenotypes or generalized or severe generalized OA as defined by Ushiyama and heterozygosity for rs2234693 and rs9340799, although in metaanalysis with the former study this heterozygosity remained significantly associated with generalized or severe generalized OA. Conclusion. We found no significant association between hand OA and the investigated polymorphisms of ESR1 or ESR2 despite published reports of association and a priori hypotheses implicating their potential roles. However, we could not absolutely exclude associations with rs2234693, rs9340799, or rs944460.

Association between estrogen receptor α gene variation and cardiovascular disease

Estrogen and related hormones activate estrogen receptors, which in turn regulate genes for some cardiovascular disease (CVD) risk factors. Variants of the estrogen receptor a gene (ESR1) have been investigated, in small study populations, in relation to coronary artery disease and variation in levels of high-density lipoprotein (HDL) cholesterol, but little is known about the effects of genetic variation in ESR1 on CVD risk. This prospective study attempted to determine whether the ESR1 c.454-397T>C polymorphism correlates with CVD risk. Participants were 1739 unrelated men and women, ranging in age from 28 to 62 years, from the population-based offspring cohort of the Framingham Heart Study. Total atherosclerotic CVD events (recognized or unrecognized myocardial infarction [MI], angina pectoris, coronary insufficiency, intermittent claudication, death from coronary heart disease, atherothrombotic stroke) were present in 178 individuals followed up from 1971 to 1998. Major atherosclerotic CVD (recognized acute MI, coronary insufficiency, fatal coronary heart disease, atherothrombotic stroke) was found in 83 participants. Fifty-nine persons were recognized as having acute MI. One fifth of those participating in this study were homozygous for the ESR1c.454-397C allele. After adjusting for numerous covariates (age, gender, body mass index, hypertension, diabetes, total and high-density lipoprotein cholesterol, cigarette smoking), the CC genotype correlated significantly with major atherosclerotic CVD (odds ratio, 2.0; 95% confidence interval [CI], 1.3-3.2) compared with the CT or TT genotype. The risk of MI was 3-fold greater in those with the CC genotype (95% CI, 1.7-5.2). Comparable results were obtained when analyzing only men. Total atherosclerotic CVD did not appear to be associated with genotype. This study disclosed an association between a common estrogen receptor genotype, ESR1c.454-397CC, and an increased risk of MI. It seems likely that variations in estrogen receptors could help to explain the apparent effects of combination hormone therapy on the risk of CVD in women.