Parasitic infections and immune function: effect of helminth infections in a malaria endemic area.

According to the hygiene hypothesis, reduced exposure to infections could explain the rise of atopic diseases in high-income countries. Helminths are hypothesised to alter the host's immune response in order to avoid elimination and, as a consequence, also reduce the host responsiveness to potential allergens. To elucidate the effect of current helminth infections on immune responsiveness in humans, we measured cytokine production in a rural Ghanaian population in an area with multiple endemic parasites including malaria, intestinal helminths and protozoa. Multiplex real-time PCR in stool samples was used for the detection of four gastrointestinal helminths, of which only Necator americanus was commonly present. A similar assay was used to test for Giardia lamblia in stool samples and malaria infection in venous blood samples. Levels of the cytokines interleukin (IL)-10, tumour necrosis factor (TNF)-α, IL-17, IL-6, IL-13, and interferon (IFN)-γ were determined in whole-blood samples ex vivo-stimulated either with lipopolysaccharide (LPS) and zymosan (for innate cytokine production) or the T-cell mitogen phytohaemagglutinin (PHA). There were no significant differences in either innate or PHA-stimulated cytokine production dependent on current N. americanus infection. Plasmodium falciparum malarial infection was associated with a pro-inflammatory response indicated by increased innate production of TNF-α, IL-17 and IL-6. There was no clear pattern in cytokine responses dependent on G. lamblia-infection. In conclusion, in this rural Ghanaian population current N. americanus infections are not associated with altered immune function, while infection with P. falciparum is associated with pro-inflammatory innate immune responses.

Genetic association of sequence variants near AGER/NOTCH4 and dementia.

We performed a survey of sequence variation in a series of 20 genes involved in inflammation-related pathways for association with dementia risk in twin and unrelated case-control samples consisting in total of 1462 Swedish dementia casesand 1929 controls. For a total of 218 tested genetic markers, strong evidence was obtained implicating a region near AGER and NOTCH4 on chromosome 6p with replication across both samples and maximum combined significance at marker rs1800625 (OR = 1.37, 95% CI 1.19­1.56, p = 1.36×10(­6)). Imputation of the associated genomic interval provided an improved signal atrs8365, near the 3UTR of AGER (p = 7.34×10(­7)). The associated region extends 120 kb encompassing 11 candidate genes.While AGER encodes a key receptor for amyloid-ß protein, an analysis of network context based upon genes now confirmed to contribute to dementia risk (AßPP, PSEN1, PSEN2, CR1, CLU, PICALM, and APOE) suggested strong functional coupling to NOTCH4, with no significant coupling to the remaining candidates. The implicated region occurs in the broad HLA locus on chromosome 6p, but associated markers were not in strong LD with known variants that regulate HLA gene function, suggesting that this may represent a signal distinct from immune-system pathways.

Associations of gene sequence variation and serum levels of C-reactive protein and interleukin-6 with Alzheimer's disease and dementia.

Inflammatory mechanisms have been implicated in Alzheimer's disease (AD) and dementia. We therefore sought to study DNA sequence variation and serum levels of the potent inflammatory mediators Interleukin-6 (IL6) and C-reactive protein (CRP) in relation to AD and dementia. Tagging single nucleotide polymorphisms (tagSNPs) were chosen to capture most variation in and around CRP and IL6 in 3937 elderly Swedish men and women (1,265 AD cases). A sub-set of the population (n = 723) with serum measurements of CRP and IL6 was included in 1) a nested case-control study of incident dementia cases, and 2) a case-control study of prevalent dementia cases. None of the SNPs or haplotypes was significantly associated with AD or dementia after correcting for multiple testing nor were elevated baseline levels of hsCRP or IL6 (measured on average 4.3 years before dementia onset) significantly associated with risk of future AD or dementia. However, prevalent AD cases had higher levels of IL6 (measured on average 5.5 years after dementia onset) than age- and gender-matched controls, OR 2.24 (95% CI 1.27-3.95), p-value 0.006. In summary, this data suggests that AD patients have an altered immune profile with higher circulating levels of IL6 than age- and gender-matched controls. However, neither variation in the CRP and IL6 genes nor circulating levels of their respective protein products were associated with an increased risk of developing late-life dementias.

Macrophage inhibitory cytokine-1 (MIC-1/GDF15): a new marker of all-cause mortality.

Macrophage inhibitory cytokine-1 (MIC-1/GDF15) is a member of the TGF-b superfamily, previously studied in cancer and inflammation. In addition to regulating body weight, MIC-1/GDF15 may be used to predict mortality and/or disease course in cancer, cardiovascular disease (CVD), chronic renal and heart failure, as well as pulmonary embolism. These data suggested that MIC-1/GDF15 may be a marker of all-cause mortality. To determine whether serum MIC-1/GDF15 estimation is a predictor of all-cause mortality, we examined a cohort of 876 male subjects aged 35-80 years, selected from the Swedish Population Registry, and followed them for overall mortality. Serum MIC-1/GDF15 levels were determined for all subjects from samples taken at study entry. A second (independent) cohort of 324 same-sex twins (69% female) from the Swedish Twin Registry was similarly examined. All the twins had telomere length measured and 183 had serum levels of interleukin 6 (IL-6) and C-reactive protein (CRP) available. Patients were followed for up to 14 years and had cause-specific and all-cause mortality determined. Serum MIC-1/GDF15 levels predicted mortality in the all-male cohort with an adjusted odds ratio (OR) of death of 3.38 (95%CI 1.38-8.26). This finding was validated in the twin cohort. Serum MIC-1/GDF15 remained an independent predictor of mortality when further adjusted for telomere length, IL-6 and CRP. Additionally, serum MIC-1/GDF15 levels were directly correlated with survival time independently of genetic background. Serum MIC-1/GDF15 is a novel predictor of all-cause mortality.

Analysis of lipid pathway genes indicates association of sequence variation near SREBF1/TOM1L2/ATPAF2 with dementia risk.

We conducted dense linkage disequilibrium (LD) mapping of a series of 25 genes putatively involved in lipid metabolism in 1567 dementia cases [including 1270 with Alzheimer disease (AD)] and 2203 Swedish controls. Across a total of 448 tested genetic markers, the strongest evidence of association was as anticipated for APOE (rs429358 at P approximately 10(-72)) followed by a previously reported association of ABCA1 (rs2230805 at P approximately 10(-8)). In the present study, we report two additional markers near the SREBF1 locus on chromosome 17p that were also significant after multiple testing correction (best P = 3.1 x 10(-6) for marker rs3183702). There was no convincing evidence of association for remaining genes, including candidates highlighted from recent genome-wide association studies of plasma lipids (CELSR2/PSRC1/SORT1, MLXIPL, PCSK9, GALNT2 and GCKR). The associated markers near SREBF1 reside in a large LD block, extending more than 400 kb across seven candidate genes. Secondary analyses of gene expression levels of candidates spanning the LD region together with an investigation of gene network context highlighted two possible susceptibility genes including ATPAF2 and TOM1L2. Several markers in strong LD (r(2) > 0.7) with rs3183702 were found to be significantly associated with AD risk in recent genome-wide association studies with similar effect sizes, providing independent support of the current findings.

Interaction between smoking and genetic factors in the development of chronic bronchitis.

RATIONALE: Smoking is a primary risk factor for chronic bronchitis, emphysema, and chronic obstructive pulmonary disease, but since not all smokers develop disease, it has been suggested that some individuals may be more susceptible to exogenous factors, such as smoking, and that this susceptibility could be genetically determined. OBJECTIVES: The aim of the present study was to assess, in a population-based sample of twins, the following: (1) to what extent genetic factors contribute to the development of chronic bronchitis, including emphysema, taking sex into consideration, and (2) whether the genetic influences on chronic bronchitis, including emphysema, are separate from those for smoking behavior. METHODS: Disease cases and smoking habits were identified in 44,919 twins older than 40 years from the Swedish Twin Registry. Disease was defined as self-reported chronic bronchitis or emphysema, or recurrent cough with phlegm. Individuals who had smoked 10 pack-years or more were defined as smokers. Univariate and bivariate structural equation models were used to estimate the heritability specific for chronic bronchitis and that in common with smoking. MEASUREMENTS AND MAIN RESULTS: The heritability estimate for chronic bronchitis was a moderate 40% and only 14% of the genetic influences were shared with smoking. CONCLUSIONS: Genetic factors independent of those related to smoking habits play a role in the development of chronic bronchitis.