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.

Sequence variation in SORL1 and dementia risk in Swedes.

The gene encoding the neuronal sortilin-related receptor SORL1 has been claimed to be associated with Alzheimer's disease (AD) by independent groups and across various human populations. We evaluated six genetic markers in SORL1 in a sample of 1,558 Swedish dementia cases (including 1,270 AD cases) and 2,179 controls. For both single-marker-based and haplotype-based analyses, we found no strong support for SORL1 as a dementia or AD risk-modifying gene in our sample in isolation nor did we observe association with AD/dementia-related traits, including cerebrospinal fluid beta-amyloid(1-42), tau levels, or age at onset. However, meta-analyses of markers in this study together with previously published studies on SORL1 encompassing in excess of 13,000 individuals does suggest significant association with AD (best odds ratio = 1.097; 95% confidence interval = 1.038-1.158, p = 0.001). All six markers were significant in meta-analyses and it is notable that they occur in two distinct linkage disequilibrium blocks. These data are consistent with either allelic heterogeneity or the existence of as yet untested functional variants and these will be important considerations in further attempts to evaluate the importance of sequence variation in SORL1 with AD risk.

Nonstroke cardiovascular disease and risk of Alzheimer disease and dementia.

Unresolved issues in dementia research include (1) the association between nonstroke cardiovascular disease (CVD) and Alzheimer disease (AD) and (2) whether the association between CVD and dementia is mediated by familial factors (ie, genes and early life environment). We therefore conducted a study with both a longitudinal and a co-twin control design in 2214 Swedish twins with clinical dementia evaluation and apolipoprotein E (ApoE) genotyping. The analyses were then replicated in a register-based cohort of 18,405 individuals. Results show that CVD increases the risk of AD in carriers (but not noncarriers) of the ApoE4 allele (hazard ratio 2.39, 95% confidence interval 1.15-4.96). CVD was also associated with an almost 2-fold increased risk of developing late-life dementia (hazard ratio 1.83, 95% confidence interval 1.23-2.72). Within twin pairs, the dementia-affected twin was more likely to have had CVD than the nondemented twin partner (odds ratio 1.86, 95% confidence interval 1.11-3.13). In conclusion, this study shows that (1) nonstroke CVD increases the risk of late-life dementia but that it is only a risk factor for AD in carriers of the ApoE4 allele and (2) the association between CVD and dementia is not explained by genetic or early life environmental factors in common to both disorders.

A survey of ABCA1 sequence variation confirms association with dementia.

We and others have conducted targeted genetic association analyses of ABCA1 in relation to Alzheimer disease risk with a resultant mixture of both support and refutation, but all previous studies have been based upon only a few markers. Here, a detailed survey of genetic variation in the ABCA1 region has been performed in a total of 1,567 Swedish dementia cases (including 1,275 with Alzheimer disease) and 2,203 controls, providing evidence of association with maximum significance at marker rs2230805 (odds ratio [OR]=1.39; 95% confidence interval [CI] 1.23-1.57, p=7.7x10(-8)). Haplotype-based tests confirmed association of this genomic region after excluding rs2230805, and imputation did not reveal additional markers with greater support. Significantly associating markers reside in two distinct linkage disequilibrium blocks with maxima near the promoter and in the terminal exon of a truncated ABCA1 splice form. The putative risk allele of rs2230805 was also found to be associated with reduced cerebrospinal fluid levels of beta-amyloid. The strongest evidence of association was obtained when all forms of dementia were considered together, but effect sizes were similar when only confirmed Alzheimer disease cases were assessed. Results further implicate ABCA1 in dementia, reinforcing the putative involvement of lipid transport in neurodegenerative disease.

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.

Asthma, eczema, rhinitis and the risk for dementia.

BACKGROUND: Inflammation is associated with Alzheimer's disease (AD) and dementia. In light of the chronic inflammatory properties of the atopic disorders asthma, eczema and rhinitis, we hypothesized an association with dementia. METHODS: Self-reported asthma, eczema or rhinitis was assessed (prior to dementia follow-up) through questionnaires in the 1960s or 1970s in twins from the population-based Swedish Twin Registry. Dementia was assessed both longitudinally (n = 22,188), through linkages to two population-based registers, and cross-sectionally (n = 7,800), through telephone cognitive screening followed by a clinical evaluation of suspects of dementia. Risk ratios were estimated with Cox and logistic regression models controlling for vascular disease and genetic confounding. RESULTS: In the longitudinal study, a history of atopy was positively associated with dementia (HR = 1.16; 1.01-1.33). In the cross-sectional study we found overall lower risks, none of which was statistically significant. Asthma was associated with a shorter survival time following AD onset. CONCLUSIONS: Atopy is associated with a modestly increased risk of AD and dementia that is not mediated by vascular disease or due to genetic confounding. A history of asthma is associated with shorter life expectancy after AD diagnosis.

Genetic variants determining survival and fertility in an adverse African environment: a population-based large-scale candidate gene association study.

Human survival probability and fertility decline strongly with age. These life history traits have been shaped by evolution. However, research has failed to uncover a consistent genetic determination of variation in survival and fertility. As an explanation, such genetic determinants have been selected in adverse environments, in which humans have lived during most of their history, but are almost exclusively studied in populations in modern affluent environments. Here, we present a large-scale candidate gene association study in a rural African population living in an adverse environment. In 4387 individuals, we studied 4052 SNPs in 148 genes that have previously been identified as possible determinants of survival or fertility in animals or humans. We studied their associations with survival comparing newborns, middle-age adults, and old individuals. In women, we assessed their associations with reported and observed numbers of children. We found no statistically significant associations of these SNPs with survival between the three age groups nor with women's reported and observed fertility. Population stratification was unlikely to explain these results. Apart from a lack of power, we hypothesise that genetic heterogeneity of complex phenotypes and gene-environment interactions prevent the identification of genetic variants explaining variation in survival and fertility in humans.

Determinants of epidemiologic transition in rural Africa: the role of socioeconomic status and drinking water source.

BACKGROUND: Many African countries experience a protracted epidemiologic transition, different from the classical transition in western societies. The factors driving this protracted transition are largely unknown. In northeast Ghana, we studied an ongoing epidemiologic transition and investigated the effects of socioeconomic status and drinking water source on the transition. METHODS: During a 9-year period, we followed a cohort of almost 30 000 individuals and collected information on mortality and fertility rates. In addition, using the standards set out by the WHO, we obtained the causes of death by verbal autopsy. Individuals were stratified according to their socioeconomic status and the households' use of an improved or unimproved drinking water source. RESULTS: Mortality rates decreased by -5.0% annually (p<0.001) and the main cause of death shifted from infectious to non-infectious diseases (p=0.014). General fertility rates and child-women ratios decreased annually by -12.7% (p<0.001) and -11.9% (p<0.001), respectively. There was no difference in the decline of mortality and fertility depending on socioeconomic status or drinking water source. CONCLUSIONS: Factors other than socioeconomic status and drinking water source are responsible for the observed declines in mortality and fertility observed during the protracted epidemiologic transition. Identifying the specific determinants of the ongoing transition is of importance, as they could be targeted in order to further improve public health in rural African countries.

Seasonal variation in child and old-age mortality in rural Ghana.

BACKGROUND: Mortality in tropical countries varies considerably from season to season. As many of these countries have seen mortality moving from child to old-age mortality, we have studied seasonal variation in child and old-age mortality in a rural area in Ghana that currently undergoes an epidemiologic transition. METHODS: In an annual survey from 2002 through to 2011, we followed 29 642 individuals and obtained the cause and month of death from 1406 deceased individuals by making use of verbal autopsies. RESULTS: When comparing the seasons, we observed a trend for higher mortality during the wet season. When comparing separate months, we observed 34% more deaths than expected in September (95% CI 1.04-1.69; p = 0.024) at the end of the wet season and 43% more deaths in April (95% CI 1.13-1.80; p = 0.004) at the end of the dry season, while there were 42% less deaths than expected in December (95% CI 0.52-0.70; p = 0.003), shortly after the wet season. Cause-specific analysis indicated that the peak at the end of the wet season was due to excess mortality from infectious diseases in children and older people alike, whereas the peak in old-age mortality at the end of the dry season was due to non-infectious causes in older people only. CONCLUSIONS: Taken together, our data suggest that during the epidemiologic transition, mortality not only shifts from child to old-age and from infectious to non-infectious, but also from the wet to the dry season.

Low C-reactive protein levels in a traditional West-African population living in a malaria endemic area.

BACKGROUND: C-reactive protein (CRP) levels are reported to be elevated in populations of African descent living in affluent environments compared to populations of European ancestry. However, the natural history of CRP levels in populations of African descent living under adverse environments remains largely unknown. METHODS: CRP levels were measured with a high sensitivity assay in 624 apparently healthy individuals who contributed blood as part of a study on innate immune responsiveness in a traditional Ghanaian population living under adverse environmental conditions in a malaria endemic area. As a comparison, we included CRP measurements from 2931 apparently healthy individuals from the Dutch population that were included in the same batch of CRP analyses. Associations between CRP and body mass index (BMI), immune responsiveness, and P. falciparum parasitaemia were investigated. RESULTS: In an age- and sex-adjusted model, CRP levels were 0.54 mg/L lower in the Ghanaian compared to the Dutch cohort (1.52 vs. 0.98 mg/L, p<0.001). When accounting for the substantially higher average BMI in the Dutch compared to the Ghanaians (25.6 vs. 18.4 kg/m(2)) the difference in CRP levels disappeared. BMI associated positively with CRP in the Dutch but not in the Ghanaians. In individuals with an acute phase response, CRP levels were higher in the Ghanaian compared to the Dutch cohort (24.6 vs. 17.3 mg/L, p = 0.04). Levels of CRP were positively related to immune responsiveness and P. falciparum parasitaemia (all p<0.001) among Ghanaians. CONCLUSIONS: Our study demonstrates that West-Africans do not exhibit an inherently high inflammatory state. The role of genes, environment and gene-environment interaction in explaining reports of elevated CRP levels in populations of African ancestry when compared to other ethnicities living in affluent environments thus merits further investigation.

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.

Ancestral stories of Ghanaian Bimoba reflect millennia-old genetic lineages.

Oral history and oral genealogies are mechanisms of collective memory and a main cultural heritage of many populations without a writing system. In the effort to analytically address the correspondence between genetic data and historical genealogies, anthropologists hypothesised that genealogies evolve through time, ultimately containing three parts: literal--where the most recent ancestry is truthfully represented; intended--ancestry is inferred and reflects political relations among groups; and mythical--that does not represent current social reality. While numerous studies discuss oral genealogies, to our knowledge no genetic studies have been able to investigate to what extent genetic relatedness corresponds to the literal and intended parts of oral genealogies. We report on the correspondence between genetic data and oral genealogies among Bimoba males in a single village in North-Eastern Ghana. We compared the pairwise mismatch distribution of Y chromosome short tandem repeat (Y-STR) haplotypes among all lineages present in this village to the self-reported (oral) relatedness. We found that Bimoba are able to correctly identify unrelated individuals in 92% of the cases. In contrast, they are able to correctly identify related individuals only in 38% of the cases, which can be explained by three processes: (1) the compression of genealogies, leading to increasing inaccuracy with increasing genealogical distance, (2) inclusions into the lineage from intended relations such as clan co-option or adoptions, and (3) false paternities, which in this study were found to have a minor effect on the correspondence between genetic data and oral genealogies. In addition, we observed that 70% of unrelated pairs have from six to eight Y-STR differences, a diversification peak which we attribute to an ancient West African expansion dating around 9454 years ago. We conclude that, despite all caveats, oral genealogies are reflecting ancient lineages more accurately than previously thought.

Clustering of child mortality in a contemporary polygamous population in Africa.

Child mortality, defined here as mortality under age five, is not evenly distributed but found in clusters. In a contemporary polygamous population in Ghana with extended families, we separate clustering at the parental and household levels, which are often overlapping and inseparable in other historical studies. For eight years, we followed 28,994 individuals, including 9,288 children under the age of five, in 1,703 households. We identified four determinants that had a significant effect on child mortality: sex of the child, age of the child, drinking source, and socioeconomic status. After correcting for these determinants, we still identified significant clustering of child mortality at the level of the village (covariance [cov] = 0.02, p = .04), household (cov = 0.14, p = .003), father (cov = 0.24, p = .001), and mother (cov = 0.18, p = .05). The present data provide clues regarding the levels at which to look for unidentified determinants of child mortality and suggest that the importance of the father could be larger than previously thought.

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.

Low levels of antibodies against phosphorylcholine in Alzheimer's disease.

Phosphorylcholine (PC) may play an important role in the atherogenic and pro-inflammatory effects of oxidized low density lipoproteins. We recently demonstrated that low levels of IgM antibodies against PC (anti-PC) are associated with development of myocardial infarction and stroke. We here evaluate the association between anti-PC and dementia and Alzheimer's disease (AD). We conducted a nested case-control study of 182 incident dementia cases (serum collected before onset of dementia) matched to 366 controls and a case-control study of 97 prevalent dementia cases (serum collected after dementia onset) matched to 205 controls. Controls were matched on gender and age at blood draw (+/- 1 year). Participants were from the Swedish Twin Registry. Anti-PC levels were measured by ELISA. The odds ratio (OR) of dementia was modeled using conditional logistic regression. Patients with dementia had significantly lower mean anti-PC levels than controls (39.1 versus 49.5 U/ml). The likelihood of having dementia or AD was doubled for individuals with the lowest 25% anti-PC levels (OR=2.04 and 2.70, respectively). The results were similar after adjustments for potential confounders. There was no association between anti-PC levels and incident dementia. Low levels of atheroprotective anti-PC could play a role in AD and dementia. Potential mechanisms include decreased anti-inflammatory potential and effects on the vasculature. Further attention is merited to elucidate the role of anti-PC in AD development and the usefulness of anti-PC as a part of risk prediction, prognosis, diagnosis, or treatment.

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.