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PubMed1994

Effect of genetic variation on induced neutrophilia in mice.

Mice from a variety of strains were injected with a sterile irritant (Brewer's thioglycolate) and killed bacteria (Staphylococcus aureus, Staphylococcus epidermidis, or Escherichia coli) to determine their effect on accumulation of neutrophils in the peritoneal cavity. Peak accumulation occurred around 15 h postinjection and showed significant strain-related variation. C57BL/10 mice were identified as having a high-responder phenotype and BALB/c mice a low-responder phenotype. Inheritance of the high-responder phenotype followed simple Mendelian genetics: (BALB/c x C57BL/10)F1 mice were found to be more responsive than either parental phenotype. Major histocompatibility complex H-2d haplotype was found to convey an augmented neutrophil response in conjunction with B10 background high-responder genes (B10.D2/n) but the H-2d haplotype per se was not the only factor in determining high responsiveness. Gram-positive and gram-negative bacteria appeared to activate different immune mechanisms. Both gram-negative bacteria and lipopolysaccharides (LPS) induced a response similar to, but less potent than, that induced by Brewer's thioglycollate. Neutralization of the LPS content of Brewer's thioglycolate abrogated the response.

Animals↗
PubMed2003

Natural genetic variation as a tool in understanding the role of CETP in lipid levels and disease.

Since the identification of cholesteryl ester transfer protein (CETP), its role in the modulation of HDL levels and cardiovascular disease has been debated. With the early detection of genetic variants followed by the finding of families deficient in CETP, genetic studies have played a large role in the attempts to understand the association of CETP with lipids and disease; however, results of these studies have often led to disparate conclusions. With the availability of a greater variety of genetic polymorphisms and larger studies in which disease has been examined, it is now possible to compare the breadth of CETP genetic studies and draw better conclusions. The most broadly studied polymorphism is TaqIB for which over 10,000 individuals have been genotyped and had HDL levels determined. When these studies are subjected to a meta-analysis, the B2B2 homozygotes are found to have higher HDL levels than B1B1 homozygotes (0.12 mmol/l, 95% CI = 0.11-0.13, P < 0.0001). A similar analysis of the I405V polymorphism yields 0.05 mmol/l higher HDL levels in 405VV homozygotes than in 405II homozygotes (95% CI = 0.03-0.07, P < 0.0001). The implications of these studies for cardiovascular disease will be addressed.

Analysis of Variance↗
PubMed2006

Genetic variation in IL6 gene and type 2 diabetes: tagging-SNP haplotype analysis in large-scale case-control study and meta-analysis.

Interleukin-6 (IL-6, gene symbol IL6) is a proinflammatory cytokine. High circulating IL-6 levels have been associated with insulin resistance and greater risk of type 2 diabetes. Using a linkage disequilibrium (LD)-based approach, we sought to investigate the associations of the common polymorphisms comprehensively defining the genetic variability at the IL6 locus with diabetes risk. We conducted a case-control study of 2691 cases of type 2 diabetes (1692 women and 999 men) and 3237 control subjects (2238 women and 999 men) from the Nurses' Health Study and the Health Professional Follow-up Study. Pairwise LD analysis indicated that all the IL6 polymorphisms (rs2069827, rs1800797, rs1800795, rs1554606, rs2069849, rs2069861 and rs1818879) were in strong LD. We did not find significant associations between IL6 polymorphisms and the risk of type 2 diabetes in women or men, individually or in haplotypes. In addition, none of the IL6 polymorphisms was significantly associated with the plasma levels of IL-6 in the control subjects. Our meta-analysis of 5383 diabetes case and 12 069 controls indicated a null association between the best-studied 5' promoter polymorphism--174G>C (rs1800795)--and diabetes risk. Diversity in adiposity, age and sex could not account for the heterogeneity across different studies. In summary, the data in this study do not support substantial associations between the common polymorphisms in IL6 gene and circulating IL-6 levels and the risk of type 2 diabetes.

Adult↗
PubMed1982

A new genetic variation of the malate dehydrogenase-like enzyme (MDL-1) in inbred rats and its possible linkage.

A new polymorphism in the mitochondrial fraction of kidney homogenates was found by using discontinuous polyacrylamide gel electrophoresis. The polymorphism is tentatively designated MDL-1, since the enzyme was visualized with the staining solution for NADP-malate dehydrogenase (MOD) but differs from MOD. MDL-1 expresses three phenotypes: MDL-1A (fast), MDL-1AB (intermediate), and MDL-1B (slow). Progeny testing from genetic crosses indicates that its expression is determined by two codominant alleles, Mdl-1a and Mdl-1b, which segregate in a simple Mendelian fashion. Preliminary linkage data suggest that the locus for MDL-1 is probably linked to the nonagouti-agouti locus in rat linkage group IV.

Alleles↗
PubMed1989

Molecular analysis of cytoplasmic genetic variation in Holstein cows.

Mitochondrial DNA from Holstein maternal lineages implicated to express cytoplasmic genetic effects on lactation traits was subcloned and screened for molecular polymorphisms. Sixteen of 35 lineages sampled differed from the most common mitochondrial DNA form by at least one restriction endonuclease cleavage site in the 4.3 kilobase segment examined. Variation existed in the region that regulates DNA replication and transcription as well as in transfer and ribosomal ribonucleic acid coding regions of the DNA. The index of nucleotide diversity calculated from polymorphism frequencies indicated that the minimum extent of variation between two random lineages was 1.16 x 10(-4) nucleotide differences per base pair in the segment examined. Presence of a HpaII marker near nucleotide 360 was associated with lower (P less than .001) milk fat percentages. Molecular markers indicated that pedigrees may not be sufficient to separate true cytoplasmic lineages for quantitative genetic analyses. These findings provide a molecular genetic basis for further study of cytoplasmic effects on phenotypic variation in Holstein cattle.

Animals↗
PubMed1997

Genetic variation among 129 substrains and its importance for targeted mutagenesis in mice.

Targeted mutagenesis in mice, a powerful tool for the analysis of gene function and human disease, makes extensive use of 129 mouse substrains. Although all are named 129, we document that outcrossing of these substrains, both deliberate and accidental, has lead to extensive genetic variability among substrains and embryonic stem cells derived from them. This clearer understanding of 129 substrain variability allows consideration of its negative impact on targeting technology, including: homologous recombination frequencies, preparation of inbred animals, and availability of appropriate controls. Based on these considerations we suggest a number of recommendations for future experimental design.

Animals↗
PubMed2007

Genetic variation in comC, the gene encoding competence-stimulating peptide (CSP) in Streptococcus mutans.

The genetic variability in comC, the gene encoding the quorum-sensing molecule, competence-stimulating peptide (CSP) in Streptococcus mutans is reported. Seven comC alleles encoding three distinct mature CSPs were identified among 36 geographically diverse strains, although, compared with Streptococcus pneumoniae, the amount of predicted amino acid sequence variation is low. In agreement with other studies, significant variation was found in the natural competence for DNA uptake in these strains. However, there was no correlation between the CSP genotype and the ability to transform these strains. Representative strains encoding each of the CSP variants became competent in response to synthetic CSPs of each type. Therefore, in contrast to S. pneumoniae, comC alleles in S. mutans are functionally equivalent and there is no evidence of pherotype specificity.

Alleles↗
PubMed2005

Genetic variation and geographic distribution of porcine reproductive and respiratory syndrome virus in Japan.

Porcine reproductive and respiratory syndrome virus (PRRSV) has two genotypes, the North American-type (NA-type) and the European-type (EU-type), and each genotype is also genetically diverged. We sequenced the ORF5 gene of 30 PRRSVs isolated from 23 prefectures of Japan during 1992 and 1993 and during 2000 and 2001. All of the isolates were of the NA-type. Phylogenetic analysis of the overall NA-type viruses isolated from around the world identified five major genetic clusters. The 1992-1993 Japanese samples belonged to only two genetic clusters, while the 2000-2001 samples included more diverged ORF5 genomes. One genetic cluster, which included 63% (20/32) of Japanese isolates, one Taiwanese isolate and one Chinese isolate, was mainly found in the eastern part of Japan. Another genetic cluster, which was found in various areas around the world, was distributed in the western part of Japan.

Animals↗
PubMed2005

PTPN22 genetic variation: evidence for multiple variants associated with rheumatoid arthritis.

The minor allele of the R620W missense single-nucleotide polymorphism (SNP) (rs2476601) in the hematopoietic-specific protein tyrosine phosphatase gene, PTPN22, has been associated with multiple autoimmune diseases, including rheumatoid arthritis (RA). These genetic data, combined with biochemical evidence that this SNP affects PTPN22 function, suggest that this phosphatase is a key regulator of autoimmunity. To determine whether other genetic variants in PTPN22 contribute to the development of RA, we sequenced the coding regions of this gene in 48 white North American patients with RA and identified 15 previously unreported SNPs, including 2 coding SNPs in the catalytic domain. We then genotyped 37 SNPs in or near PTPN22 in 475 patients with RA and 475 individually matched controls (sample set 1) and selected a subset of markers for replication in an additional 661 patients with RA and 1,322 individually matched controls (sample set 2). Analyses of these results predict 10 common (frequency >1%) PTPN22 haplotypes in white North Americans. The sole haplotype found to carry the previously identified W620 risk allele was strongly associated with disease in both sample sets, whereas another haplotype, identical at all other SNPs but carrying the R620 allele, showed no association. R620W, however, does not fully explain the association between PTPN22 and RA, since significant differences between cases and controls persisted in both sample sets after the haplotype data were stratified by R620W. Additional analyses identified two SNPs on a single common haplotype that are associated with RA independent of R620W, suggesting that R620W and at least one additional variant in the PTPN22 gene region influence RA susceptibility.

Arthritis, Rheumatoid↗
PubMedDate not supplied

Genetic variation in north-east England.

Phenotype and gene frequencies of polymorphic systems in blood specimens from 796 donors in Northumberland and Durham (north-east England) were analysed according to region of residence. Significant differences exist among the five geographically defined subpopulations, and it is argued that these derive from patterns of historical settlement.

Blood Group Antigens↗
PubMed2000

Genetic variations of the apolipoprotein E gene determine the plasma triglyceride levels after heart transplantation.

OBJECTIVES: To study whether the presence of the polymorphism in the apolipoprotein E (apo E) gene influences the lipid profile in heart-transplant recipients. METHODS: A cohort of 103 recipients of heart transplant (93 men and 10 women, with a mean age of 47 +/- 13 years) under triple immunosuppressive therapy were submitted to a genetic study of the apo E gene region. Anthropometric and analytical data, including lipid profile and arterial blood pressure were collected prior to transplantation and 3, 6, 12, and 24 months after it. RESULTS: 65 subjects present the genotype E3E3, 27 the genotype E3E4, 6 the genotype E2E3, and 5 the genotype E2E4. Carriers of the E2 allele (that is, genotypes E3E2 and E4E2) had higher total plasma triglyceride (TG) levels after 3 months (3.47 +/- 1.88 mmol/liter p < 0.001) and after 1 year of transplantation (3.13 +/- 1.77 mmol/liter p < 0.05) than the other genotypes. There were no differences in the plasma levels of total cholesterol (TC), LDL-cholesterol (LDL-C), and HDL-cholesterol (HDL-C). Multiple regression analysis revealed that the apoprotein E gene polymorphism determines 5% (p = 0.0425) and age 8.7% (p < 0.009) of the variants in TG levels. CONCLUSIONS: The presence of the E2 allele in heart-transplant recipients produces a greater rise in total TG plasma levels than the other genotypes.

Apolipoprotein A-I↗