Table 1. Non-HLA and non-classical HLA gene polymorphisms associated with differential susceptibility to pemphigus.
| Disease | Gene symbol | Gene product | Location | Variant, marker, haplotype or genotype | Susceptibility or Protection? | Comments | Country or Population | References |
|---|---|---|---|---|---|---|---|---|
| PV | HLA-E | Major Histocompatibility Complex, Class I, E | 6p22.1 | genotype 01:03/01:03 | susc | Not due to LD with HLA DRB1 or DQB1 | USA | Bhanusali et at., 2012 |
| PV | HLA-G | Major Histocompatibility Complex, Class I, G | 6p22.1 | rs371194629 (14bp del) | susc | Israel Ashkenazi Jews | Gazit et al.,2004 | |
| EPF | HSPA1L | Heat Shock Protein Family A (Hsp70) Member 1 Like | 6p21.33 | rs2227956 C>T (Thr493Met) allele T | susc | Tunisia | Toumi et at., 2015 | |
| EPF | HSPA1A | Heat Shock Protein Family A (Hsp70) Member 1A | 6p21.33 | rs1043618G > C (a 5' UTR SNP) genotype C/C | susc | Tunisia | Toumi et at., 2015 | |
| EPF | HSPA1B | Heat Shock Protein Family A (Hsp70) Member IB | 6p21.33 | rs1061581 G > A (a synonymous variant) genotype G/G | susc | Tunisia | Toumi et at., 2015 | |
| PV | TAP1, TAP2 | Transporters 1 and 2, ATP Binding Cassette Subfamily B Member | 6p21.32 | polymorphic amino acid residue frequencies | susc | Israeli Jews | Slomov et al., 2005 | |
| PV + PF | TAP1, TAP2 | none | Japan | Niizeki et al., 2004 | ||||
| FS | MHC2TA (CIITA) | Class II Major Histocompatibility Complex Transactivator | 16p13.13 | rs3087456 G/G plus G/A genotypes | susc | Strong additive interaction between MHC2TA rs3087456 and HLA-DRB1 genotypes. No association with rs4774 (Gly500Ala) | Brazil general population | Piovezan and Petzl-Erler, 2013 |
| PF, EPF. (FS) | DSG1 | Desmoglein 1 | 18q12.1 | allele C (especially in genotype C/C) of the synonymous SNP rs12967407 (809T > C) | susc | ns for FS (p=0.079). Interaction between DSG1 and HLA was observed by Martel et at (2002). Haplotypes of rs8091003, rs8091117, rs16961689, rs61730306, rs34302455 not associated | France, Tunisia, Brazil | Martel et at., 2001; Ayed et at., 2002 ; Petzl-Erler and Malheiros, 2005 |
| PV | DSG3 | Desmoglein 3 | 18q12.1 | Two related haplotypes were associated | susc | Association with the haplotype possibly due to an (additional) regulatory SNP (Capon et al., 2009) | British and Indian populations | Capon et al., 2006 |
| FS | KIR | Killer Cell Immunoglobulin Like Receptor gene complex | 19q13.42 | More than three activating KIR and higher ratios activating/inhibitory KIR. Presence of both the activating KIR3DS1 gene and its HLA-Bw4 ligand | prot | Brazil general population | Augusto et al., 2012 | |
| FS | KIR3DL2 | Killer Cell Immunoglobulin Like Receptor KIR3DL2 | 19q13.42 | Allele KIR3DL2*001; rs3745902 allele T (376Met) | susc; prot | The risk was higher for KIR3DL2*001/001 homozygotes than for 001/x heterozygotes; the risk was higher for presence of KIR3DL2*001 together with the ligands HLA-A3 or HLA-A11 than for presence of 001 in the absence of these KIR3DL2 ligands. SNP rs3745902 T (376Met) associated with reduced risk | Brazil general population | Augusto et al., 2015 |
| FS | LAIR1 | Leukocyte Associated Immunoglobulin Like Receptor 1 | 19q13.42 | rs56802430 allele G; rs11084332 allele C | susc; prot | Alleles of four SNPs mark increased mRNA expression: rs3826753 G, rs74463408 C, rs3745444 T, rs56802430 G. However, no link between LAIR1 expression and the disease was observed | Brazil general population | Camargo et at., 2016 |
| FS | LAIR2 | Leukocyte Associated Immunoglobulin Like Receptor 2 | 19q13.42 | rs2287828 allele T; haplotype G-T-C-A of rs2042287, rs2287828, rs2277974, rs114834145 | susc | The G-T-C-A haplotype is associated with both FS and higher LAIR2 mRNA levels | Brazil general population | Camargo et al., 2016 |
| FS | KLRG1 | Killer Cell Lectin Like Receptor G1 | 12p13.31 | rs1805672 G allele (A/G genotype) | susc | rs1805672*G allele a miR-584-5p binding site in the 3' UTR of KLRG1 | Brazil general population | Cipolla et al., 2016 |
| FS | IL6 | Interleukin 6 | 7p15.3 | rs1800795 (-174G>C) C/C genotype | prot | rs1800795 is in the gene promoter | Brazil general population | Pereira et al., 2004 |
| FS, EPF | IL4 | Interleukin 4 | 5q31.1 | rs2243250 (also known as −590C > T or −589C > T) genotype T/T | susc | rs2243250 is in the gene promoter | Brazil, Tunisia | Pereira et al., 2004, Toumi et al., 2013 |
| EPF | IL4 + IL4R | Interleukin 4, Interleukin 4 Receptor | 5q31.1, 16p12.1 | T;A-C-A combination for rs2243250 (of IL4), and rs4787948-rs3024622-rs3024530 (of IL4R) | susc | Tunisia | Toumi et at., 2013 | |
| EPF | IL23R | Interleukin 23 Receptor | 1p31.3 | rs11209026 G/G genotype | susc | Tunisia | Ben Jmaa et al., 2018 | |
| EPF | IL17A | Interleukin 17A | 6p12.2 | rs3748067 C/C genotype | susc | Tunisia | Ben Jmaa et al., 2018 | |
| EPF | IL17F | Interleukin 17F | 6p12.2 | rs763780 C allele | susc | Tunisia | Ben Jmaa et al., 2018 | |
| EPF | TNF | Tumor Necrosis Factor | 6p21.33 | rs1800629 (-308G>A) A allele (in both the A/A and A/G genotypes) | susc | Tunisia | Ben Jmaa et al., 2018 | |
| FS | CD40LG # | CD40 Ligand | Xq26.3 | rs3092945 (-726T > C) allele T | susc | No association was seen for the 3'UTR(CA) STR rs56074249 | Brazil general population | Malheiros and Petzl-Erler, 2009 |
| FS | CD40 # | CD40 Molecule | 20q13.12 | rs1883832 (-1C>T) allele T | prot | rs1883832 is in the Kozak sequence that includes the translation initiation codon (AUG) and is important for ribosome binding to the mRNA | Brazil general population | Malheiros and Petzl-Erler, 2009 |
| FS | TNFSF13B # (BAFF; BLYS) | TNF Superfamily Member 13b | 13q33.3 | rs9514828 SNP (-871C> T) allele T | prot | rs9514828 is in the binding site for transcription factor MZF1 and may change its affinity, resulting in altered levels of BAFF | Brazil general population | Malheiros and Petzl-Erler, 2009 |
| FS | CTLA4 | Cytotoxic T-Lymphocyte Associated Protein 4 | 2q33.2 | rs5742909 (-318C>T) allele T | prot | 8 SNPs and 3 STR were analyzed, ranging from the promoter region of the CD28 gene to the intergenic region between CTLA4 and ICOS. rs5742909*T marks increased expression of CTLA4, which could lower the risk of Ads | Brazil general population | Dalla-Costa et al., 2010 |
| FS | CTLA4 | Cytotoxic T-Lymphocyte Associated Protein 4 | rs733618 (-1722TC) allele C | susc | rs733618*C might lead to altered alternative splicing and decreased expression and function of membrane-bound CTLA4 | Brazil general population | Dalla-Costa et at., 2010 | |
| FS | CD86 | CD86 Molecule | 3q13.33 | rs1129055 (1057G> A, Ala304Thr) allele A | prot | rs1129055*A may alter the signal transduction pathways controlled by CD86 on antigen presenting cells. Association was significant in the sample of predominantly African ancestry, but not in Euro-Brazilians | Brazil general population | Dalla-Costa et al., 2010 |
| FS | PDCD1 (PD-1) | Programmed Cell Death 1 | 2q37.3 | rs10204525 (PD1.6) allele A | susc | rs10204525 may influence binding of microRNA and transcription factors. Association was reported for the sample of European but not of predominantly African ancestry | Brazil general population | Braun-Prado and Petzl-Erler, 2007 |
| PV + PF | ICOS | Inducible T Cell Costimulator | 2q33.2 | rs10932029 (IVS1+173T> C) allele C | susc | Poland | Narbutt et al., 2010 | |
| FS | CD59 | CD59 Molecule (CD59 Blood Group) | 11p13 | rs1047581 and other five SNPs. Haplotype G-G-C-C-A-A | susc | 6 SNPs that might affect alternative splicing or mRNA stability were analyzed. Haplotype G-G-C-C-A-A also marks increased CD59 expression | Brazil general population | Salviano-Silva et al., 2017 |
| FS | C3 | Complement component C3 | 19p13.3 | rs4807895 allele T | susc | Brazil general population | Bumiller-Bini et al., 2018 analyzed 992 SNPs of 44 complement system genes. Polymorphisms of 25% of them were associated with PF. | |
| FS | C5AR1 | Complement C5a Receptor 1 | 19q13.32 | rs10404456 allele C | susc | Brazil general population | Bumiller-Bini et al., 2018 | |
| FS | C8A | Complement C8 Alpha Chain | 1p32.2 | rs11206934 allele C | susc | Brazil general population | Bumiller-Bini et al., 2018 | |
| FS | C9 | Complement component C9 | 5p13.1 | rs700218 allele T | prot | Brazil general population | Bumiller-Bini et al., 2018 | |
| FS | C9 | rs187875 allele T | susc | Brazil general population | Bumiller-Bini et al., 2018 | |||
| FS | CFH | Complement Factor H | 1q31.3 | rs34388368 genotype T/T | susc | rs34388368*T is associated with higher CFH mRNA levels in the hypodermis | Brazil general population | Bumiller-Bini et al., 2018 |
| FS | CR1 | Complement C3b/C4b Receptor 1 (Knops Blood Group) | 1q32.2 | haplotype with rs6656401 | susc | Brazil general population | Oliveira et al., 2019 | |
| FS | CR2 | Complement C3d Receptor 2 | 1q32.2 | rs2182911 allele C | prot | Brazil general population | Bumiller-Bini et al., 2018 | |
| FS | ITGAM (CR3) | Integrin Subunit Alpha M / Complement Component 3 Receptor 3 Subunit | 16p11.2 | rs12928810 allele A | prot | Brazil general population | Bumiller-Bini et al., 2018 | |
| FS | ITGAX (CR4) | Integrin Subunit Alpha X / Complement Component 3 Receptor 4 Subunit | 16p11.2 | rs11574637 allele C | prot | Brazil general population | Bumiller-Bini et al., 2018 | |
| FS | MASP1 | Mannan Binding Lectin Serine Peptidase 1 | 3q27.3 | rs13094773 genotype G/G; rs850309G/G;rs72549154 (Arg576Met) allele T | prot | higher MASP-3 levels may lower the PF risk | Brazil general population | Bumiller-Bini et al., 2018 |
| FS | MASP1 | rs3864098 allele C; rs698104 allele T | susc | higher MASP-1 levels may contribute to PF | Brazil general population | Bumiller-Bini et al., 2018 | ||
| PV + PF | FCGR2B | Low Affinity Receptor IIb for Fc Fragment of IgG | 1q23.3 | rs3219018 (-386G>C) allele C | prot | rs3219018 is shared by the promoters of FCGR2C and FCGR2B and leads to higher expression levels of FcgRIIb | Germany | Recke et al., 2015 |
| PV + PF | FCGR2C | Low Affinity Receptor IIc for Fc Fragment of IgG | 1q23.3 | rs183547105 (an ORF/Stop polymorphism) ORF allele | susc | FCGR2C expression occur only in the presence of the ORF allele. FcgRIIb expression was increased by the presence of FCGR2C ORF. The inhibitory FcgRIIb is involved in tolerance of B lymphocytes, which may be counterbalanced by FcgRIIc expression | Germany | Recke et al., 2015 |
| EPF + PF | FOXP3 | Forkhead Box P3 | Xp11.23 | G-A-15-C-Chaplotype of rs3761547-rs3761548-(GT)n-rs3761549-rs2294021 | susc | the four SNPs mark three different LD blocks | Tunisia | Ben Jmaa et al., 2017 |
| PV | ST18 | ST18 C2H2C-Type Zinc Finger Transcription Factor | 8q11.23 | rs2304365 allele A; rs17315309 allele G | susc | both SNPs present LD in Jews. Possibly rs17315309*G, which drives ST18 upregulation is the causal polymorphism. Association was not seen in Germans (Sarig et al., 2012) and in Chinese (Yue et al., 2014) | Israel (Jews); Egypt; Iran | Sarig et al., 2012; Vodo et al., 2016; Etesami et al., 2018 |
| FS | AL110292.1 | lncRNA AL110292.1 | 14q12 | rs7144332 allele T | susc | Lobo-Alves et al., 2019b. A total of 2 080 SNPs located in long ncRNAs (lncRNAs) genes were analyzed. | ||
| FS | LINC01176 | Long Intergenic Non-Protein Coding RNA 1176 | 7p14.3 | rs6942557 allele C | susc | Lobo-Alves et al., 2019b | ||
| FS | LINC01119 | Long Intergenic Non-Protein Coding RNA 1119 | 2p21 | rs17774133 allele T | susc | Lobo-Alves et al., 2019b | ||
| FS | lnc-PREX1-7:1 | lncRNA lnc-PREX1-7:1 | 20q13 | rs6095016 allele A | prot | Lobo-Alves et al., 2019b | ||
| FS | AC009121.1 | lncRNA AC009121.1 | 16p13.13 | rs7195536 allele G | prot | Lobo-Alves et al., 2019b | ||
| FS | AC133785.1 | lncRNA AC133785.1 | 2q21.1 | rs1542604 allele T | prot | Lobo-Alves et al., 2019b |
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Gene-gene interactions were observed between BAFF and both CD40 and CD40LG: The protective effects of CD40LG rs3092945 C and CD40 rs1883832 T alleles only manifest in BAFF rs9514828 T-positive individuals, and vice versa.
susc, prot: respectively, increased and decreased pemphigus risk
PV: pemphigus vulgaris, PF: sporadic pemphigus foliaceus, EPF: endemic pemphigus foliaceus in Tunisia, FS: fogo selvagem, the endemic form of pemphigus foliaceus in Brazil. LD: linkage disequilibrium, lncRNA: long non-coding RNA, ns: non-significant,