| 1. |
- Estrada, Karol, et al.
(författare)
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Genome-wide meta-analysis identifies 56 bone mineral density loci and reveals 14 loci associated with risk of fracture.
- 2012
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Ingår i: Nature genetics. - 1546-1718. ; 44:5, s. 491-501
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Tidskriftsartikel (refereegranskat)abstract
- Bone mineral density (BMD) is the most widely used predictor of fracture risk. We performed the largest meta-analysis to date on lumbar spine and femoral neck BMD, including 17 genome-wide association studies and 32,961 individuals of European and east Asian ancestry. We tested the top BMD-associated markers for replication in 50,933 independent subjects and for association with risk of low-trauma fracture in 31,016 individuals with a history of fracture (cases) and 102,444 controls. We identified 56 loci (32 new) associated with BMD at genome-wide significance (P < 5 × 10(-8)). Several of these factors cluster within the RANK-RANKL-OPG, mesenchymal stem cell differentiation, endochondral ossification and Wnt signaling pathways. However, we also discovered loci that were localized to genes not known to have a role in bone biology. Fourteen BMD-associated loci were also associated with fracture risk (P < 5 × 10(-4), Bonferroni corrected), of which six reached P < 5 × 10(-8), including at 18p11.21 (FAM210A), 7q21.3 (SLC25A13), 11q13.2 (LRP5), 4q22.1 (MEPE), 2p16.2 (SPTBN1) and 10q21.1 (DKK1). These findings shed light on the genetic architecture and pathophysiological mechanisms underlying BMD variation and fracture susceptibility.
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| 2. |
- Lindkvist, Björn, et al.
(författare)
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Prospective cohort study of metabolic risk factors and gastric adenocarcinoma risk in the Metabolic Syndrome and Cancer Project (Me-Can)
- 2013
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Ingår i: Cancer Causes and Control. - 0957-5243. ; 24:1, s. 107-116
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: Little is known about the association between the metabolic syndrome (MetS) and the risk of gastric adenocarcinoma. The aim of this study was to investigate whether metabolic risk factors, together or combined, were associated with the risk of gastric adenocarcinoma. Methods: The Metabolic Syndrome and Cancer Project (Me-Can) is a pooling of prospective cohorts in Austria, Norway, and Sweden with information on blood pressure, lipids, glucose, and BMI available in 578,700 individuals. Cox proportional hazards analysis was used to calculate hazard ratio (HR) of gastric adenocarcinoma using metabolic risk factors categorized into quintiles and transformed into z-scores (with mean = 0 and SD = 1). The standardized sum of all z-scores created a composite MetS score. Results: In total, 1,210 incident cases of gastric adenocarcinoma were identified. Glucose was significantly associated with the risk of gastric adenocarcinoma [calibrated HR 1.58 (1.14-2.20) per one unit increment in z-score] in women. There was a statistically significant association between triglycerides and risk of gastric adenocarcinoma per mmol increment in triglycerides [HR 1.20 (1.06-1.36) per mmol] but not for the adjusted z-score in women. There were no significant association between any metabolic factors and gastric cancer among men. The composite MetS score was associated with the risk of gastric adenocarcinoma in women [HR 1.18 (1.00-1.38) per one unit increment in z-score] but not in men. Conclusions: Glucose and high levels of the composite MetS score were associated with an increased risk of gastric adenocarcinoma in women but not in men.
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| 3. |
- van Meurs, Joyce B J, et al.
(författare)
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Large-scale analysis of association between LRP5 and LRP6 variants and osteoporosis.
- 2008
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Ingår i: JAMA : the journal of the American Medical Association. - 1538-3598. ; 299:11, s. 1277-90
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Tidskriftsartikel (refereegranskat)abstract
- Context: Mutations in the low-density lipoprotein receptor–related protein 5 (LRP5) gene cause rare syndromes characterized by altered bone mineral density (BMD). More common LRP5 variants may affect osteoporosis risk in the general population.Objective: To generate large-scale evidence on whether 2 common variants ofLRP5 (Val667Met, Ala1330Val) and 1 variant of LRP6 (Ile1062Val) are associated with BMD and fracture risk.Design and Setting: Prospective, multicenter, collaborative study of individual-level data on 37 534 individuals from 18 participating teams in Europe and North America. Data were collected between September 2004 and January 2007; analysis of the collected data was performed between February and May 2007. Bone mineral density was assessed by dual-energy x-ray absorptiometry. Fractures were identified via questionnaire, medical records, or radiographic documentation; incident fracture data were available for some cohorts, ascertained via routine surveillance methods, including radiographic examination for vertebral fractures.Main Outcome Measures: Bone mineral density of the lumbar spine and femoral neck; prevalence of all fractures and vertebral fractures.Results: The Met667 allele of LRP5 was associated with reduced lumbar spine BMD (n = 25 052 [number of participants with available data]; 20-mg/cm2 lower BMD per Met667 allele copy; P = 3.3 × 10−8), as was the Val1330 allele (n = 24 812; 14-mg/cm2 lower BMD per Val1330 copy; P = 2.6 × 10−9). Similar effects were observed for femoral neck BMD, with a decrease of 11 mg/cm2(P = 3.8 × 10−5) and 8 mg/cm2 (P = 5.0 × 10−6) for the Met667 and Val1330 alleles, respectively (n = 25 193). Findings were consistent across studies for bothLRP5 alleles. Both alleles were associated with vertebral fractures (odds ratio [OR], 1.26; 95% confidence interval [CI], 1.08-1.47 for Met667 [2001 fractures among 20 488 individuals] and OR, 1.12; 95% CI, 1.01-1.24 for Val1330 [1988 fractures among 20 096 individuals]). Risk of all fractures was also increased with Met667 (OR, 1.14; 95% CI, 1.05-1.24 per allele [7876 fractures among 31 435 individuals)]) and Val1330 (OR, 1.06; 95% CI, 1.01-1.12 per allele [7802 fractures among 31 199 individuals]). Effects were similar when adjustments were made for age, weight, height, menopausal status, and use of hormone therapy. Fracture risks were partly attenuated by adjustment for BMD. Haplotype analysis indicated that Met667 and Val1330 variants both independently affected BMD. The LRP6Ile1062Val polymorphism was not associated with any osteoporosis phenotype. All aforementioned associations except that between Val1330 and all fractures and vertebral fractures remained significant after multiple-comparison adjustments.Conclusions: Common LRP5 variants are consistently associated with BMD and fracture risk across different white populations. The magnitude of the effect is modest. LRP5 may be the first gene to reach a genome-wide significance level (a conservative level of significance [herein, unadjusted P < 10−7] that accounts for the many possible comparisons in the human genome) for a phenotype related to osteoporosis.
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| 4. |
- Nyholm, Maria, et al.
(författare)
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Exploring dietary patterns, obesity and sources of bias: the Västerbotten Intervention Programme (VIP).
- 2013
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Ingår i: Public Health Nutrition. ; 16:4, s. 631-638
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: Dietary patterns capture the overall diet and thereby provide information on how nutrients are consumed in combinations, and have been suggested to be a better method than studying single nutrients. The present study explored the relationship between dietary patterns at baseline and incidence of obesity at 10-year follow-up in women.DESIGN: A longitudinal study using baseline measurements from 1992-1996, including food intake, medication, heredity, socio-economic status, lifestyle and measured body composition, and follow-up data collected in 2002-2006 including measured body composition.SETTING: Data from the Västerbotten Intervention Programme (VIP) in Sweden. SUBJECTS: A total of 6545 initially non-obese women aged 30-50 years.RESULTS: Among women reporting plausible energy intakes, the 'Fruit and vegetables cluster' predicted the highest incidence of obesity (OR = 1·76, 95 % CI 1·11, 2·76; P = 0·015) compared with women in the other food pattern groups combined. When adjusting for metabolic factors and BMI at baseline, the risk for obesity in the 'Fruit and vegetables cluster' was attenuated to non-significance. In contrast, high intake of fruit per se was associated with a decreased risk of developing obesity (OR = 0·69, 95 % CI 0·51, 0·91; P = 0·010).CONCLUSIONS: Dietary pattern groups identified by cluster analysis are likely to reflect characteristics in addition to diet, including lifestyle, previous and current health status and risk factors for future disease, whereas intake of fruit per se was a stable indicator and less affected by baseline characteristics. These results underscore the need for complementary methods in understanding diet-disease relationships.
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| 5. |
- Tognon, Gianluca, et al.
(författare)
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The Mediterranean diet score and mortality are inversely associated in adults living in the subarctic region.
- 2012
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Ingår i: The Journal of nutrition. - 1541-6100. ; 142:8, s. 1547-53
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Tidskriftsartikel (refereegranskat)abstract
- The Mediterranean diet has been widely promoted and may be associated with chronic disease prevention and a better overall health status. The aim of this study was to evaluate whether the Mediterranean diet score inversely predicted total or cause-specific mortality in a prospective population study in Northern Sweden (Vasterbotten Intervention Program). The analyses were performed in 77,151 participants (whose diet was measured by means of a validated FFQ) by Cox proportional hazard models adjusted for several potential confounders. The Mediterranean diet score was inversely associated with all-cause mortality in men [HR = 0.96(95% Cl = 0.93, 0.99)] and women [HR = 0.95 (95% Cl = 0.91, 0.99)], although not in obese men. In men, but not in women, the score was inversely associated with total cancer mortality [HR = 0.92 (95% Cl = 0.87, 0.98)], particularly for pancreas cancer [HR = 0.82 (95% Cl = 0.68, 0.99)]. Cardiovascular mortality was inversely associated with diet only in women [HR = 0.90(95% Cl = 0.82, 0.99)]. Except for alcohol [HR = 0.83(95% Cl = 0.76, 0.90)] and fruit intake [HR = 0.90 (95% Cl = 0.83, 0.98)], no food item of the Mediterranean diet score independently predicted mortality. Higher scores were associated with increasing age, education, and physical activity. Moreover, healthful dietary and lifestyle-related factors additively decreased the mortality likelihood. Even in a subarctic region, increasing Mediterranean diet scores were associated with a longer life, although the protective effect of diet was of small magnitude compared with other healthful dietary and lifestyle-related factors examined. J. Nutr. 142: 1547-1553, 2012.
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| 6. |
- Daka, Bledar, et al.
(författare)
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Low agreement between radio binding assays in analyzing glutamic acid decarboxylase (GAD65Ab) autoantibodies in patients classified with type 2 diabetes.
- 2009
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Ingår i: Autoimmunity. - 1607-842X. ; 42:6, s. 507
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Tidskriftsartikel (refereegranskat)abstract
- Autoantibodies against glutamic acid decarboxylase (GAD65Ab) are used in the classification of diabetes in adults. We assessed the concordance in GAD65 autoantibody levels within subjects between three different GAD65Ab radio binding assays (RBA). Plasma samples from 112 diabetes patients (median age 50 years) initially classified with type 2 diabetes was randomly selected from a local diabetes registry. Coded samples were analyzed with two RBA employing (35)S-labeled GAD65. The first used the pEx9 plasmid (pEx9 RBA), the second employed the pThGAD65 plasmid (pThGAD65 RBA) to label GAD65 by in vitro transcription translation. We also used a commercial kit employing plasmid pGAD17 labelled with (125)I (pGAD17 RBA). Subsequent analyses followed standard procedures. Two different cut-offs for GAD65Ab positivity were used in all three assays. We calculated the correlation, concordance, and agreement between the assays. The proportion of GAD65Ab positivity differed between assays when low cut-offs were used (pEx9 RBA 25%, pThGAD65 RBA 17.9%, and pGAD17 RBA 12.5%, respectively). When high cut-offs were applied, the concordance between the pEx9 RBA and the pThGAD65 RBA was 97.3 while their concordance to the pGAD17 RBA was lower (88.4 and 87.4, respectively). There was a low agreement between both pEx9 RBA and pGAD17 RBA (0.45, 95% CI 0.20-0.70) and between pThGAD65 RBA and pGAD17 RBA (0.43, 95% CI 0.18-0.68). We found discrepancies in determining the GAD65Ab positivity, which constitutes a problem when GAD65Ab are used clinically. Further methodological GAD65Ab assays studies are warranted.
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| 7. |
- Deloukas, Panos, et al.
(författare)
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Large-scale association analysis identifies new risk loci for coronary artery disease
- 2013
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Ingår i: Nature Genetics. - 1061-4036. ; 45:1, s. 25-33
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Tidskriftsartikel (refereegranskat)abstract
- Coronary artery disease (CAD) is the commonest cause of death. Here, we report an association analysis in 63,746 CAD cases and 130,681 controls identifying 15 loci reaching genome-wide significance, taking the number of susceptibility loci for CAD to 46, and a further 104 independent variants (r2 < 0.2) strongly associated with CAD at a 5% false discovery rate (FDR). Together, these variants explain approximately 10.6% of CAD heritability. Of the 46 genome-wide significant lead SNPs, 12 show a significant association with a lipid trait, and 5 show a significant association with blood pressure, but none is significantly associated with diabetes. Network analysis with 233 candidate genes (loci at 10% FDR) generated 5 interaction networks comprising 85% of these putative genes involved in CAD. The four most significant pathways mapping to these networks are linked to lipid metabolism and inflammation, underscoring the causal role of these activities in the genetic etiology of CAD. Our study provides insights into the genetic basis of CAD and identifies key biological pathways.
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| 8. |
- Lundin, Eva, et al.
(författare)
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Selected polymorphisms in sex hormone-related genes, circulating sex hormones and risk of endometrial cancer
- 2012
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Ingår i: Cancer epidemiology. - Elsevier. - 1877-783X. ; 36:5, s. 445-452
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Tidskriftsartikel (refereegranskat)abstract
- Background: The role of estrogen and progesterone in the development of endometrial cancer is well documented. Few studies have examined the association of genetic variants in sex hormone-related genes with endometrial cancer risk. Methods: We conducted a case-control study nested within three cohorts to examine the association of endometrial cancer risk with polymorphisms in hormone-related genes among 391 cases (92% postmenopausal at diagnosis) and 712 individually-matched controls. We also examined the association of these polymorphisms with circulating levels of sex hormones and SHBG in a cross-sectional analysis including 596 healthy postmenopausal women at blood donation (controls from this nested case-control study and from a nested case-control study of breast cancer in one of the three cohorts). Results: Adjusting for endometrial cancer risk factors, the A allele of rs4775936 in CYP19 was significantly associated (OR(per allele)=1.22, 95% CI=1.01-1.47, p(trend)=0.04), while the T allele of rs10046 was marginally associated with increased risk of endometrial cancer (OR(per allele)=1.20, 95% CI=0.99-1.45, p(trend)=0.06). PGR rs1042838 was also marginally associated with risk (OR(per allele)=1.25, 95% CI=0.96-1.61, p(trend)=0.09). No significant association was found for the other polymorphisms, i.e. CYP1B1 rs1800440 and rs1056836, UGT1A1 rs8175347, SHBG rs6259 and ESR1 rs2234693. Rs8175347 was significantly associated with postmenopausal levels of estradiol, free estradiol and estrone and rs6259 with SHBG and estradiol. Conclusion: Our findings support an association between genetic variants in CYP19, and possibly PGR, and risk of endometrial cancer.
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| 9. |
- Manning, Alisa K., et al.
(författare)
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A genome-wide approach accounting for body mass index identifies genetic variants influencing fasting glycemic traits and insulin resistance
- 2012
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Ingår i: Nature Genetics. - New York : Nature Publishing Group. - 1061-4036. ; 44:6, s. 659-669
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Tidskriftsartikel (refereegranskat)abstract
- Recent genome-wide association studies have described many loci implicated in type 2 diabetes (T2D) pathophysiology and beta-cell dysfunction but have contributed little to the understanding of the genetic basis of insulin resistance. We hypothesized that genes implicated in insulin resistance pathways might be uncovered by accounting for differences in body mass index (BMI) and potential interactions between BMI and genetic variants. We applied a joint meta-analysis approach to test associations with fasting insulin and glucose on a genome-wide scale. We present six previously unknown loci associated with fasting insulin at P < 5 x 10(-8) in combined discovery and follow-up analyses of 52 studies comprising up to 96,496 non-diabetic individuals. Risk variants were associated with higher triglyceride and lower high-density lipoprotein (HDL) cholesterol levels, suggesting a role for these loci in insulin resistance pathways. The discovery of these loci will aid further characterization of the role of insulin resistance in T2D pathophysiology.
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| 10. |
- Nagel, Gabriele, et al.
(författare)
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Metabolic factors and blood cancers among 578,000 adults in the metabolic syndrome and cancer project (Me-Can)
- 2012
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Ingår i: Annals of Hematology. - New York : Springer-Verlag New York. - 0939-5555. ; 91:10, s. 1519-1531
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Tidskriftsartikel (refereegranskat)abstract
- We investigated associations between metabolic factors and blood cancer subtypes. Data on body mass index (BMI), blood pressure, blood glucose, total cholesterol, and triglycerides from seven prospective cohorts were pooled (n = 578,700; mean age = 44 years). Relative risks of blood cancers were calculated from Cox regression models. During mean follow-up of 12 years, 2,751 incident and 1,070 fatal cases of blood cancers occurred. Overall, higher BMI was associated with an increased blood cancer risk. In gender-specific subgroup analyses, BMI was positively associated with blood cancer risk (p = 0.002), lymphoid neoplasms (p = 0.01), and Hodgkin's lymphoma (p = 0.02) in women. Further associations with BMI were found for high-grade B-cell lymphoma (p = 0.02) and chronic lymphatic leukemia in men (p = 0.05) and women (p = 0.01). Higher cholesterol levels were inversely associated with myeloid neoplasms in women (p = 0.01), particularly acute myeloid leukemia (p = 0.003), and glucose was positively associated with chronic myeloid leukemia in women (p = 0.03). In men, glucose was positively associated with risk of high-grade B-cell lymphoma and multiple myeloma, while cholesterol was inversely associated with low-grade B-cell lymphoma. The metabolic syndrome score was related to 48 % increased risk of Hodgkin's lymphoma among women. BMI showed up as the most consistent risk factor, particularly in women. A clear pattern was not found for other metabolic factors.
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