Alopecia areata susceptibility variant in MHC region impacts expressions of genes contributing to hair keratinization and is involved in hair loss

Oka, Akira; Takagi, Atsushi; Komiyama, Etsuko; Yoshihara, Nagisa; Mano, Shuhei; Hosomichi, Kazuyoshi; Suzuki, Shingo; Haida, Yuko; Motosugi, Nami; Hatanaka, Tomomi; Kimura, Minoru; Ueda, Mahoko Takahashi; Nakagawa, So; Miura, Hiromi; Ohtsuka, Masato; Tanaka, Masayuki; Komiyama, Tomoyoshi; Otomo, Asako; Hadano, Shinji; Mabuchi, Tomotaka; Beck, Stephan; Inoko, Hidetoshi; Ikeda, Shigaku

doi:10.1016/j.ebiom.2020.102810

Cited by 23 publications

(27 citation statements)

References 69 publications

(74 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Among these mice, 2 (12.5%) of the 16 heterozygous mice and 15 (55.5%) of 27 homozygous mice showed patchy alopecia after birth without any stimulation (assessed for up to 10 months). Both the genomeedited mice and AA patients with the risk allele displayed morphologically impaired hair growth and comparable differential expression of hair-related genes, including p. 9 genes encoding hair keratin and keratin-associated proteins (KRTAPs) [6]. These results were consistent with the microarray analysis in this study; the upregulation of keratins, the KRTAP gene, and the Padi3, S100A3 and Hoxc13 genes was confirmed (Fig.…”

Section: Discussionsupporting

confidence: 89%

See 1 more Smart Citation

The alopecia areata phenotype is induced by the water avoidance stress test incchcr1-deficient mice

Zhao

Yoshihara

Takagi

et al. 2020

Preprint

Self Cite

View full text Add to dashboard Cite

BackgroundWe recently discovered a nonsynonymous variant in the coiled-coil alpha-helical rod protein 1 (CCHCR1) gene within the alopecia areata (AA) risk haplotype; mice engineered to carry the risk allele displayed a hair loss phenotype.ObjectiveTo further investigate the involvement of the CCHCR1 gene in AA pathogenesis.MethodsWe developed an AA model using C57BL/6N cchcr1 gene knockout mice. Mice (6-8 weeks) were divided into two groups: cchcr1-/- mice and wild-type (WT) mice. Both groups were subjected to a water avoidance stress (WAS) test.ResultsEight weeks after the WAS test, 25% of cchcr1 mice exhibited noninflammatory foci of alopecia on the dorsal skin. The foci resembled human AA in terms of gross morphology, trichoscopic findings and histological findings.ConclusionsOur results strongly suggest that CCHCR1 is associated with AA pathogenesis and that cchcr1-/- mice are a good model for investigating AA.Author summaryAlopecia areata is thought to affect 1-2% of the population. In severe alopecia areata, changes in appearance significantly reduce the patient’s quality of life, but there is no established treatment. Its pathogenic mechanism is thought to cause an autoimmune disease of the hair bulb of growing hair. Many genes and factors associated with AA onset form a background that easily causes such an immune reaction, and the causative genes related to alopecia areata are being elucidated worldwide. We were able to identify the CCHCR1 gene as one of the causative genes by genome analysis. In this study, we created CCHCR1-deficient mice using Cre/loxP technology and confirmed that 25% of CCHCR1-deficient mice that underwent the WAS test for psychological stimulation developed hair loss similar to that observed in human alopecia areata. This suggests that the CCHCR1 gene is a disease susceptibility gene for alopecia areata.

show abstract

Section: Discussionsupporting

confidence: 89%

“…We further identified keratin abnormalities in the hair shaft and comparative differential expression of hair-related keratin genes not only in alopecic mice but also in hair follicles from AA patients with the risk variant. Thus, our study identified a novel AA susceptibility variant that was validated by functional analysis [6].…”

Section: Introductionmentioning

confidence: 77%

The alopecia areata phenotype is induced by the water avoidance stress test incchcr1-deficient mice

Zhao

Yoshihara

Takagi

et al. 2020

Preprint

Self Cite

View full text Add to dashboard Cite

show abstract

“…Its exact function remains unknown, but it has been shown to play a wide variety of roles in steroidogenesis, proliferation, differentiation and cytoskeletal organization [44,45]. Interestingly, Oka et al [36] have identified a missense variant in CCHCR1 that is associated with alopecia areata, an autoimmune disease affecting the hair follicle. We found several functional candidate variants within CCHCR1 that had large differences in allele frequency between CHCU and CHFR.…”

Section: Discussionmentioning

confidence: 99%

“…Regarding hair development, 133 SNPs were found within the CCHCR1 gene, which is involved in hair loss [36]. Three SNPs (rs110552603, rs207611773 and rs381805999) are located within the 3′UTR and two SNPs (rs17871433 and rs377855638) can potentially impact splicing.…”

Section: Putative Selective Sweeps Between Cuban and French Charolaismentioning

confidence: 99%

Whole-genome sequencing reveals insights into the adaptation of French Charolais cattle to Cuban tropical conditions

et al. 2021

View full text Add to dashboard Cite

Background In the early 20th century, Cuban farmers imported Charolais cattle (CHFR) directly from France. These animals are now known as Chacuba (CHCU) and have become adapted to the rough environmental tropical conditions in Cuba. These conditions include long periods of drought and food shortage with extreme temperatures that European taurine cattle have difficulty coping with. Results In this study, we used whole-genome sequence data from 12 CHCU individuals together with 60 whole-genome sequences from six additional taurine, indicus and crossed breeds to estimate the genetic diversity, structure and accurate ancestral origin of the CHCU animals. Although CHCU animals are assumed to form a closed population, the results of our admixture analysis indicate a limited introgression of Bos indicus. We used the extended haplotype homozygosity (EHH) approach to identify regions in the genome that may have had an important role in the adaptation of CHCU to tropical conditions. Putative selection events occurred in genomic regions with a high proportion of Bos indicus, but they were not sufficient to explain adaptation of CHCU to tropical conditions by Bos indicus introgression only. EHH suggested signals of potential adaptation in genomic windows that include genes of taurine origin involved in thermogenesis (ATP9A, GABBR1, PGR, PTPN1 and UCP1) and hair development (CCHCR1 and CDSN). Within these genes, we identified single nucleotide polymorphisms (SNPs) that may have a functional impact and contribute to some of the observed phenotypic differences between CHCU and CHFR animals. Conclusions Whole-genome data confirm that CHCU cattle are closely related to Charolais from France (CHFR) and Canada, but also reveal a limited introgression of Bos indicus genes in CHCU. We observed possible signals of recent adaptation to tropical conditions between CHCU and CHFR founder populations, which were largely independent of the Bos indicus introgression. Finally, we report candidate genes and variants that may have a functional impact and explain some of the phenotypic differences observed between CHCU and CHFR cattle.

show abstract

“…3 Although the genome-wide association studies (GWAS) have identified associations of several genes with AA, [4][5][6] a few of them have been so far reported as a cause of the disease or functionally validated for the pathogenesis of AA. 7 In AA, lymphocyte infiltration contributes to changes in the hair follicles, which may cause hair loss. 8 Herein, altered expressions of chemokines in the hair bulbs are important in attracting immune cells around the hair bulb.…”

Section: Introductionmentioning

confidence: 99%

The MCP‐1 rs1024611 and MTHFR rs1801133 gene variations and expressions in alopecia areata: A pilot study

Tabatabaei-Panah

Moravvej

Hajihasani

et al. 2021

Immunity Inflam & Disease

View full text Add to dashboard Cite

Background: Monocyte chemoattractant protein-1 (MCP-1) is highly expressed by lymphocytes at skin sites affected by alopecia areata (AA). Variations in MCP-1 as well as in methylene-tetrahydrofolate reductase (MTHFR), a key enzyme related to many inflammatory pathologies, have been associated with several autoimmune disorders. This study was designed to test a possible association between MCP-1 and MTHFR variations and altered expression of their genes and the risk of AA. Methods: Blood samples of patients (60) suffering from AA as well as healthy subjects (60) were collected. Gene expression levels of MCP-1 and MTHFR were evaluated by real-time reverse-transcription polymerase chain reaction analysis. Moreover, MCP-1 rs1024611 (A-2518G) and MTHFR rs1801133 (C677T) polymorphisms were genotyped by using polymerase chain reactionrestriction fragment length polymorphism assays. Results:In contrast to MCP-1, the MTHFR gene expression was found to be significantly higher in patients than in controls. Further stratification of the patients revealed that polymorphic genotypes in MCP-1 (AG + GG) and MTHFR (CT + TT) could significantly alter gene expression levels. Elevation of MCP-1 expression was significantly associated with the total number of variant MCP-1 and MTHFR alleles. However, no statistically significant difference was noticed in the genotypic distribution of MCP-1 and MTHFR variations between patients and controls. Conclusion:In summary, despite MCP-1 rs1024611 and MTHFR rs1801133 variations are not associated with AA risk, they may implicate the disease pathogenesis by influencing MCP-1 activity.

show abstract

Alopecia areata susceptibility variant in MHC region impacts expressions of genes contributing to hair keratinization and is involved in hair loss

Cited by 23 publications

References 69 publications

The alopecia areata phenotype is induced by the water avoidance stress test incchcr1-deficient mice

The alopecia areata phenotype is induced by the water avoidance stress test incchcr1-deficient mice

Whole-genome sequencing reveals insights into the adaptation of French Charolais cattle to Cuban tropical conditions

The MCP‐1 rs1024611 and MTHFR rs1801133 gene variations and expressions in alopecia areata: A pilot study

Contact Info

Product

Resources

About