Are bone turnover markers associated with volumetric bone density, size, and strength in older men and women? The AGES-Reykjavik study.

UNLABELLED: Association between serum bone formation and resorption markers and bone mineral, structural, and strength variables derived from quantitative computed tomography (QCT) in a population-based cohort of 1745 older adults was assessed. The association was weak for lumbar spine and femoral neck areal and volumetric bone mineral density. INTRODUCTION: The aim of this study was to examine the relationship between levels of bone turnover markers (BTMs; osteocalcin (OC), C-terminal cross-linking telopeptide of type I collagen (CTX), and procollagen type 1N propeptide (P1NP)) and quantitative computed tomography (QCT)-derived bone density, geometry, and strength indices in the lumbar spine and femoral neck (FN). METHODS: A total of 1745 older individuals (773 men and 972 women, aged 66-92 years) from the Age, Gene/Environment Susceptibility (AGES)-Reykjavik cohort were studied. QCT was performed in the lumbar spine and hip to estimate volumetric trabecular, cortical, and integral bone mineral density (BMD), areal BMD, bone geometry, and bone strength indices. Association between BTMs and QCT variables were explored using multivariable linear regression. RESULTS: Major findings showed that all BMD measures, FN cortical index, and compressive strength had a low negative correlation with the BTM levels in both men and women. Correlations between BTMs and bone size parameters were minimal or not significant. No associations were found between BTMs and vertebral cross-sectional area in women. BTMs alone accounted for only a relatively small percentage of the bone parameter variance (1-10 %). CONCLUSION: Serum CTX, OC, and P1NP were weakly correlated with lumbar spine and FN areal and volumetric BMD and strength measures. Most of the bone size indices were not associated with BTMs; thus, the selected bone remodeling markers do not reflect periosteal bone formation. These results confirmed the limited ability of the most sensitive established BTMs to predict bone structural integrity in older adults.

Association of bone turnover markers with volumetric bone loss, periosteal apposition, and fracture risk in older men and women: the AGES-Reykjavik longitudinal study.

Association between serum bone formation and resorption markers and cortical and trabecular bone loss and the concurrent periosteal apposition in a population-based cohort of 1069 older adults was assessed. BTM levels moderately reflect the cellular events at the endosteal and periosteal surfaces but are not associated with fracture risk. INTRODUCTION: We assessed whether circulating bone formation and resorption markers (BTM) were individual predictors for trabecular and cortical bone loss, periosteal expansion, and fracture risk in older adults aged 66 to 93 years from the AGES-Reykjavik study. METHODS: The sample for the quantitative computed tomography (QCT)-derived cortical and trabecular BMD and periosteal expansion analysis consisted of 1069 participants (474 men and 595 women) who had complete baseline (2002 to 2006) and follow-up (2007 to 2011) hip QCT scans and serum baseline BTM. During the median follow-up of 11.7 years (range 5.4-12.5), 54 (11.4 %) men and 182 (30.6 %) women sustained at least one fracture of any type. RESULTS: Increase in BTM levels was associated with faster cortical and trabecular bone loss at the femoral neck and proximal femur in men and women. Higher BTM levels were positively related with periosteal expansion rate at the femoral neck in men. Markers were not associated with fracture risk. CONCLUSION: This data corroborates the notion from few previous studies that both envelopes are metabolically active and that BTM levels may moderately reflect the cellular events at the endosteal and periosteal surfaces. However, our results do not support the routine use of BTM to assess fracture risk in older men and women. In light of these findings, further studies are justified to examine whether systemic markers of bone turnover might prove useful in monitoring skeletal remodeling events and the effects of current osteoporosis drugs at the periosteum.

Novel loci associated with usual sleep duration: the CHARGE Consortium Genome-Wide Association Study.

Usual sleep duration is a heritable trait correlated with psychiatric morbidity, cardiometabolic disease and mortality, although little is known about the genetic variants influencing this trait. A genome-wide association study (GWAS) of usual sleep duration was conducted using 18 population-based cohorts totaling 47 180 individuals of European ancestry. Genome-wide significant association was identified at two loci. The strongest is located on chromosome 2, in an intergenic region 35- to 80-kb upstream from the thyroid-specific transcription factor PAX8 (lowest P=1.1 × 10(-9)). This finding was replicated in an African-American sample of 4771 individuals (lowest P=9.3 × 10(-4)). The strongest combined association was at rs1823125 (P=1.5 × 10(-10), minor allele frequency 0.26 in the discovery sample, 0.12 in the replication sample), with each copy of the minor allele associated with a sleep duration 3.1 min longer per night. The alleles associated with longer sleep duration were associated in previous GWAS with a more favorable metabolic profile and a lower risk of attention deficit hyperactivity disorder. Understanding the mechanisms underlying these associations may help elucidate biological mechanisms influencing sleep duration and its association with psychiatric, metabolic and cardiovascular disease.

Associations of current and remitted major depressive disorder with brain atrophy: the AGES-Reykjavik Study.

BACKGROUND: To examine whether lifetime DSM-IV diagnosis of major depressive disorder (MDD), including age at onset and number of episodes, is associated with brain atrophy in older persons without dementia. METHOD: Within the population-based Age, Gene/Environment Susceptibility (AGES)-Reykjavik Study, 4354 persons (mean age 76 ± 5 years, 58% women) without dementia had a 1.5-T brain magnetic resonance imaging (MRI) scan. Automated brain segmentation total and regional brain volumes were calculated. History of MDD, including age at onset and number of episodes, and MDD in the past 2 weeks was diagnosed according to DSM-IV criteria using the Mini-International Neuropsychiatric Interview (MINI). RESULTS: Of the total sample, 4.5% reported a lifetime history of MDD; 1.5% had a current diagnosis of MDD (including 75% with a prior history of depression) and 3.0% had a past but no current diagnosis (remission). After adjusting for multiple covariates, compared to participants never depressed, those with current MDD (irrespective of past) had more global brain atrophy [B = -1.25%, 95% confidence interval (CI) -2.05 to -0.44], including more gray- and white-matter atrophy in most lobes, and also more atrophy of the hippocampus and thalamus. Participants with current, first-onset MDD also had more brain atrophy (B = -1.62%, 95% CI -3.30 to 0.05) whereas those remitted did not (B = 0.06%, 95% CI -0.54 to 0.66). CONCLUSIONS: In older persons without dementia, current MDD, irrespective of prior history, but not remitted MDD was associated with widespread gray- and white-matter brain atrophy. Prospective studies should examine whether MDD is a consequence of, or contributes to, brain volume loss and development of dementia.

Retinopathy in old persons with and without diabetes mellitus: the Age, Gene/Environment Susceptibility--Reykjavik Study (AGES-R).

AIMS/HYPOTHESIS: We aimed to describe the prevalence of retinopathy in an aged cohort of Icelanders with and without diabetes mellitus. METHODS: The study population consisted of 4,994 persons aged ≥ 67 years, who participated in the Age, Gene/Environment Susceptibility-Reykjavik Study (AGES-R). Type 2 diabetes mellitus was defined as HbA(1c) ≥ 6.5% (>48 mmol/mol). Retinopathy was assessed by grading fundus photographs using the modified Airlie House adaptation of the Early Treatment Diabetic Retinopathy Study protocol. Associations between retinopathy and risk factors were estimated using odds ratios obtained from multivariate analyses. RESULTS: The overall prevalence of retinopathy in AGES-R was 12.4%. Diabetes mellitus was present in 516 persons (10.3%), for 512 of whom gradable fundus photos were available, including 138 persons (27.0%, 95% CI 23.2, 31.0) with any retinopathy. Five persons (1.0%, 95% CI 0.3, 2.3) had proliferative retinopathy. Clinically significant macular oedema was present in five persons (1.0%, 95% CI 0.3, 2.3). Independent risk factors for retinopathy in diabetic patients in a multivariate model included HbA(1c), insulin use and use of oral hypoglycaemic agents, the last two being indicators of longer disease duration. In 4478 participants without diabetes mellitus, gradable fundus photos were available for 4,453 participants, with retinopathy present in 476 (10.7%, 95% CI 9.8, 11.6) and clinically significant macular oedema in three persons. Independent risk factors included increasing age and microalbuminuria. CONCLUSIONS/INTERPRETATION: Over three-quarters (78%) of retinopathy cases were found in persons without diabetes and a strong association between microalbuminuria and non-diabetic retinopathy was found. These results may have implications for patient management of the aged.

Lifelong physical activity in maintaining bone strength in older men and women of the Age, Gene/Environment Susceptibility-Reykjavik Study.

UNLABELLED: We examined if lifelong physical activity is important for maintaining bone strength in the elderly. Associations of quantitative computerized tomography-acquired bone measures (vertebral and femoral) and self-reported physical activity in mid-life (mean age, 50 years), in old age (≥65 years), and throughout life (recalled during old age) were investigated in 2,110 men and 2,682 women in the AGES-Reykjavik Study. Results conclude lifelong physical activity with continuation into old age (≥65 years) best maintains better bone health later in life. INTRODUCTION: Skeletal loading is thought to modulate the loss of bone in later life, and physical activity is a chief means of affecting bone strength by skeletal loading. Despite much discussion regarding lifelong versus early adulthood physical activity for preventing bone loss later in life, inconsistency still exists regarding how to maintain bone mass later in life (≥65 years). METHODS: We examined if lifelong physical activity is important for maintaining bone strength in the elderly. RESULTS: The associations of quantitative computerized tomography-acquired vertebral and femoral bone measures and self-reported physical activity in mid-life (mean age, 50 years), in old age (≥65 years), and throughout life (recalled during old age) were investigated in 2,110 men and 2,682 women in the AGES-Reykjavik Study. CONCLUSION: Our findings conclude that lifelong physical activity with continuation into old age (≥65 years) best maintains better bone health in the elderly.

The interaction of adiposity with the CRP gene affects CRP levels: age, gene/environment susceptibilty-Reykjavik study.

OBJECTIVE: Common diseases often have an inflammatory component reflected by associated markers such as serum C-reactive protein (CRP) levels. Circulating CRP levels have also been associated with adipose tissue as well as with specific CRP genotypes. We examined the interaction between measures of body mass index (BMI), waist circumference and fat percent (total fat measured by bioimpedance) with genotypes of the CRP gene in the determination of CRP levels. METHODS: The first 2296 participants (mean age 76+/-6 years, 42% men) in the Age, Gene/Environment Susceptibility-Reykjavik Study, a multidisciplinary epidemiological study to determine risk factors in aging, were genotyped for 10 single nucleotide polymorphisms (SNPs) in the CRP gene. General linear models with age and terms for interaction of CRP genotypes with BMI, waist circumference and percent fat were used to evaluate the association of genotypes to CRP levels (high-sensitivity method, range 0-10 mg l(-1)) in men and women separately. RESULTS: We focused on the SNP rs1205 that represents the allele that captures the strongest effects of the gene on CRP levels. Carriers of the rs1205 G allele had significantly higher CRP levels than noncarriers in a dose-dependent manner. Compared to the AA genotype, the slope of the increase in CRP with increasing BMI (P=0.045) and waist circumference (P=0.014) was different for the G allele carriers and of similar magnitude in both men and women. The rs1205 interactions were not significant for fat mass percent, suggesting a possible association with fat localization. CONCLUSIONS: This study further illuminates the known association between measures of adiposity and CRP levels and is shown to be dependent on variation in the rs1205 SNP of the CRP gene. The correlated increase in CRP levels with adiposity is accentuated by presence of the G allele.

Hand osteoarthritis in older women is associated with carotid and coronary atherosclerosis: the AGES Reykjavik study.

OBJECTIVE: There is evidence that atherosclerosis may contribute to the initiation or progression of osteoarthritis. To test this hypothesis, the presence and severity of hand osteoarthritis (HOA) was compared with markers of atherosclerotic vascular disease in an elderly population. PATIENTS AND METHODS: The AGES Reykjavik Study is a population-based multidisciplinary study of ageing in the elderly population of Reykjavik. In a study of 2264 men (mean age 76 years; SD 6) and 3078 women (mean age 76 years; SD 6) the severity of HOA, scored from photographs, was compared with measures of atherosclerosis. These included carotid intimal thickness and plaque severity, coronary calcifications (CAC) and aortic calcifications and reported cardiac and cerebrovascular events. RESULTS: After adjustment for confounders, both carotid plaque severity and CAC were significantly associated with HOA in women, with an odds ratio of 1.42 (95% CI 1.14 to 1.76, p = 0.002) for having CAC and 1.25 (95% CI 1.04 to 1.49, p = 0.016) for having moderate or severe carotid plaques. Both carotid plaques and CAC also exhibited significant linear trends in relation to HOA severity in women in the whole AGES Reykjavik cohort (p<0.001 and p = 0.027, respectively, for trend). No significant associations were seen in men. Despite this evidence of increased atherosclerosis, women with HOA did not report proportionally more previous cardiovascular or cerebrovascular events. CONCLUSIONS: The results indicate a linear association between the severity of HOA and atherosclerosis in older women. The pathological process of HOA seems to have some components in common with atherosclerosis. Prospective studies may help elucidate the possible mechanisms of this relationship.

High hand joint mobility is associated with radiological CMC1 osteoarthritis: the AGES-Reykjavik study.

OBJECTIVE: Previous studies have indicated that joint hypermobility may affect the development of clinical and radiological hand osteoarthritis (OA), but this question has not been addressed in epidemiological studies. Our objective was to investigate this relationship in a population-based study. PATIENTS AND METHODS: The study group consisted of 384 unselected older participants in the Age, Gene/Environment Susceptibility-Reykjavik Study (161 males, median age 76, range 69-90, and 223 females median age 75, range 69-92). The criterion used for joint mobility was the single maximal degree of hyperextension of digits 2 and 5 on both hands (HYP degrees). RESULTS: HYP degrees was more prevalent in females and on the left hand in both men and women. Both genders had a positive association between the degree of mobility measured by HYP degrees and radiological scores for the first carpometacarpal joint (CMC1) OA. Thus, those with HYP degrees >or=70 had an odds ratio of 3.05 (1.69-5.5, P<0.001) of having a Kellgren-Lawrence score of >or=3 in a CMC1 joint. There was also a trend towards a negative association between HYP degrees and proximal interphalangeal joint scores. CONCLUSION: Hand joint mobility, defined as hyperextension in the metacarpophalangeal joints (HYP degrees ) is more prevalent in females and on the left side. It was associated with more severe radiographic OA in the CMC1 joints in this population. The reasons for this relationship are not known, but likely explanations involve ligament laxity and CMC1 joint stability. These findings may relate to the left-sided predominance of radiographic OA in the CMC1 joints observed in many prevalence studies.

Cerebral microbleeds in the population based AGES-Reykjavik study: prevalence and location.

BACKGROUND AND PURPOSE: Incidental foci of signal loss suggestive of cerebral microbleeds (CMBs) are frequent findings on gradient echo T2* weighted MRI (T2* MRI) of patients with haemorrhagic or ischaemic stroke. There are few prevalence data on older populations. This paper reports on the prevalence and location of CMBs in a community based cohort of older men and women (born 1907-1935) who participated in the Age Gene/Environment Susceptibility (AGES)-Reykjavik Study, a population based cohort study that followed the Reykjavik Study METHODS: As part of the examination, all eligible and consenting cohort members underwent a full brain MRI, and blood was drawn for genotyping. Results are based on the first 1962 men (n = 820) and women (n = 1142), mean age 76 years, with complete MRI and demographic information available. RESULTS: Evidence of CMBs was found in 218 participants (11.1% (95% CI 9.8% to 12.6%)); men had significantly more CMBs than women (14.4% vs 8.8%; p = 0.0002, age adjusted). The prevalence of CMBs increased with age (p = 0.0001) in both men (p = 0.006) and women (p = 0.007). CMBs were located in the cerebral lobes (70%), the basal ganglia region (10.5%) and infratentorium (18.6%). Having a CMB was significantly associated with a homozygote Apo E epsilon4epsilon4 genotype (p = 0.01). CONCLUSION: Cerebral microbleeds are common in older persons. The association with homozygote Apo E epsilon4 genotype and finding a relative predominance in the parietal lobes might indicate an association with amyloid angiopathy.

Associations between Proportion of Plasma Phospholipid Fatty Acids, Depressive Symptoms and Major Depressive Disorder. Cross-Sectional Analyses from the AGES Reykjavik Study.

BACKGROUND: Deficits in n-3 fatty acids may be associated with depression. However, data are scarce from older adults who are at greater risk of poor dietary intake and of developing depression. OBJECTIVE: To investigate proportion of plasma phospholipid fatty acids with respect to depressive symptoms and major depressive disorder in community dwelling older adults. METHODS: Cross-sectional analyses of 1571 participants in the Age, Gene/Environment Susceptibility (AGES)-Reykjavik Study aged 67-93 years. Depressive symptoms were measured using the 15-item Geriatric Depression Scale (GDS-15). Major depressive disorder was assessed according to Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) criteria using the Mini-International Neuropsychiatric Interview (MINI). RESULTS: Depressive symptoms were observed in 195 (12.4%) subjects and there were 27 (1.7%) cases of major depressive disorder. Participants with depressive symptoms were less educated, more likely to be smokers, less physically active and consumed cod liver oil less frequently. Difference in GDS-15 scores by tertiles of n-3 fatty acid proportion was not significant. Proportion of long chain n-3 fatty acids (Eicosapentaenoic- + Docosahexaenoic acid) were inversely related to major depressive disorder, (tertile 2 vs. tertile 1) OR: 0.31 (95% CI: 0.11, 0.86); tertile 3 vs. tertile 1, OR: 0.45 (95% CI: 0.17, 1.21). CONCLUSION: In our cross sectional analyses low proportions of long chain n-3 fatty acids in plasma phospholipids appear to be associated with increased risk of major depressive disorder. However, the results from this study warrant further investigation in prospective setting with sufficiently long follow-up.

15q11.2 CNV affects cognitive, structural and functional correlates of dyslexia and dyscalculia.

Several copy number variants have been associated with neuropsychiatric disorders and these variants have been shown to also influence cognitive abilities in carriers unaffected by psychiatric disorders. Previously, we associated the 15q11.2(BP1-BP2) deletion with specific learning disabilities and a larger corpus callosum. Here we investigate, in a much larger sample, the effect of the 15q11.2(BP1-BP2) deletion on cognitive, structural and functional correlates of dyslexia and dyscalculia. We report that the deletion confers greatest risk of the combined phenotype of dyslexia and dyscalculia. We also show that the deletion associates with a smaller left fusiform gyrus. Moreover, tailored functional magnetic resonance imaging experiments using phonological lexical decision and multiplication verification tasks demonstrate altered activation in the left fusiform and the left angular gyri in carriers. Thus, by using convergent evidence from neuropsychological testing, and structural and functional neuroimaging, we show that the 15q11.2(BP1-BP2) deletion affects cognitive, structural and functional correlates of both dyslexia and dyscalculia.

Cholesteryl ester transfer protein TaqIB variant, high-density lipoprotein cholesterol levels, cardiovascular risk, and efficacy of pravastatin treatment: individual patient meta-analysis of 13,677 subjects.

BACKGROUND: Several studies have reported that the cholesteryl ester transfer protein (CETP) TaqIB gene polymorphism is associated with HDL cholesterol (HDL-C) levels and the risk of coronary artery disease (CAD), but the results are inconsistent. In addition, an interaction has been implicated between this genetic variant and pravastatin treatment, but this has not been confirmed. METHODS AND RESULTS: A meta-analysis was performed on individual patient data from 7 large, population-based studies (each >500 individuals) and 3 randomized, placebo-controlled, pravastatin trials. Linear and logistic regression models were used to assess the relation between TaqIB genotype and HDL-C levels and CAD risk. After adjustment for study, age, sex, smoking, body mass index (BMI), diabetes, LDL-C, use of alcohol, and prevalence of CAD, TaqIB genotype exhibited a highly significant association with HDL-C levels, such that B2B2 individuals had 0.11 mmol/L (0.10 to 0.12, P<0.0001) higher HDL-C levels than did B1B1 individuals. Second, after adjustment for study, sex, age, smoking, BMI, diabetes, systolic blood pressure, LDL-C, and use of alcohol, TaqIB genotype was significantly associated with the risk of CAD (odds ratio=0.78 [0.66 to 0.93]) in B2B2 individuals compared with B1B1 individuals (P for linearity=0.008). Additional adjustment for HDL-C levels rendered a loss of statistical significance (P=0.4). Last, no pharmacogenetic interaction between TaqIB genotype and pravastatin treatment could be demonstrated. CONCLUSIONS: The CETP TaqIB variant is firmly associated with HDL-C plasma levels and as a result, with the risk of CAD. Importantly, this CETP variant does not influence the response to pravastatin therapy.

High incidence of loss of heterozygosity in breast tumors from carriers of the BRCA2 999del5 mutation.

Germ-line mutation in the BRCA2 gene confers an increased risk of breast cancer. An elevation of additional genetic defects in tumors of patients with germ-line mutation in the BRCA2 gene compared with sporadic breast tumors has been reported. To evaluate the nature of the difference, we did detailed mapping of chromosomes 1p, 3p, 6q, 11, 13q, 16q, 17, and 20q, using microsatellite markers. We found that the frequency of loss of heterozygosity was similar at some chromosomal regions in the BRCA2 999del5 and sporadic tumors but significantly different at others. These others include chromosomal arms 3p, 6q, 11p, 11q, 13q, and 17p. Loss of heterozygosity mapping suggests that the same chromosome regions are involved in both tumor groups but at elevated frequencies in BRCA2 999del5 tumors. This higher frequency of genetic aberrations could pinpoint genes that selectively promote tumor progression in individuals predisposed to breast cancer due to the BRCA2 999del5 germ-line mutation. Accumulation of somatic genetic changes during tumor progression may follow a specific and more aggressive pathway of chromosome damage in these individuals.

High prevalence of the 999del5 mutation in icelandic breast and ovarian cancer patients.

Studies on Icelandic breast cancer families have shown that most of them segregate a 999del5 BRCA2 mutation. Here, we report the frequency of the 999del5 BRCA2 mutation in an Icelandic control population and four different groups of cancer patients diagnosed with (a) breast cancer; (b) ovarian cancer; (c) prostate cancer (patients younger than 65 years); and (d) other cancer types. The proportions of individuals carrying the mutation were 0.4% in the control population and in the patient groups 8.5%, 7.9%, 2.7%, and 1.0%, respectively. Our results indicate that BRCA2 confers a very high risk of breast cancer and is responsible for a substantial fraction of breast and ovarian cancer in Iceland, but only a small proportion of other cancers.

High incidence of loss of heterozygosity at chromosome 17p13 in breast tumours from BRCA2 mutation carriers.

Breast tumours from BRCA1 and BRCA2 mutation carriers are genetically instable and display specific patterns of chromosomal aberrations, suggestive of distinct genetic pathways in tumour progression. The frequency of abnormalities affecting chromosome 17p and the TP53 gene was determined in 27 breast tumours from 26 female patients carrying the Icelandic BRCA2 founder mutation (999del5). Loss of heterozygosity (LOH) was detected in 23 of the 27 tumours (85%). The majority of tumours manifesting LOH had lost a large region on 17p, although a more restricted loss, including the TP53 locus was seen in a few tumours. Positive p53 immunostaining was observed in 18 of 26 tumours (69%). However, mutations in the TP53 gene were detected in only three tumours (11%), including a missense (codon 139) and a nonsense mutation (codon 306) in two tumours with moderate p53 expression and a frameshift deletion (codon 182) in a tumour with no detectable p53 expression. Positive p53 immunostaining, mainly weak, was observed in 16 of the 24 tumours (66%) without TP53 mutation. The high frequency of LOH at chromosome 17p13 suggests that one or more genes from this region are involved in the development of BRCA2-induced breast cancer. The frequent finding of weak overexpression of, presumably wild type p53 protein, suggests an alternative mechanism of TP53 involvement specific to these tumours.

Polyunsaturated fatty acids in relation to incident mobility disability and decline in gait speed; the Age, Gene/Environment Susceptibility-Reykjavik Study.

BACKGROUND/OBJECTIVES: Low intake of long chain polyunsaturated fatty acids (PUFAs) are associated with physical disability; however, prospective studies of circulating PUFAs are scarce. We examined associations between plasma phospholipid n-3 and n-6 PUFAs with risk of incident mobility disability and gait speed decline. SUBJECTS/METHODS: Data are from a subgroup of the Age, Gene/Environment Susceptibility-Reykjavik Study, a population-based study of risk factors for disease and disability in old age. In this subgroup (n = 556, mean age 75.1 ± 5.0 years, 47.5% men), plasma phospholipid PUFAs were assessed at baseline using gas chromatography. Mobility disability and usual gait speed were assessed at baseline and after 5.2 ± 0.2 years. Mobility disability was defined as the following: having much difficulty, or being unable to walk 500 m or climb up 10 steps; decline in gait speed was defined as change ⩾ 0.10 m/s. Logistic regression analyses were performed to determine associations between sex-specific s.d. increments in PUFAs with risk of incident mobility disability and gait speed decline. Odds ratios (95% confidence intervals) adjusted for demographics, follow-up time, risk factors and serum vitamin D were reported. RESULTS: In women, but not men, every s.d. increment increase of total n-3 PUFAs and docosahexaenoic acid (DHA) was associated with lower mobility disability risk, odds ratio 0.48 (0.25; 0.93) and odds ratio 0.45 (0.24; 0.83), respectively. There was no association between n-6 PUFAs and the risk of incident mobility disability or gait speed decline. CONCLUSIONS: Higher concentrations of n-3 PUFAs and, particularly, DHA may protect women from impaired mobility but does not appear to have such an effect in men.

Chromosome imbalance at the 3p14 region in human breast tumours: high frequency in patients with inherited predisposition due to BRCA2.

Our previous studies have indicated that genetic aberrations in the 3p14 region are more frequent in malignant tumours from hereditary breast cancer patients than sporadic breast cancers. The main purpose of this study was to test if BRCA2 susceptibility alleles contribute to imbalance in the 3p14 region. We mapped allelic imbalance at 3p14 in tumours from Icelandic sisters affected with breast cancer using a set of 10 microsatellite markers (tel-D3S1295-D3S1234-D3S1300-D3S1600-D3S1233+ ++-D3S1217-D3S1261-D3S1296-D3S1210- D3S1284-cen). The patients were of known carrier status with respect to the 999del5 mutation in BRCA2 which is the most common cause of hereditary breast cancer in Iceland. Of 103 patients, 32 in the group were mutation carriers. A high degree of imbalance was observed in tumours from BRCA2 mutation carriers, ranging from 44 to 88% for individual markers. This was significantly higher than the percentage of imbalance in tumours from non-carriers, where the frequency ranged from 25 to 43%. In both groups, we noted elevated 3p14 imbalance in patients with bilateral disease. Allelic imbalance was most commonly observed near the marker D3S1210 (3p14.1-p12) and the FHIT gene (3p21.1-p14.2) for both groups. We conclude that genomic aberrations in 3p14 are especially frequent in tumours with BRCA2 gene defects, and suggest that this is caused by regional loss of chromosome stability rather than selection.

Mapping loss of heterozygosity at chromosome 13q: loss at 13q12-q13 is associated with breast tumour progression and poor prognosis.

Several chromosome regions exhibit loss of heterozygosity (LOH) in human breast carcinoma and are thought to harbour tumour suppressor genes (TSG). At chromosome 13q, two TSGs have been identified, RB1 at 13q14 and BRCA2 at 13q12-q13. In this study, 139 sporadic breast tumours were analysed with 18 polymorphic microsatellite markers for detailed mapping of LOH at chromosome 13q and evaluation of an association with known progression factors. LOH with at least one marker was observed in 71 (51%) of the tumours analysed. The deletion mapping indicated three LOH target regions, 13q12-q13, 13q14 and 13q31-q34. LOH at chromosome 13q12-q13 was associated with low progesterone receptor content, a high S phase fraction and aneuploidy. Multivariate analysis adjusting for lymph node involvement and S phase fraction showed that patients with tumours exhibiting LOH at 13q12-q13 have a 3-4-fold increased risk of recurrence and death compared with other patients. Our results suggest there are at least three separate LOH target regions at chromosome 13q and inactivation of one or more genes at chromosome 13q12-q13 results in poor prognosis for breast cancer patients.

The -629C>A polymorphism in the CETP gene does not explain the association of TaqIB polymorphism with risk and age of myocardial infarction in Icelandic men.

The aim of this study was to examine whether the well-established effect of the common TaqIB polymorphism in intron 1 of the gene for cholesterol ester transfer protein (CETP) on high density lipoprotein cholesterol (HDL-C) concentration and increased risk of myocardial infarction (MI), could be explained by the recently identified -629C>A functional polymorphism in the promoter. Non-fatal MI cases (388 male) and a control group of 794 healthy men were recruited from the 30 year long prospective Reykjavik Study. In the healthy men the frequency of the TaqIB B2 allele was 0.47 (95% CI: 0.44-0.50) and there was a strong allelic association with the -629A allele (D=-0.21, P<0.0001), which had a frequency of 0.52 (95% CI: 0.49-0.56). B2B2 homozygotes displayed 15% higher HDL-C levels than subjects homozygous for the B1 allele (P<0.0001). Homozygotes for the -629A allele displayed 14% higher HDL-C concentrations than subjects homozygous for the -629C allele (P<0.0001). The frequencies of the alleles associated with lower HDL-C were significantly higher in cases compared with controls, 0.59 versus 0.53 (TaqIB B1) and 0.52 versus 0.48 (-629 C) respectively (P<0.05 for both). There was a significantly higher risk for MI in B1B1 homozygotes (OR=1.44, 95% CI: 1.10-1.87, P<0.01), compared to the other genotypes combined. This was not observed for the CC homozygotes (OR=1.16, 95% CI: 0.87-1.54). In addition, homozygotes for the TaqI B2 allele experienced a first MI 2 years later than men with other genotypes, 59 versus 61 years (P<0.05). This effect was not seen for the promoter polymorphism. These results strongly confirm the role of the CETP gene and the TaqIB variant as a risk factor for MI and suggest that another functional polymorphism is yet to be discovered in the CETP gene, that will explain the effect on MI associated with TaqIB observed in this study.