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PubMed2026

Machine Learning-Driven Prediction of Coronary Artery Disease Risk Based on UK Biobank Plasma Proteomics.

BACKGROUND: Coronary artery disease (CAD) is a leading global cause of mortality, yet the predictive accuracy of conventional risk models is limited. Here, we integrate conventional risk factors, polygenic risk scores, and large-scale proteomics to develop a unified model for enhanced CAD risk prediction. METHODS: Using data from UK Biobank, participants with plasma proteomics and genetic risk data were included after excluding prevalent CAD. Participants from England were split into training (n=32 330) and internal validation (n=13 857) sets, and Scotland/Wales participants formed an external validation set (n=5775). Incident CAD was ascertained from linked health records. A 202-protein proteomic risk score was derived by least absolute shrinkage and selection operator Cox regression, and CatBoost models were trained using conventional risk factors alone and with incremental addition of polygenic risk scores and protein proteomic risk scores; Shapley Additive Explanations-guided forward selection identified a compact protein panel. RESULTS: Across cohorts, the median age was 58 years and ∼45% were men. Protein proteomic risk score was dose-dependently associated with CAD risk. Compared with conventional risk factors alone, integrating polygenic risk scores and protein proteomic risk scores improved discrimination, with the area under the curve increasing from 0.750 (95% CI, 0.732-0.767) to 0.789 (95% CI, 0.772-0.805) in internal validation and from 0.717 (95% CI, 0.683-0.750) to 0.762 (95% CI, 0.732-0.791) in external validation. A 9-protein panel (GDF15 [growth differentiation factor 15], MMP12 [matrix metalloproteinase 12], NPPB [natriuretic peptide B], PGF [placental growth factor], REN [renin], ADGRG2 [adhesion G-protein coupled receptor], ACE2 [angiotensin-converting enzyme 2], CDCP1 [CUB domain-containing protein 1], CXCL17 [C-X-C motif chemokine ligand 17)]) captured most proteomic predictive information. CONCLUSIONS: Our findings demonstrate that integrating conventional risk factors, polygenic risk scores, and proteomic data improves CAD risk prediction. This study highlights the utility of proteomics in precision cardiovascular medicine and simplified risk stratification tools.

Humans↗

PubMed2005

Identification of a major QTL together with several minor additive or epistatic QTLs for resistance to fire blight in apple in two related progenies.

Although fire blight, caused by the bacterium Erwinia amylovora, is one of the most destructive diseases of apple (Malus x domestica) worldwide, no major, qualitative gene for resistance to this disease has been identified to date in apple. We conducted a quantitative trait locus (QTL) analysis in two F(1) progenies derived from crosses between the cultivars Fiesta and either Discovery or Prima. Both progenies were inoculated in the greenhouse with the same strain of E. amylovora, and the length of necrosis was scored 7 days and 14 days after inoculation. Additive QTLs were identified using the MAPQTL: software, and digenic epistatic interactions, which are an indication of putative epistatic QTLs, were detected by two-way analyses of variance. A major QTL explaining 34.3--46.6% of the phenotypic variation was identified on linkage group (LG) 7 of Fiesta in both progenies at the same genetic position. Four minor QTLs were also identified on LGs 3, 12 and 13. In addition, several significant digenic interactions were identified in both progenies. These results confirm the complex polygenic nature of resistance to fire blight in the progenies studied and also reveal the existence of a major QTL on LG7 that is stable in two distinct genetic backgrounds. This QTL could be a valuable target in marker-assisted selection to obtain new, fire blight-resistant apple cultivars and forms a starting point for discovering the function of the genes underlying such QTLs involved in fire blight control.

Analysis of Variance↗

PubMed2006

Isolation of three dormancy QTLs as Mendelian factors in rice.

Seed dormancy is a key adaptive trait under polygenic control in many plants. We introduced the chromosomal regions containing the dormancy QTLs qSD1, qSD7-1, and qSD12 from an accession of weedy rice into a nondormant genetic background to examine component genetic effects and their interactions with time of afterripening (DAR). A BC4F2 plant, which was heterozygous for the three loci, was selected to develop the BC4F3 population. Single point analysis detected only qSD7-1 and qSD12 (R2 = 38-72%) at 10, 30, and 50 DAR in the population. However, multiple linear regression analysis detected genetic effects of the three QTLs and their trigenic epistasis, an environmental effect of DAR (E), and interactions of E with qSD12 and with the qSD1 x qSD7-1 and qSD7-1 x qSD12 epistases. The linear model demonstrates that QTL main effects varied with DAR, and that some epistasis or epistasis-by-DAR interactions partially counteract the main effects. The three QTLs were isolated as single Mendelian factors from the BC4F3 population and estimated for component genic effects based on the BC4F4 populations. Isolation improved estimation of the qSD1 effect and confirmed the major effect of qSD12. The qSD1 and qSD12 loci displayed a gene-additive effect. The qSD7-1, which was further narrowed to a chromosomal region encompassing the red pericarp color gene Rc, displayed gene additive and dominant effects.

Adaptation, Physiological↗

PubMed1993

[Diagnosis of primary hyperlipoproteinemia during a preventive examination].

The study analyses the occurrence and etiology of hyperlipoproteinemia (HLP) in healthy middle-aged probands who participated in a preventive examination. Frequency of HLP was 35%. After a 2-month low-cholesterol-diet, a control biochemical examination was done. The concentration of serum triglycerides decreased significantly (3.02 +/- 1.47, 2.02 +/- 1.14, p < 0.05, respectively). The occurrence of type IV HLP decreased from 51.6% to 24.4% (p < 0.003). For the analysis of etiology of HLP we divided the hyperlipemic probands on the basis of presence of normolipemy (I. group), or HLP (II. group) in the control, and compared the lipid levels between them. We found out that the cholesterol levels in the II. group were significantly higher than in the I. group already before the diet-period (7.0 +/- 0.87 mmol/l, 5.85 +/- 0.81 respectively, p < 0.001), although the both groups did not differ in the triglyceride levels. Genetic examination in families revealed familial combined HLP in 24.4%, primary hypercholesterolemia in 12%, familial hypertriglyceridemia in 2% polygenic hypertriglyceridemia in 18%. We found out not only very high incidence of HLP in a sample of Slovak population but also that the most cases have the genetic background. The most frequent type of HLP was type IV. Since the triglyceride levels give poor information about the coronary risk, we recommend to examine the HDL-cholesterol already in the screening preventive programs.

Adult↗

PubMed2000

Simvastatin inhibits the monocyte expression of proinflammatory cytokines in patients with hypercholesterolemia.

OBJECTIVE: The purpose of this study was to assess if simvastatin has an anti-inflammatory activity in patients with hypercholesterolemia. BACKGROUND: Simvastatin, an inhibitor of 3-hydroxy-methyl-glutaryl coenzyme A (HMG-CoA) reductase, reduced cardiovascular events in patients with myocardial infarction and hypercholesterolemia. METHODS: Sixteen patients with polygenic hypercholesterolemia were randomly allocated to diet (n = 8) or diet plus 20 mg/day simvastatin (n = 8) for eight weeks. Before and at the end of treatment period, lipid profile and monocyte expression of tumor necrosis factor-alpha (TNF) and interleukin-1beta (IL-1beta) were measured. RESULTS: At baseline no difference in lipid profile and monocyte expression of TNF and IL-1beta were observed between the two groups. In patients allocated to diet alone, no change in lipid profile and monocyte expression of TNF and IL-1beta was seen. In patients with diet plus simvastatin, significant decreases of total cholesterol (-27%, p<0.02), low density lipoprotein-cholesterol (-33%, p<0.02), and monocyte expression of TNF (-49%, p<0.02) and IL-1beta (-35%, p<0.02) were observed. At the end of treatment period, patients treated with simvastatin had lower cholesterol and monocyte TNF and IL-1beta than did patients assigned to diet alone. CONCLUSION: This study suggests that simvastatin possesses anti-inflammatory activity via the inhibition of pro-inflammatory cytokines TNF and IL-1beta expressed by monocytes.

Adult↗

PubMed2004

Case-control study and transmission/disequilibrium tests of the genes encoding GABRA5 and GABRB3 in a Chinese population affected by childhood absence epilepsy.

BACKGROUND: Childhood absence epilepsy (CAE) is one of the most frequently recognized syndromes among the idiopathic generalized epilepsies (IGEs). CAE is considered to be a genetic disease, with a possible polygenic inheritance pattern. The genes responsible for CAE have not been identified yet. The object of this study was to investigate whether or not CAE is associated with the gene encoding the gamma-aminobutyric acid (GABA) type-A receptor subunits alpha5 (GABRA5) and beta3 (GABRB3) in a Chinese population. METHODS: Five microsatellite DNA repeats, 69CA, 85CA, 155CA1, 155CA2, and A55CA1, adjoining chromosome 15q11-q13, were used as genetic markers. Both case-control study and transmission/disequilibrium tests (TDTs), as well as fluorescence-based semi-automated genotyping techniques, were used in 90 CAE patient-mother-father trios and 100 normal controls of Han ethnicity to conduct association analysis. RESULTS: The frequencies of allele 5 of 69CA, alleles 2 and 8 of 85CA, alleles 6 and 7 of 155CA1, allele 2 of 155CA2, and alleles 1 and 11 of A55CA1 were significantly higher in CAE patients than in normal controls. To prevent spurious associations arising from population admixture, we further conducted TDT tests in the 90 CAE trios. The results of TDT analysis further suggested that microsatellite DNA repeats 85CA, 155CA1, and 155CA2 were associated with CAE. CONCLUSIONS: GABA type-A receptor subunit genes GABRA5 and GABRB3 may be either directly involved in the etiology of CAE in the Chinese population or in linkage disequilibrium with disease-predisposing sites.

Adolescent↗

PubMed1997

Clustering of Caucasian Leber hereditary optic neuropathy patients containing the 11778 or 14484 mutations on an mtDNA lineage.

Leber hereditary optic neuropathy (LHON) is a type of blindness caused by mtDNA mutations. Three LHON mtDNA mutations at nucleotide positions 3460, 11778, and 14484 are specific for LHON and account for 90% of worldwide cases and are thus designated as "primary" LHON mutations. Fifteen other "secondary" LHON mtDNA mutations have been identified, but their pathogenicity is unclear. mtDNA haplotype and phylogenetic analysis of the primary LHON mutations in North American Caucasian patients and controls has shown that, unlike the 3460 and 11778 mutations, which are distributed throughout the European-derived (Caucasian) mtDNA phylogeny, patients containing the 14484 mutation tended to be associated with European mtDNA haplotype J. To investigate this apparent clustering, we performed chi2-based statistical analyses to compare the distribution of LHON patients on the Caucasian phylogenetic tree. Our results indicate that, unlike the 3460 and 11778 mutations, the 14484 mutation was not distributed on the phylogeny in proportion to the frequencies of the major Caucasian mtDNA haplogroups found in North America. The 14484 mutation was next shown to occur on the haplogroup J background more frequently that expected, consistent with the observation that approximately 75% of worldwide 14484-positive LHON patients occur in association with haplogroup J. The 11778 mutation also exhibited a moderate clustering on haplogroup J. These observations were supported by statistical analysis using all available mutation frequencies reported in the literature. This paper thus illustrates the potential importance of genetic background in certain mtDNA-based diseases, speculates on a pathogenic role for a subset of LHON secondary mutations and their interaction with primary mutations, and provides support for a polygenic model for LHON expression in some cases.

Chi-Square Distribution↗

PubMed1999

Towards a permanent solution for controlling cattle ticks.

Acaricides are essential in the short-term but do not offer a permanent solution to tick control. This situation will not change without a change of approach. A vaccine against Boophilus microplus confers partial long-term control but has little immediate effect on tick burdens. The effectiveness of acaricides and vaccination is greatest for breeds of high tick resistance. High host resistance is the key to effective long-term tick control with total resistance the ultimate aim. While improvements to acaricides and vaccines are continuously pursued, improvements to the most important single factor controlling ticks, host resistance, have been neglected. Resistance is as heritable as milk yield or growth and in tropical breeds can be increased to very high levels by selection. Despite this there are no current examples of sustained selection for tick resistance. Temperate breeds have low resistance but because of high production potentials are favoured for crossbreeding with tropical breeds. This perpetuates the need for reliance on acaricides. Selection to increase polygenic resistance of temperate breeds is impractical. However, a quantum increase can be achieved by introgressing major resistance genes. Such a gene occurs in the Belmont Adaptaur and in suitable genetic backgrounds confers 100% resistance. Total resistance is achievable and provides a permanent solution to ticks.

Animals↗

PubMed1975

Gene substitutions and geotaxis in Drosophila melanogaster.

Tightly linked gene markers at the white locus of Drosophila were placed, by repeated backcrossing, on each of two genetic backgrounds. Ten genotypes representing various combinations of homo- and heterozygosity were studied in a Hirsch-type geotactic maze. In general, the effects of genetic background, dominance, and epistasis were found to exceed the additive effects of gene substitutions. The results domonstrate the feasibility of analyzing the contributions of single genes to behaviors known to be polygenically determined.

Animals↗

PubMed2006

Role of Bim and other Bcl-2 family members in autoimmune and degenerative diseases.

Apoptosis is essential for the development, function and homeostasis of the immune system. Experiments with transgenic and gene knock-out mice have shown that defects in the control of apoptosis in the hematopoietic system can promote the development of autoimmunity or hematological malignancy. In contrast, excessive apoptosis of normally long-lived hemopoietic cells can lead to lymphopenia and immunodeficiency. In mammals, cell death in response to developmental cues and many cell stress signals is regulated by the opposing factions of the Bcl-2 family of proteins. In particular, the pro-apoptotic subgroup called BH3-only proteins, which includes Bim, is critical in the initiation of apoptosis in response to many death stimuli. Bim has been found to be an important regulator of the negative selection of B lymphocytes in the bone marrow and of T lymphocytes both in the thymus and the periphery. Mice lacking Bim accumulate self-reactive lymphocytes, develop autoantibodies and on certain genetic backgrounds succumb to SLE-like autoimmune disease. Abnormalities in Bim expression and the thymic deletion of auto-reactive lymphocytes have also been implicated as a component of the complex, polygenic predisposition to autoimmune diabetes seen in NOD mice. Bim is also an essential regulator of T lymphocyte apoptosis during the termination of an immune response. This chapter focuses on the role of Bim in the development and function of the immune system and its potential role in autoimmunity. Degenerative disorders due to increased apoptosis mediated by Bim are also discussed.

Animals↗

PubMed1996

A polygenic mouse model of psoriasiform skin disease in CD18-deficient mice.

Previously, a hypomorphic mutation in CD18 was generated by gene targeting, with homozygous mice displaying increased circulating neutrophil counts, defects in the response to chemically induced peritonitis, and delays in transplantation rejection. When this mutation was backcrossed onto the PL/J inbred strain, virtually all homozygous mice developed a chronic inflammatory skin disease with a mean age of onset of 11 weeks after birth. The disease was characterized by erythema, hair loss, and the development of scales and crusts. The histopathology revealed hyperplasia of the epidermis, subcorneal microabscesses, orthohyperkeratosis, parakeratosis, and lymphocyte exocytosis, which are features in common with human psoriasis and other hyperproliferative inflammatory skin disorders. Repetitive cultures failed to demonstrate bacterial or fungal organisms potentially involved in the pathogenesis of this disease, and the dermatitis resolved rapidly after subcutaneous administration of dexamethasone. Homozygous mutant mice on a (PL/J x C57BL/6J)F1 background did not develop the disease and backcross experiments suggest that a small number of genes (perhaps as few as one), in addition to CD18, determine susceptibility to the disorder. This phenotype provides a model for inflammatory skin disorders, may have general relevance to polygenic human inflammatory diseases, and should help to identify genes that interact with the beta2 integrins in inflammatory processes.

Animals↗

PubMed2005

Genetics of type 2 diabetes mellitus.

The clinical picture of type 2 diabetes mellitus (T2DM) is formed by impairment in insulin secretion and resistance to insulin action. As a result of intensive efforts of the scientists around the world mutations and polymorphisms in a number of genes were linked with monogenic and polygenic forms of T2DM. Two major strategies were used in this research: genome scanning and the candidate gene approach. Monogenic forms, despite their rarity, constitute a field where substantial progress has been made in the dissection of the molecular background of T2DM. Monogenic forms of T2DM with profound defect in insulin secretion include subtypes of maturity onset diabetes of the young (MODY), maternally inherited diabetes with deafness (MIDD) caused by mitochondrial mutations, and rare cases resulting from insulin gene mutations. The majority of proteins associated with MODY are transcription factors, such as hepatocyte nuclear factor 4alpha (HNF-4alpha), HNF-1alpha, insulin promoter factor-1 (IPF-1), HNF-1beta, and NEUROD1. They influence expression of the other genes through regulation of mRNA synthesis. Only MODY2 form is associated with glucokinase, a key regulatory enzyme of the beta cell. There are striking differences in the clinical picture of MODY associated with glucokinase and MODY associated with transcription factors. Three monogenic forms of T2DM characterized by severe insulin resistance are the consequence of mutations in the PPARgamma, ATK2, and insulin receptor genes. Patients with monogenic T2DM, particularly with MODY, sometimes, develop discrete extra-pancreatic phenotypes; for example, lipid abnormalities or a variety of cystic renal diseases. Efforts aiming to identify genes responsible for more common, polygenic forms of T2DM were less effective. These forms of T2DM have a middle/late age of onset and occur with both impaired insulin secretion and insulin resistance. Their clinical picture is created by the interaction of environmental and genetic factors, such as frequent polymorphisms of many genes, not just of one. These polymorphisms may be localized in the coding or regulatory parts of the genes and are present, although with different frequencies, in T2DM patients as well as in healthy populations. Sequence differences in a few genes have been associated, so far, with complex, polygenic forms of T2DM, for example, calpain 10, PPARgamma, KCJN11, and insulin. In addition, some evidence exists that genes, such as adiponectin, IRS-1, and some others may also influence the susceptibility to T2DM. It is expected that in the nearest future more T2DM susceptibility genes will be identified.

Diabetes Mellitus, Type 2↗

PubMed2026

Deep learning and statistical methods identify novel asthma risk variants in Europeans.

BACKGROUND: Asthma is a common heritable respiratory disorder with a complex genetic basis. Although large-scale genome-wide association studies have identified many risk loci, the full spectrum of its polygenic architecture remains to be defined. OBJECTIVE: We refined the genetic landscape of asthma in individuals of European ancestry and improve polygenic risk prediction through statistical and deep learning-based methods. METHODS: We conducted the largest genome-wide association study meta-analysis of asthma in individuals of European ancestry, combining data from the Global Biobank Meta-analysis Initiative (121,940 cases, 1,254,131 controls) and the Million Veteran Program (36,823 cases, 398,278 controls). To enhance discovery, we applied pleiotropy-informed multitrait analysis and conditional false discovery rate approaches, each incorporating eosinophil counts as a secondary trait. In parallel, we used a Transformer-based deep learning framework to further prioritize variants and improve polygenic risk prediction. RESULTS: The meta-analysis identified 69 independent genome-wide significant loci (P < 5 × 10-8) not previously reported in asthma. Multitrait analysis of genome-wide association studies, conditional false discovery rate, and deep learning approaches uncovered additional candidate loci. Functional annotation and expression quantitative trait locus mapping implicated novel genes in immune regulation, airway remodeling, and metabolic processes. Polygenic risk score models derived from deep learning-prioritized variants outperformed those based on conventional genome-wide association study and standard statistical approaches. CONCLUSIONS: Our study yields a comprehensive map of asthma-associated loci in European ancestry populations, improves genetic risk prediction, and informs future mechanistic studies.

Humans↗

PubMed1997

Genetics of stroke.

Stroke is a very common cause of death and disability. Several lines of evidence point to stroke as a polygenic multifactoral phenotype and there are also a number of well studied single gene Mendelian stroke conditions. Rat models have identified several chromosomal sites linked to stroke, and this together with other background information provides a strategy for both cross-sectional and gene scanning approach to defining the genetics of human stroke.

Animals↗

PubMed1988

Resistance to Plasmodium chabaudi in B10 mice: influence of the H-2 complex and testosterone.

Resistance to Plasmodium chabaudi has been examined in different inbred mouse strains bearing identical H-2 haplotypes on different genetic backgrounds as well as in H-2-congenic mouse strains on B10 background. Resistance is expressed in terms of percent survival after a challenge with 10(6) P. chabaudi-infected erythrocytes. We can show that murine resistance to P. chabaudi is under complex polygenic control involving a non-H-2 gene(s) as well as genes in both I-A and I-E subregions of the H-2 complex. Our data indicate in particular that malaria protective antigens can be presented in context with I-Ab molecules but not in context with I-Ak molecules. Resistance controlled by I-Ab does not become apparent when I-Ek molecules are coincidentally expressed. Moreover, testosterone abrogates I-Ab-controlled resistance to P. chabaudi.

Animals↗

PubMed2001

[Effect of genetic background on the ratios between different types of dermatoglyphic patterns: recessive genodermatoses].

The ratios between dermatoglyphic patterns of different types were studied in males and females with and without hereditary diseases of the skin. It was found that ridge patterns of fingers are determined by special polygenes. Patients with monogenic dermatoses (X-linked ichthyosis and autosomal recessive ichthyosiform erythroderma) exhibited a suppressed formation of the loop pattern compared to control subjects.

Dermatoglyphics↗

PubMed1996

Measuring selective effects of modifier gene polymorphisms on the Bare locus of Drosophila subobscura.

An attempt to quantify the effects of modifier gene polymorphisms on the operation of natural selection on a major locus has been carried out. The modifier system we have investigated is constituted by a set of polygenic modifier loci affecting the morphological expression of the Bare (Ba) bristle mutant of Drosophila subobscura. Ba is a dominant mutant that is lethal in homozygous condition and both the polygenic modifiers and Ba are located on the O chromosome of this species. Experimental populations were found with Ba/+ individuals and two different types of populations were started according to their modifier genetic background: populations with wild O chromosomes of either high or low modifier effect (cages H and L, respectively). Fitness estimates (total fitness, viability and fertility) for genotypes of the Ba locus were obtained under the two different modifier backgrounds. In the populations with high modifier background the total fitness of the Ba/+ heterozygote was very similar to that of the +/+ homozygote (fitness equal to 1). However, in cages with low modifier background a strong selection against the Ba/+ heterozygote was detected (average of total fitnesses over generations was 0.66 +/- 0.10), and fertility appears to be the fitness component responsible for this effect (mean fertility was 0.55 +/- 0.08). These findings demonstrate that modifier gene polymorphisms affecting the expression of the Ba mutant may be associated with large selective effects on the major locus.

Animals↗

PubMed2004

The intricate role of complement component C4 in human systemic lupus erythematosus.

It was observed about 50 years ago that low serum complement activity or low protein concentrations of complement C4 concurred with disease activities of systemic lupus erythematosus (SLE). Complete deficiencies of complement components C4A and C4B, albeit rare in human populations, are among the strongest genetic risk factors for SLE or lupus-like disease, across HLA haplotypes and racial backgrounds. However, whether heterozygous or partial deficiency of C4A (C4AQ0) or C4B (C4BQ0) is a predisposing factor for SLE has been a highly controversial topic. In this review we critically analyzed past epidemiologic studies on deficiency of C4A or C4B in human SLE. Cumulative results from more than 35 different studies revealed that heterozygous and homozygous deficiencies of C4A were present in 40-60% of SLE patients from almost all ethnic groups or races investigated, which included northern and central Europeans, Anglo-Saxons, Caucasians in the US, African Americans, Asian Chinese, Koreans and Japanese. In addition, French SLE and control populations had relatively low frequencies of C4AQ0, but the difference between the patient and control groups was statistically significant. The relative risk of C4AQ0 in SLE varied between 2.3 and 5.3 among different ethnic groups. In Caucasian and African SLE patients, the two major causes for C4AQ0 are (1) the presence of a mono-S RCCX (RP-C4-CYP21-TNX) module with a single, short C4B gene in the major histocompatibility complex; and (2) a 2-bp insertion into the sequence for codon 1213 at exon 29 of the mutant C4A gene. Both mono-S structures and 2-bp insertion in exon 29 are absent or extremely rare in the C4AQ0 of Oriental SLE patients. The highly significant association of C4AQ0 with SLE across multiple HLA haplotypes and ethnic groups, and the presence of different mechanisms leading to a C4A protein deficiency among SLE patients suggested that deficiency or low expression level of C4A protein is a primary risk factor for SLE disease susceptibility per se. On the other hand, Spanish, Mexican, Australian Aborigine SLE patients had increased frequencies of C4B deficiency instead of C4A deficiency. Such observations underscore the importance of both C4A and C4B proteins in the fine control of autoimmunity. Different racial and genetic backgrounds could change the thresholds for the requirement of C4A or C4B protein levels in immune tolerance and immune regulation. Most past epidemiological studies of C4 in human SLE did not consider the polygenic and gene size variations of C4A and C4B. In addition, many studies were overly dependent on phenotypic observations or methods that did not distinguish differential C4A and C4B protein expression caused by unequal gene number or different gene size from the absence of a functional C4A or C4B gene. For further longitudinal studies on clinical manifestations of SLE, it would be informative to stratify the patients with accurately defined C4A and C4B genotypes. Likewise, elucidation of epistatic genetic factors interacting with C4AQ0 would provide important insights into the intricate roles of C4 in SLE disease susceptibility and pathogenesis.

Alleles↗