Apolipoprotein E genotype and association between smoking and early onset Alzheimer's disease.

OBJECTIVE--To investigate the hypothesis that differential survival between smokers and non-smokers leading to a decrease in the frequency of the e4 allele of the apolipoprotein E gene may explain the inverse relation between smoking history and early onset Alzheimer''s disease. DESIGN--A population based case-control study. SETTING--The four northern provinces of the Netherlands and metropolitan Rotterdam. SUBJECTS--175 patients with early onset Alzheimer''s disease and two independent control groups of 159 and 457 subjects. MAIN OUTCOME MEASURES--Frequencies of the apolipoprotein e4 allele and relative risk of early onset Alzheimer''s disease. RESULTS--The inverse association between smoking history and early onset Alzheimer''s disease could not be explained by a decrease in the frequency of the apolipoprotein e4 allele. Among carriers of this allele with a family history of dementia subjects with a history of smoking had a strongly reduced risk of early onset Alzheimer''s disease (odds ratio 0.10 (95% confidence interval 0.01 to 0.87)). CONCLUSIONS--The results suggest that the inverse relation between smoking history and early onset Alzheimer''s disease cannot be explained by an increased mortality in carriers of the apolipoprotein e4 allele who smoke. The association is strongly modified by the presence of the apolipoprotein e4 allele as well as by a family history of dementia.     

Simple and efficient analysis of disease association with missing genotype data

Missing genotype data arise in association studies when the single-nucleotide polymorphisms (SNPs) on the genotyping platform are not assayed successfully, when the SNPs of interest are not on the platform, or when total sequence variation is determined only on a small fraction of individuals. We present a simple and flexible likelihood framework to study SNP-disease associations with such missing genotype data. Our likelihood makes full use of all available data in case-control studies and reference panels (e.g., the HapMap), and it properly accounts for the biased nature of the case-control sampling as well as the uncertainty in inferring unknown variants. The corresponding maximum-likelihood estimators for genetic effects and gene-environment interactions are unbiased and statistically efficient. We developed fast and stable numerical algorithms to calculate the maximum-likelihood estimators and their variances, and we implemented these algorithms in a freely available computer program. Simulation studies demonstrated that the new approach is more powerful than existing methods while providing accurate control of the type I error. An application to a case-control study on rheumatoid arthritis revealed several loci that deserve further investigations.     

Significant association between GSTT1 null genotype and susceptibility to pancreatic cancer

Many studies have investigated the association between glutathione S-transferase T1 (GSTT1) polymorphism and risk for pancreatic cancer, but those studies have yielded contradictory findings on the association. We performed a comprehensive search in the PubMed, EMBASE, and the Chinese National Knowledge Infrastructure databases to identify relevant studies. A meta-analysis was performed to examine the association between GSTT1 polymorphism and susceptibility to pancreatic cancer by calculating the pooled odds ratios (ORs) and corresponding 95 % confidence intervals (95 % CIs). Eight studies involving a total of 4,437 individuals were included. Overall, significantly increased pancreatic cancer risk was associated with GSTT1 null genotype when all studies were pooled into the meta-analysis (random effects OR = 1.61, 95 % CI 1.06–2.44; P = 0.025). Significantly increased risk of pancreatic cancer was also found for GSTT1 null genotype in Asians when stratified by ethnicity (fixed effects OR = 2.67, 95 % CI 1.74–4.09; P < 0.001). The findings demonstrate that GSTT1 null genotype have a modest effect on the genetic susceptibility to pancreatic cancer, and GSTT1 null genotype is associated with increased risk of pancreatic cancer.     

Haplotype association analysis of human disease traits using genotype data of unrelated individuals

Haplotype inference has become an important part of human genetic data analysis due to its functional and statistical advantages over the single-locus approach in linkage disequilibrium mapping. Different statistical methods have been proposed for detecting haplotype - disease associations using unphased multi-locus genotype data, ranging from the early approach by the simple gene-counting method to the recent work using the generalized linear model. However, these methods are either confined to case - control design or unable to yield unbiased point and interval estimates of haplotype effects. Based on the popular logistic regression model, we present a new approach for haplotype association analysis of human disease traits. Using haplotype-based parameterization, our model infers the effects of specific haplotypes (point estimation) and constructs confidence interval for the risks of haplotypes (interval estimation). Based on the estimated parameters, the model calculates haplotype frequency conditional on the trait value for both discrete and continuous traits. Moreover, our model provides an overall significance level for the association between the disease trait and a group or all of the haplotypes. Featured by the direct maximization in haplotype estimation, our method also facilitates a computer simulation approach for correcting the significance level of individual haplotype to adjust for multiple testing. We show, by applying the model to an empirical data set, that our method based on the well-known logistic regression model is a useful tool for haplotype association analysis of human disease traits.     

ApoE and ApoC-I polymorphisms: association of genotype with cardiovascular disease phenotype in African Americans

Apolipoproteins (apo) E and C-I are components of triglyceride (TG)-rich lipoproteins and impact their metabolism. Functional polymorphisms have been established in apoE but not in apoC-I. We studied the relationship between apoE and apoC-I gene polymorphisms and plasma lipoproteins and coronary artery disease (CAD) in 211 African Americans and 306 Caucasians. In African Americans but not in Caucasians, apoC-I H2-carriers had significantly lower total and LDL cholesterol and apoB levels, and higher glucose, insulin, and HOMA-IR levels compared with H1 homozygotes. Differences across CAD phenotypes were seen for the apoC-I polymorphism. African-American H2-carriers without CAD had significantly lower total cholesterol (P < 0.001), LDL cholesterol (P < 0.001), and apoB (P < 0.001) levels compared with H1 homozygotes, whereas no differences were found across apoC-I genotypes for African Americans with CAD. Among African-American apoC-I H1 homozygotes, subjects with CAD had a profile similar to the metabolic syndrome (i.e., higher triglyceride, glucose, and insulin) compared with subjects without CAD. For African-American H2-carriers, subjects with CAD had a pro-atherogenic lipid pattern (i.e., higher LDL cholesterol and apoB levels), compared with subjects without CAD. ApoC-I genotypes showed an ethnically distinct phenotype relationship with regard to CAD and CAD risk factors.     

Genetic considerations on association between HLA and disease

Summary Blood specimens from a random sample of 981 South African Negroid females were typed electrophoretically inter alia for their G-6-PD phenotypes. The allele frequency for Gd^B and Gd^nonB was found to be 0.8126 and 0.1874 respectively. Calculating the number of individuals expected for each phenotypic class, a highly significant deviation from the Hardy-Weinberg equilibrium became manifest, i.e. there was a deficit of 24.6% of heterozygotes and an excess of 12.3% of each of the two classes of homozygotes.Several possible reasons for this discrepancy e.g. the effects of pooling sub-samples, selection and misclassifications due to insufficient staining were examined and were found not to be likely explanations for the observed phenomenon. Instead, the result is interpreted as due to only 3–4 stem cells which give rise to the haematopoetic system in man.Part of this work was presented at the biennial Congress of the Deutsche Gesellschaft für Anthropologie und Humangenetik held in Vienna, September 22–25, 1975Supported by a research fellowship (1975/76) granted by the Alexander von Humboldt-Stiftung, Bonn-Bad GodesbergSupported by the Deutsche Forschungsgemeinschaft (DFG), Bonn-Bad Godesberg     

The association between rheumatoid arthritis and periodontal disease

Chronic, plaque-associated inflammation of the gingiva and the periodontium are among the most common oral diseases. Periodontitis (PD) is characterized by the inflammatory destruction of the periodontal attachment and alveolar bone, and its clinical appearance can be influenced by congenital as well as acquired factors. The existence of a rheumatic or other inflammatory systemic disease may promote PD in both its emergence and progress. However, there is evidence that PD maintains systemic diseases. Nevertheless, many mechanisms in the pathogenesis have not yet been examined sufficiently, so that a final explanatory model is still under discussion, and we hereby present arguments in favor of this. In this review, we also discuss in detail the fact that oral bacterial infections and inflammation seem to be linked directly to the etiopathogenesis of rheumatoid arthritis (RA). There are findings that support the hypothesis that oral infections play a role in RA pathogenesis. Of special importance are the impact of periodontal pathogens, such as Porphyromonas gingivalis on citrullination, and the association of PD in RA patients with seropositivity toward rheumatoid factor and the anti-cyclic citrullinated peptide antibody.     

Assessment of the association between GSTM1 null genotype and risk of type 2 diabetes

Many studies have investigated the association between Glutathione S-Transferase M1 (GSTM1) null genotype and risk of diabetes mellitus, but the impact of GSTM1 null genotype on diabetes mellitus is unclear owing to the obvious inconsistence among those studies. This study aimed to quantify the strength of association between GSTM1 null genotype and risk of diabetes mellitus. We searched the PubMed, Embase and Wangfang databases for studies relating the association between GSTM1 null genotype and risk of diabetes mellitus. We estimated summary odds ratio (OR) with their 95 % confidence interval (95 % CI) to assess the association. Subgroup analyses were performed by type of diabetes and ethnicity. 10 case–control studies with 7, 054 subjects were included into this meta-analysis. Meta-analysis of total 10 studies showed GSTM1 null genotype was associated increased risk of diabetes mellitus (OR = 1.59, 95 % CI 1.14–2.22, P = 0.007). Subgroup analyses by type of diabetes mellitus suggested GSTM1 null genotype was associated increased risk of type 2 diabetes (OR = 1.90, 95 % CI 1.37–2.64, P < 0.001), but was not associated with risk of type 1 diabetes (OR = 0.84, 95 % CI 0.66–1.07, P = 0.153). Subgroup analysis by ethnicity further identified the obvious association between GSTM1 null genotype and increased risk of type 2 diabetes. The cumulative meta-analyses showed a trend of obvious association between GSTM1 null genotype and risk of type 2 diabetes as information accumulated. No evidence of publication bias was observed. Thus, evidence from current meta-analysis suggests an association between GSTM1 null genotype and risk of type 2 diabetes.     

Evolutionary perspectives on the links between mitochondrial genotype and disease phenotype

Background

Disorders of the mitochondrial respiratory chain are heterogeneous in their symptoms and underlying genetics. Simple links between candidate mutations and expression of disease phenotype typically do not exist. It thus remains unclear how the genetic variation in the mitochondrial genome contributes to the phenotypic expression of complex traits and disease phenotypes.

Scope of review

I summarize the basic genetic processes known to underpin mitochondrial disease. I highlight other plausible processes, drawn from the evolutionary biological literature, whose contribution to mitochondrial disease expression remains largely empirically unexplored. I highlight recent advances to the field, and discuss common-ground and -goals shared by researchers across medical and evolutionary domains.

Major conclusions

Mitochondrial genetic variance is linked to phenotypic variance across a variety of traits (e.g. reproductive function, life expectancy) fundamental to the upkeep of good health. Evolutionary theory predicts that mitochondrial genomes are destined to accumulate male-harming (but female-friendly) mutations, and this prediction has received proof-of-principle support. Furthermore, mitochondrial effects on the phenotype are typically manifested via interactions between mitochondrial and nuclear genes. Thus, whether a mitochondrial mutation is pathogenic in effect can depend on the nuclear genotype in which is it expressed.

General significance

Many disease phenotypes associated with OXPHOS malfunction might be determined by the outcomes of mitochondrial–nuclear interactions, and by the evolutionary forces that historically shaped mitochondrial DNA (mtDNA) sequences. Concepts and results drawn from the evolutionary sciences can have broad, but currently under-utilized, applicability to the medical sciences and provide new insights into understanding the complex genetics of mitochondrial disease. This article is part of a Special Issue entitled Frontiers of Mitochondrial Research.     

Significant association between GSTT1 null genotype and risk of asthma during childhood in Caucasians

Asthma is a complex multifactorial disorder and its management requires a better understanding of its various pathogenesis and mechanisms. Previous studies assessing the association between glutathione S-transferase T1 (GSTT1) null genotype and asthma risk during childhood reported conflicting results. To get a more precise estimation of the association between GSTT1 null genotype and risk of asthma during childhood, we performed a meta-analysis of 16 studies with a total of 18,558 subjects. Subgroup analyses were performed by ethnicity. The pooled odds ratio (OR) with corresponding 95 % confidence interval (95 %CI) was used to assess the association. Overall, there was a significant association between GSTT1 null genotype and increased risk of children asthma (OR = 1.25, 95 % CI, 1.02–1.54; P = 0.032). Subgroup analyses showed GSTT1 null genotype was associated with increased risk of children asthma in Caucasians (OR = 1.46, 95 % CI, 1.04–2.03; P = 0.027), but not in Asians (OR = 1.03, 95 % CI, 0.55–1.94; P = 0.928) and Africans (OR = 1.33, 95 % CI, 0.92–1.91; P = 0.127). There was no evidence of publication bias in the subgroup analysis of Caucasians. In conclusion, there is a significant association between GSTT1 null genotype and risk of asthma during childhood in Caucasians. More well-designed epidemiological studies are needed to further assess this association in Asians and Africans.     

Allelic association and disease mapping.

The application of allelic association to map genes for complex traits, particularly using high-density maps of single nucleotide polymorphisms in candidate regions, is an area of very active research. Here we present some aspects of the methodology and applications to both major gene mapping, which illustrates the effectiveness of the method, and oligogenes, where methods are still in flux and for which there have been relatively few successes to date. Several important considerations emerge, including the selection of the optimal metric for measuring association and the importance of modelling the decline in association with distance given the variability in association in a candidate region. The Malecot model of association with distance is shown to have a resolution of greater than 50 kilobases but the available evidence suggests that considerably higher resolution might be achieved with dense single nucleotide polymorphism (SNP) maps.     

Measures of ecological association

Summary The relationships of photosynthetic characteristics to the competitive interactions of a C₃ plant, Chenopodium album, and a C₄ plant, Amaranthis retroflexus, were investigated in different temperature and water supply regimes. Both species had similar photosynthetic rates at 25°C, but at higher temperatures, Amaranthus had substantially greater rates than Chenopodium. Conversely, at lower temperatures, Chenopodium had an advantage. The competitive abilities in mixtures exhibited a close parallel to the photosynthetic performances with Amaranthus having an advantage at high temperatures and Chenopodium an advantage at low temperatures. These competitive outcomes were determined primarily by differences in relative growth rates prior to canopy closure. In the respective, temperature regimes, the species having the highest photosynthetic rate, which resulted an more rapid growth, overtopped and shaded the other species at the time of canopy closure. These results demonstrate that differences in photosynthetic temperature response between C₄ and C₃ plants can be an important determinant in competitive interactions, but at least in this case, the influence is primarily through, events prior to the actual initiation of competition.In contrast to temperature, growth of the plants under limited water supply had no influence on the competitive interactions. Thus, the presence of the C₄ pathway alone was not sufficient to yield a competitive advantage over the C₃ species under water limited conditions.     

Preliminary evidence for an association between LRP-1 genotype and body mass index in humans

Background/Aims

The LDL receptor-related protein-1 gene (LRP-1) has been associated with obesity in animal models, but no such association has yet been reported in humans. As data suggest this increase in fat mass may be mediated through a mechanism involving the clearance of plasma triglyceride-rich lipoproteins (TGRL), where the LRP interacts with apolipoprotein E (ApoE) on chylomicron remnants, we aimed to examine (1) whether there was an association between 3 single nucleotide polymorphisms (SNPs) on LRP-1 with body mass index (BMI) and (2) whether any association between LRP-1 SNPs and BMI could be modified by polymorphisms on the ApoE gene when comparing the wild type ε3/ε3 genotype against mutant ApoE allele (ε2/ε4) carriers.

Methods/Results

We used data from 1,036 men and women (mean age±SD = 49±16 y) participating in the Genetics of Lipid Lowering Drugs and Diet Network (GOLDN) Study. Mixed linear models, which controlled for age, sex, alcohol intake and smoking, as well as family pedigree and center of data collection were calculated. Models that used LRP-1 genotype as a predictor of BMI revealed that individuals who were homozygous for the minor allele at the LRP-1 {"type":"entrez-protein","attrs":{"text":"I10701","term_id":"592781","term_text":"I10701"}}I10701 locus had BMIs, on average, 1.03 kg/m² higher than major allele carriers (P = 0.03). In subsequent mixed linear models that included main effects of LRP-1 {"type":"entrez-protein","attrs":{"text":"I10701","term_id":"592781","term_text":"I10701"}}I10701 SNP and ApoE alleles, and an interaction term the two genotypes, there was no interaction detected between the LRP-1 {"type":"entrez-protein","attrs":{"text":"I70701","term_id":"3006836","term_text":"gb|I70701.1|I70701"}}I70701 genotype with either the ApoE ε2 or ε4 allele carriers (P>0.05).

Conclusions

This has implications for starting to understand pathways from genotype to human BMI, which may operate through TGRL uptake at the LRP-1 receptor. This may pave the way for future research into individualized dietary interventions.     

Linkage and association between inflammatory bowel disease and a locus on chromosome 12.

Genetic epidemiological studies have shown that genetic factors are important in the pathogenesis of the idiopathic inflammatory bowel diseases (IBD), Crohn disease (CD), and ulcerative colitis (UC). A genome screen in the United Kingdom found linkage of IBD to a 41-cM region of chromosome 12, surrounding D12S83. We aimed to replicate this linkage and to narrow the region of interest. Nonparametric linkage analyses at microsatellites surrounding D12S83 were performed in 122 North American Caucasian families containing 208 genotyped IBD-affected relative pairs. Transmission/disequilibrium tests (TDTs) were also performed. We confirmed that IBD is linked to chromosome 12 (peak GENEHUNTER-PLUS LOD* score 2.76 [P = .00016] between D12S1724 and D12S90). The evidence for linkage is contributed by both the group of CD-affected relative pairs (peak GENEHUNTER-PLUS LOD* score 1.79 [P = .0021] between D12S1724 and D12S90) and the group of UC-affected relative pairs (peak GENEHUNTER-PLUS LOD* score 1.82 [P = .0019] at D12S335). The TDT is positive at the D12S83 locus (global chi2 = 16.41, 6 df, P = .012). In conclusion, we have independently confirmed linkage of IBD to the chromosome 12 region that we investigated. A positive TDT at D12S83 suggests that we have greatly narrowed the chromosome 12 region that contains an IBD locus.     

Testing for association between disease and linked marker loci: a log-linear-model analysis.

One approach frequently used for identifying genetic factors involved in the process of a complex disease is the comparison of patients and controls for a number of genetic markers near a candidate gene. The analysis of such association studies raises some specific problems because of the fact that genotypic and not gametic data are generally available. We present a log-linear-model analysis providing a valid method for analyzing such studies. When studying the association of disease with one marker locus, the log-linear model allows one to test for the difference between allelic frequencies among affected and unaffected individuals, Hardy-Weinberg (H-W) equilibrium in both groups, and interaction between the association of alleles at the marker locus and disease. This interaction provides information about the dominance of the disease susceptibility locus, with dominance defined using the epidemiological notion of odds ratio. The degree of dominance measured at the marker locus depends on the strength of linkage disequilibrium between the marker locus and the disease locus. When studying the association of disease with several linked markers, the model becomes rapidly complex and uninterpretable unless it is assumed that affected and unaffected populations are in H-W equilibrium at each locus. This hypothesis must be tested before going ahead in the analysis. If it is not rejected, the log-linear model offers a stepwise method of identification of the parameters causing the difference between populations. This model can be extended to any number of loci, alleles, or populations.     

APOL1 G1 genotype modifies the association between HDLC and kidney function in African Americans

Background

Despite evidence of an association between variants at the apolipoprotein L1 gene (APOL1) locus and a spectrum of related kidney diseases, underlying biological mechanisms remain unknown. An earlier preliminary study published by our group showed that an APOL1 variant (rs73885319) modified the association between high-density lipoprotein cholesterol (HDLC) and estimated glomerular filtration rate (eGFR) in African Americans. To further understand this relationship, we evaluated the interaction in two additional large cohorts of African Americans for a total of 3,592 unrelated individuals from the Howard University Family Study (HUFS), the Natural History of APOL1-Associated Nephropathy Study (NHAAN), and the Atherosclerosis Risk in Communities Study (ARIC). The association between HDLC and eGFR was determined using linear mixed models, and the interaction between rs73885319 genotype and HDLC was evaluated using a multiplicative term.

Results

Among individuals homozygous for the risk genotype, a strong inverse HDLC-eGFR association was observed, with a positive association in others (p for the interaction of the rs73885319 × HDLC =0.0001). The interaction was similar in HUFS and NHAAN, and attenuated in ARIC. Given that ARIC participants were older, we investigated an age effect; age was a significant modifier of the observed interaction. When older individuals were excluded, the interaction in ARIC was similar to that in the other studies.

Conclusions

Based on these findings, it is clear that the relationship between HDLC and eGFR is strongly influenced by the APOL1 rs73885319 kidney risk genotype. Moreover, the degree to which this variant modifies the association may depend on the age of the individual. More detailed physiological studies are warranted to understand how rs73885319 may affect the relationship between HDLC and eGFR in individuals with and without disease and across the lifespan.

Electronic supplementary material

The online version of this article (doi:10.1186/s12864-015-1645-7) contains supplementary material, which is available to authorized users.     

The association between prolonged fatigue and cardiovascular disease in World War II veteran twins.

Reports of fatigue preceding cardiac events have recently been confirmed by large prospective studies. To assess for genetic confounding, we investigated prolonged fatigue and cardiovascular disease (CVD) in a cohort of World War II veteran twins. We examined data from a questionnaire mailed to members of the National Academy of Sciences-National Research Council (NAS-NRC) World War II Twins Registry in 1998 and 1999 which included questions on demographics, medical conditions and symptoms of fatigue. Data from twins discordant for prolonged fatigue lasting a month or more were analyzed using conditional logistic regression. Among 1955 twin pairs, 157 monozygotic and 174 dizygotic pairs (mean age 74 years) were discordant for prolonged fatigue. An association was found between prolonged fatigue and a history of myocardial infarction or coronary artery surgery adjusting for age, socioeconomic status, smoking, alcohol use and depression (OR [Odds Ratio]: 2.2; 95% CI: 1.3-4.0). When analyses were performed separately by zygosity, the association was slightly larger for monozygotic (OR: 3.3; 95% CI: 1.2-9.1) than dizygotic twins (OR: 1.9; 95% CI: 0.9-4.0). These data corroborate the association of fatigue with CVD and suggest that it is not influenced by a common genetic factor. Further studies are needed to clarify the relationship and to better understand the biologic mechanisms.     

Lack of association of ACE/angiotensinogen genotype with renal function in autosomal dominant polycystic kidney disease

ACE polymorphisms have recently been shown to associate with worse renal and or cardiovascular outcome, with the D allele widely reported as a risk factor for cardiovascular disease. In autosomal dominant polycystic kidney disease (ADPKD), there are conflicting reports of an association between ACE polymorphisms and disease phenotype. There are no previous reports of any association between angiotensinogen polymorphisms and clinical phenotype in ADPKD. We examined the ACE I/D and angiotensinogen M235T polymorphisms in 176 patients with ADPKD. Patients are categorized into three groups according to the reason for initial investigation. Clinical history and examination findings were recorded at the time of first referral. A cohort of 17 patients had progressive renal impairment observed after 3 or more years of follow-up. Reciprocal creatinine against time was plotted in this group. From the patient population of 176, a total of 33 patients reached end-stage renal failure (ESRF) or a serum creatinine greater than 500 microm/liter. ACE genotype and M235T polymorphism frequencies were compared across groups. Serum creatinine and presence of hypertension and onset of ESRF were taken as outcome variables; age and source of referral were taken as confounding variables. There was no association of any genotype or allele with either creatinine, inverse creatinine, hypertension, or age at end-stage renal failure. These findings do not support the proposition that ACE genotype or angiotensinogen polymorphisms are associated with a worse prognosis in patients with ADPKD.     

No association of COMT (Val158Met) genotype with brain structure differences between men and women

We examined the effect of the catechol-O-methyltransferase (COMT) Val158Met polymorphism (rs4680), on brain structure in a subset (N = 82) of general population members of the Northern Finland 1966 Birth Cohort, selected through a randomization procedure, aged 33-35. Optimised voxel-based morphometry was used to produce grey matter maps from each subject's high resolution T1 weighted brain magnetic resonance images, which were subsequently entered into a general linear model with COMT genotype as defined by Met allele loading, gender and genotype by gender interaction as independent variables. Additional analyses were carried out on grey matter volumes within the dorsal lateral pre-frontal cortex (DLPFC) to examine effects on overall DLPFC volume and also using the DLPFC as a mask for voxelwise analyses, as this is an area previously reported as associated with Met allele loading. We failed to find any statistically significant association with grey matter volume and Met allele loading in the COMT gene or interaction affects between COMT and gender in either the whole brain voxel-wise analysis or in the area of the DLPFC.