IHR-PVS National Bridging Workshop in Cameroon: An interactive and participatory approach to engage stakeholders in the development of a One Health road map.

Introduction: Stakeholders involved in the implementation of the One Health (OH) welcome support for the operationalization of the approach and advice on how to address OH collaboration challenges. The IHR/PVS National Bridging Workshop (NBW) is an operational and outcome-oriented tool approach that allows animal health, human health and other relevant sectors to focus on their coordination. This paper describes how Cameroon leveraged on the NBW success factors to engage stakeholders in strengthening multisectoral collaboration. Methods: Stakeholder's engagement was implemented in two phases. Phase one consisted of engaging the multisectoral national task team for the preparation of the workshop. Phase two consisted of the bridging exercise itself during a three day workshop. The WOAH-WHO standardized IHR/PVS NBW toolkit was used throughout the workshop. Results: A total of 66 participants took part in the exercise. In total, 36% each came from human and animal health sectors with 23% and 5% from the environmental health and other sectors respectively. A total of 55% participants came from the national level and 39% from the regional level. The joint roadmap contained 55 activities and 13 objectives. Priority objectives were the establishment of a OH platform at all levels (62% of the vote) and building stakeholder's capacity on the OH approach (56% of the vote). A total of 67% of the activities required low or moderate cost and 87% would have a high impact on multisectoral collaboration. Conclusion: The NBW allowed consensus on operational activities to fill the gaps in coordination to build health security capacities. It enabled Cameroon to create a joint road map for enhanced multisectoral collaboration for health security. The output will be integrated in the National Action Plan for Health Security operational plan and support operational One Health activities. It would be crucial to develop global capacity assessment frameworks for environmental health, which could be included in the NBW, to incorporate interconnections with environmental sector. This should allow for a stronger multisectoral linkage of sectors all together for a more the robust OH approach in responding to emerging public health threats.

Assessing core capacities for addressing public health emergencies of international concern at designated points of entry in cameroon during the COVID-19 Pandemic.

BACKGROUND: Points of Entry (POEs) are at the frontline for prevention, detection and response to international spread of diseases. The objective of this assessment was to ascertain the current level of existing International Health Regulations (IHR) core capacities of designated airports, ports and ground crossings in Cameroon and identify critical gaps for capacity building for prevention, early warning and response to public health threats including COVID-19. METHODS: Data were collected from April to May 2020 in 5 designated POEs: Yaounde Nsimalen International Airport (YIA), Douala international Airport (DIA), Douala Autonomous Port (DAP), Garoua-Boulai ground crossing, Kye-Ossi ground crossing which were all selected for their high volume of passenger and goods traffic. The World Health Organization (WHO) assessment tool for core capacity requirements at designated airports, ports and ground crossings was used to collect data on three technical capacities: (i) communication and coordination, (ii) Capacities at all times and (iii) capacities to respond to Public Health Emergencies of International Concern (PHEIC). RESULTS: All the investigated POEs scored below 50% of capacities in place. YIA recorded the highest percentage for all groups of capacities, coordination and communication and for core capacity at all times with a percentage of 42%, 58% and 32% respectively. For core capacity to respond to PHEIC, all the POEs recorded below 50%. The DAP and all ground crossings lacked trained personnel for inspection of conveyances. Only DIA had a public health emergency plan. There is no isolation/quarantine and transport capacity at the POEs. CONCLUSION: All POEs assessed did not meet IHR standards and need significant improvement to fulfill the IHR requirements. Unstructured communication channels between stakeholders make the implementation of IHR challenging. A coordination mechanism, with clear functions and structure, is necessary for well-coordinated response efforts to health emergencies at POEs. This assessment will serve as a baseline to inform planning and IHR implementation at designated POEs in Cameroon.

Health Security Planning: Developing the Cameroon National Action Plan for Health Security.

The health security planning process transforms recommendations from various evaluations into priority actions to strengthen countries' capacity for emergency preparedness using the One Health approach. Although the World Health Organization (WHO) has developed many tools to facilitate the planning process of a National Action Plan for Health Security (NAPHS) across the various components, a series of multisectoral workshops is still needed to complete the process. In this article, we report on the process of developing Cameroon's NAPHS and propose an innovative solution to improve the process. The NAPHS development process was conducted from May to December 2018. The WHO NAPHS framework, adapted to the local context, guided the process. The WHO planning matrix was used to plan activities and the WHO NAPHS costing tool was used to facilitate the costing exercise. A total of 84 Joint External Evaluation recommendations were translated into activities included in Cameroon's NAPHS. Among these activities, the majority (56%) were of medium priority. The total cost of a 5-year NAPHS was US$87,668,356, with almost half (49%) of the budget allocated to activities in the "Prevent" category and more than a third (35%) allocated to the "Detect" category. The top 3 cost drivers were immunization (22%), the national laboratory system (21%), and antimicrobial resistance (16%). The NAPHS informed policymakers of planned activities and funding needs to fast-track the development of health security capacities. Running gaps in funding will be addressed during a resource mapping exercise. To improve the overall planning process, a web-based support solution, where stakeholders select from a menu of recommendations from the Joint External Evaluation to develop a NAPHS, should be developed to improve the NAPHS development process.

Perception on cervical cancer and enhancing strategies to screening uptake among women in Bamenda, Cameroon: A qualitative method

The treatment of cervical cancer has a good prognosis if diagnosed early. Hence, screening is very vital. The aim of this study was to evaluate the perception of women on cervical cancer and strategies to enhance its screening uptake in the city of Bamenda, Cameroon. Qualitative study was carried out from July, 2019 to August, 2019. Eight focus group discussions were organized in five different quarters in the city of Bamenda. These quarters and participants were purposively selected and each group constituted 6 to 8 Participants. Ethical clearance and administrative authorization for the study were obtained prior to the study. Data was analyzed using thematic analysis with the help of QDA Miner. A total of 53 study participants took part in this study. Their ages ranged between 21 to 45 years. Most participants did not know about cervical cancer. Their perceived barriers to cervical cancer screening included: inadequate sensitization; financial challenges and embarrassing testing strategies; lack of awareness on the availability of screening centers; poor attitude of health personnel. Proposed strategies to enhance cervical cancer screening were: sensitization of the population, recruitment of more competent staff, testing centers should be located closed to the target population, less embarrassing screening methods should be used, health care workers should demonstrate positive attitudes during care, female staff should manage the screening units, screening cost should be subsidized. Due to the Small purposive sample size and qualitative nature of this study, the findings are not generalizable

Evaluation of inpatients Clostridium difficile prevalence and risk factors in Cameroon.

BACKGROUND: Clostridium difficile, rarely found in hospitals, is a bacterium responsible for post-antibiotic diarrhea and Pseudomembranous Colitis (CPM). C. difficile selective pressure represents potential public health problem due to the production of toxins A and B serious pathologies effects/consequences. A transversal and analytic study was to assess the risk factors of C. difficile infection and to determine the prevalence of C. difficile in patients received in randomly selected five hospitals in Yaoundé, Cameroon. METHODS: A total of 300 stool samples were collected from consented patients using a transversal and analytic study conducted from 10th July to 10th November 2018 in five hospitals in Cameroon. The detection or diagnostic kit was CerTest C. difficile Glutamate Dehydrogenase + Toxin A + Toxin B based on immuno-chromatographic assay. A univariate and multivariate analysis allowed us to highlight the associated factors. RESULTS: The results showed a prevalence of C. difficile of 27.33% (82/300 stool patients'samples taken). Of these 27.33%, the production of Toxin A and Toxin B were 37.80 and 7.31% respectively. In univariate analysis, hospitalization was a significant (P = 0.01) risk factor favoring C. difficile infection. In multivariate analysis, corticosteroids and quinolones use/administration were significantly (adjusted Odd Ratio, aOR = 14.09, 95% CI: 1.62-122.54, P = 0.02 and aOR = 3.39, 95% CI: 1.00-11.34, P = 0.05 respectively) risk factor for this infection. CONCLUSION: The prevalence of C. difficile infections (CDI) remain high in these settings and may be related not only to permanent steroids and antibiotics. Promoting education to both medical staff and patients on the prevalence and public health impact of C. difficile can be core inimproving rationale prescription of steroids and antibiotics to patients and promote human health and exponential growth in Cameroon.

Identification of heart rate-associated loci and their effects on cardiac conduction and rhythm disorders.

Elevated resting heart rate is associated with greater risk of cardiovascular disease and mortality. In a 2-stage meta-analysis of genome-wide association studies in up to 181,171 individuals, we identified 14 new loci associated with heart rate and confirmed associations with all 7 previously established loci. Experimental downregulation of gene expression in Drosophila melanogaster and Danio rerio identified 20 genes at 11 loci that are relevant for heart rate regulation and highlight a role for genes involved in signal transmission, embryonic cardiac development and the pathophysiology of dilated cardiomyopathy, congenital heart failure and/or sudden cardiac death. In addition, genetic susceptibility to increased heart rate is associated with altered cardiac conduction and reduced risk of sick sinus syndrome, and both heart rate-increasing and heart rate-decreasing variants associate with risk of atrial fibrillation. Our findings provide fresh insights into the mechanisms regulating heart rate and identify new therapeutic targets.

Reproducibility of peroneal motor nerve conduction measurement in older adults.

OBJECTIVE: While neuropathy is common in the elderly, nerve conduction (NC) reproducibility in older adults is not well-established. We sought to evaluate intraobserver reproducibility of peroneal motor NC measures in a diverse sample of older adults. METHODS: We measured peroneal motor NC amplitude and velocity in a subset of participants (mean age=82.9±2.7, n=62, 50% female, 51.6% black, 35.5% DM) in the Health, Aging, and Body Composition Study. Using coefficients of variation (CVs), intraclass correlation coefficients (ICCs), and Bland Altman Plots, we compared two sets of measurements taken by the same examiner hours apart on the same day. RESULTS: Low CVs (2.15-4.24%) and moderate to high ICCs (0.75-0.99) were observed. No systematic variation was found across measures. Despite small numbers in some subgroups, we found no differences in reproducibility by diabetes, race or study site. CONCLUSION: NC measures have moderate to high intraobsever reproducibility in older adults and are not affected by diabetes, race, or gender. SIGNIFICANCE: These data provide evidence to support use of these measures in aging research.

Habitual sleep/wake patterns in the Old Order Amish: heritability and association with non-genetic factors.

STUDY OBJECTIVES: We sought to evaluate the contribution of genetic and non-genetic factors on habitual sleep/wake patterns in a community-dwelling agrarian population using a physical activity monitoring device, the Actical. DESIGN: Cross-sectional population-based study of healthy Old Order Amish enrolled in the Heredity and Phenotype Intervention (HAPI) Heart Study. SETTING: Lancaster County, PA, USA. PARTICIPANTS: 723 healthy adults (54% men) with a mean age of 43.3 ± 13.8 years (range: 20-80). 96% of the subjects were connected into one 5-generation pedigree. INTERVENTIONS: N/A. MEASUREMENTS: Participants wore Actical accelerometers 24 hours/day for 7 days to determine physical activity level, as well as habitual wake time, bedtime, and sleep duration. Participants completed the Horne-Östberg Morningness-Eveningness Questionnaire (MEQ), a modified Epworth Sleepiness Scale (ESS), and a lifestyle questionnaire. A sub-study of 164 participants kept sleep diaries. RESULTS: Habitual wake time and bedtime determined by Actical were highly correlated with results from sleep diaries (r = 0.82 for wake time and 0.72 for bedtime, both P < 0.0001). After adjustment for age, sex, occupation, and season, higher activity level was associated with earlier wake time but not with bedtime, and correspondingly with shorter sleep duration. After adjustment for the aforementioned factors and the effects of a shared household, habitual wake time, MEQ score, and ESS score showed significant heritability (wake time h(2) = 0.20, MEQ h(2) = 0.21, and ESS h(2) = 0.17). CONCLUSIONS: Objectively measured wake time, self-reported morningness-eveningness preference, and daytime sleepiness appear heritable and wake time may be associated with physical activity level.

Replication and extension of association between common genetic variants in SIM1 and human adiposity.

Haplo-insufficiency of the bHLH (basic helix-loop-helix) transcription factor single-minded 1 (SIM1) causes severe obesity in mice and humans. We hypothesized that common genetic variations in/near SIM1 could exert more subtle effects on its function and associate with human adiposity. First, SIM1 coding regions were sequenced in severely obese subjects, and two common nonsynonymous single-nucleotide polymorphisms (nsSNPs) in complete linkage disequilibrium (LD) were identified: Pro352Thr (rs3734354) and Ala371Val (rs3734355). We next carried out a SNP association study of five adiposity traits (BMI, % body fat, abdominal visceral and subcutaneous fat, and leptin concentrations) in 1,699 whites and 1,173 blacks. TagSNPs covering SIM1 and nearby conserved regions, and the only common nsSNP in SIM1's binding partner aryl-hydrocarbon receptor nuclear translocator 2 (ARNT2) (Gly679Ser/rs4072568), were investigated. The effects of rs3734355/4 on SIM1 activity were tested using an in vitro reporter assay. We replicated previous observations that homozygosity for the 371Val allele was associated with higher BMI in white males (P = 0.003). Together with previous findings in white males (combined n = 3,479), BMI was increased by 1.10 kg/m(2) in 371Val homozygotes (95% confidence interval (CI): 0.25-1.95 kg/m(2), P = 0.01). In vitro, the 352Thr-371Val haplotype impaired SIM1 transcriptional activity by 22% (P < 0.0001). TagSNP analysis of SIM1 revealed two SNPs in the 3' region (rs9390322 and rs7746743) and another in intron 5 (rs3734353) to be significantly associated with various adiposity measures in ethnicity- and sex-specific manners after multiple testing correction. In white males, rs4072568 in ARNT2 was also associated with BMI (P = 9 × 10(-4)) and % body fat (P = 0.001). Our findings implicate heritable defects of the SIM1-ARNT2 axis in the predisposition to human obesity.

A common variant in the telomerase RNA component is associated with short telomere length.

BACKGROUND: Telomeres shorten as cells divide. This shortening is compensated by the enzyme telomerase. We evaluated the effect of common variants in the telomerase RNA component (TERC) gene on telomere length (TL) in the population-based Health Aging and Body Composition (Health ABC) Study and in two replication samples (the TwinsUK Study and the Amish Family Osteoporosis Study, AFOS). METHODOLOGY: Five variants were identified in the TERC region by sequence analysis and only one SNP was common (rs2293607, G/A). The frequency of the G allele was 0.26 and 0.07 in white and black, respectively. Testing for association between TL and rs2293607 was performed using linear regression models or variance component analysis conditioning on relatedness among subjects. RESULTS: The adjusted mean TL was significantly shorter in 665 white carriers of the G allele compared to 887 non-carriers from the Health ABC Study (4.69±0.05 kbp vs. 4.86±0.04 kbp, measured by quantitative PCR, p = 0.005). This association was replicated in another white sample from the TwinsUK Study (6.90±0.03 kbp in 301 carriers compared to 7.06±0.03 kbp in 395 non-carriers, measured by Southern blots, p = 0.009). A similar pattern of association was observed in whites from the family-based AFOS and blacks from the Health ABC cohort, although not statistically significant, possibly due to the lower allele frequency in these populations. Combined analysis using 2,953 white subjects from 3 studies showed a significant association between TL and rs2293607 (ß = -0.19±0.04 kbp, p = 0.001). CONCLUSION: Our study shows a significant association between a common variant in TERC and TL in humans, suggesting that TERC may play a role in telomere homeostasis.

HFE gene mutations increase the risk of coronary heart disease in women.

The purpose of the present study is to examine HFE gene mutations in relation to newly diagnosed (incident) coronary heart disease (CHD). In a population-based follow-up study of 7,983 individuals aged 55 years and older, we compared the risk of incident CHD between HFE carriers and non-carriers, overall and stratified by sex and smoking status. HFE mutations were significantly associated with an increased risk of incident CHD in women but not in men (hazard ratio [HR] for women = 1.7, 95% confidence interval [CI] 1.2-2.4 versus HR for men = 0.9, 95% CI 0.7-1.2). This increased CHD risk associated with HFE mutations in women was statistically significant in never smokers (HR = 1.8, 95% CI 1.1-2.8) and current smokers (HR = 3.1, 95% CI 1.4-7.1), but not in former smokers (HR = 1.3, 95% CI 0.7-2.4). HFE mutations are associated with increased risk of incident CHD in women.

Association between oxidized LDL, obesity and type 2 diabetes in a population-based cohort, the Health, Aging and Body Composition Study.

BACKGROUND: Accumulating evidence suggests a cross-sectional association between oxidative stress and type 2 diabetes (T2D). Systemic oxidative stress, as measured by oxidized LDL (oxLDL), has been correlated with visceral fat. We examined the relationship between oxLDL, and T2D- and obesity-related traits in a bi-racial sample of 2985 subjects at baseline and after 7 years of follow-up. METHODS: We examined six T2D-related traits (T2D status, HbA(1c), fasting glucose, insulin, adiponectin and HOMA-IR) as well as six obesity-related traits (obesity status, BMI, leptin, % body fat, visceral and subcutaneous fat mass) using logistic and linear regression models. RESULTS: In all subjects at baseline, oxLDL was positively associated with T2D (OR = 1.3, 95% CI:1.1-1.5), fasting glucose (ss = 0.03 +/- 0.006), HbA(1c) (ss = 0.02 +/- 0.004), fasting insulin (ss = 0.12 +/- 0.02), HOMA-IR (ss = 0.13 +/- 0.02) and negatively with adiponectin (ss = -0.16 +/- 0.03), (all p < 0.001). The strength and magnitude of these associations did not differ much between blacks and whites. In both blacks and whites, oxLDL was also associated with obesity (OR = 1.3, 95% CI:1.1-1.4) and three of its related traits (ss = 0.60 +/- 0.14 for BMI, ss = 0.74 +/- 0.17 for % body fat, ss = 0.29 +/- 0.06 for visceral fat; all p < 0.001). Furthermore, of four traits measured after 7 years of follow-up (fasting glucose, HbA1c, BMI and % fat), their relationship with oxLDL was similar to baseline observations. No significant association was found between oxLDL and incident T2D. Interestingly, oxLDL was significantly associated with % change in T2D- and obesity-related traits in whites but not in blacks. CONCLUSION/INTERPRETATION: Our data suggest that systemic oxidative stress may be a novel risk factor for T2D and obesity.

Association between telomere length, specific causes of death, and years of healthy life in health, aging, and body composition, a population-based cohort study.

Although telomere length (TL) is known to play a critical role in cellular senescence, the relationship of TL to aging and longevity in humans is not well understood. In a large biracial population-based cohort, we tested the hypotheses that elderly persons with shorter TL in peripheral white blood cells have poorer survival, shorter life span, and fewer years of healthy life (YHL). Associations were evaluated using Cox proportional hazard models and linear regression analyses where appropriate. TL (in kilo base pairs) was not associated with overall survival (hazard ratio 1.0; 95% confidence interval 0.9-1.1) or death from any specific underlying cause including infectious diseases, cancer, or cardiac and cerebrovascular diseases. TL, however, was positively associated with more YHL (beta = 0.08 +/- 0.04, p = .03). Findings suggest that TL may not be a strong biomarker of survival in older individuals, but it may be an informative biomarker of healthy aging.

Telomere length is paternally inherited and is associated with parental lifespan.

Telomere length (TL) is emerging as a biomarker for aging and survival. To evaluate factors influencing this trait, we measured TL in a large homogeneous population, estimated the heritability (h(2)), and tested for parental effects on TL variation. Our sample included 356 men and 551 women, aged 18-92 years, from large Amish families. Mean TL in leukocytes was measured by quantitative PCR (mean: 6,198 +/- 1,696 bp). The h(2) of TL was 0.44 +/- 0.06 (P < 0.001), after adjusting for age, sex, and TL assay batch. As expected, TL was negatively correlated with age (r = -0.40; P < 0.001). There was no significant difference in TL between men and women, consistent with our previous findings that Amish men lived as long as Amish women. There was a stronger and positive correlation and association between TL in the offspring and paternal TL (r = 0.46, P < 0.001; beta = 0.22, P = 0.006) than offspring and maternal TL (r = 0.18, P = 0.04; beta = -0.02, P = 0.4). Furthermore, we observed a positive correlation and association between daughter's TL and paternal lifespan (r = 0.20, P < 0.001; beta = 0.21, P = 0.04), but not between daughter's TL and maternal lifespan (r = -0.01, beta = 0.04; both P = not significant). Our data, which are based on one of the largest family studies of human TL, support a link between TL and aging and lifespan and suggest a strong genetic influence, possibly via an imprinting mechanism, on TL regulation.

The association between H63D mutations in HFE and amyotrophic lateral sclerosis in a Dutch population.

BACKGROUND: Mutations in HFE, a gene defect that can disrupt iron metabolism, have been implicated in increasing the risk of developing amyotrophic lateral sclerosis (ALS). OBJECTIVE: To further establish the association between ALS and HFE mutations by investigating whether HFE mutations are associated with an increased risk of developing ALS in a population in The Netherlands and by pooling our results with those from previous studies. DESIGN: Retrospective study. SETTING: Tertiary referral center for neuromuscular disorders. PARTICIPANTS: Genotyping for 2 common HFE mutations was performed in 289 patients with ALS and 5886 population-based controls in The Netherlands between January 1, 2000, and December 31, 2004. MAIN OUTCOME MEASURES: Development of ALS and clinical phenotype were compared among the different HFE genotypes, adjusting for known prognostic factors such as age at onset and sex. RESULTS: Homozygosity for H63D was associated with an increased risk of developing ALS (odds ratio [OR], 2.2; 95% confidence interval [CI], 1.1-4.1). After pooling our results with those from previous studies, a positive association between H63D homozygotes (OR, 2.7; 95% CI, 1.7-4.4), heterozygotes (OR, 1.5; 95% CI, 1.0-2.1), and mutation carriers (OR, 1.7; 95% CI, 1.1-2.5) was found. Within the patient group, heterozygosity for the H63D mutation was associated with a higher age at onset. CONCLUSIONS: These findings suggest that H63D mutations in HFE play a role in the pathogenesis of ALS in various populations. This association might involve a later-onset subset of ALS.

An insulin-like growth factor-I promoter polymorphism is associated with increased mortality in subjects with myocardial infarction in an elderly Caucasian population.

We investigated whether an insulin-like growth factor I (IGF-I) promoter polymorphism is associated with excess mortality in elderly subjects with myocardial infarction (MI). This association was assessed in 7,983 subjects of the Rotterdam Study during 14 years of follow-up. Among 345 subjects who developed a MI, the risk of mortality was 1.49 times higher in the variant carriers of the IGF-I promoter polymorphism than in the nonvariant carriers (95% confidence interval 1.10 to 2.10, p = 0.02). The risk of death increased with the number of variant alleles. Our study suggests that genetically determined low IGF-I activity is an important determinant of mortality in subjects with MI.

Angiotensin-converting enzyme gene insertion/deletion polymorphism and breast cancer risk.

BACKGROUND: The renin-angiotensin system plays an important role in homeostasis and lately, its main effector, angiotensin II, has been attributed with angiogenic and growth factor actions in the breast tissue. Previous studies have shown that the insertion/deletion (I/D) polymorphism in the angiotensin-converting enzyme (ACE) gene accounts for the variability of ACE plasma concentrations. The use of ACE inhibitors and the ACE I/D polymorphism may be linked to breast cancer risk. In this study, we evaluate the relationship of the ACE I/D polymorphism with breast cancer risk in Caucasian postmenopausal women. METHODS: The ACE I/D polymorphism was genotyped in 4,117 women participants in the Rotterdam Study. Baseline information was obtained through a questionnaire. We conducted a logistic regression and survival analysis to assess the risk of breast cancer by the ACE genotype. RESULTS: The DD carriers showed a significantly increased risk of developing breast cancer when compared with the II carriers (odds ratio, 1.86; 95% confidence interval, 1.06-3.27; P = 0.03). This association remained after adjusting for other risk factors, including body mass index, age at menarche, age at menopause, hormone replacement therapy, and hypertension. Our survival analysis showed that the cancer-free survival was significantly reduced in DD compared with II carriers (hazard ratio, 1.80; 95% confidence interval, 1.07-3.01; P = 0.03). CONCLUSIONS: Our results suggest that the ACE I/D polymorphism plays an important role in breast cancer risk and disease-free survival in Caucasian postmenopausal women.

The -514 C->T hepatic lipase promoter region polymorphism and plasma lipids: a meta-analysis.

Investigations of the -514 C-->T single nucleotide polymorphism (SNP) in the hepatic lipase (HL) gene promoter region (LIPC) have yielded contradictory results regarding its association with changes in plasma lipids. The current study is a meta-analysis of 25 publications on this SNP, comprising over 24,000 individuals, and its relationship with total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol (HDL), triglycerides, and HL activity. Significant decreases were observed in HL activity for both the CT and TT genotypes compared with the CC genotype [weighted mean difference (WMD), -5.83 mmol/liter.h (95% confidence interval, -8.48, -3.17) and -11.05 mmol/liter.h (95% confidence interval, -14.74, -7.36), respectively]. Moreover, significant increases in HDL were found; the CT to CC comparison showed an increase in WMD of 0.04 mmol/liter (95% confidence interval, 0.02, 0.05) mmol/liter, and the increase in the TT vs. CC difference was WMD of 0.09 mmol/liter (95% confidence interval, 0.07, 0.12). These changes appear to be stepwise, implying an allele dosage effect. All P values for these associations were less than 0.001. This meta-analysis demonstrates the importance of the -514C-->T SNP in determining HL activity and plasma HDL concentration and helps quantify the role that hepatic lipase plays in the metabolism of HDL.

Does bilirubin protect against hemochromatosis gene (HFE) related mortality?

Serum bilirubin is an important antioxidant that is found at increased levels in hereditary hemochromatosis patients. We hypothesized that increased levels of serum bilirubin may play a protective role against oxidative stress induced by iron overload in carriers of mutations in the hereditary hemochromatosis gene (HFE). We studied the relation between serum total bilirubin, serum iron levels, the HFE C282Y and H63D mutations, and mortality. The study was conducted in 2,332 randomly selected subjects from the Rotterdam Study, a population-based follow-up study of people aged 55 years or over. Serum bilirubin levels were significantly correlated with serum iron (Pearson's correlation coefficient (r) = 0.4, P < 0.001), transferrin saturation (r = 0.4, P < 0.001), and serum ferritin (r = 0.2, P < 0.05). Carriers of the HFE mutations had higher levels of bilirubin compared to wild-type homozygotes. The relation was the strongest in H63D heterozygotes or homozygotes and C282Y heterozygotes. High levels of serum bilirubin were associated with a 2.8 (95% CI 0.9-8.8) fold reduction in mortality in H63D homozygotes and a 2.2 (1.0-4.7) fold reduction in mortality in C282Y heterozygotes. Taken together, our data suggest that the high levels of the antioxidant bilirubin may counteract the adverse effect of oxidative stress induced by iron overload. This may explain in part the reduced penetrance of the HFE mutations.

Is genetic screening for hemochromatosis worthwhile?

Hereditary hemochromatosis is an iron overload disorder and is the most common recessive disease in Caucasians. About 80% of hemochromatosis patients are homozygous for the C282Y mutation in the HFE gene. Since iron accumulation can be prevented by phlebotomy, there is increasing interest in screening populations for hemochromatosis. Hemochromatosis is a disease that meets all the criteria for screening as set by the World Health Organization (WHO) or the US preventive services task force criteria for a screening program. However, there is no consensus on the value of a screening program for hemochromatosis. Moreover, there is no agreement on whether this screening should be based on the phenotype i.e. biochemical levels of serum iron parameters or on the genotype i.e. based on the presence of mutations in the HFE gene. Other important concerns are the lack of important data in evaluating screening as well as the psychosocial impact of a screening program. The present review analyses the current situation from a genetic-epidemiological perspective. We conclude that general population screening may be helpful to identify high-risk groups or individuals in the early stage of the disease so that treatment can be started. We suggest a two-phase screening program based on the first instance on serum iron levels and then a genetic test to only those with elevated serum iron parameters.