Factors associated with statin discontinuation near end of life in a Danish primary health care cohort.

BACKGROUND: Long-term preventive treatment such as treatment with statins should be reassessed among patients approaching end of life. The aim of the study was to describe the rate of discontinuation of statin treatment and factors associated with discontinuation in the 6 months before death. METHODS: This study is a retrospective cohort study using national registers and blood test results from primary health care patients. Patients in the Copenhagen municipality, Denmark who died between 1997 and 2018 and were statin users during the 10-year period before death were included. We calculated the proportion who remained statin users in the 6-month period before death. Factors associated with discontinuation were tested using logistic regression. RESULTS: A total of 55,591 decedents were included. More patients continued treatment (64%, n = 35,693) than discontinued (36%, n = 19,898) the last 6 months of life. The 70 and 80 age groups had the lowest odds of discontinuing compared to the 90 (OR 1.59, 95% CI 0.93-2.72) and 100 (OR 3.11, 95% CI 2.79-3.47) age groups. Increasing comorbidity score (OR 0.89, 95% CI 0.87; 0.90 per 1-point increase) and use of statins for secondary prevention (OR 0.89, 95% CI 0.85; 0.93) reduced the likelihood of discontinuation as did a diagnosis of dementia, heart failure, or cancer. CONCLUSION: A substantial portion of patients continued statin treatment near end of life. Efforts to promote rational statin use and discontinuation are required among patients with limited life expectancy, including establishing clear, practical recommendations about statin discontinuation, and initiatives to translate recommendations into clinical practice.

Associations between education level, blood-lipid measurements and statin treatment in a Danish primary health care population from 2000 to 2018.

OBJECTIVE: To examine whether education level influences screening, monitoring, and treatment of hypercholesterolemia. DESIGN: Epidemiological cohort study. SETTING: Department of Clinical Biochemistry, Copenhagen University Hospital Hvidovre. SUBJECTS: Cholesterol blood test results ordered by general practitioners in Greater Copenhagen were retrieved from 2000-2018. Using the International Standard Classification of Education classification, the population was categorized by length of education in three groups (basic education; up to 10 years, intermediate education; 11-12 years, advanced education; 13 years or more). The database comprised 13,019,486 blood sample results from 653,903 patients. MAIN OUTCOME MEASURES: Frequency of lipid measurement, prevalence of statin treatment, age and comorbidity at treatment initiation, total cholesterol threshold for statin treatment initiation, and achievement of treatment goal. RESULTS: The basic education group was measured more frequently (1.46% absolute percentage difference of total population measured [95% CI 0.86%-2.05%] in 2000 and 9.67% [95% CI 9.20%-10.15%] in 2018) over the period compared to the intermediate education group. The advanced education group was younger when receiving first statin prescription (1.87 years younger [95% CI 1.02-2.72] in 2000 and 1.06 years younger [95% CI 0.54-1.58 in 2018) compared to the intermediate education group. All education groups reached the treatment goals equally well when statin treatment was initiated. CONCLUSION: Higher education was associated with earlier statin prescription, although the higher educated group was monitored less frequently. There was no difference in reaching treatment goal between the three education groups. These findings suggest patients with higher education level achieve an earlier dyslipidemia prevention intervention with an equally satisfying result compared to lower education patients.Key PointsLittle is known about the role of social inequality as a possible barrier for managing hypercholesterolemia in general practice.Increasing education level was associated to less frequent measurement and less frequent statin treatment.Patients with higher education level were younger, and less comorbidity at first statin prescription.Education level had no effect on frequency of statin treatment-initiated patients reaching the treatment goal was found.

Hospital-acquired anemia among patients in a university hospital and the affiliated general practices in the capital region of Denmark, 2019.

INTRODUCTION: Approximately 25% of the patients with hospital acquired anemia (HAA) develop moderate to severe HAA during hospitalization. This is related to an increased risk of prolonged stay, readmission and mortality. The primary aim was during one year to characterize a population with very frequent phlebotomies based on a university hospital in the Capital Region of Denmark and the related general practitioners. MATERIAL AND METHODS: We conducted a retrospective cohort study using administrative data on phlebotomies from 1 January 2019 to 31 December 2019 analyzed at a university hospital. RESULTS: A total of 203,811 patients had 10,083,207 requisitions and 1,373,013 tubes. One percent, 1985 patients, had an extreme of frequent phlebotomies >60 tubes and formed the basis for the study population. The study population was significantly older as compared to the excluded patients (<60 tubes) (mean 65.7 vs. 51.6 years, p < .001).The likelihood of hemoglobin decrease per 100 mL blood drawn were calculated at four levels of decreases: Hemoglobin decrease of 2 mmol/L (adjusted OR; 95%; 2.03, CI 1.79-2.31), hemoglobin decrease of 3 mmol/L (adjusted OR; 95%, 1.36, CI 1.28-1.45), hemoglobin decrease of 4 mmol/L, (adjusted OR; 95%, 1.27, CI 1.19-1.35) and hemoglobin decrease of 5 mmol/L, (adjusted OR; 95% 1.22, CI 1.13-1.31). CONCLUSIONS: Moderate to severe HAA occurred in a limited group with excessive many phlebotomies. It was a worrisome trend that the frailest patients had the highest risk of developing HAA.

Decreased plasma lipid levels in a statin-free Danish primary health care cohort between 2001 and 2018.

BACKGROUND: Lipid levels in blood have decreased considerably during the past decades in the general population partly due to use of statins. This study aims to investigate the trends in lipid levels between 2001 and 2018 in a statin-free population from primary health care, overall and by sex and age. METHODS: In a cohort of 634,119 patients from general practice with no diagnoses or medical treatments that affected lipid levels of total cholesterol (TC; n = 1,574,339) between 2001 and 2018 were identified. Similarly, measurements of low-density lipoprotein cholesterol (LDL-C; n = 1,302,440), high-density lipoprotein cholesterol (HDL-C; n = 1,417,857) and triglycerides (TG; n = 1,329,477) were identified. RESULTS: Mean TC decreased from 5.64 mmol/L (95% CI: 5.63-5.65) in 2001 to 5.17 mmol/L (95% CI: 5.16-5.17) in 2018 while LDL-C decreased from 3.67 mmol/L (95% CI: 3.66-3.68) to 3.04 mmol/L (95% CI: 3.03-3.04). Women aged 70-74 years experienced the largest decreases in TC levels corresponding to a decrease of 0.7 mmol/L. The decrease in LDL-C levels was most pronounced in men ≥85 years with a decrease of 0.9 mmol/L. For both genders, TC and LDL-C levels increased with advancing age until around age 50. After menopause the women had higher TC and LDL-C levels than the men. The median (geometric mean) TG level decreased by 0.4 mmol/L from 2001 to 2008, after which it increased slightly by 0.1 mmol/L until 2018. During life the TG levels of the men were markedly higher than the women's until around age 65-70. HDL-C levels showed no trend during the study period. CONCLUSIONS: The levels of TC and LDL-C decreased considerably in a statin-free population from primary health care from 2001 to 2018. These decreases were most pronounced in the elderly population and this trend is not decelerating. For TG, levels have started to increase, after an initial decrease.

A compulsory pop-up form reduces the number of vitamin D requests from general practitioners by 25 percent.

OBJECTIVE: Healthcare costs, including costs for laboratory tests, are increasing worldwide. One example is the measurement of vitamin D. General practitioners in the Capital Region of Denmark include a vitamin D status in approximately 20% of all laboratory requisitions. This study intended to examine the effect of a compulsory pop-up form in the electronic request system on the number of vitamin D tests and to monitor the indications. DESIGN: From 1 January 2017, we introduced a compulsory pop-up form in which the general practitioners had to state the indication for measuring vitamin D, choosing from a predefined set of indications. Intervention practitioners were compared with control practitioners before and after the intervention. SETTING: General practices in the Capital Region of Denmark. SUBJECTS: In total, 572 general practitioners and 383,964 patients were included in the period from 1 January 2016 to 31 December 2018. MAIN OUTCOME MEASURES: Number of vitamin D tests and distribution of indications. RESULTS: We observed a drop in number of vitamin D requisitions to 70% (in 2017) and 75% (in 2018) relative to 2016. During the same period, the number of requisitions increased by 33% in a non-intervention group of practitioners. The indication 'Monitoring of treatment with vitamin D' was the most frequently used indication, recorded in 121,475 patients. CONCLUSION: A compulsory pop-up form reduces the number of vitamin D requests from general practitioners by 25%. The implication is that pop-up forms can be used to decrease healthcare costs.

Biochemical markers of inflammation are associated with increased mortality in hip fracture patients: the Bispebjerg Hip Fracture Biobank.

PURPOSE: The purpose of this study was to examine the possible association between mortality following a hip fracture and known biochemical markers of inflammation. METHODS: The study population was identified using two local databases from Bispebjerg Hospital (Copenhagen, Denmark): the Hip Fracture Database containing all patients admitted to the hospital with a fractured hip from 1996 to 2012 and the Hip Fracture Biobank, containing whole blood, serum and plasma taken in relation to admission on a subgroup of patients from the Hip Fracture Database, consecutively collected over a period of 2.5 years from 2008 to 2011. The following biochemical markers of inflammation were included: C-reactive protein (CRP), the soluble urokinase plasminogen activating receptor (suPAR), ferritin and transferrin. The association between the blood markers and mortality was examined using Cox proportional hazards models. Hazard ratios (HR) were expressed per quartile increase in the biochemical markers. RESULTS: A total of 698 patients were included, 69 (9.9%) died within 30 days after sustaining a hip fracture. The HR for 30-day mortality was significantly increased with increasing quartiles of suPAR, CRP and ferritin and with decreasing quartiles of transferrin. CONCLUSION: This study shows that 30-day mortality after a hip fracture is associated with elevated levels of suPAR, CRP and ferritin as well as with lower levels of transferrin. This excess inflammatory response is likely caused by muscle damage associated with the hip fracture. However, this needs to be further clarified.

Hyperkalemia is Associated with Increased 30-Day Mortality in Hip Fracture Patients.

Abnormal plasma concentrations of potassium in the form of hyper- and hypokalemia are frequent among hospitalized patients and have been linked to poor outcomes. In this study, we examined the prevalence of hypo- and hyperkalemia in patients admitted with a fractured hip as well as the association with 30-day mortality in these patients. A total of 7293 hip fracture patients (aged 60 years or above) with admission plasma potassium measurements were included. Data on comorbidity, medication, and death was retrieved from national registries. The association between plasma potassium and mortality was examined using Cox proportional hazards models adjusted for age, sex, and comorbidities. The prevalence of hypo- and hyperkalemia on admission was 19.8% and 6.6%, respectively. The 30-day mortality rates were increased for patients with hyperkalemia (21.0%, p < 0.0001) compared to normokalemic patients (9.5%), whereas hypokalemia was not significantly associated with mortality. After adjustment for age, sex, and individual comorbidities, hyperkalemia was still associated with increased risk of death 30 days after admission (HR = 1.93 [1.55-2.40], p < 0.0001). After the same adjustments, hypokalemia remained non-associated with increased risk of 30-day mortality (HR = 1.06 [0.87-1.29], p = 0.6). Hyperkalemia, but not hypokalemia, at admission is associated with increased 30-day mortality after a hip fracture.

Reference intervals for mean platelet volume and immature platelet fraction determined on a sysmex XE5000 hematology analyzer.

BACKGROUND: New parameters describing the platelet population of the blood are mean platelet volume (MPV), which is a crude estimate of thrombocyte reactivity, and immature platelet fraction (IPF), which reflects megakaryopoietic activity. This study aimed to define reference intervals for MPV and IPF and to investigate whether separate reference intervals according to smoking status, age or sex are necessary. METHODS: Blood samples were obtained from subjects participating in The Danish General Suburban Population Study. MPV and IPF measurements were performed by the use of the Sysmex XE-5000 hematology analyzer. Reference intervals were established by a non-parametric method. RESULTS: In total, 1674 apparently healthy individuals (910 females and 764 males) were included. No significant age, sex or smoking status difference was observed. The reference interval was 9.6-13.1 fL for MPV and 1.3-9.0% for IPF, respectively. CONCLUSION: We have generated reference intervals for MPV and IPF in a large, adult Danish population and found those parameters remarkably stable across age, sex and smoking status.

Association of lipoprotein levels with mortality in subjects aged 50 + without previous diabetes or cardiovascular disease: a population-based register study.

OBJECTIVE: This study aimed to investigate the association of lipoprotein and triglyceride levels with all-cause mortality in a population free from diabetes and cardiovascular disease (CVD) at baseline. The European Guidelines on cardiovascular disease prevention state that in general total cholesterol (TC) should be < 5 mmol/L (190 mg/dL) and low-density lipoprotein cholesterol (LDL-C) should be < 3 mmol/L (115 mg/dL). DESIGN: A population-based register study in the period 1999-2007 including 118 160 subjects aged 50 + without statin use at baseline. All-cause mortality was related to lipoprotein and triglyceride levels and adjusted for statin use after inclusion. RESULTS: All-cause mortality was lower in the groups with TC or LDL-C above the recommended levels. Compared with subjects with TC < 5 mmol/L, adjusted hazard ratios for the group aged 60-70 years ranged from 0.68 (95% confidence interval (CI) 0.61-0.77) for TC 5-5.99 mmol/L to 0.67 (95% CI 0.59-0.75) for TC 6-7.99 mmol/L and 1.02 (95% CI 0.68-1.53) for TC ≥ 8 mmol/L in males and from 0.57 (95% CI 0.48-0.67) to 0.59 (95% CI 0.50-0.68) and 1.02 (95% CI: 0.77-1.37) in females. For triglycerides, ratios compared with the group < 1 mmol/L in the females aged 60-70 years ranged from 1.04 (95% CI 0.88-1.23) to 1.35 (95% CI 1.10-1.66) and 1.25 (95% CI 1.05-1.48) for triglycerides 1-1.39 mmol/L, 1.4-1.69 mmol/L, and ≥ 1.7 mmol/L, respectively. Statin treatment after inclusion provided a survival benefit. CONCLUSION: These associations indicate that high lipoprotein levels do not seem to be definitely harmful in the general population. However, high triglyceride levels in females are associated with decreased survival.

The 10 most frequently requested blood tests in the Capital Region of Denmark, 2010-2019 and simulated effect of minimal retesting intervals.

As healthcare costs continue to rise throughout the world, critical assessment of the appropriateness of expenses gain focus. OBJECTIVES: We aimed to describe the developments in test numbers of the 10 most frequently requested tests, and to simulate the effect of introducing minimal retesting intervals. DESIGN & METHODS: Data from the blood tests - albumin, alanine transaminase, cholesterol, creatinine, C-reactive protein, hemoglobin, hemoglobin A1c, potassium, sodium, and thyrotropin - from 2,687,589 patients handled by the Capital Region of Denmark from 2010 to 2019 was used. Tallies of each test per year were graphed. A simulation of the effect of minimal retesting intervals on test count and blood sampling volume was performed by virtually removing requests made prior to a set of possible minimal retesting intervals. RESULTS: Increases in requests were observed both from hospitals and general practitioners. The number of requests for hemoglobin A1c increased more than the other tests. The increases could not be accounted for by an increase in population size and aging of the population, and therefore suggests possible inappropriate increase in monitoring of patients. The simulated effect of applying minimal retesting intervals showed large reductions in tests and blood sampled. CONCLUSIONS: For hospitals, the simulation suggested that applying minimal retesting intervals could lead to significant reductions in both the number of blood tests performed and in the amount of blood drawn for testing. For general practitioners, the simulation showed only minimal reductions in number of tests and blood volume drawn.

Identification of quantitative trait loci for fibrin clot phenotypes: the EuroCLOT study.

OBJECTIVE: Fibrin makes up the structural basis of an occlusive arterial thrombus, and variability in fibrin phenotype relates to cardiovascular risk. The aims of the current study from the EU consortium EuroCLOT were to (1) determine the heritability of fibrin phenotypes and (2) identify QTLs associated with fibrin phenotypes. METHODS AND RESULTS: 447 dizygotic (DZ) and 460 monozygotic (MZ) pairs of healthy UK white female twins and 199 DZ twin pairs from Denmark were studied. D-dimer, an indicator of fibrin turnover, was measured by ELISA and measures of clot formation, morphology, and lysis were determined by turbidimetric assays. Heritability estimates and genome-wide linkage analysis were performed. Estimates of heritability for d-dimer and turbidometric variables were in the range 17% to 46%, with highest levels for maximal absorbance which provides an estimate of clot density. Genome-wide linkage analysis revealed 6 significant regions with LOD >3 on 5 chromosomes (5, 6, 9, 16, and 17). CONCLUSIONS: The results indicate a significant genetic contribution to variability in fibrin phenotypes and highlight regions in the human genome which warrant further investigation in relation to ischemic cardiovascular disorders and their therapy.

[Therapeutic drug monitoring of ß-lactam antibiotics].

Traditional ß-lactam antibiotic dosing does not consider physiological changes in medical conditions such as sepsis. Optimal antibiotic exposure could be achieved by therapeutic drug monitoring (TDM). This review gives a brief summary. Current studies are sparse, but suggestive of a potential beneficial role of TDM to patients with reduced renal function, obese patients and the critically ill. TDM can potentially reduce adverse effects and optimise antibiotic exposure. However, standardised TDM methods are lacking and randomised clinical studies are warranted in order to prove clinical benefit.

Telomere length and mortality: a study of leukocytes in elderly Danish twins.

Leukocyte telomere length, representing the mean length of all telomeres in leukocytes, is ostensibly a bioindicator of human aging. The authors hypothesized that shorter telomeres might forecast imminent mortality in elderly people better than leukocyte telomere length. They performed mortality analysis in 548 same-sex Danish twins (274 pairs) aged 73-94 years, of whom 204 pairs experienced the death of one or both co-twins during 9-10 years of follow-up (1997-2007). From the terminal restriction fragment length (TRFL) distribution, the authors obtained the mean TRFL (mTRFL) and the mean values of the shorter 50% (mTRFL(50)) and shortest 25% (mTRFL(25)) of TRFLs in the distribution and computed the mode of TRFL (MTRFL). They analyzed the proportions of twin pairs in which the co-twin with the shorter telomeres died first. The proportions derived from the intrapair comparisons indicated that the shorter telomeres predicted the death of the first co-twin better than the mTRFL did (mTRFL: 0.56, 95% confidence interval (CI): 0.49, 0.63; mTRFL(50): 0.59, 95% CI: 0.52, 0.66; mTRFL(25): 0.59, 95% CI: 0.52, 0.66; MTRFL: 0.60, 95% CI: 0.53, 0.67). The telomere-mortality association was stronger in years 3-4 than in the rest of the follow-up period, and it grew stronger with increasing intrapair difference in all telomere parameters. Leukocyte telomere dynamics might help explain the boundaries of the human life span.

Denaturing high-performance liquid chromatography mutation analysis in patients with reduced Protein S levels.

BACKGROUND: Patients with congenital Protein S deficiency have increased risk of venous thromboembolism. However, Protein S levels show large intra-individual variation and the biochemical assays have low accuracy and a high interlaboratory variability. Genetic analysis might aid in a more precise diagnosis and risk estimation. The aim was to design a high-throughput genetic analysis based on denaturing high-performance liquid chromatography to identify sequence variations in the gene coding for Protein S. PATIENTS: In total, 55 patients referred to the Section of Thrombosis and Haemostasis, Odense University Hospital, in the period 1998-2004 were included in the study. RESULTS: Mutations were found in ten of the 55 patients: Six different variants were identified, of which four were not previously reported: One were a nonsense mutation substituting a glutamine with a stopcodon (c.790C>T) and the rest were missense mutations (c.932T>G; c.1367A>G; c.1378T>C). Furthermore, four patients carried the same mutation (c.1045G>A), while two carried the Heerlen mutation (c.1378T>C). CONCLUSIONS: The reported method will be useful for rapidly detecting sequence variations in the gene coding for Protein S, giving a precise diagnosis and subsequently a better risk estimation.

Candidate gene polymorphisms in the serotonergic pathway: influence on depression symptomatology in an elderly population.

BACKGROUND: Depressed mood is a major concern in the elderly, with consequences for morbidity and mortality. Previous studies have demonstrated that genetic factors in depression and subsyndromal depressive symptoms are no less important in the elderly than during other life stages. Variations in genes included in the serotonin system have been suggested as risk factors for various psychiatric disorders but may also serve as candidates for normal variations in mood. METHODS: This study included 684 elderly Danish twins to investigate the influence of 11 polymorphisms in 7 serotonin system genes on the mean level of depression symptomatology assessed over several years, reflecting individuals' underlying mood level. RESULTS: A suggestive association of sequence variations in genes responsible for the synthesis (TPH), recognition (5-HTR2A), and degradation (MAOA) of serotonin with depression symptomatology was found, although the effect was generally restricted to men. We also found that a specific haplotype in VMAT2, the gene encoding the vesicular monoamine transporter, was significantly associated with depression symptoms in men (p= .007). CONCLUSIONS: These results suggest that variations in genes encoding the components of serotonin metabolism may influence the basic mood level and that different genetic factors may apply in men and women.

Genetic association analysis of human longevity in cohort studies of elderly subjects: an example of the PON1 gene in the Danish 1905 birth cohort.

Although the case-control or the cross-sectional design has been popular in genetic association studies of human longevity, such a design is prone to false positive results due to sampling bias and a potential secular trend in gene-environment interactions. To avoid these problems, the cohort or follow-up study design has been recommended. With the observed individual survival information, the Cox regression model has been used for single-locus data analysis. In this article, we present a novel survival analysis model that combines population survival with individual genotype and phenotype information in assessing the genetic association with human longevity in cohort studies. By monitoring the changes in the observed genotype frequencies over the follow-up period in a birth cohort, we are able to assess the effects of the genotypes and/or haplotypes on individual survival. With the estimated parameters, genotype- and/or haplotype-specific survival and hazard functions can be calculated without any parametric assumption on the survival distribution. In addition, our model estimates haplotype frequencies in a birth cohort over the follow-up time, which is not observable in the multilocus genotype data. A computer simulation study was conducted to specifically assess the performance and power of our haplotype-based approach for given risk and frequency parameters under different sample sizes. Application of our method to paraoxonase 1 genotype data detected a haplotype that significantly reduces carriers' hazard of death and thus reveals and stresses the important role of genetic variation in maintaining human survival at advanced ages.

Methylenetetrahydrofolate reductase 677C>T and methionine synthase 2756A>G mutations: no impact on survival, cognitive functioning, or cognitive decline in nonagenarians.

BACKGROUND: Several reports have shown an association between homocysteine, cognitive functioning, and survival among the oldest-old. Two common polymorphisms in the genes coding for methylenetetrahydrofolate reductase (MTHFR 677C>T) and methionine synthase (MTR 2756A>G) have an impact on plasma homocysteine level. METHODS: We examined the effect of the MTHFR 677C>T and MTR 2756A>G genotypes on baseline cognitive functioning, cognitive decline over 5 years measured in three assessments, and survival in a population-based cohort of 1581 nonagenarians. Cognitive functioning was assessed by using the Mini-Mental State Examination (MMSE) and five brief cognitive tests (cognitive composite). RESULTS: There are no differences in MMSE score (p =.83) or in cognitive composite (p =.56) at intake as a function of genotype tested by analysis of variance, whereas sex and social group have a impact on MMSE (p < or =.03), and social group on the cognitive composite (p <.01). The mean MMSE was lower for women than for men. However, considering the group participating in all three assessments, there were no sex-related differences in MMSE (p =.34). The cognitive decline in the group participating in all three assessments was investigated using regression models for the relationship between cognitive performance and genotype, age, sex, and social group and revealed no significant difference. Furthermore, the MTHFR 677T and MTR 2756A heterozygous and homozygous genotype had no significant impact on survival, with hazard ratios of 1.05 (95% confidence interval [CI], 0.93-1.17), 0.93 (95% CI, 0.77-1.14), 1.05 (95% CI, 0.94-1.18), and 0.97 (95% CI, 0.74-1.28). CONCLUSIONS: MTHFR and MTR genotypes are not associated with cognitive functioning, cognitive decline, or survival among nonagenarians.

Association between combined properdin and mannose-binding lectin deficiency and infection with Neisseria meningitidis.

BACKGROUND: Individuals genetically deficient of properdin are more susceptible to meningococcal disease. Likewise low concentration or decreased biological activity of mannose-binding lectin (MBL) is associated with higher incidence of bacterial infections during childhood. In this study we report our findings in a Danish family with a remarkably high incidence of meningococcal meningitis-in total four cases, one of them fatal. METHODS: Properdin and MBL were quantified by ELISA and the properdin gene was screened for sequence variations using denaturing high-performance liquid chromatography (DHPLC) and subsequent sequencing of abnormal patterns. The MBL gene was genotyped for the three known variant alleles (B, C and D) as well as three promoter polymorphisms (-221Y/X, -550H/L and +4P/Q). RESULTS: Two out of six males with undetectable properdin activity had meningitis. They had also low MBL serum levels or carried an MBL variant allele, whereas high MBL concentrations were measured in three out of four properdin deficient males--without meningitis. A splice site mutation in exon 10 (c.1487-2A>G) was found in the properdin gene and co segregated with biochemically measured properdin deficiency. CONCLUSION: Our results indicate that a combined deficiency of both properdin and MBL increases the risk of infection with Neisseria meningitidis and stress the importance of epistatic genetic interactions in disease susceptibility.