Variation of rs3754689 at lactase gene and inhibitors in admixed Brazilian patients with hemophilia A

Zuccherato, Luciana W.; Elói-Santos, Silvana Maria; Jardim, Letícia Lemos; Camelo, Ricardo Mesquita; Chaves, Daniel Gonçalves; Souza, Renan P.; Hollox, Edward J.; Rezende, Suely Meireles

doi:10.3324/haematol.2019.220608

Cited by 3 publications

(1 citation statement)

References 13 publications

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“…ethnicity) of the SIPPET cohort consisting of several populations (mainly Indian, Egyptian and Iranian). Recently, the association of the LCT p.Val219Ile missense variant (rs3754689) to inhibitor development in patients with severe HA has been found in Afghans 36 but not confirmed in Brazilian and Iranian populations 36,37 . Since the allele frequencies of all the identified variants reported in the 1000 Genome project are similar in the European and the South Asian populations but are markedly different in the Italian population (Table 1), a replication study performed in an independent cohort of Italian patients could be suitable to overcome the problem of poor reproducibility of genotyping results.…”

Section: Discussionmentioning

confidence: 99%

Genetic variants at the chromosomal region 2q21.3 underlying inhibitor development in patients with severe haemophilia A

et al. 2022

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Introduction Inhibitor development affects about 30% of patients with severe haemophilia A (HA) and results from different environmental and genetic risk factors. Previously, we identified the missense variant rs3754689 in the LCT gene linked with this predisposition. Since rs3754689 variant is benign and is located in a conserved haplotype region, we hypothesized that the association signal captured by this variant is located in coinherited, neighbouring genes. Aim To identify novel genetic risk factors associated with inhibitor development in coding regions of R3HDM1, UBXN4, CXCR4, MCM6, DARS and miR128‐1 genes. Methods Targeted sequencing was performed in 246 severe HA patients (72 with and 174 without inhibitor): 181 previously and 65 newly enrolled. Results Forty‐one common and 152 rare variants passed the quality control. Logistic regression analysis of common variants identified rs3754689 and four additional variants (.011 < P < .047; FDR ranging .2‐.38). Logistic regression analysis performed only in the 220 Italian patients showed similar results (.004 < P < .05; FDR ranging .12‐.22). Three of these variants (rs3213892 and rs3816155 in the LCT intron 13 and rs961360 in the R3HDM1 intron10‐exon11 junction) may affect the expression of UBXN4 and R3HDM1, respectively. Rare variants did not show association with inhibitor development. Identified variants were not replicated in the multi‐ethnic SIPPET cohort of 230 severe HA patients. Conclusion Due to the limited sample size that may be responsible of the high FDR values, we could not confirm with certainty the analysed association. Further evaluation of the expression levels of analysed genes will confirm or not their role in inhibitor development.

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Section: Discussionmentioning

confidence: 99%

Genetic variants at the chromosomal region 2q21.3 underlying inhibitor development in patients with severe haemophilia A

et al. 2022

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Investigating the influence of LCT rs3754689 polymorphism on inhibitor development in Iranian and Afghan patients with severe hemophilia A

Zadegan

Mousavi

Damavandi

et al. 2020

Blood Coagulation &Amp; Fibrinolysis

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Development of alloantibodies against factor VIII (FVIII) in patients with severe hemophilia A is the main complication of FVIII replacement therapy. There are many studies indicating several genetic factors associated with inhibitor development. A recent study showed that there is a correlation between the risk of inhibitor development and LCT rs3754689 polymorphism among Italian hemophilia A patients. The aim of this study was to speculate whether LCT rs3754689 polymorphism is correlated to inhibitor development in Afghan and Iranian patients. In addition, we assessed the association of F8 gene mutations and inhibitor development in Iranian patients. This case–control study was conducted on 33 severe hemophilia A patients with inhibitor and 119 samples without inhibitor. Genotyping was performed by Sanger sequencing, inverse and multiplex PCR. According to the obtained data, we found a significant correlation between LCT rs3754689 polymorphism and the risk of inhibitor development in Afghan patients (observed risk, 0.11; 95% confidence interval, 0.01–0.88; P = 0.012). Among Iranian patients, rs3754689 polymorphism showed no significant association with inhibitor development against FVIII (P > 0.05). However, we found a significant correlation between the risk of inhibitor formation and large deletions and nonsense mutations in F8 gene among Iranian patients (observed risk, 7.25; 95% confidence interval, 1.93–27.18; P = 0.003). Lack of association of rs3754689 polymorphism in Iranian population shows the various effects of genetic markers in different populations. More studies in different ethnicities or larger sample sizes are recommended.

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Recent Advances in Genetic and Non-Genetic Factors Related to the Development of Hemophilia Inhibitors

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2024

ACM

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Variation of rs3754689 at lactase gene and inhibitors in admixed Brazilian patients with hemophilia A

Cited by 3 publications

References 13 publications

Genetic variants at the chromosomal region 2q21.3 underlying inhibitor development in patients with severe haemophilia A

Genetic variants at the chromosomal region 2q21.3 underlying inhibitor development in patients with severe haemophilia A

Investigating the influence of LCT rs3754689 polymorphism on inhibitor development in Iranian and Afghan patients with severe hemophilia A

Recent Advances in Genetic and Non-Genetic Factors Related to the Development of Hemophilia Inhibitors

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