Background and purpose
This study aimed to analyze the gender-specific association of the filaggrin (FLG) gene polymorphisms with atopic dermatitis (AD) in Caucasians from the central region of Russia.
The study sample consisted of 906 female (including 474 patients with AD and 432 controls) and 406 male (such as 226 patients with AD and 180 controls) participants. Genotyping of ten polymorphisms of the FLG gene was done. The logistic regression was used to analyze the associations. A total of 125 SNPs (seven AD-associated SNPs and 118 proxy SNPs, r2≥0.8) FLG gene were used for the in silico functional annotation analysis in the females.
Significant associations were identified between seven SNPs of the FLG gene (rs12130219, rs61816761, rs558269137, rs12144049, rs3126085, rs471144, rs6661961) and AD in females: rs12144049 was associated independent individually (for allele C OR = 1.71, 95%Сl 1.19–2.46, рperm = 0.004 and OR = 1.76, 95%Сl 1.18–2.63, рperm = 0.006 according to the additive and dominant genetic models, respectively) and seven SNPs of the FLG gene within 14 haplotypes. Haplotype GGT [rs61816761-rs3126085-rs12144049] showed the strongest association (OR = 0.55, рperm = 0.001). No association between the analyzed SNPs and AD was determined in the male group. The subsequent bioinformatic analysis predicted the SNPs of the FLG gene that possessed epigenetic and non-synonymous effects, were involved in the control of gene expression and alternative splicing of genes that contribute to AD pathophysiology.
Citation: Dvornyk V, Ponomarenko I, Belyaeva T, Reshetnikov E, Churnosov M (2021) Filaggrin gene polymorphisms are associated with atopic dermatitis in women but not in men in the Caucasian population of Central Russia. PLoS ONE 16(12): e0261026. https://doi.org/10.1371/journal.pone.0261026
Editor: Dong Keon Yon, Seoul National University College of Medicine, REPUBLIC OF KOREA
Received: May 4, 2021; Accepted: November 22, 2021; Published: December 9, 2021
Copyright: © 2021 Dvornyk et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Data Availability: All relevant data are within the paper and its Supporting Information files.
Funding: The authors received no specific funding for this work.
Competing interests: The authors have declared that no competing interests exist.
Atopic dermatitis (AD), also called eczema, is a chronic, relapsing, pruritic, inflammatory skin disease . The prevalence of AD is high, up to 16% in the general practice population (lifetime ever diagnosed) with about 20% of the affected individuals having moderate to severe symptoms . AD is characterized by chronic lichenified or excoriated plaques occurring in typical areas, such as the head, neck, flexural areas, and extensive itching lesions . Patients with AD are more likely to have allergic rhinitis and asthma ; they frequently suffer from concomitant depression, anxiety, and attention deficit hyperactivity disorder [5,6]. AD may also be a risk factor for schizophrenia, eating disorder, and obsessive-compulsive disorder . AD significantly decreases the quality of life of patients and their families, affecting physical and psychological well-being, social functioning, and economic costs .
AD has a higher incidence among females than males [2,4,7]. In particular , documented the higher prevalence of eczema during adolescence in females and the two-fold predominance throughout the reproductive period in a population sample of 266,733 from Scotland. Similar results were reported for atopic eczema in a sample of about 30,000 subjects from Great Britain: individuals with adult-onset atopic eczema are more likely to be women (OR = 1.66–1.75) . In a systematic review and meta-analysis of risk factors associated with AD , reported a pooled OR for gender (male) equal to 0.67, thus suggesting a higher prevalence of the disease in females.
Profound alterations in skin barrier function and immunologic abnormalities are considered the key factors affecting the development and severity of AD . The etiology of AD is multifactorial involving interactions between genetics, immune, and environmental factors [10,11]. Familial and twin studies have demonstrated that AD is a highly heritable disease: genetic factors account for nearly 90% of the disease susceptibility variance [12,13].
The filaggrin (FLG) gene is one of the most significant known risk factors for AD . The gene is located on chromosome 1q21.3 in a region of the epidermal differentiation complex and encodes the structural protein, which is a major element in the stratum corneum . FLG plays a key role in the development of the epidermis and the skin barrier . FLG is also broken down into organic acids, which maintain the pH gradient and antimicrobial activity of the epidermis . A meta-analysis of 24 studies on FLG null mutations determined a 3-fold increased risk of AD in the carriers of one or more null variants . More than 300 FLG loss-of-function variants were identified  and more than 20 of them were associated with susceptibility to AD . Several genome-wide association studies (GWAS) identified more than ten additional susceptibility loci of the FLG gene for AD [18–23].
However, despite the ample evidence about the FLG gene association with AD (see  for review) and a role of the female gender as a non-modifiable risk factor for the disease [8–10], the studies of the gender-specific relationships between the FLG gene and risk for AD are limited [24,25]. We hypothesized that gender might influence the association between FLG gene polymorphisms and AD. The present study was aimed to analyze gender-specific associations of the FLG gene with AD in Caucasians from the central region of Russia.
Materials and methods
All participants of the study provided informed consent before enrolment. The study protocol was approved by the Ethical Review Committee of Belgorod State University. In total, 906 females (including 474 patients with AD and 432 controls) and 406 males (such as 226 patients with AD and 180 controls) of Russian origin, born and living in the central region of Russia [26,27] were recruited during the 2010–2018 period through dermatovenerological dispensaries at Belgorod and Kursk Regions. The diagnosis of AD was verified by qualified dermatologists. Patients were diagnosed with AD according to the UK Diagnostic Criteria . AD severity was assessed using the Eczema Area and Severity Index (EASI) . All controls were clinically assessed to have no AD, other skin and atopic diseases (asthma, hay fever, allergic conjunctivitis, sensitization to allergens (air pollutants, food, medication, domestic animals, indoor allergens, etc.)), a family history of atopic diseases . The cases and control group without any severe chronic disorders . Baseline and clinical characteristics of the case and control groups are shown in Table 1. Among females and males, the control groups were matched to the AD patients by age, body mass index, and the other characteristics (p>0.05).
Ten common SNPs of the FLG gene (rs61816761, rs12130219, rs3126085, rs558269137, rs6661961, rs10888499, rs471144, rs4363385, rs77199844, and rs12144049) were selected for the study based on the following criteria [32,33]: previously reported associations with AD (eczema) and functional relevance. The functionality of the selected loci was examined using the HaploReg database (in silico analysis) .
All ten selected loci were AD-associated according to the previous reports (nine SNPs were GWAS-significant) (S1 Table) and had regulatory significance (S2 Table). Also, five loci were previously showed association with some allergic disorders of the skin (psoriasis, ichthyosis vulgaris) and other organs (hay fever, asthma, etc.) (S1 Table).
SNP genotyping was performed using the MALDI-TOF mass spectrometry iPLEX platform (Agena Bioscience Inc., San Diego, CA, USA). For the quality control, about 5% of the samples were selected randomly and subjected to the repeatability test [37,38] that yielded 100% reproducibility.
The chi-squire test was applied to check the observed allele and genotype frequencies for correspondence to the Hardy–Weinberg equilibrium . Logistic regression was used to analyze the association between the SNPs of the FLG gene and AD . Age and BMI were applied as quantitative covariates. The adaptive permutation test was utilized to correct for multiple comparisons . All the above computations were performed using the PLINK package . The Bonferroni adjusted value Pperm ≤ 0.008 (0.05/6) was accepted as statistically significant given the numbers of the analyzed genetic models n = 3 , and the number of the groups compared (n = 2). The given sample sizes for females (474 patients with AD and 432 controls) and males (226 patients with AD and 180 controls) were sufficient to detect differences in allelic frequencies between the affected subjects and controls, respectively, at OR = 1.31–1.75 and OR = 1.49–2.25 for the additive model, OR = 1.53–1.79 and OR = 1.91–2.35 for the dominant model, OR = 1.56–19.0 and OR = 1.93–115.00 for the recessive model (at 80% power, ɑ = 0.05 for 2-sided test). Statistical power for each SNP was estimated using Quanto 1.2.4 . The «Four gamete frequencies» algorithm of linkage disequilibrium with D’ > 0.80 realized in the Haploview software  was selected to infer haplotype blocks. For the haplotype association, value pperm ≤ 0.025 was adopted as statistically significant (based on the numbers of groups compared n = 2).
SNPs functionality effects
To estimate the potential downstream functional effects of the AD-associated variants and their proxies (r2≥0.8) [46,47], we used the available data of epigenetic effects (HaploReg ), non-synonymous functional predictions (SIFT and PolyPhen-2 databases [48,49]), expression and alternative splicing quantitative traits (GTExconsortium atlas, ). HaploReg and European population data of the 1000 Genomes Project Phase 1 were used to identify variants in close linkage disequilibrium (r2 ≥ 0.8) with the AD-associated variants [51,52].
SNP association analyses
S3 Table shows the allele and genotype distribution of the studied SNPs in females and males. No departure from the Hardy–Weinberg equilibrium was observed in both studied groups (p>0.005 and pbonf>0.05). Variant allele C rs12144049 was found to be significantly associated with the increased AD risk in the additive (OR = 1.71, 95%Сl 1.19–2.46, р = 0.004, рperm = 0.004, power—99.71%) and dominant (OR = 1.76, 95%Сl 1.18–2.63, р = 0.006, рperm = 0.006, power—98.53%) genetic models only among females (Table 2). No statistically significant association between SNPs of the FLG gene and AD was observed in the male group (Table 2).
Haplotype association analyses
The LD of the FLG gene SNPs was analyzed separately in females and males. The haploblock structures were different between 1) AD patients and controls in both females and males and 2) males and females in both the patients and controls (Fig 1). The haplotypes manifested the association with the disease only in women but not men (Table 3). The strongest association was demonstrated by haplotype GGT [rs61816761-rs3126085-rs12144049] (OR = 0.55, p = 0.00006, рperm = 0.001).
Linkage disequilibrium (LD) between ten studied SNPs of the FLG gene in females (A and B) and males (C and D). A and C—AD patients, B and D—control group. LD values are presented as Lewontin’s standardized coefficient D′ (Figure sections 1) and the square of the Pearson’s correlation coefficient (r2) (Figure sections 2) between the SNPs.
Functional SNP predictions
Regulatory and non-synonymous effects.
The results of the bioinformatic analysis of the genomic and epigenetic effects for the seven AD risk loci of the FLG gene and 118 proxy SNPs (r2≥0.8) in females are given in S4 Table. According to the HaploReg database, 30 SNPs were located in exons of the FLG gene. Among them, locus rs61816761 is a nonsense mutation (R501X) and rs558269137 is a frameshift variant (2282delACTG). More than 20 SNPs were in strong LD with rs3126085 (S5 Table). One SNP, rs201584430, linked to the risk SNP rs12130219, was located in the FLG-AS1 gene splice donor site. Ten proxy SNPs were found in introns and 85 loci were located in the 3’- or/and 5’-UTR regions of seven genes (FLG, FLG-AS1, FLG2, LCE5A, CRNN, RP1-91G5.3, and HRNR) (S4 Table).
Most of the proxy SNPs have significant epigenetic effects. For example, rs201584430, which is in strong LD with the risk locus rs12130219, has a DNA position in the histone modification region corresponding to enhancer and promoter elements (24 and 6 tissues respectively), DNase hypersensitivity chromatin state region (4 tissues), and a genomic region with 25 transcription factors binding loci. Another proxy, rs17597997 (inked to the risk SNP rs6661961), was highly enriched for promoters (14 tissues), enhancers (18 tissues), and DNase hypersensitive (42 tissues) regions across multiple cell lines, tissues, and organs.
Expression and splicing QTLs.
All seven AD risk SNPs were expression quantitative trait loci associated with transcription of 16 target genes (S6 Table); six risk SNPs had the skin-specific transcript associations with six genes (CRNN, FLG, FLG2, FLG-AS1, LINGO4, RP1-91G5.3) (S7 Table). The 100 proxy SNPs of the five AD risk loci affected mRNA transcript abundance of twelve genes (S8 Table), including six genes with the skin-specific expression (S9 Table).
The effects of the analyzed SNPs on the alternative splicing are shown in S10 Table. The rs6661961 locus individually and 21 SNPs linked to it and rs3126085 were the splicing quantitative trait loci for two genes (RP11-107M16.2 and CRNN).
In the present study, we found that polymorphisms of the FLG gene are associated with AD in women but not in men in the Caucasian population of the central region of Russia. Locus rs12144049 was associated with the disease individually (OR = 1.71–1.76, рperm≤0.006) and seven SNPs were associated within 14 haplotypes. Importantly, the OR value for the risk allele C rs12144049 of the FLG gene determined in the present study (OR = 1.71–1.76) was similar to those previously reported by the GWAS of European populations: OR = 1.53  and OR = 1.39 .
FLG is an important structural protein that is responsible for the keratinization, moisturization, and antimicrobial functions of the skin stratum corneum [15,53]. It is necessary for the generation of the natural moisturizing factor, which is produced upon FLG deamination and breakdown. The natural moisturizing factor is important for the maintenance of stratum corneum hydration and also reduces its pH to about 5.5 . Epidermal insufficiency of FLG increases trans-epidermal water loss, causing the drying and cracking of the epidermis; FLG insufficiency also leads to aberrant keratinocyte differentiation, resulting in inadequate skin lipid content . The insufficiency in the epidermal barrier results in the penetration of allergens and microorganisms . Skin barrier defects have been considered an initial step in developing AD .
The key role of the null mutations (R501X, 2282del4, etc.) of the FLG gene in the epidermal barrier deficiency and AD was previously demonstrated [11,56,57]. Besides, several recent GWAS of AD suggested SNPs of the FLG gene as possible risk factors for the disease [18–23], which was supported by the results of the present study too. Importantly, both loss-of-function mutations and SNPs of the FLG gene are also a risk factor for other atopic conditions, e.g., asthma and hay fever thus suggesting that FLG deficiency may have a broader systemic significance [58–61]. For example, the rs61816761 variant of the FLG gene was 1.32-fold more common in patients suffering only from eczema when compared to those suffering only from hay fever and 1.26-fold more common as compared with asthma-only cases . Likewise, variant rs12144049 was significantly associated with both AD [22,23]; present study) and asthma .
The present study showed the association of the FLG gene with AD only in women. There is a limited number of studies of gender-related differences in associations of candidate genes and AD [24,62] found no evidence of an interaction between FLG genotypes and sex in children aged 6 months to 11 years. On the other hand, there is evidence about the higher prevalence of AD among females at adolescence and adulthood [2,4,7–10] that may suggest a role of sex hormones on the expression of this allergic disease . The female sex steroids, oestrogens and progesterone, may produce the immune stimulatory effects . The reactivity to allergens increases in women during a mid-menstrual cycle that suggests important modulation of immune responses by sex steroid levels . Oestrogen and testosterone produce opposite effects: pro-inflammatory and anti-inflammatory, respectively [63,65]. The effects of sex steroids may explain the significant sex differences and reversals observed in atopy (asthma, AD, etc.)  particularly the gender reversal in prevalence occurring at the time of hormonal changes. AD has a male predominance during childhood and female predominance after adolescence [4,8,10]. Apparently, during the reproductive years, particularly during puberty, higher levels of female sex hormones elevate an atopic predisposition in females, while male hormones may have a protective effect . Given this, it is reasonable to suppose that sex hormones may modulate phenotypic effects of the FLG gene in the course of AD and determine the observed gender‐related differences in the associations of the FLG gene polymorphisms with AD.
The in silico analysis suggested relationships of the seven risk SNPs FLG gene and 118 proxy SNPs (r2≥0.8) with the skin-specific expression of several genes (CRNN, FLG, FLG2, FLG-AS1). Specifically, variant rs12144049 predicted independently associated with AD was suggested to affect the mRNA level of CRNN in the skin. The cornulin gene (CRNN) encodes a calcium-binding protein belonging to the "fused gene" family and may play a role in the mucosal/epithelial immune response and epidermal differentiation (http://www.genecards.org/, [66–68].
The CRNN gene was previously associated with AD (eczema) [66,67] as well as with the severe course of the disease, elevated IgE levels, eosinophilia, and concomitant asthma . The CRNN gene is downregulated in the AD-like skin in the mouse model and human AD [66–68]. On the other hand, the GTExconsortium atlas data suggests that the AD risk allele of the CRNN gene (A of rs941934 ) is associated with the elevated CRNN expression in the healthy skin, and so is the disease risk variant C rs12144049 of the FLG gene (determined in the present study). One of the possible explanations of this inconsistency is that AD risk alleles indeed increase the CRNN gene expression in the healthy skin in some way, but this effect becomes opposite in the AD-like skin due to the significantly modified expression of the other cornified envelope proteins (FLG, FLG2, LOR, CRNN, SPRR3v1, RPTN, HRNR, SPRR1Av1) . However, this assumption needs further experimental testing.
The present study determined no significant differences in the distribution of the FLG gene alleles and genotypes between male and female AD patients, which is in agreement with the previous report . However, such differences were detected between affected and control females for allele C of rs12144049 within the additive and dominant genetic models. Several studies reported the higher susceptibility of females to AD [70–72]. The observed gender differences may be related to the influence of sex hormones (see, e.g., ).
Some limitations of the study should be acknowledged though. In particular, the male sample size was about two-fold smaller than that of females. This does not allow for making assumptions about a possible contribution of the FLG gene polymorphisms to AD in males.
The results of the present study provide further support for the possible contribution of the FLG gene to AD in Caucasians from Central Russia. This contribution is apparently gender-specific and its exact mechanisms need clarifying.
S1 Table. The literature data about associations of the studied polymorphisms of the FLG genes (1q21.3) with AD (eczema) and some skin (psoriasis, ichthyosis vulgaris) and others allergic disorders (asthma, hay fever, etc.).
S2 Table. The regulatory potential of the studied SNPs.
S3 Table. Gender-specific population parameters of the studied SNPs of the FLG gene in the AD and control groups.
S4 Table. Regulatory effects of the AD-associated SNPs of the FLG gene and SNPs in high LD (r2≥0.80).
S5 Table. Non-synonymous SNPs in high LD (r2≥0.80) with the AD-associated locus rs3126085 of the FLG gene in females (HaploReg, v4.1, http://archive.broadinstitute.org/mammals/haploreg/haploreg.php).
S6 Table. The eQTL effects of the AD-associated SNPs FLG gene in various tissues/organs.
S7 Table. eQTL values of AD-associated polymorphisms FLG gene in skin.
S8 Table. eQTL values of SNPs in high LD (r2≥0.80) with the AD-associated polymorphisms FLG gene.
S9 Table. eQTL values of SNPs in high LD (r2≥0.80) with the AD-associated polymorphisms FLG gene in skin.
S10 Table. sQTL values of the studied SNPs of the FLG gene and SNPs linked to them (r2≥0.80).
- 1. Bieber T. Atopic dermatitis. N Engl J Med 2008;358:1483–94. pmid:18385500
- 2. Chidwick K, Busingye D, Pollack A, Osman R, Yoo J, Blogg S, et al. Prevalence, incidence and management of atopic dermatitis in Australian general practice using routinely collected data from Medicine Insight. Australas J Dermatol 2020;61(3):e319–27. pmid:32173859
- 3. Feldman SR, Cox LS, Strowd LC, Gerber RA, Faulkner S, Sierka D, et al. The Challenge of Managing Atopic Dermatitis in the United States. Am Health Drug Benefits 2019;12(2):83–3. pmid:31057694
- 4. Hwang CY, Chen YJ, Lin MW, Chen TJ, Chu SY, Chen CC, et al. Prevalence of atopic dermatitis, allergic rhinitis and asthma in Taiwan: a national study 2000 to 2007. Acta Derm Venereol 2010;90(6):589–94. pmid:21057741
- 5. Kage P, Zarnowski J, Simon JC, Treudler R. Atopic dermatitis and psychosocial comorbidities—What’s new?. Allergol Select 2020;4:86–96. pmid:33195970
- 6. Drucker AM, Wang AR, Li WQ, Sevetson E, Block JK, Qureshi AA. The burden of atopic dermatitis: summary of a report for the national eczema association. J Invest Dermatol 2017;137:26–30. pmid:27616422
- 7. Barbarot S, Auziere S, Gadkari A, Girolomoni G, Puig L, Simpson EL, et al. Epidemiology of atopic dermatitis in adults: Results from an international survey. Allergy. 2018;73(6):1284–93. pmid:29319189
- 8. Osman M, Hansell AL, Simpson CR, Hollowell J, Helms PJ. Gender-specific presentations for asthma, allergic rhinitis and eczema in primary care. Prim Care Respir J 2007;16(1):28–35. pmid:17297524
- 9. Abuabara K, Ye M, McCulloch CE, Sullivan A, Margolis DJ, Strachan DP, et al. Clinical onset of atopic eczema: Results from 2 nationally representative British birth cohorts followed through midlife. J Allergy Clin Immunol 2019;144(3):710–9. pmid:31260715
- 10. Ng YT, Chew FT. A systematic review and meta-analysis of risk factors associated with atopic dermatitis in Asia. World Allergy Organ J 2020;13(11):100477. pmid:33204388
- 11. Schultz Larsen FV, Holm NV. Atopic dermatitis in a population based twin series. Concordance rates and heritability estimation. Acta dermato-venereologica Suppl. 1985;114:159.
- 12. van Beijsterveldt CE, Boomsma DI. Genetics of parentally reported asthma, eczema and rhinitis in 5-year-old twins. Euro Respir J 2007;29(3):516–21.
- 13. Martin MJ, Estravís M, García-Sánchez A, Dávila I, Isidoro-García M, Sanz C. Genetics and Epigenetics of Atopic Dermatitis: An Updated Systematic Review. Genes (Basel). 2020;11(4):442.
- 14. Kim J, Kim BE, Leung DYM. Pathophysiology of atopic dermatitis: Clinical implications. Allergy Asthma Proc 2019;40(2):84–92. pmid:30819278
- 15. Yang G, Seok JK, Kang HC, Cho YY, Lee HS, Lee JY. Skin Barrier Abnormalities and Immune Dysfunction in Atopic Dermatitis. Int J Mol Sci 2020;21(8):2867. pmid:32326002
- 16. Rodríguez E, Baurecht H, Herberich E, Wagenpfeil S, Brown SJ, Cordell HJ, et al. Meta-analysis of filaggrin polymorphisms in eczema and asthma: Robust risk factors in atopic disease. J Allergy Clin Immunol 2009;123:1361–1370. pmid:19501237
- 17. Margolis DJ, Mitra N, Gochnauer H, Wubbenhorst B, D’Andrea K, Kraya A, et al. Uncommon Filaggrin Variants Are Associated with Persistent Atopic Dermatitis in African Americans. J Investig Dermatol 2018;138:1501–6. pmid:29428354
- 18. Sun LD, Xiao FL, Li Y, Zhou WM, Tang HY, Tang XF, et al. Genome-wide association study identifies two new susceptibility loci for atopic dermatitis in the Chinese Han population. Nat Genet. 2011;43:690–694. pmid:21666691
- 19. Weidinger S, Willis-Owen SA, Kamatani Y, Baurecht H, Morar N, Liang L, et al. A genome-wide association study of atopic dermatitis identifies loci with overlapipng effects on asthma and psoriasis. Hum Mol Genet 2013;22(23):4841–56. pmid:23886662
- 20. Paternoster L, Standl M, Waage J, Baurecht H, Hotze M, Strachan DP, et al. Multi-ancestry genome-wide association study of 21,000 cases and 95,000 controls identifies new risk loci for atopic dermatitis. Nat Genet 2015;47(12):1449–56. pmid:26482879
- 21. Marenholz I, Esparza-Gordillo J, Rüschendorf F, Bauerfeind A, Strachan DP, Spycher BD, et al. Meta-analysis identifies seven susceptibility loci involved in the atopic march. Nat Commun 2015;6:8804. pmid:26542096
- 22. Baurecht H, Hotze M, Brand S, Büning C, Cormican P, Corvin A, et al. Genome-wide comparative analysis of atopic dermatitis and psoriasis gives insight into opposing genetic mechanisms [published correction appears in Am J Hum Genet. 2015 Dec 3;97(6):933]. Am J Hum Genet. 2015;96(1):104–20. pmid:25574825
- 23. Schaarschmidt H, Ellinghaus D, Rodríguez E, Kretschmer A, Baurecht H, Lipinski S, et al. A genome-wide association study reveals 2 new susceptibility loci for atopic dermatitis. J Allergy Clin Immunol 2015;136(3):802–6. pmid:25865352
- 24. Henderson J, Northstone K, Lee SP, Liao H, Zhao Y, Pembrey M, et al. The burden of disease associated with filaggrin mutations: a population‐based, longitudinal birth cohort study. J Allergy Clin Immunol 2008;21:872–7.e9. pmid:18325573
- 25. Blakeway H, Van-de-Velde V, Allen VB, Kravvas G, Palla L, Page MJ, et al. What is the evidence for interactions between filaggrin null mutations and environmental exposures in the aetiology of atopic dermatitis? A systematic review. Br J Dermatol 2020;183(3):443–51. pmid:31794059
- 26. Litovkina O, Nekipelova E, Dvornyk V, Polonikov A, Efremova O, Zhernakova N, et al. Genes involved in the regulation of vascular homeostasis determine renal survival rate in patients with chronic glomerulonephritis. Gene 2014;546(1):112–6. pmid:24727057
- 27. Reshetnikov EA, Akulova LY, Dobrodomova IS, Dvornyk VY, Polonikov AV, Churnosov MI. The insertion-deletion polymorphism of the ACE gene is associated with increased blood pressure in women at the end of pregnancy. J Renin Angiotensin Aldosterone Syst 2015;16(3):623–32. pmid:24150610
- 28. Williams HC, Burney PG, Pembroke AC, Hay RJ. The U.K. Working Party’s Diagnostic Criteria for Atopic Dermatitis. III. Independent hospital validation. Br J Dermatol 1994;131(3):406–16. pmid:7918017
- 29. Hanifin JM, Thurston M, Omoto M, Cherill R, Tofte SJ, Graeber M. The eczema area and severity index (EASI): assessment of reliability in atopic dermatitis. EASI Evaluator Group. Exp Dermatol 2001;10(1):11–8. pmid:11168575
- 30. Belyaeva TM. Study of associations of haplotypes of FLG gene polymorphism with the development of chronic true eczema in men. Research Results in Biomedicine 2020;6(2):160–71. (In Russian).
- 31. Ponomarenko I, Reshetnikov E, Polonikov A, Sorokina I, Yermachenko A, Dvornyk V, et al. Candidate genes for age at menarche are associated with endometrial hyperplasia. Gene 2020;757:144933. pmid:32640302
- 32. Reshetnikov E, Zarudskaya O, Polonikov A, Bushueva O, Orlova V, Krikun E, et al. Genetic markers for inherited thrombophilia are associated with fetal growth retardation in the population of Central Russia. J Obstet Gynaecol Res 2017;43(7):1139–44. pmid:28544373
- 33. Ponomarenko I, Reshetnikov E, Altuchova O, Polonikov A, Sorokina I, Yermachenko A, et al. Association of genetic polymorphisms with age at menarche in Russian women. Gene 2019;686:228–236. pmid:30453067
- 34. Ward LD, Kellis M. HaploReg v4: systematic mining of putative causal variants, cell types, regulators and target genes for human complex traits and disease. Nucleic Acids Res 2016;D1:D877–D881. pmid:26657631
- 35. Ponomarenko I, Reshetnikov E, Polonikov A, Verzilina I, Sorokina I, Elgaeva EE, et al. Candidate genes for age at menarche are associated with endometriosis. Reprod Biomed Online 2020;41(5):943–56. pmid:33051137
- 36. Eliseeva N, Ponomarenko I, Reshetnikov E, Dvornyk V, Churnosov M. LOXL1 gene polymorphism candidates for exfoliation glaucoma are also associated with a risk for primary open-angle glaucoma in a Caucasian population from central Russia. Mol Vis 2021;27:262–269. pmid:34012228
- 37. Golovchenko O, Abramova M, Ponomarenko I, Reshetnikov E, Aristova I, Polonikov A, et al. Functionally significant polymorphisms of ESR1and PGR and risk of intrauterine growth restriction in population of Central Russia. Eur J Obstet Gynecol Reprod Biol 2020;253:52–7. pmid:32777541
- 38. Eliseeva N, Ponomarenko I, Reshetnikov E, Dvornyk V, Churnosov M. The haplotype of the CDKN2B-AS1 gene is associated with primary open-angle glaucoma and pseudoexfoliation glaucoma in the Caucasian population of Central Russia. Ophthalmic Genetics 2021. pmid:34387529
- 39. Tikunova E, Ovtcharova V, Reshetnikov E, Dvornyk V, Polonikov A, Bushueva O, et al. Genes of tumor necrosis factors and their receptors and the primary open angle glaucoma in the population of Central Russia. Int J Ophthalmol 2017; 10:1490–1494. pmid:29062765
- 40. Moskalenko MI, Milanova SN, Ponomarenko IV, Polonikov AV, Churnosov MI. Study of associations of polymorphism of matrix metalloproteinases genes with the development of arterial hypertension in men. Kardiologiia 2019;59(7S):31–39. (In Russian). pmid:31441739
- 41. Che R, Jack JR, Motsinger-Reif AA, Brown CC. An adaptive permutation approach for genome-wide association study: evaluation and recommendations for use. BioData Min 2014;7:9. pmid:24976866
- 42. Purcell S, Neale B, Todd-Brown K, Thomas L, Ferreira MA, Bender D, et al. PLINK: a tool set for whole-genome association and population-based linkage analyses. Am J Hum Genet 2007;81(3):559–75. pmid:17701901
- 43. Starikova D, Ponomarenko I, Reshetnikov E, Dvornyk V, Churnosov M. Novel data about association of the functionally significant polymorphisms of the MMP-9 gene with exfoliation glaucoma in the Caucasian population of Central Russia. Ophthalmic Res (2020) pmid:33099542
- 44. Gauderman WJ. Sample size requirements for matched case-control studies of gene-environment interaction. Stat Med 2002;21(1):35–50. pmid:11782049
- 45. Barrett JC, Fry B, Maller J, Daly MJ. Haploview: analysis and visualization of LD and haplotype maps. Bioinformatics 2005;21(2):263–5. pmid:15297300
- 46. Ponomarenko I, Reshetnikov E, Polonikov A, Verzilina I, Sorokina I, Yermachenko A, et al. Candidate genes for age at menarche are associated with uterine leiomyoma. Front Genet 2021;11:512940. pmid:33552117
- 47. Moskalenko M, Ponomarenko I, Reshetnikov E, Dvornyk V, Churnosov M. Polymorphisms of the matrix metalloproteinase genes are associated with essential hypertension in a Caucasian population of Central Russia. Sci Rep 2021;11(1):5224. pmid:33664351
- 48. Kumar P, Henikoff S, Ng PC. Predicting the effects of coding non-synonymous variants on protein function using the SIFT algorithm. Na Protoc 2009;7,1073–81. pmid:19561590
- 49. Adzhubei I, Jordan DM, Sunyaev SR. Predicting functional effect of human missense mutations using PolyPhen-2. Curr Protoc Hum Genet 2013;Chapter 7:Unit7.20. pmid:23315928
- 50. Consortium GTEx. The GTEx Consortium atlas of genetic regulatory effects across human tissues. Science 2020;369(6509):1318–30. pmid:32913098
- 51. Dvornyk V, Ponomarenko I, Minyaylo O, Reshetnikov E, Churnosov M. Association of the functionally significant polymorphisms of the MMP9 gene with H. pylori-positive gastric ulcer in the Caucasian population of Central Russia. PLoS One 2021;16(9):e0257060. pmid:34492072
- 52. Minyaylo O, Ponomarenko I, Reshetnikov E, Dvornyk V, Churnosov M. Functionally significant polymorphisms of the MMP-9 gene are associated with peptic ulcer disease in the Caucasian population of Central Russia. Sci Rep 2021;11(1):13515. pmid:34188075
- 53. Kim BE, Leung DYM. Significance of Skin Barrier Dysfunction in Atopic Dermatitis. Allergy Asthma Immunol Res. 2018;10(3):207–15. pmid:29676067
- 54. Nedoszytko B, Reszka E, Gutowska-Owsiak D, Trzeciak M, Lange M, Jarczak J, et al. Genetic and Epigenetic Aspects of Atopic Dermatitis. Int J Mol Sci. 2020;21(18):6484. pmid:32899887
- 55. Kawasaki H, Nagao K, Kubo A, Hata T, Shimizu A, Mizuno H, et al. Altered stratum corneum barrier and enhanced percutaneous immune responses in filaggrin-null mice. J Allergy Clin Immunol 2012;129:1538–46. pmid:22409988
- 56. Palmer CNA, Irvine AD, Terron-Kwiatkowski A, Zhao Y, Liao H, Lee SP, et al. Common loss-of-function variants of the epidermal barrier protein filaggrin are a major predisposing factor for atopic dermatitis. Nature genetics. 2006;38:441–6. pmid:16550169
- 57. Irvine AD, McLean WH, Leung DY. Filaggrin mutations associated with skin and allergic diseases. N Engl J Med 2011;365:1315–27. pmid:21991953
- 58. Ferreira MA, Vonk JM, Baurecht H, Marenholz I, Tian C, Hoffman JD, et al. Shared genetic origin of asthma, hay fever and eczema elucidates allergic disease biology. Nat Genet 2017;49(12):1752–7. pmid:29083406
- 59. Zhu Z, Zhu X, Liu CL, Shi H, Shen S, Yang Y, et al. Shared genetics of asthma and mental health disorders: a large-scale genome-wide cross-trait analysis. Eur Respir J 2019;54(6):1901507. pmid:31619474
- 60. Ferreira MAR, Mathur R, Vonk JM, Szwajda A, Brumpton B, Granell R, et al. Genetic Architectures of Childhood- and Adult-Onset Asthma Are Partly Distinct. Hum Genet. 2019;104(4):665–84. pmid:30929738
- 61. Olafsdottir TA, Theodors F, Bjarnadottir K, Bjornsdottir US, Agustsdottir AB, Stefansson OA, et al. Eighty-eight variants highlight the role of T cell regulation and airway remodeling in asthma pathogenesis. Nat Commun 2020;11(1):393. pmid:31959851
- 62. Banihani SA, Abu-Alia KF, Khabour OF, Alzoubi KH. Association between Resistin Gene Polymorphisms and Atopic Dermatitis. Biomolecules. 2018;8(2):17. pmid:29584687
- 63. Whitacre CC, Reingold SC, O’Looney PA. A gender gap in autoimmunity. Science 1999;283(5406):1277–8. pmid:10084932
- 64. Kalogeromitros D, Katsarou A, Armenaka M, Rigopoulos D, Zapanti M, Stratigos I. Influence of the menstrual cycle on skin-prick test reactions to histamine, morphine and allergen. Clin Exp Allergy 1995;25(5):461–6. pmid:7553250
- 65. Osman M. Therapeutic implications of sex differences in asthma and atopy. Arch Dis Child 2003;88(7):587–90. pmid:12818904
- 66. Liedén A, Ekelund E, Kuo IC, Kockum I, Huang CH, Mallbris L, et al. Cornulin, a marker of late epidermal differentiation, is down-regulated in eczema. Allergy 2009;64(2):304–11. pmid:19133922
- 67. Trzeciak M, Sakowicz-Burkiewicz M, Wesserling M, Gleń J, Dobaczewska D, Bandurski T, et al. Altered Expression of Genes Encoding Cornulin and Repetin in Atopic Dermatitis. Int Arch Allergy Immunol. 2017;172(1):11–9. pmid:28219068
- 68. Trzeciak M, Olszewska B, Sakowicz-Burkiewicz M, Sokołowska-Wojdyło M, Jankau J, Nowicki RJ, et al. Expression Profiles of Genes Encoding Cornified Envelope Proteins in Atopic Dermatitis and Cutaneous T-Cell Lymphomas. Nutrients 2020;12(3):862. pmid:32213830
- 69. Belyaeva T, Ponomarenko I, Reshetnikov E, Polonikov A, Aristova I, Elykova A, et al. Dataset of allele, genotype and haplotype frequencies of four polymorphisms filaggrin gene in Russian patients with atopic dermatitis. Data Brief 2020;29:105307. pmid:32140520
- 70. Harrop J, Chinn S, Verlato G, Olivieri M, Norbäck D, Wjst M, et al. Eczema, atopy and allergen exposure in adults: a population-based study. Clin Exp Allergy 2007;37:526–535. pmid:17430349
- 71. Leynaert B, Neukirch C, Kony S, Guénégou A, Bousquet J, Aubier M, et al. Association between asthma and rhinitis according to atopic sensitization in a population-based study. J Allergy Clin Immunol 2004;113:86–93. pmid:14713912
- 72. Saeki H, Tsunemi Y, Fujita H, Kagami S, Sasaki K, Ohmatsu H, et al. Prevalence of atopic dermatitis determined by clinical examination in Japanese adults. J Dermatol 2006;33:817–819. pmid:17074002
- 73. Chen W, Mempel M, Schober W, Behrendt H, Ring J. Gender difference, sex hormones, and immediate type hypersensitivity reactions. Allergy 2008;63(11):1418–27. pmid:18925878