Christina Ellervik

CHEK2*1100delC Genotyping for Clinical Assessment of Breast Cancer Risk: Meta-Analyses of 26,000 Patient Cases and 27,000 Controls

PURPOSE CHEK2*1100delC heterozygosity may be associated with an increased risk of breast cancer; however, it is unclear whether the evidence is sufficient to recommend genotyping in clinical practice. PATIENTS AND METHODS We identified studies on CHEK2*1100delC heterozygosity and the risk of unselected, early-onset, and familial breast cancer through comprehensive, computer-based searches of PubMed, EMBASE, and Web of Science. Aggregated risk estimates were compared with previous estimates for BRCA1 and BRCA2 mutation heterozygotes. RESULTS By using fixed-effect models for CHEK2*1100delC heterozygotes versus noncarriers, we found aggregated odds ratios of 2.7 (95% CI, 2.1 to 3.4) for unselected breast cancer, 2.6 (95% CI, 1.3 to 5.5) for early-onset breast cancer, and 4.8 (95% CI, 3.3 to 7.2) for familial breast cancer. For familial breast cancer, this corresponds to a cumulative risk of breast cancer at age 70 years in CHEK2*1100delC heterozygotes of 37% (95% CI, 26% to 56%), which compares with similar previous estimates of 57% (95% CI, 47% to 66%) for BRCA1 mutation heterozygotes and 49% (95% CI, 40% to 57%) for BRCA2 mutation heterozygotes. CONCLUSION These meta-analyses emphasize that CHEK2*1100delC is an important breast cancer-predisposing gene, which increases the risk three- to five-fold. Because the cumulative risk of breast cancer at age 70 years among familial patient cases for CHEK2*1100delC heterozygotes is almost as high as that for BRCA1 and BRCA2 mutation heterozygotes, genotyping for CHEK2*1100delC should be considered together with BRCA1 and BRCA2 mutation screening in women with a family history of breast cancer.

Meta-analysis of psoriasis, cardiovascular disease, and associated risk factors

BACKGROUND The possible connection between psoriasis with cardiovascular disease and associated risk factors has been implied, but inconsistent results have been reported. OBJECTIVE We sought to create an overview and statistical summary of the previous literature with elucidating subgroup analysis. METHODS This was a meta-analysis of observational studies using random effect statistics. A systematic search of observational studies of psoriasis as study variable and cardiovascular disease and associated risk factors as outcome, published before October 25, 2012, was conducted. RESULTS Of 835 references in the original search, 75 relevant articles were identified. We included 503,686 cases and 29,686,694 controls. Psoriasis was associated with cardiovascular disease in total (odds ratio [OR] 1.4; 95% confidence interval [CI] 1.2-1.7), ischemic heart disease (OR 1.5; 95% CI 1.2-1.9), peripheral vascular disease (OR 1.5; 95% CI 1.2-1.8), atherosclerosis (OR 1.1; 95% CI 1.1-1.2), diabetes (OR 1.9; 95% CI 1.5-2.5), hypertension (OR 1.8; 95% CI 1.6-2.0), dyslipidemia (OR 1.5; 95% CI 1.4-1.7), obesity by body mass index (OR 1.8; 95% CI 1.4-2.2), obesity by abdominal fat (OR 1.6; 95% CI 1.2-2.3), and the metabolic syndrome (OR 1.8; 95% CI 1.2-2.8), but not associated with cerebrovascular disease (OR 1.1; 95% CI 0.9-1.3) and cardiovascular mortality (OR 0.9; 95% CI 0.4-2.2). The strongest associations were seen in hospital-based studies and psoriatic arthritis. Population-based studies did not show significant associations, with the exception of dyslipidemia. LIMITATIONS The heterogeneity of the studies makes clinical interpretation challenging. CONCLUSIONS In aggregate, psoriasis was associated with ischemic heart disease and cardiovascular risk factors. The association was only significant for hospital-based studies, except for dyslipidemia, which was also significant in population-based studies.

Hemochromatosis genotypes and risk of 31 disease endpoints: Meta‐analyses including 66,000 cases and 226,000 controls

Hemochromatosis genotypes have been associated with liver disease, diabetes mellitus, heart disease, arthritis, porphyria cutanea tarda, stroke, neurodegenerative disorders, cancer, and venous disease. We performed meta‐analyses including 202 studies with 66,263 cases and 226,515 controls to examine associations between hemochromatosis genotypes C282Y/C282Y, C282Y/H63D, C282Y/wild type, H63D/H63D, and H63D/wild type versus wild type/wild type and 9 overall endpoints and 22 endpoint subgroups. We also explored potential sources of heterogeneity. For liver disease, the odds ratio for C282Y/C282Y versus wild type/wild type was 3.9 (99% confidence interval: 1.9–8.1) overall, 11 (3.7–34) for hepatocellular carcinoma, 4.1 (1.2–14) for hepatitis C, and 10 (2.1–53) for nonalcoholic steatohepatitis. For porphyria cutanea tarda, the odds ratios were 48 (24–95) for C282Y/C282Y, 8.1 (3.9–17) for C282Y/H63D, 3.6 (1.8–7.3) for C282Y/wild type, 3.0 (1.6–5.6) for H63D/H63D, and 1.7 (1.0–3.1) for H63D/wild type versus wild type/wild type. Finally, for amyotrophic lateral sclerosis, the odds ratio was 3.9 (1.2–13) for H63D/H63D versus wild type/wild type. These findings were consistent across individual studies. The hemochromatosis genotypes were not associated with risk for diabetes mellitus, heart disease, arthritis, stroke, cancer, or venous disease in the overall analyses; however, the odds ratio for C282Y/C282Y versus wild type/wild type was 3.4 (1.1–11) for diabetes mellitus among North Europeans. Conclusion: In aggregate, clinically ascertained cases who are homozygous for the C282Y mutation are associated with a 4–11–fold risk of liver disease, whereas all 5 hemochromatosis genotypes are associated with a 2–48–fold risk of porphyria cutanea tarda, and H63D/H63D is associated with a 4‐fold risk of amyotrophic lateral sclerosis. These results, mainly from case‐control studies, cannot necessarily be extrapolated to the general population. (HEPATOLOGY 2007.)

Prevalence of hereditary haemochromatosis in late-onset type 1 diabetes mellitus: a retrospective study

BACKGROUND Although genotyping studies suggest that hereditary haemochromatosis is one of the most common genetic disorders in white people, it is still thought of as an uncommon disease. Our aim was to test the hypothesis that hereditary haemochromatosis is a disease often overlooked in patients with late-onset type 1 diabetes mellitus, a late manifestation of untreated iron overload. METHODS We did a retrospective study in which we genotyped for the C282Y and H63D mutations in the haemochromatosis gene in 716 unselected Danish patients who developed type 1 diabetes mellitus after age 30 years and 9174 controls from the general Danish population. We also screened for hereditary haemochromatosis by assessment of transferrin saturation. FINDINGS More patients with diabetes (n=9, relative frequency 1.26%, 95% CI 0.58-2.37) than controls (23, 0.25%, 0.16-0.38) were homozygous for C282Y (odds ratio 4.6, 2.0-10.1, p=0.0001). These patients had unrecognised signs of haemochromatosis. Transferrin saturation and ferritin concentrations ranged from 57% to 102% and 17 microg/L to 8125 microg/L, respectively. Frequency of compound heterozygosity (C282Y/H63D) did not differ between patients with diabetes (eight) and controls (131) (odds ratio 0.8, 95% CI 0.4-1.7). Positive and negative predictive values of transferrin saturation greater than 50%, in identification of C282Y homozygosity, were 0.26 and 1.00, respectively. A saturation of less than 50% therefore excluded C282Y homozygosity, whereas a saturation of more than 50% suggested C282Y homozygosity. INTERPRETATION Measurement of transferrin saturation followed by genetic testing could prevent liver and heart problems and improve life expectancy in patients with diabetes. Population screening before the onset of diabetes might improve the outlook of patients even further, but will be less cost effective.

RNA modifications by oxidation: a novel disease mechanism?

The past decade has provided exciting insights into a novel class of central (small) RNA molecules intimately involved in gene regulation. Only a small percentage of our DNA is translated into proteins by mRNA, yet 80% or more of the DNA is transcribed into RNA, and this RNA has been found to encompass various classes of novel regulatory RNAs, including, e.g., microRNAs. It is well known that DNA is constantly oxidized and repaired by complex genome maintenance mechanisms. Analogously, RNA also undergoes significant oxidation, and there are now convincing data suggesting that oxidation, and the consequent loss of integrity of RNA, is a mechanism for disease development. Oxidized RNA is found in a large variety of diseases, and interest has been especially devoted to degenerative brain diseases such as Alzheimer disease, in which up to 50-70% of specific mRNA molecules are reported oxidized, whereas other RNA molecules show virtually no oxidation. The iron-storage disease hemochromatosis exhibits the most prominent general increase in RNA oxidation ever observed. Oxidation of RNA primarily leads to strand breaks and to oxidative base modifications. Oxidized mRNA is recognized by the ribosomes, but the oxidation results in ribosomal stalling and dysfunction, followed by decreased levels of functional protein as well as the production of truncated proteins that do not undergo proper folding and may result in protein aggregation within the cell. Ribosomal dysfunction may also signal apoptosis by p53-independent pathways. There are very few reports on interventions that reduce RNA oxidation, one interesting observation being a reduction in RNA oxidation by ingestion of raw olive oil. High urinary excretion of 8-oxo-guanosine, a biomarker for RNA oxidation, is highly predictive of death in newly diagnosed type 2 diabetics; this demonstrates the clinical relevance of RNA oxidation. Taken collectively the available data suggest that RNA oxidation is a contributing factor in several diseases such as diabetes, hemochromatosis, heart failure, and β-cell destruction. The mechanism involves free iron and hydrogen peroxide from mitochondrial dysfunction that together lead to RNA oxidation that in turn gives rise to truncated proteins that may cause aggregation. Thus RNA oxidation may well be an important novel contributing mechanism for several diseases.

Estrogen Receptor α Polymorphism and Risk of Cardiovascular Disease, Cancer, and Hip Fracture Cross-Sectional, Cohort, and Case–Control Studies and a Meta-Analysis

Background— We hypothesized that the estrogen receptor α (ESR1) IVS1-397T/C polymorphism affects high-density lipoprotein cholesterol response to hormone replacement therapy and risk of cardiovascular disease (CVD), cancer of reproductive organs, and hip fracture. Methods and Results— We studied cross-sectionally 9244 individuals from the Danish general population and followed them up for 23 to 25 years. End points were CVD (ischemic heart disease, myocardial infarction, angina pectoris, ischemic cerebrovascular disease, ischemic stroke, other ischemic cerebrovascular disease, venous thromboembolism, deep vein thrombosis, and pulmonary embolism), cancer of reproductive organs (breasts, ovaries, uterus, and prostate), and hip fracture. We also studied patients with ischemic heart disease (n=2495), ischemic cerebrovascular disease (n=856), and breast cancer (n=1256) versus general population controls. The CC, CT, and TT genotypes had general population frequencies of 21%, 50%, and 29%, respectively. Cross-sectionally, genotype did not influence high-density lipoprotein cholesterol response to hormone replacement therapy. In the cohort study, there were no differences in risks of CVD, cancer of reproductive organs, or hip fracture between genotypes. In case–control studies, risk of CVD did not differ between genotypes; however, the odds ratio for breast cancer in women with TT versus CC genotypes was 1.4 (95% CI, 1.1 to 1.7). Meta-analysis in men of 6 previous and the present 2 studies, including 4799 cases and 12 190 controls, showed odds ratios in CC versus CT and TT genotypes for fatal and nonfatal myocardial infarction of 0.81 (95% CI, 0.59 to 1.12) and 1.08 (95% CI, 0.97 to 1.21). Conclusions— ESR1 IVS1-397T/C polymorphism does not influence high-density lipoprotein cholesterol response to hormone replacement therapy or risk of CVD, most cancers of reproductive organs, or hip fracture.

The prevalence of inverse recurrent suppuration: a population‐based study of possible hidradenitis suppurativa

Hidradenitis suppurativa (HS) is a chronic inflammatory disease involving inverse recurrent suppuration (IRS). The epidemiology of the disease is not well described, with previous studies reporting prevalence estimates from 0·00033% to 4%.

Hereditary Hemochromatosis and Risk of Ischemic Heart Disease A Prospective Study and a Case-Control Study

Background—We tested the hypothesis that the hereditary hemochromatosis genotypes C282Y/C282Y, C282Y/H63D, or C282Y/wild-type are risk factors for ischemic heart disease (IHD) and myocardial infarction (MI). Methods and Results—We performed a prospective study of 9178 individuals from the Danish general population followed up for 24 years, during which 1035 and 511 developed IHD and MI, respectively, and a case-control study of 2441 and 1113 IHD and MI cases versus 8080 controls. C282Y/C282Y, C282Y/H63D, and C282Y/wild-type versus wild-type/wild-type individuals were not associated with increased risk of IHD or MI in prospective studies, overall or stratified by gender. We had 90% power to detect a hazard ratio for IHD of 3.4 for C282Y/C282Y, 1.9 for C282Y/H63D, and 1.3 for C282Y/wild-type versus wild-type/wild-type. Furthermore, these genotypes were not associated with increased risk of IHD or MI in case-control studies, overall or stratified by gender. We had 90% power to detect an odds ratio for IHD of 3.6 for C282Y/C282Y, 1.8 for C282Y/H63D, and 1.3 for C282Y/wild-type versus wild-type/wild-type. Conclusions—In these studies, hereditary hemochromatosis C282Y/C282Y, C282Y/H63D, and C282Y/wild-type genotypes were not associated with IHD or MI; however, the study lacked the power to exclude the possibility that C282Y/C282Y and C282Y/H63D individuals have a modestly increased risk of IHD or MI.

Preanalytical Variables Affecting the Integrity of Human Biospecimens in Biobanking

BACKGROUND Most errors in a clinical chemistry laboratory are due to preanalytical errors. Preanalytical variability of biospecimens can have significant effects on downstream analyses, and controlling such variables is therefore fundamental for the future use of biospecimens in personalized medicine for diagnostic or prognostic purposes. CONTENT The focus of this review is to examine the preanalytical variables that affect human biospecimen integrity in biobanking, with a special focus on blood, saliva, and urine. Cost efficiency is discussed in relation to these issues. SUMMARY The quality of a study will depend on the integrity of the biospecimens. Preanalytical preparations should be planned with consideration of the effect on downstream analyses. Currently such preanalytical variables are not routinely documented in the biospecimen research literature. Future studies using biobanked biospecimens should describe in detail the preanalytical handling of biospecimens and analyze and interpret the results with regard to the effects of these variables.

Elevated transferrin saturation and risk of diabetes: three population-based studies.

OBJECTIVE We tested the hypothesis that elevated transferrin saturation is associated with an increased risk of any form of diabetes, as well as type 1 or type 2 diabetes separately. RESEARCH DESIGN AND METHODS We used two general population studies, The Copenhagen City Heart Study (CCHS, N = 9,121) and The Copenhagen General Population Study (CGPS, N = 24,195), as well as a 1:1 age- and sex-matched population-based case-control study with 6,129 patients with diabetes from the Steno Diabetes Centre and 6,129 control subjects, totaling 8,535 patients with diabetes and 37,039 control subjects. RESULTS In the combined studies, odds ratios in those with transferrin saturation ≥50% vs. <50% were 2.1 (95% CI 1.3–3.4; P = 0.003) for any form of diabetes; 2.6 (1.2–5.6; P = 0.01) for type 1 diabetes; and 1.7 (1.4–2.1; P = 0.001) for type 2 diabetes. CONCLUSIONS Elevated transferrin saturation confers a two- to threefold increased risk of developing any form of diabetes, as well as type 1 and type 2 diabetes separately.