Early life residency associated with the risk of developing type 2 diabetes - the population-based Reykjavík study

Neðst á síðunni er hægt að nálgast greinina í heild sinni með því að smella á hlekkinn View/OpenInngangur: Kyrrseta og ofneysla orkuríkrar fæðu tengjast aukinni áhættu á að fá sykursýki af tegund 2 en áhrif aðbúnaðar í uppvexti á slíka áhættu síðar á ævinni hafa lítt verið athuguð. Tilgangur þessarar rannsóknar var að kanna tengsl búsetu í dreifbýli fyrstu 20 æviárin við áhættu á að fá sykursýki 2 miðað við búsetu í Reykjavík frá fæðingu. Efniviður og aðferðir: Í lýðgrunduðu þýði 17.811 karla (48%) og kvenna, meðalaldur 53 ár (aldursbil 33-81), sem tóku þátt í Reykjavíkurrannsókn Hjartaverndar á árunum 1967-1991, bjuggu 29% í sveit og 35% í sjávarþorpum að meðaltali í 20 ár áður en þeir fluttu til Reykjavíkur, en 36% bjuggu í Reykjavík frá fæðingu. Reiknuð var hlutfallsleg áhætta á að fá sykursýki 2 eftir búsetu. Niðurstöður: Hlutfallsleg áhætta á að fá sykursýki 2 var 43% lægri í körlum (RR 0,57; 95% CI 0,43-0,77) og 26% lægri í konum (RR 0,74; 95% CI 0,56-0,99) sem bjuggu í sveit fyrstu 20 ár ævinnar í samanburði við þá sem bjuggu í Reykjavík frá fæðingu. Hið lága algengi meðal þeirra sem ólust upp í sveit fannst bæði í aldurshópunum 55-64 ára og 65 ára og eldri. Ályktanir: Niðurstöður okkar benda til þess að þeir sem bjuggu í sveit á fyrri hluta 20. aldar á Íslandi voru í minni hættu á að fá sykursýki 2 síðar á ævinni, en jafnaldrar þeirra sem bjuggu í Reykjavík frá fæðingu. Við vörpum fram þeirri tilgátu að aðbúnaður snemma á ævinni hafi langvarandi áhrif á sykurefnaskipti líkamans.Sedentary lifestyle and energy rich food have been associated with the risk of developing type 2 diabetes; limited data are available on environmental conditions in childhood on this risk later in life. The objective was to study if residency in the first 20 years of life affected the risk of developing type 2 diabetes. In a cohort of 17811 men (48%) and women, mean age 53 years (range 33-81) participating in the population-based Reykjavík Study from 1967-91, 29% grew up in rural and 35% in coastal areas for an average of 20 years before moving to urban Reykjavík, but 36% lived in Reykjavík from birth. The prevalence of type 2 diabetes according to residency in early life was examined. The relative risk of developing type 2 diabetes was 43% lower in men (RR 0.57; 95% CI 0.43-0.77) and 26% lower (RR 0.74; 95% CI 0.56-0.99) in women living in rural areas for the first 20 years of their life compared with those living in urban Reykjavík from birth. The low prevalence among those that grew up in rural areas was maintained through the age categories of 55-64 years and 65 years and older. Our findings indicate that persons growing up in rural areas in early 20th century Iceland had lower risk of developing type 2 diabetes later in life when compared with peers living in Reykjavík from birth. We postulate a prolonged effect of early development on glucose metabolism and risk of developing type 2 diabetes

Large scale international replication and meta-analysis study confirms association of the 15q14 locus with myopia. The CREAM consortium

Myopia is a complex genetic disorder and a common cause of visual impairment among working age adults. Genome-wide association studies have identified susceptibility loci on chromosomes 15q14 and 15q25 in Caucasian populations of European ancestry. Here, we present a confirmation and meta-analysis study in which we assessed whether these two loci are also associated with myopia in other populations. The study population comprised 31 cohorts from the Consortium of Refractive Error and Myopia (CREAM) representing 4 different continents with 55,177 individuals; 42,845 Caucasians and 12,332 Asians. We performed a meta-analysis of 14 single nucleotide polymorphisms (SNPs) on 15q14 and 5 SNPs on 15q25 using linear regression analysis with spherical equivalent as a quantitative outcome, adjusted for age and sex. We calculated the odds ratio (OR) of myopia versus hyperopia for carriers of the top-SNP alleles using a fixed effects meta-analysis. At locus 15q14, all SNPs were significantly replicated, with the lowest P value 3.87 × 10 -12 for SNP rs634990 in Caucasians, and 9.65 × 10 -4 for rs8032019 in Asians. The overall meta-analysis provided P value 9.20 × 10 -23 for the top SNP rs634990. The risk of myopia versus hyperopia was OR 1.88 (95 % CI 1.64, 2.16, P < 0.001) for homozygous carriers of the risk allele at the top SNP rs634990, and OR 1.33 (95 % CI 1.19, 1.49, P < 0.001) for heterozygous carriers. SNPs at locus 15q25 did not replicate significantly (P value 5.81 × 10 -2 for top SNP rs939661). We conclude that common variants at chromosome 15q14 influence susceptibility for myopia in Caucasian and Asian populations world-wide. © The Author(s) 2012

Loss of heterozygosity at chromosome 1p in human breast cancer: Association with high S-phase, reduced patient survival and deletions at other chromosome regions

232 human primary invasive breast tumors were analyzed with 13 polymorphic microsatellite markers specific to chromosome 1p. Loss of heterozygosity (LOH) was observed in 126 cases or 54% of the tumors. One marker, D1S496, at the 1p35 region showed the highest LOH, 28%. High frequencies of LOH were also detected by the markers, D1S488, D1S167 and D1S435, at the 1p31 region, 25%, 24% and 26% LOH, respectively. This suggests the presence of tumor suppressor genes at these two regions. Tumors with and without LOH at 1p were tested for association with clinico-pathological features of the tumors such as estrogen- and progesterone-receptor content (ER and PgR), age at diagnosis, tumor size, node status, histological type, S-phase fraction, ploidy, survival and LOH at chromosomes 3p, 6q, 9p, 11p, 11q, 13q, 16q, 17p and 17q. A significant association was found between LOH at chromosome 1p and high S-phase fraction and lower survival rate. Association was also found between LOH at 1p and chromosome regions 3p, 6q, 9p and 17q. A multivariate model including prognostic variables, showed that LOH at 1p is an independent prognostic variable and patients who have breast tumors with LOH at 1p have approximately a two-fold increase in relative risk of death. We conclude that screening for 1p deletions gives additional prognostic information that might be useful in breast cancer treatment.This work was financially supported by the University of Iceland Graduate Research fund, the Icelandic Research Council and the Nordic Council of Ministers

Linkage analysis and allelic imbalance in human breast cancer kindreds using microsatellite markers from the short arm of chromosome 3

Eight Icelandic breast cancer kindreds were subjected to linkage analyses with respect to 28 microsatellite loci dispersed along the short arm of chromosome 3. Breast tumors derived from these kindreds were concurrently scored for allelic imbalance with ten of the markers. Linkage to most markers could be excluded on the basis of negative LOD scores and haplotype analyses, although some moderately positive LOD scores resulted. A high frequency of imbalance in the familial tumors was seen with two of the markers in comparison with results obtained from sporadic material. The highest frequency (68%) of imbalance was detected with the marker D3S1217, which is located on 3p14.2-p14.1. Imbalance at the D3S1211 locus, which is more telomeric (3p24.2-p22), was not significantly elevated in the familial tumors. We suggest that the genetic defect responsible for breast cancer susceptibility in these families either promotes instability in the 3p14.2-p14.1 region or enhances the selective advantage of such changes.The Nordic primer bank that provided the microsatellite markers is supported by the Nordic Council of Ministers. This work was supported by the Nordic Cancer Union, Icelandic Cancer Society, the Science Fund of Iceland, the University of Iceland Research Fund the Science Fund of the University Hospital of Iceland and the Memorial Fund of Bergthora Magnusdottir and Jakob B. Bjarnason

Dietary supplement use in the older population of Iceland and association with mortality.

Dietary supplements are often used by the elderly to improve their nutritional status. However, intake above the recommended dietary levels may be detrimental, and uncertainty exists on the potential health benefits of supplementation in this population. The aim of this study was to describe supplement use among Icelandic older adults and to assess its association with total mortality and CVD-related mortality. This study used data from the Age Gene/Environment Susceptibility-Reykjavik study, which recruited 5764 participants aged 66-98 years in 2002-2006. Intake of vitamins and minerals from dietary supplements was estimated from interviews. Hazard ratios (HR) for mortality were estimated in multivariate analyses with follow-up ending in 2009. The results showed that most (77 %) of the participants used supplements. Overall, the consumption of vitamins and minerals from supplements was moderate although 22 and 14 % of users exceeded the upper recommended intake levels for vitamin B6 and Zn, respectively. Supplement users followed in general a healthier lifestyle than non-users. There were 1221 deaths including 525 CVD-related deaths during the follow-up period. When comparing multivitamin users with non-users in multivariable models, no associations with total mortality (HR 0·91; 95 % CI: 0·77, 1·08) or CVD-related mortality (HR 0·91; 95 % CI 0·70, 1·18) were observed. In conclusion, users of supplements generally lead healthier lifestyles than non-users and supplements did not confer any added advantage or harm relative to mortality risk. However, the intake of vitamin B6 and Zn from dietary supplements exceeded the recommended daily intake for almost a quarter of the supplement users.University of Iceland Research Fun

Loss of heterozygosity at chromosome 11 in breast cancer: Association of prognostic factors with genetic alterations

We examined DNA from 116 female and four male breast cancer patients for loss of heterozygosity (LOH). DNA was analysed by polymerase chain reaction using ten microsatellite markers on chromosome 11. Three distinct regions of LOH were identified: 11p15.5, 11q13 and 11q22-qter with a LOH frequency of 19, 23 and 37-43% respectively. The marker D11S969 showing the highest frequency of LOH (43%) is located at the 11q24.1-q25 region. No previous molecular genetic studies have shown frequent LOH at the region telomeric to q23 on chromosome 11. Southern analysis revealed that LOH at 11q13 was due to amplification, whereas LOH at 11q22-qter was due to deletion. LOH at 11p15.5 was associated with paucity of hormone receptor proteins, high S-phase and positive node status. An association was found between LOH at 11q13 and positive node status. LOH at the 11q22-qter region correlated with a high S-phase fraction. A significant association was found between LOH at 11p15 and chromosome regions 17q21 (the BRCA1 region) and 3p.Nordic Council of Ministers, University of Iceland Graduate Research Fund, the Nordic Cancer Union, the Icelandic Cancer Society, the Memorial Fund of Bergthora Magnusdottir and Jakob B Bjarnason, the Science Fund of Iceland and the Science Fund of the University Hospital of Iceland

Loss of heterozygosity at chromosome 6q correlates with tumor progression and patient survival

Several chromosome regions exhibit loss of heterozygosity (LOH) in human breast carcinoma and are thought to carry tumor suppressor genes. We have analysed human breast tumors with 9 polymorphic microsatellite markers that are specific to chromosome 6q. The mapping of smallest region of overlap (SRO) indicated location of candidate suppressor genes at 6q23 and 6q27. Variations in estrogen receptor (ER) expression were independent of the number of copies of the corresponding gene. Tumors with and without LOH on chromosome 6q were tested for association with clinicopathological factors. A significant association was found between LOH at 6q and the following: high S-phase, aneuploidy, deletions at chromosomes 3p and 9p and lower survival rate. In a multivariate model LOH at 6q is an independent prognostic variable and patients having tumors with LOH have approximately twofold increase in relative risk of death. It can be concluded that the 6q deletions give additional prognostic information that might be useful in breast cancer treatment.The Nordic primer bank that provided the microsatellite markers is supported by the Nordic Council of Ministers. This work was supported by the Students' innovation fund, Nordic Cancer Union, Icelandic Cancer Society, the Science Fund of Iceland, the Science Fund of the University Hospital of Iceland and the Memorial Fund of Bergthora Magnusdottir and Jakob B. Bjarnason

High frequency of LOH at chromosome 18q in human breast cancer: Association with high S-phase fraction and low progesterone receptor content

Human primary breast cancers were analysed for somatic loss of heterozygosity (LOH) at chromosome 18 with 15 polymorphic microsatellite markers. LOH was observed in 148 of the 228 cases analyzed (65%). Three smallest common deletion regions (SCDR) were detected on the long arm of chromosome 18. The marker D18S51 at the region 18q22 showed the highest LOH (42%). Tumors with and without LOH at 18q were tested for association with clinico-pathological features of the tumors, such as estrogen and progesterone receptor content, age at diagnosis, tumor size, node status, histological type, S-phase fraction DNA ploidy and LOH at other chromosomal regions. A significant association was found between LOH at 18q and high S-phase fraction (99.9% confidence interval) and low progesterone receptor. content (99%, confidence interval). Furthermore, an association was found between LOH at 18q and LOH at 1p, 7q, 9p, 13q and 17q. We conclude that there are three separate LOH target regions at chromosome 18q and that inactivation of one or. mole genes at these regions might be important for human breast carcinogenesis.The Icelandic Research Council and the Icelandic Cancer Societ

Replication error in human breast cancer: Comparison with clinical variables and family history of cancer

Replication errors (RER) at microsatellite repeats indicate genomic instability in hereditary nonpolyposis colorectal cancer (HNPCC) and in some sporadic cancers. We have studied genomic instability in 313 sporadic breast tumors and in 106 tumors from BRCA2, 999del5 carriers at 43 genomic loci on 13 chromosomes. RER was observed in 8/419 (1.9%) of the cases at one or more chromosomal loci. The frequencies of type I and type II RER were similar. The majority of RER+ tumors showed ER+, PgR+, high S-phase fraction, tumor size >2 cm and LOH at 2p, 2q and 3p. All 8 RER+ tumors were of the ductal histotype. The breast cancer cases with RER are not part of an HNPCC syndrome and a family history of colorectal cancer growth is not detected in relatives, with the exception of one case. However, four of the RER+ cases are from individuals carrying the BRCA2, 999del5 mutation. We conclude that RER is a rare somatic event during human breast carcinogenesis and may be associated with progression of breast carcinomas.The Icelandic Research Council, The University of Iceland Science fund and The Icelandic Cancer Societ

Chromosome alterations and E-cadherin gene mutations in human lobular breast cancer

We have studied a set of 40 human lobular breast cancers for loss of heterozygosity (LOH) at various chromosome locations and for mutations in the coding region plus flanking intron sequences of the E-cadherin gene. We found a high frequency of LOH (100%, 31/31) at 16q21-q22.1. A significantly higher level of LOH was detected in ductal breast tumours at chromosome arms 1p, 3p, 9p, 11q, 13q and 18q compared to lobular breast tumours. Furthermore, we found a significant association between LOH at 16q containing the E-cadherin locus and lobular histological type. Six different somatic mutations were detected in the E-cadherin gene, of which three were insertions, two deletions and one splice site mutation. Mutations were found in combination with LOH of the wild type E-cadherin locus and loss of or reduced E-cadherin expression detected by immunohistochemistry. The mutations described here have not previously been reported. We compared LOH at different chromosome regions with E-cadherin gene mutations and found a significant association between LOH at 13q and E-cadherin gene mutations. A significant association was also detected between LOH at 13q and LOH at 7q and 11q. Moreover, we found a significant association between LOH at 3p and high S phase, LOH at 9p and low ER and PgR content, LOH at 17p and aneuploidy. We conclude that LOH at 16q is the most frequent chromosome alteration and E-cadherin is a typical tumour suppressor gene in lobular breast cancer.The Icelandic Research Council and the Icelandic Cancer Societ