A Case-Control Study of the Relationship Between Genetic Polymorphism and Cretinism in Xinjiang

Overview

Journal Pharmgenomics Pers Med

Publisher Dove Medical Press

Date 2023 Aug 29

PMID 37641720

Authors

Jia Huang

Haiyan Wu

Guiqiang Zhao

Yan Ma

Yunping An

Li Sun

Fuye Li

Shengling Wang

Affiliations

Soon will be listed here.

Abstract

Background: Cretinism is a subtype of congenital hypothyroidism, an endocrine disorder resulting from inadequate thyroid hormone production or receptor deficiency. Genetic abnormalities play a major role in the development of thyroid dysfunction.

Methods: We recruited 183 participants with cretinism and 119 healthy participants from the Xinjiang Uyghur Autonomous Region and randomly selected 29 tag single nucleotide polymorphisms (tSNPs) in , and in all participants. We compared genotype and allele frequencies between cases and controls utilizing the chi-squared test, logistic regression analysis, and haplotype analysis.

Results: Using the chi-squared test, a single SNP was found to be associated with cretinism (recessive model: rs3754363, OR = 0.46, 95% CI = 0.27-0.80, P = 0.00519; genotype model: P = 0.01677). We stratified neurological, myxedematous, and mixed type and determined that another SNP was associated with a higher risk when comparing myxedematous type to the neurological type (rs2277923).

Conclusion: rs3754363 has a statistically significant protective effect on people with cretinism, while rs2277923 may play a greater role in promoting the development of neurocretinism.

References

Halpern J, Boyages S, Maberly G, Collins J, Eastman C, Morris J . The neurology of endemic cretinism. A study of two endemias. Brain. 1991; 114 ( Pt 2):825-41. DOI: 10.1093/brain/114.2.825. View

Gomes-Lima C, Wartofsky L, Burman K . Can Reverse T3 Assay Be Employed to Guide T4 vs. T4/T3 Therapy in Hypothyroidism?. Front Endocrinol (Lausanne). 2020; 10:856. PMC: 6917573. DOI: 10.3389/fendo.2019.00856. View

Kim E, Magen A, Ast G . Different levels of alternative splicing among eukaryotes. Nucleic Acids Res. 2006; 35(1):125-31. PMC: 1802581. DOI: 10.1093/nar/gkl924. View

Hulur I, Hermanns P, Nestoris C, Heger S, Refetoff S, Pohlenz J . A single copy of the recently identified dual oxidase maturation factor (DUOXA) 1 gene produces only mild transient hypothyroidism in a patient with a novel biallelic DUOXA2 mutation and monoallelic DUOXA1 deletion. J Clin Endocrinol Metab. 2011; 96(5):E841-5. PMC: 3085204. DOI: 10.1210/jc.2010-2321. View

Nagasaki K, Asami T, Ogawa Y, Kikuchi T, Uchiyama M . A study of the etiology of congenital hypothyroidism in the Niigata prefecture of Japan in patients born between 1989 and 2005 and evaluated at ages 5-19. Thyroid. 2011; 21(4):361-5. DOI: 10.1089/thy.2010.0005. View

Wang Z, Zou L, Zhong R, Zhu B, Chen W, Shen N . Associations between two genetic variants in NKX2-5 and risk of congenital heart disease in Chinese population: a meta-analysis. PLoS One. 2013; 8(8):e70979. PMC: 3732287. DOI: 10.1371/journal.pone.0070979. View

Roy S, Hartl D . Very little intron loss/gain in Plasmodium: intron loss/gain mutation rates and intron number. Genome Res. 2006; 16(6):750-6. PMC: 1473185. DOI: 10.1101/gr.4845406. View

Gabriel S, Ziaugra L, Tabbaa D . SNP genotyping using the Sequenom MassARRAY iPLEX platform. Curr Protoc Hum Genet. 2009; Chapter 2:Unit 2.12. DOI: 10.1002/0471142905.hg0212s60. View

McCarrison R . Observations on Endemic Cretinism in the Chitral and Gilgit Valleys. Ind Med Gaz. 2017; 43(12):441-449. PMC: 5183164. View

10.

De Marco G, Agretti P, Montanelli L, Di Cosmo C, Bagattini B, De Servi M . Identification and functional analysis of novel dual oxidase 2 (DUOX2) mutations in children with congenital or subclinical hypothyroidism. J Clin Endocrinol Metab. 2011; 96(8):E1335-9. DOI: 10.1210/jc.2010-2467. View

11.

Chen W, Feng P, Lin H, Chou K . iRSpot-PseDNC: identify recombination spots with pseudo dinucleotide composition. Nucleic Acids Res. 2013; 41(6):e68. PMC: 3616736. DOI: 10.1093/nar/gks1450. View

12.

Banghova K, Al Taji E, Cinek O, Novotna D, Pourova R, Zapletalova J . Pendred syndrome among patients with congenital hypothyroidism detected by neonatal screening: identification of two novel PDS/SLC26A4 mutations. Eur J Pediatr. 2007; 167(7):777-83. DOI: 10.1007/s00431-007-0588-7. View

13.

Maniatis T, Reed R . An extensive network of coupling among gene expression machines. Nature. 2002; 416(6880):499-506. DOI: 10.1038/416499a. View

14.

Roy M, Kim N, Xing Y, Lee C . The effect of intron length on exon creation ratios during the evolution of mammalian genomes. RNA. 2008; 14(11):2261-73. PMC: 2578852. DOI: 10.1261/rna.1024908. View

15.

Khatami M, Heidari M, Tabesh F, Ordooei M, Salehifar Z . Mutation analysis of the NKX2.5 gene in Iranian pediatric patients with congenital hypothyroidism. J Pediatr Endocrinol Metab. 2017; 30(8):857-862. DOI: 10.1515/jpem-2017-0084. View

16.

Teissier R, Guillot L, Carre A, Morandini M, Stuckens C, Ythier H . Multiplex Ligation-dependent Probe Amplification improves the detection rate of NKX2.1 mutations in patients affected by brain-lung-thyroid syndrome. Horm Res Paediatr. 2012; 77(3):146-51. DOI: 10.1159/000337214. View

17.

Bland J, Altman D . Statistics notes. The odds ratio. BMJ. 2000; 320(7247):1468. PMC: 1127651. DOI: 10.1136/bmj.320.7247.1468. View

18.

Fawcett J, Rouze P, Van de Peer Y . Higher intron loss rate in Arabidopsis thaliana than A. lyrata is consistent with stronger selection for a smaller genome. Mol Biol Evol. 2011; 29(2):849-59. DOI: 10.1093/molbev/msr254. View

19.

Cherella C, Wassner A . Congenital hypothyroidism: insights into pathogenesis and treatment. Int J Pediatr Endocrinol. 2017; 2017:11. PMC: 5625825. DOI: 10.1186/s13633-017-0051-0. View

20.

Guil S, Soler M, Portela A, Carrere J, Fonalleras E, Gomez A . Intronic RNAs mediate EZH2 regulation of epigenetic targets. Nat Struct Mol Biol. 2012; 19(7):664-70. DOI: 10.1038/nsmb.2315. View