The worldwide distribution of the VHL 598C>T mutation indicates a single founding event

Blood ◽  
2004 ◽  
Vol 103 (5) ◽  
pp. 1937-1940 ◽  
Author(s):  
Enli Liu ◽  
Melanie J. Percy ◽  
Christopher I. Amos ◽  
Yongli Guan ◽  
Sanjay Shete ◽  
...  
Keyword(s):  
Linkage Disequilibrium ◽  
Human Evolution ◽  
Haplotype Analysis ◽  
Strong Linkage Disequilibrium ◽  
Healthy Controls ◽  
Polymorphic Markers ◽  
Strong Linkage ◽  
Vhl Gene ◽  
Worldwide Distribution ◽  
Common Defect

Abstract The first congenital defect of hypoxia-sensing homozygosity for VHL 598C>T mutation was recently identified in Chuvash polycythemia. Subsequently, we found this mutation in 11 unrelated individuals of diverse ethnic backgrounds. To address the question of whether the VHL 598C>T substitution occurred in a single founder or resulted from recurrent mutational events in human evolution, we performed haplotype analysis of 8 polymorphic markers covering 340 kb spanning the VHL gene on 101 subjects bearing the VHL 598C>T mutation, including 72 homozygotes (61 Chuvash and 11 non-Chuvash) and 29 heterozygotes (11 Chuvash and 18 non-Chuvash), and 447 healthy unrelated individuals from Chuvash and other ethnic groups. The differences in allele frequencies for each of the 8 markers between 447 healthy controls (598C) and 101 subjects bearing the 598T allele (P < 10–7) showed strong linkage disequilibrium. Haplotype analysis indicated a founder effect. We conclude that the VHL 598C>T mutation, the most common defect of congenital polycythemia yet found, was spread from a single founder 14 000 to 62 000 years ago.

scholarly journals Genetically Determined TNF-α Secretion Influences the Development of Dermatomyositis and Systemic Lupus Erythematosus

Folia Medica ◽  
2018 ◽  
Vol 60 (2) ◽  
pp. 216-220 ◽  
Author(s):  
Lyubomir A. Dourmishev ◽  
Maria H. Hristova ◽  
Zornitsa G. Kamenarska ◽  
Alexey S. Savov ◽  
Anton I. Vinkov ◽  
...  
Keyword(s):  
Systemic Lupus Erythematosus ◽  
Linkage Disequilibrium ◽  
Significant Role ◽  
Lupus Erythematosus ◽  
Strong Linkage Disequilibrium ◽  
Healthy Controls ◽  
Systemic Lupus ◽  
Strong Linkage ◽  
Tnf Α ◽  
Genetically Determined

Abstract Background: Abnormal secretion of TNF-α is known to play a role in the pathogenesis of dermatomyositis and systemic lupus erythematosus. Materials and methods: In the present study we have analyzed the concentrations of TNF-α in the sera of 30 patients with systemic lupus erythematosus (SLE), 28 with dermatomyositis (DM) and 30 healthy controls by standard ELISA tests. Results: We have found that -308A allele increases TNF-α secretion, while -1031C and -863A alleles decrease it. The -857C/T and 489G/A polymorphisms appeared in strong linkage disequilibrium (D’=0.93) but they did not seem to affect TNF-α secretion. Conclusion: TNF-α polymorphisms play a significant role in its secretion and influence the development of DM and SLE.

Association of multiple nucleotide variations in the pituitary glutaminyl cyclase gene QPC with low radial BMD in adult women.

2020 ◽  
Author(s):  
Lungwani Muungo
Keyword(s):  
Linkage Disequilibrium ◽  
Multiple Regression ◽  
Genetic Variations ◽  
Strong Linkage Disequilibrium ◽  
Adult Women ◽  
Nucleotide Polymorphisms ◽  
Haplotype Estimation ◽  
Factors Affecting ◽  
Glutaminyl Cyclase ◽  
Strong Linkage

Correlation between 13 genetic variations of the glutaminyl-peptide cyclotransferase gene andadjusted aBMD was tested among 384 adult women. Among 13 variations with strong linkage disequilibrium,R54W showed a prominent association (p ? 0.0003), which was more striking when examined among 309 eldersubjects (>50 years; p ? 0.0001). Contribution for postmenopausal bone loss was suggested.Introduction: Alterations in homeostatic regulation of estrogen through the hypothalamus-pituitary-gonadal axis(HPG axis) importantly affect the pathogenesis of osteoporosis. Osteoporosis-susceptibility genes have beenproposed in this hormonal axis, such as estrogen receptor genes and the gonadotropin-releasing hormone gene(GnRH). Here we report another example of genes: glutaminyl-peptide cyclotransferase gene (QPCT), an essentialmodifier of pituitary peptide hormones, including GnRH.Materials and Methods: Analyses of association of 13 single nucleotide polymorphisms (SNPs) at the QPCT locuswith adjusted areal BMD (adj-aBMD) were carried out among 384 adult women. Linkage disequilibrium (LD) wasanalyzed by haplotype estimation and calculation of D? and r2. Multiple regression analysis was applied forevaluating the combined effects of the variations.Results and Conclusions: LD analysis indicated strong linkage disequilibrium within the entire 30-kb region of theQPCT gene. Significant correlations were observed between the genotypes of the six SNPs and the radial adj-aBMD,among which R54W (nt ? 160C?T) presented the most prominent association (p ? 0.0003). Striking associationwas observed for these SNPs among the 309 subjects ?50 years of age (R54W, p ? 0.0001; ?1095T?C, p ?0.0002; ?1844C?T, p ? 0.0002). Multiple regression analyses indicated that multiple SNPs in the gene might actin combination to determine the radial adj-aBMD. These results indicate that genetic variations in QPCT are theimportant factors affecting the BMD of adult women that contribute to susceptibility for osteoporosis. The datashould provide new insight into the etiology of the disease and may suggest a new target to be considered duringtreatment.J Bone Miner

Valine 11 and phenylalanine 13 have a greater impact on the T-cell response to citrullinated peptides than the 70–74 shared epitope of the DRB1 molecule in macaques

2019 ◽  
Vol 78 (7) ◽  
pp. 917-921 ◽  
Author(s):  
Samuel Bitoun ◽  
Pierre Roques ◽  
Bernard Maillere ◽  
Roger Le Grand ◽  
Xavier Mariette
Keyword(s):  
Rheumatoid Arthritis ◽  
Linkage Disequilibrium ◽  
T Cell ◽  
Cell Response ◽  
Shared Epitope ◽  
Interferon Γ ◽  
T Cell Response ◽  
Strong Linkage Disequilibrium ◽  
Strong Linkage

ObjectivesVarious rheumatoid arthritis (RA) HLA-DRB-1 risk haplotypes have been regrouped under the shared epitope (SE) in position 70–74. The presence of Valine in position 11 (Val11) and phenylalanine in position 13 (Phe13) are also associated with RA, but it is impossible to differentiate their role compared with the SE since they are in strong linkage disequilibrium (LD) in humans. Similar to humans, certain macaques express the SE (H6). We analysed the effect of various DRB1 haplotypes on T-cell response to citrullinated peptides (Cit-P) in macaques.MethodsSix H6 and six non-H6 macaques were immunized with four Cit-P. T-cell response was assessed using Interferon γ enzyme-linked immunospot.ResultsAnimals developed a specific anti-Cit-P T-cell response. Surprisingly, H6 animals had a significantly lower T-cell response than non-H6. In macaques, the 70–74 SE and the Val11 are on separate haplotypes. Presence of Val11 was strongly associated with the anti-Cit-P T-cell response, whatever the 70–74 sequence was. This response was amplified in case of presence of Phe13.ConclusionThe absence of LD between Val11 and SE in macaques allowed us to demonstrate that the most important HLA positions to induce a T-cell response against Cit-P were Val11 and Phe13 and not the 70–74 SE.

Strong linkage disequilibrium of HLA DPw11 with the HLA B44-DR7-DQw2 extended haplotype*

1992 ◽  
Vol 39 (1) ◽  
pp. 35-37 ◽  
Author(s):  
J. D. Bignon ◽  
M. L. Cheneau ◽  
P. Herry ◽  
F. Bonneville ◽  
A. Cesbron ◽  
...  
Keyword(s):  
Linkage Disequilibrium ◽  
Strong Linkage Disequilibrium ◽  
Extended Haplotype ◽  
Strong Linkage

scholarly journals Association ofPTPN22Haplotypes (−1123G>C/+1858C>T) with Rheumatoid Arthritis in Western Mexican Population

2017 ◽  
Vol 2017 ◽  
pp. 1-5 ◽  
Author(s):  
Yeniley Ruiz-Noa ◽  
Jorge Ramón Padilla-Gutiérrez ◽  
Jorge Hernández-Bello ◽  
Claudia Azucena Palafox-Sánchez ◽  
Yeminia Valle ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Linkage Disequilibrium ◽  
Immune Tolerance ◽  
Tyrosine Phosphatase ◽  
Mexican Population ◽  
Strong Linkage Disequilibrium ◽  
Strong Linkage ◽  
Western Mexico ◽  
Pcr Rflp ◽  
Polymorphic Variants

Rheumatoid arthritis (RA) is an autoimmune disease characterized by the presence of antibodies against cyclic citrullinated peptide (anti-CCP), a consequence of the breakdown of immune tolerance. The lymphoid tyrosine phosphatase (Lyp) protein has significant effects on maintenance of peripheral immune tolerance. Two polymorphic variants (−1123G>C and +1858C>T) atPTPN22gene that encodes this protein have been associated with autoimmune disorders and found in strong linkage disequilibrium in Caucasian population. We evaluated whetherPTPN22haplotypes (−1123G>C/+1858C>T) are associated with anti-CCP antibodies, as well as susceptibility to RA in a Western Mexican population. A total of 315 RA patients and 315 control subjects (CS) were included. The polymorphisms were genotyped by PCR-RFLP and the anti-CCP antibodies were determined by ELISA. ThePTPN22polymorphisms were in strong linkage disequilibrium (D′ = 1.00 in CS). The susceptibility haplotype CT was significantly more frequent in RA patients than in CS (OR 2.18, 95% CI 1.15–4.16,p=0.01). No association between haplotypes and anti-CCP antibodies levels was observed. In conclusion, this study confirmed that −1123G>C and +1858C>TPTPN22polymorphisms are in strong linkage disequilibrium and the CT haplotype is a susceptibility marker to RA in Western Mexico. However, thePTPN22haplotypes are not associated with anti-CCP antibodies.

Strong linkage disequilibrium at the nucleotide analogue transporter ABCC5 gene locus

2005 ◽  
Vol 15 (2) ◽  
pp. 91-104 ◽  
Author(s):  
Pai Chung Gwee ◽  
Kun Tang ◽  
Pui Hoon Sew ◽  
Edmund J.D. Lee ◽  
Samuel S. Chong ◽  
...  
Keyword(s):  
Linkage Disequilibrium ◽  
Gene Locus ◽  
Strong Linkage Disequilibrium ◽  
Strong Linkage ◽  
Nucleotide Analogue
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