How Often Do Duplicated Genes Evolve New Functions?

A recently duplicated gene can either fix a null allele (becoming a pseudogene) or fix an (advantageous) allele giving a slightly different function, starting it on the road to evolving a new function. Here we examine the relative probabilities of these two events under a simple model. Null alleles are assumed to be neutral; linkage effects are ignored, as are unequal crossing over and gene conversion. These assumptions likely make our results underestimates for the probability that an advantageous allele is fixed first. When new advantageous mutations are additive with selection coefficient s and the ratio of advantageous to null mutations is ρ, the probability an advantageous allele is fixed first is ([1 - e(-S)]/[ρS] + 1)(-1), where S = 4N(e)s with N(e) the effective population size. The probability that a duplicate locus becomes a pseudogene, as opposed to evolving a new gene function, is high unless ρS & 1. However, even if advantageous mutations are very rare relative to null mutations, for sufficiently large populations ρS & 1 and new gene function, rather than pseudogene formation, is the expected fate of most duplicated genes.     

Selection Response in Finite Populations

Formulae were derived to predict genetic response under various selection schemes assuming an infinitesimal model. Account was taken of genetic drift, gametic (linkage) disequilibrium (Bulmer effect), inbreeding depression, common environmental variance, and both initial segregating variance within families (σ(AW0)(2)) and mutational (σ(M)(2)) variance. The cumulative response to selection until generation t(CR(t)) can be approximated as & where N(e) is the effective population size, σ(AW &)(2) = N(e)σ(M)(2) is the genetic variance within families at the steady state (or one-half the genic variance, which is unaffected by selection), and D is the inbreeding depression per unit of inbreeding. R(0) is the selection response at generation 0 assuming preselection so that the linkage disequilibrium effect has stabilized. β is the derivative of the logarithm of the asymptotic response with respect to the logarithm of the within-family genetic variance, i.e., their relative rate of change. R(0) is the major determinant of the short term selection response, but σ(M)(2), N(e) and β are also important for the long term. A selection method of high accuracy using family information gives a small N(e) and will lead to a larger response in the short term and a smaller response in the long term, utilizing mutation less efficiently.     

Evolutionarily stable mutation rate in a periodically changing environment

Evolution of mutation rate controlled by a neutral modifier is studied for a locus with two alleles under temporally fluctuating selection pressure. A general formula is derived to calculate the evolutionarily stable mutation rate μ(ess) in an infinitely large haploid population, and following results are obtained. (I) For any fluctuation, periodic or random: (1) if the recombination rate r per generation between the modifier and the main locus is 0, μ(ess) is the same as the optimal mutation rate μ(op) which maximizes the long-term geometric average of population fitness; and (2) for any r, if the strength s of selection per generation is very large, μ(ess) is equal to the reciprocal of the average number T of generations (duration time) during which one allele is persistently favored than the other. (II) For a periodic fluctuation in the limit of small s and r, μ(ess)T is a function of sT and rT with properties: (1) for a given sT, μ(ess)T decreases with increasing rT; (2) for sT </= 1, μ(ess)T is almost independent of sT, and depends on rT as μ(ess)T & 1.6 for rT << 1 and μ(ess)T & 6/rT for rT >> 1; and (3) for sT >/= 1, and for a given rT, μ(ess)T decreases with increasing sT to a certain minimum less than 1, and then increases to 1 asymptotically in the limit of large sT. (III) For a fluctuation consisting of multiple Fourier components (i.e., sine wave components), the component with the longest period is the most effective in determining μ(ess) (low pass filter effect). (IV) When the cost c of preventing mutation is positive, the modifier is nonneutral, and μ(ess) becomes larger than in the case of neutral modifier under the same selection pressure acting at the main locus. The value of c which makes μ(ess) equal to μ(op) of the neutral modifier case is calculated. It is argued that this value gives a critical cost such that, so long as the actual cost exceeds this value, the evolution rate at the main locus must be smaller than its mutation rate μ(ess).     

Possible Role of a Cell Surface Carbohydrate in Evolution of Resistance to Viral Infections in Old World Primates

Due to inactivation of the α1,3-galactosyltransferase gene (GGTA1, or the α1,3GT gene) approximately 28 million years ago, the carbohydrate αGal (Galα1,3Galβ1,4GlcNAc) is not expressed on the cells of Old World monkeys and apes (including humans) but is expressed in all other mammals. The proposed selective advantage of this mutation for these primates is the ability to produce anti-Gal antibodies, which may be an effective immune component in neutralizing αGal-expressing pathogens. However, loss of α1,3GT expression may have been advantageous by providing natural resistance against viral pathogens that exploited the α1,3GT pathway or cell surface αGal for infection. Infections of paired cell lines with differential expression of α1,3GT showed that Sindbis viruses (SINV) preferentially replicate in α1,3GT-positive cells, whereas herpes simplex viruses type 1 and type 2 (HSV-1 and HSV-2) preferentially grow in cells lacking α1,3GT. Viral growth and spread correlated with the ability of the different viruses to successfully initiate infection in the presence or absence of α1,3GT expression. GT knockout (KO) suckling mice infected with SINV strains (AR339 and S.A.AR86) experienced significant delay in onset of disease symptoms and mortality compared to wild-type (WT) B6 suckling mice. In contrast, HSV-2-infected GT KO mice had higher viral titers in spleen and liver and exhibited significantly more focal hepatic necrosis than WT B6 mice. This study demonstrates that α1,3GT activity plays a role in the course of infections for certain viruses. Furthermore, this study has implications for the evolution of resistance to viral infections in primates.     

The effect of epistasis on the structure of hybrid zones

Within hybrid zones that are maintained by a balance between selection and dispersal, linkage disequilibrium is generated by the mixing of divergent populations. This linkage disequilibrium causes selection on each locus to act on all other loci, thereby steepening clines, and generating a barrier to gene flow. Diffusion models predict simple relations between the strength of linkage disequilibrium and the dispersal rate, sigma, and between the barrier to gene flow, B, and the reduction in mean fitness, W. The aim of this paper is to test the accuracy of these predictions by comparison with an exact deterministic model of unlinked loci (r = 0.5). Disruptive selection acts on the proportion of alleles from the parental populations (p,q): W = exp[-S(4pq)beta], such that the least fit genotype has fitness e-s. Where beta < 1, fitness is reduced for a wide range of intermediate genotypes; where beta > 1, fitness is only reduced for those genotypes close to p = 0.5. Even with strong epistasis, linkage disequilibria are close to sigma 2p'ip'j/rij, where p'i, p'j are the gradients in allele frequency at loci i, j. The barrier to gene flow, which is reflected in the steepening of neutral clines, is given by [formula: see text] where r, the harmonic mean recombination rate between the neural and selected loci, is here 0.5. This is a close approximation for weak selection, but underestimates B for strong selection. The barrier is stronger for small beta, because hybrid fitness is then reduced over a wider range of p. The widths of the selected clines are harder to predict: though simple approximations are accurate for beta = 1, they become inaccurate for extreme beta because, then, fitness changes sharply with p. Estimates of gene number, made from neutral clines on the assumption that selection acts against heterozygotes, are accurate for weak selection when beta = 1; however, for strong selection, gene number is overestimated. For beta > 1, gene number is systematically overestimated and, conversely, when beta < 1, it is underestimated.     

Linkage and the Limits to Natural Selection

The probability of fixation of a favorable mutation is reduced if selection at other loci causes inherited variation in fitness. A general method for calculating the fixation probability of an allele that can find itself in a variety of genetic backgrounds is applied to find the effect of substitutions, fluctuating polymorphisms, and deleterious mutations in a large population. With loose linkage, r, the effects depend on the additive genetic variance in relative fitness, var (W), and act by reducing effective population size by (N/N(e)) = 1 + var (W)/2r(2). However, tightly linked loci can have a substantial effect not predictable from N(e). Linked deleterious mutations reduce the fixation probability of weakly favored alleles by exp(-2U/R), where U is the total mutation rate and R is the map length in Morgans. Substitutions can cause a greater reduction: an allele with advantage s < s(crit) = (π(2)/6) log(e) (S/s)[var(W)/R] is very unlikely to be fixed. (S is the advantage of the substitution impeding fixation.) Fluctuating polymorphisms at many (n) linked loci can also have a substantial effect, reducing fixation probability by exp [ &2Kn var(W)/R] [K = -1/E((u - u)(2)/uv) depending on the frequencies (u,v) at the selected polymorphisms]. Hitchhiking due to all three kinds of selection may substantially impede adaptation that depends on weakly favored alleles.     

An ITAM in a Nonenveloped Virus Regulates Activation of NF-κB,Induction of Beta Interferon,and Viral Spread

Immunoreceptor tyrosine-based activation motifs (ITAMs) are signaling domains located within the cytoplasmic tails of many transmembrane receptors and associated adaptor proteins that mediate immune cell activation. ITAMs also have been identified in the cytoplasmic tails of some enveloped virus glycoproteins. Here, we identified ITAM sequences in three mammalian reovirus proteins: μ2, σ2, and λ2. We demonstrate for the first time that μ2 is phosphorylated, contains a functional ITAM, and activates NF-κB. Specifically, μ2 and μNS recruit the ITAM-signaling intermediate Syk to cytoplasmic viral factories and this recruitment requires the μ2 ITAM. Moreover, both the μ2 ITAM and Syk are required for maximal μ2 activation of NF-κB. A mutant virus lacking the μ2 ITAM activates NF-κB less efficiently and induces lower levels of the downstream antiviral cytokine beta interferon (IFN-β) than does wild-type virus despite similar replication. Notably, the consequences of these μ2 ITAM effects are cell type specific. In fibroblasts where NF-κB is required for reovirus-induced apoptosis, the μ2 ITAM is advantageous for viral spread and enhances viral fitness. Conversely, in cardiac myocytes where the IFN response is critical for antiviral protection and NF-κB is not required for apoptosis, the μ2 ITAM stimulates cellular defense mechanisms and diminishes viral fitness. Together, these results suggest that the cell type-specific effect of the μ2 ITAM on viral spread reflects the cell type-specific effects of NF-κB and IFN-β. This first demonstration of a functional ITAM in a nonenveloped virus presents a new mechanism for viral ITAM-mediated signaling with likely organ-specific consequences in the host.     

Substitution Processes in Molecular Evolution. III. Deleterious Alleles

The substitution processes for various models of deleterious alleles are examined using computer simulations and mathematical analyses. Most of the work focuses on the house-of-cards model, which is a popular model of deleterious allele evolution. The rate of substitution is shown to be a concave function of the strength of selection as measured by α = 2Nσ, where N is the population size and σ is the standard deviation of fitness. For α<1, the house-of-cards model is essentially a neutral model; for α>4, the model ceases to evolve. The stagnation for large α may be understood by appealing to the theory of records. The house-of-cards model evolves to a state where the vast majority of all mutations are deleterious, but precisely one-half of those mutations that fix are deleterious (the other half are advantageous). Thus, the model is not a model of exclusively deleterious evolution as is frequently claimed. It is argued that there are no biologically reasonable models of molecular evolution where the vast majority of all substitutions are deleterious. Other models examined include the exponential and gamma shift models, the Hartl-Dykhuizen-Dean (HDD) model, and the optimum model. Of all those examined, only the optimum and HDD models appear to be reasonable candidates for silent evolution. None of the models are viewed as good candidates for protein evolution, as none are both biologically reasonable and exhibit the variability in substitutions commonly observed in protein sequence data.     

Kin-structured migration and the rate of advance of an advantageous gene

Hemoglobin E, an allele generally considered to confer malarial resistance in heterozygotes, is found in high frequencies across a wide area of Southeast Asia. Apparently it originated as a single-point mutation which was spread by gene flow. The rate of diffusion of this adaptive allele is studied using four computer simulation models. It is shown that in small populations deterministic equations for gene flow may overestimate rates of diffusion. Other aspects of population structure, however, such as kin-structuring of migrant groups, increase the rate of advance. Finally, population growth coupled with the spread of the allele leads to much more rapid diffusion. These results suggest that population structure can be an important factor affecting the diffusion of advantageous genes.     

Nucleotide Variation, Linkage Disequilibrium and Founder-Facilitated Speciation in Wild Populations of the Zebra Finch (Taeniopygia guttata)

The zebra finch has long been an important model system for the study of vocal learning, vocal production, and behavior. With the imminent sequencing of its genome, the zebra finch is now poised to become a model system for population genetics. Using a panel of 30 noncoding loci, we characterized patterns of polymorphism and divergence among wild zebra finch populations. Continental Australian populations displayed little population structure, exceptionally high levels of nucleotide diversity (π = 0.010), a rapid decay of linkage disequilibrium (LD), and a high population recombination rate (ρ ≈ 0.05), all of which suggest an open and fluid genomic background that could facilitate adaptive variation. By contrast, substantial divergence between the Australian and Lesser Sunda Island populations (K_ST = 0.193), reduced genetic diversity (π = 0.002), and higher levels of LD in the island population suggest a strong but relatively recent founder event, which may have contributed to speciation between these populations as envisioned under founder-effect speciation models. Consistent with this hypothesis, we find that under a simple quantitative genetic model both drift and selection could have contributed to the observed divergence in six quantitative traits. In both Australian and Lesser Sundas populations, diversity in Z-linked loci was significantly lower than in autosomal loci. Our analysis provides a quantitative framework for studying the role of selection and drift in shaping patterns of molecular evolution in the zebra finch genome.     

The Effective Size of a Subdivided Population

This paper derives the long-term effective size, N(e), for a general model of population subdivision, allowing for differential deme fitness, variable emigration and immigration rates, extinction, colonization, and correlations across generations in these processes. We show that various long-term measures of N(e) are equivalent. The effective size of a metapopulation can be expressed in a variety of ways. At a demographic equilibrium, N(e) can be derived from the demography by combining information about the ultimate contribution of each deme to the future genetic make-up of the population and Wright's F(ST)'s. The effective size is given by N(e) = 1/(1 + var ( &))<(1 - f(STi))/N(i)n>, where n is the number of demes, &(i) is the eventual contribution of individuals in deme i to the whole population (scaled such that σ(i) &(i) = n), and < > denotes an average weighted by &(i)(2). This formula is applied to a catastrophic extinction model (where sites are either empty or at carrying capacity) and to a metapopulation model with explicit dynamics, where extinction is caused by demographic stochasticity and by chaos. Contrary to the expectation from the standard island model, the usual effect of population subdivision is to decrease the effective size relative to a panmictic population living on the same resource.     

Doxorubicin-induced hepatic toxicity in rats: Mechanistic protective role of Omega-3 fatty acids through Nrf2/HO-1 activation and PI3K/Akt/GSK-3β axis modulation

Doxorubicin (DOX), a common antibiotic used to treat a variety of tumors, has several substantial adverse effects that limit its clinical use. As a result, finding effective protective agents to combat DOX-induced organ damage is a necessity. The current study was set to delineate the hepatoprotective role of omega‐3 fatty acids (ω-3FA) against DOX-mediated acute liver damage in rats and the underlined mechanism of GSK-3β inhibition. Five groups of rats were orally received either saline (groups 1 & 2) or ω-3FA (25, 50 and 100 mg/kg/day; groups 3, 4 & 5, respectively) for 28 consecutive days. Single DOX intraperitoneal injection (20 mg/kg) was used to induce hepatic toxicity in all groups except group 1 (negative control). Blood samples and liver tissues were collected 48-hr after injection. Our results revealed that pre-administration of ω-3FA (25, 50 and 100 mg/kg) to DOX-induced hepatic injured rats showed a significant reduction in serum hepatic injury biomarkers (ALT, AST, total and direct bilirubin) as well as hepatic contents of MDA, GSH, Nrf2 and HO-1. Additionally, hepatic PI3K, pAkt and GSK-3β have been restored significantly in a dose-dependent manner. Furthermore, all the hepatic histopathological features have been retained upon ω-3FA treatment together with the immunostaining intensity of tumor necrosis factor-α and caspase-3. These results suggest that ω-3FA have shown a marked activation of the Nrf2/HO-1 signaling pathway and modulation of the PI3K/pAkt/GSK-3β axis against DOX-induced hepatotoxicity.     

A Nuclear Mutation Reversing a Biased Transmission of Yeast Mitochondrial DNA

The highly biased transmission of ρ(-) mitochondrial DNA that occurs in hypersuppressive matings between ρ(-) and ρ(+) cells of the yeast Saccharomyces cerevisiae is thought to be a consequence of the replication advantage of the ρ(-) mtDNA. A nuclear gene, MGT1, that is required for this displacement of ρ(+) mtDNA from zygotic clones has been identified through mutation. When one haploid parent carries the mgt1 allele, transmission of ρ(-) mtDNA is substantially reduced. When both haploid parents carry the mgt1 allele, ρ(-) mtDNA is essentially eliminated from the zygotic progeny. Thus in the absence of the MGT1 gene there is a switch in the transmission bias; ρ(+) mtDNA rather than the hypersuppressive ρ(-) mtDNA is inherited by most zygotic clones. In contrast to its semi-dominant behavior in haploid matings, mgt1 behaves as a recessive allele in diploid matings since the ρ(+) genome in MGT1/mgt1 diploids is efficiently displaced when mated with a MGT1/mgt1 hypersuppressive ρ(-) diploid strain. We find that ρ(+) genomes can be comaintained along with hypersuppressive ρ(-) mtDNA for extended periods in clonal lines derived from MGT1 X mgt1 matings. However, as expected from the recessive nature of the mgt1 mutation, these ρ(+) genomes are eventually eliminated. Our work indicates that MGT1 plays a crucial role in the competition for inheritance between hypersuppressive ρ(-) mtDNAs and the ρ(+) mitochondrial genome. The MGT1 gene product may be a component of a mtDNA replication system that acts preferentially at the rep sequences found in hypersuppressive mtDNAs.     

The viral era: New biotechnologies give humans an unprecedented control over Nature and require appropriate safeguards

New biotechnologies such as gene drives and engineered viruses herald a viral era that would give humans exceptional power over any organism at the level of the genotype. Subject Categories: Synthetic Biology & Biotechnology, S&S: Economics & Business, Ecology

We are entering a new phase in our relationship with nature: after mechanization, automation and digitalization, a new era of autonomous technical objects is dawning. The most advanced of these technologies are characterized by viral behaviour. The COVID‐19 pandemic has again aptly demonstrated the power of viral systems: not only because of the SARS‐CoV‐2 virus'' ability to jump into and rapidly spread among the human population while wreaking havoc with human societies, but also because some of the vaccines developed against the virus are themselves based on viruses. Both developments give us some ideas of the possible impact of new biotechnologies that aim to create artefacts with viral behaviour in order to shape and control our natural environment. In this essay, the focus is on the use of genetically engineered organisms and the genetic manipulation of wild species. This change has a more direct relationship to our natural environment than autonomous software artefacts such as computer apps or digital viruses that “live” in their artificial “ecosystems” of information‐processing devices. The development of artificial biological systems will therefore require new methods for monitoring and intervention given their potential to autonomously spread within natural ecosystems.     

A Novel Family of Human Leukocyte Antigen Class II Receptors May Have Its Origin in Archaic Human Species

HLA class II α and β chains form receptors for antigen presentation to CD4⁺ T cells. Numerous pairings of class II α and β subunits from the wide range of haplotypes and isotypes may form, but most of these combinations, in particular those produced by isotype mixing, yielded mismatched dimers. It is unclear how selection of functional receptors is achieved. At the atomic level, it is not known which interactions of class II residues regulate selection of matched αβ heterodimers and the evolutionary origin of matched isotype mixed dimer formation. In this study we investigated assembly of isotype-mixed HLA class II α and β heterodimers. Assembly and carbohydrate maturation of various HLA-class II isotype-mixed α and β subunits was dependent on the groove binding section of the invariant chain (Ii). By mutation of polymorphic DPβ sequences, we identified two motifs, Lys-69 and GGPM-(84–87), that are engaged in Ii-dependent assembly of DPβ with DRα. We identified five members of a family of DPβ chains containing Lys-69 and GGPM 84–87, which assemble with DRα. The Lys/GGPM motif is present in the DPβ sequence of the Neanderthal genome, and this ancient sequence is related to the human allele DPB1*0401. By site-directed mutagenesis, we inspected Neanderthal amino acid residues that differ from the DPB1*0401 allele and aimed to determine whether matched heterodimers are formed by assembly of DPβ mutants with DRα. Because the *0401 allele is rare in the sub-Saharan population but frequent in the European population, it may have arisen in modern humans by admixture with Neanderthals in Europe.     

The Geographic Spread of the CCR5 Δ32 HIV-Resistance Allele

The Δ32 mutation at the CCR5 locus is a well-studied example of natural selection acting in humans. The mutation is found principally in Europe and western Asia, with higher frequencies generally in the north. Homozygous carriers of the Δ32 mutation are resistant to HIV-1 infection because the mutation prevents functional expression of the CCR5 chemokine receptor normally used by HIV-1 to enter CD4+ T cells. HIV has emerged only recently, but population genetic data strongly suggest Δ32 has been under intense selection for much of its evolutionary history. To understand how selection and dispersal have interacted during the history of the Δ32 allele, we implemented a spatially explicit model of the spread of Δ32. The model includes the effects of sampling, which we show can give rise to local peaks in observed allele frequencies. In addition, we show that with modest gradients in selection intensity, the origin of the Δ32 allele may be relatively far from the current areas of highest allele frequency. The geographic distribution of the Δ32 allele is consistent with previous reports of a strong selective advantage (>10%) for Δ32 carriers and of dispersal over relatively long distances (>100 km/generation). When selection is assumed to be uniform across Europe and western Asia, we find support for a northern European origin and long-range dispersal consistent with the Viking-mediated dispersal of Δ32 proposed by G. Lucotte and G. Mercier. However, when we allow for gradients in selection intensity, we estimate the origin to be outside of northern Europe and selection intensities to be strongest in the northwest. Our results describe the evolutionary history of the Δ32 allele and establish a general methodology for studying the geographic distribution of selected alleles.     

Bifidobacterium breve with α-Linolenic Acid and Linoleic Acid Alters Fatty Acid Metabolism in the Maternal Separation Model of Irritable Bowel Syndrome

The aim of this study was to compare the impact of dietary supplementation with a Bifidobacterium breve strain together with linoleic acid & α-linolenic acid, for 7 weeks, on colonic sensitivity and fatty acid metabolism in rats. Maternally separated and non-maternally separated Sprague Dawley rats (n = 15) were orally gavaged with either B. breve DPC6330 (10⁹ microorganisms/day) alone or in combination with 0.5% (w/w) linoleic acid & 0.5% (w/w) α-linolenic acid, daily for 7 weeks and compared with trehalose and bovine serum albumin. Tissue fatty acid composition was assessed by gas-liquid chromatography and visceral hypersensitivity was assessed by colorectal distension. Significant differences in the fatty acid profiles of the non-separated controls and maternally separated controls were observed for α-linolenic acid and arachidonic acid in the liver, oleic acid and eicosenoic acid (c11) in adipose tissue, and for palmitoleic acid and docosahexaenoic acid in serum (p<0.05). Administration of B. breve DPC6330 to MS rats significantly increased palmitoleic acid, arachidonic acid and docosahexaenoic acid in the liver, eicosenoic acid (c11) in adipose tissue and palmitoleic acid in the prefrontal cortex (p<0.05), whereas feeding B. breve DPC6330 to non separated rats significantly increased eicosapentaenoic acid and docosapentaenoic acid in serum (p<0.05) compared with the NS un-supplemented controls. Administration of B. breve DPC6330 in combination with linoleic acid and α-linolenic acid to maternally separated rats significantly increased docosapentaenoic acid in the serum (p<0.01) and α-linolenic acid in adipose tissue (p<0.001), whereas feeding B. breve DPC6330 with fatty acid supplementation to non-separated rats significantly increased liver and serum docosapentaenoic acid (p<0.05), and α-linolenic acid in adipose tissue (p<0.001). B. breve DPC6330 influenced host fatty acid metabolism. Administration of B. breve DPC6330 to maternally separated rats significantly modified the palmitoleic acid, arachidonic acid and docosahexaenoic acid contents in tissues. The effect was not observed in non-separated animals.     

Association between Apolipoprotein E Gene Polymorphism and the Risk of Coronary Artery Disease in Chinese Population: Evidence from a Meta-Analysis of 40 Studies

Background

Epidemiological studies have evaluated the association between apolipoprotein E (ApoE) gene polymorphism and coronary artery disease (CAD) risk which developed inconsistent conclusions. To derive a more precise estimation of the relationship in Chinese population, we performed this meta-analysis.

Methods

Databases, including PubMed, EMbase, Web of Science, CBMdisc and CNKI, were searched to get the genetic association studies. Additionally, hand searching of the references of identified articles were performed. All the statistical tests were performed using Review Manager 5.1.2 and Stata 11.0.

Results

We identified a total of 40 studies, including 4,564 CAD cases and 3,985 controls. The results showed evidence for significant association between ApoE ε4 allele and CAD risk (for ε2/ε4 vs. ε3/ε3: OR = 1.86, 95% CI = 1.42–2.43, p<0.00001; for ε3/ε4 vs. ε3/ε3: OR = 2.34, 95% CI = 2.07–2.65, p<0.00001; for ε4/ε4 vs. ε3/ε3: OR = 2.89, 95% CI = 1.87–4.47, p<0.00001; for ε4 allele vs. ε3 allele: OR = 2.11, 95% CI = 1.91–2.35, p<0.00001).

Conclusions

The present meta-analysis suggests an association between ApoE ε4 allele and increased risk of CAD in Chinese population. However, due to the small sample size in most of the included studies and the selection bias existed in some studies, the results should be interpreted with caution.