WO2020074727A1

WO2020074727A1 - Method for detecting fibrosis especially keloid

Info

Publication number: WO2020074727A1
Application number: PCT/EP2019/077652
Authority: WO
Inventors: Alain Dessein; Nicolas Duflot; Hélia DESSEIN
Original assignee: Genepred Biotechnologies
Priority date: 2018-10-11
Filing date: 2019-10-11
Publication date: 2020-04-16
Also published as: EP3864175A1

Abstract

Method for detecting a predisposition to and/or prognosing fibrosis progression of a subject in need thereof, comprising detecting at least one single nucleotide polymorphism (SNP) in at least one the following genes, in a biological sample of said subject: IL17D, IL17RD, IL2RA, IL22RA2, SFRP4, NLRP3, TLE1, NXPH1, WNT10A, JADE1, FGF1, RAC1 and SEMA6D, wherein the presence of at least one SNP in at least one of said genes is indicative of a predisposition to fibrosis or of fibrosis progression.

Description

METHOD FOR DETECTING FIBROSIS ESPECIALLY KELOID

The invention relates to a method for detecting a predisposition to and/or prognosing fibrosis progression of a subject in need thereof, comprising the detection of at least one single nucleotide polymorphism (SNP) in at least one the following genes, in a biological sample of said subject: IL17D, IL17RD, IL2RA, IL22RA2, SFRP4, NLRP3, TLE1 , NXPH1 , WNT10A, JADE1 , FGF1 , RAC1 and SEMA6D, or near NXPH1 or near JADE1 .

Fibrosis is characterized by an abnormal extracellular matrix proteins depot, occurring in a human fibrotic disease. Fibrosis may affect the liver (hepatic fibrosis), but also the skin.

Chronic liver inflammation caused by schistosome eggs, hepatitis C or B virus, toxic substances such as metabolites of alcohol or derivatives of fat, stimulate the deposition of extracellular matrix proteins (ECMP) in damaged tissues that form a dense network of fibrils referred to as fibrosis tissue.

In most patients ECMP depots are turned over and replaced by recently divided cells. In others that may represent up to 25% of the affected population, fibrosis accumulates, increases intrahepatic resistance to blood flow, promotes angiogenesis and causes a profound alteration of hepatic vascularization and the development of gastric varices. Bleeding from these varices and loss of hepatic architecture aggravate tissue necrosis, fibrosis and may cause liver failure and death.

Current diagnosis of hepatic fibrosis is mostly based on liver biopsy, elastometry and ultrasound analysis.

Liver biopsy is an invasive and costly procedure, and samples only a small portion of the liver. Thus it cannot afford a global assessment of hepatic fibrosis, and is subject to sampling variation and inter- and intra-observer error. In addition, it includes potential complications such as local hematoma, infection, pain related to the biopsy and death in less than 1% of the biopsied subjects.

Noninvasive tests such as elastography or endoscopy are also used.

Fibroscan is an approach to staging hepatic fibrosis, which is based on elastography and provides rapid measurement of mean hepatic tissue stiffness (Ziol et al, 2005). A probe is employed to transmit a vibration of low frequency and amplitude into the liver. This vibration wave triggers an elastic shear wave, whose velocity through the liver is directly proportional to tissue stiffness measured in kilopascals (kPa). It also measures the ultrasound attenuation in decibel per meter (dB/m). Fibroscan allows determining the presence and stage of hepatic fibrosis. However, the limitations of this technique are associated with attenuation of elastic waves in fluid or adipose tissue, which would impair assessment of fibrosis in patients. In addition, it is an extremely expensive instrument.

Nowadays, genetic prognosis and diagnosis of fibrosis, particularly hepatic fibrosis, is being studied.

The great majority of severe cases are observed in a limited number of families and fibrosis was shown to be dependent on the effects of a major genetic locus where mutations in two genes, CTGF and IL22RA2, have been identified as aggravating liver fibrosis. The effects of these genetic variants were described first in Chinese and Brazilians infected by schistosomes and then the results were extended to populations of Africa. Moreover, the inventors made the hypothesis that the same loci were also controlling severe fibrosis of other etiologic causes and demonstrated that cirrhosis caused by HCV is indeed strongly dependent on mutations in IL22RA2, as shown in WO2013/020904. On the other hand, WO2010/094740 identifies CTGF (CCN2) as a fibrosis susceptibility gene.

Although the already reported genetic associations were highly significant, the relative risk associated with these variants is modest. As a consequence, the fraction of heritability that was explained by the observed variants remains modest and most of these variants account for less than 2% of the phenotypic variance.

Fibrosis may also affect the skin tissue. Pathological scars, such as keloids, are characterized by an abnormality in wound healing, in which a fibrous tissue called "scar tissue" is formed during the process of skin wound healing, without regeneration of original normal tissue. A keloid may arise from a very minor wound such as an insect bite or a puncture by a vaccine or just by skin irritation or itching, and is characterized by its growth beyond the boundaries of the initial injury wound site. Generally, keloids persist for years. The lesion portions are extremely hard, thereby markedly restricting the elasticity of the skin.

Keloids may cause a functional impediment if located over a joint, such as restriction of the range of the joint motion. Keloids are also accompanied by pain and itching, which could be moderate to severe, and which is very impairing for the afflicted patients. Scratching the scar causes small lesions which stimulate further the development of the scar. Scratching also result in increasing pain. Nevertheless pain may also occur at distance from the scar. There is thus a need for an efficient and reliable method for prognosing fibrosis progression of a given subject over time, which may be noninvasive, easy and quick to perform. Such a prognosis method would have to be sensitive and specific, so as to determine the outcome of the fibrosis. There is also a need for an efficient method for detecting a predisposition to fibrosis progression in a subject.

There is also a need for a method for selecting fibrosis patients in order to target treatment for these subjects. This will increase compliance to treatment, and reduce the cost of mass treatment programs.

The inventors have surprisingly discovered that several polymorphisms in any one of, preferably all, genes chosen from IL17D, IL17RD, IL2RA, IL22RA2, SFRP4, NLRP3, TLE1 , NXPH1 , WNT10A, JADE1 , FGF1 , RAC1 and SEMA6D, or near NXPH1 or near JADE1 , aggravate fibrosis in the skin and hepatic tissue, especially on a cohort infected with Shistosoma mansoni and in a cohort of subjects with keloid scars. These polymorphisms have more pronounced effects on fibrosis, such as fibrosis of the skin tissue or hepatic fibrosis, when they are all present. Thus, these variants may then be used in a method for an efficient prognosis of fibrosis progression.

The invention provides a reliable method for predicting fibrosis progression, especially fibrosis of the skin tissue and liver fibrosis. Said method allows detecting a predisposition to fibrosis progression.

Thus, the invention provides a method for detecting a predisposition to and/or prognosing fibrosis progression of a subject in need thereof, comprising the detection of at least one single nucleotide polymorphism (SNP) in at least one of the following genes, in a biological sample of said subject: IL17D, IL17RD, IL2RA, IL22RA2, SFRP4, NLRP3, TLE1 , NXPH1 , WNT10A, JADE1 , FGF1 , RAC1 and SEMA6D, or near NXPH1 or near JADE1 .

Preferably, the method is for detecting a predisposition to and/or prognosing of keloid or keloid progression of a subject in need thereof, comprising detecting at least one SNP in at least one, preferably all, of the following genes, in a biological sample of said subject: IL17D, IL17RD, IL2RA, IL22RA2, SFRP4, NLRP3, TLE1 , NXPH1 , WNT10A, JADE1 , FGF1 , RAC1 and SEMA6D, or near NXPH1 or near JADE1 , wherein the presence of at least one SNP in at least one, preferably all, of said genes is indicative of a predisposition to keloid or keloid progression.

Preferably, the method of the invention comprises detecting, in a biological sample of said subject, at least one SNP in IL17D gene, and at least one SNP in at least one of the following genes: IL17RD, IL2RA, IL22RA2, SFRP4, NLRP3, TLE1 , NXPH1 , WNT10A, JADE1 , FGF1 , RAC1 and SEMA6D, or near NXPH1 or near JADE1 ,

wherein the presence of at least one SNP in at least one, preferably all, of said genes is indicative of a predisposition to keloid or keloid progression.

Particularly, the invention provides a method for detecting a predisposition to and/or prognosing fibrosis progression of a subject in need thereof, comprising detecting at least one single nucleotide polymorphism (SNP) in IL17D gene, in a biological sample of said subject,

wherein the presence of at least one SNP in IL17D gene is indicative of a predisposition to fibrosis or of fibrosis progression.

IL17D gene is the gene encoding for the interleukin 17D. The human gene ID in the NCBI database is 53342.

The invention also relates to a method for detecting a predisposition and/or prognosing fibrosis progression of a subject in need thereof, comprising detecting, in a biological sample of said subject, the presence of at least the following genotype in IL17D gene locus:

- genotype CG or CC with respect to SNP rs2282047,

wherein the presence of said at least one genotype in IL17D gene locus is indicative of a predisposition to fibrosis or of fibrosis progression.

In an embodiment, the presence of a C allele with respect to SNP rs2282047, more particularly of a CC or CG genotype, is deleterious for the patient, i.e. it is indicative of a patient being likely to develop abnormal deposit of ECMP, or fibrosis, especially hepatic fibrosis.

To the contrary, genotype GG with respect to SNP rs2282047 is not deleterious for the patient. The invention also relates to a method for detecting a predisposition to and/or prognosing fibrosis progression of a subject in need thereof, comprising detecting at least one single nucleotide polymorphism (SNP) in SFRP4 gene, in a biological sample of said subject, wherein the presence of at least one SNP in SFRP4 gene is indicative of a predisposition to fibrosis or of fibrosis progression.

SFRP4 gene is the gene encoding for the secreted frizzled related protein 4. The human gene ID in the NCBI database is 6424.

The invention also relates to a method for detecting a predisposition and/or prognosing fibrosis progression of a subject in need thereof, comprising detecting, in a biological sample of said subject, the presence of at least one of the following genotypes in SFRP4 gene locus:

- genotype CC with respect to SNP rs1717739,

- genotype CC or CT with respect to SNP rs2044831 ,

wherein the presence of said at least one genotype in or around SFRP4 gene locus is indicative of a predisposition to fibrosis or of fibrosis progression.

In an embodiment, the presence of a CC genotype with respect to SNP rs1717739 is deleterious for the patient, i.e. it is indicative of a patient being likely to develop abnormal deposit of ECMP, or fibrosis, especially hepatic fibrosis.

To the contrary, genotype CT or TT with respect to SNP rs1717739 is not deleterious for the patient.

In an embodiment, the presence of a C allele with respect to SNP rs2044831 , more particularly the presence of the genotype CC or CT, is deleterious for the patient, i.e. it is indicative of a patient being likely to develop abnormal deposit of ECMP, or fibrosis, especially hepatic fibrosis.

To the contrary, genotype TT with respect to SNP rs2044831 is not deleterious for the patient.

The invention provides a method for detecting a predisposition to and/or prognosing fibrosis progression of a subject in need thereof, comprising detecting at least one single nucleotide polymorphism (SNP) in NLRP3 gene, in a biological sample of said subject, wherein the presence of at least one SNP in NLRP3 gene is indicative of a predisposition to fibrosis or of fibrosis progression. NLRP3 gene is the gene encoding for the NLR family pyrin domain containing 3. The human gene ID in the NCBI database is 1 14548.

The invention also relates to a method for detecting a predisposition and/or prognosing fibrosis progression of a subject in need thereof, comprising detecting, in a biological sample of said subject the presence of at least the following genotype in NLRP3 gene locus:

- genotype GG with respect to SNP rs10925015,

wherein the presence of said genotype in NLRP3 gene locus is indicative of a predisposition to fibrosis or of fibrosis progression.

In an embodiment, the presence of a GG genotype with respect to SNP rs10925015, is deleterious for the patient, i.e. it is indicative of a patient being likely to develop abnormal deposit of ECMP, or fibrosis, especially hepatic fibrosis.

To the contrary, genotype CC or CG with respect to SNP rs10925015 is not deleterious for the patient.

The invention provides a method for detecting a predisposition to and/or prognosing fibrosis progression of a subject in need thereof, comprising detecting at least one single nucleotide polymorphism (SNP) in TLE1 gene, in a biological sample of said subject, wherein the presence of at least one SNP in TLE1 gene is indicative of a predisposition to fibrosis or of fibrosis progression.

TLE1 gene is the gene encoding for the transducing like enhancer of split 1. The human gene ID in the NCBI database is 7088.

The invention also relates to a method for detecting a predisposition and/or prognosing fibrosis progression of a subject in need thereof, comprising detecting, in a biological sample of said subject the presence of at least the following genotype in TLE1 gene locus:

- genotype CC with respect to SNP rs60259878,

wherein the presence of said genotype in TLE1 gene locus is indicative of a predisposition to fibrosis or of fibrosis progression.

In an embodiment, the presence of a CC genotype with respect to SNP rs60259878, is deleterious for the patient, i.e. it is indicative of a patient being likely to develop abnormal deposit of ECMP, or fibrosis, especially hepatic fibrosis. To the contrary, genotype CT or TT with respect to SNP rs60259878 is not deleterious for the patient.

The invention provides a method for detecting a predisposition to and/or prognosing fibrosis progression of a subject in need thereof, comprising detecting at least one single nucleotide polymorphism (SNP) near NXPH1 gene, in a biological sample of said subject, wherein the presence of at least one SNP near or in NXPH1 gene is indicative of a predisposition to fibrosis or of fibrosis progression.

NXPH1 gene is the gene encoding for the neurexophilin 1 . The human gene ID in the NCBI database is 30010.

The invention also relates to a method for detecting a predisposition and/or prognosing fibrosis progression of a subject in need thereof, comprising detecting, in a biological sample of said subject the presence of at least the following genotype near or in NXPH1 gene locus:

- genotype GT or TT with respect to SNP rs6961 161 ,

wherein the presence of said genotype in or around NXPH1 gene locus is indicative of a predisposition to fibrosis or of fibrosis progression.

In an embodiment, the presence of a T allele, such as the GT or TT genotype, with respect to SNP rs6961 161 , is deleterious for the patient, i.e. it is indicative of a patient being likely to develop abnormal deposit of ECMP, or fibrosis, especially hepatic fibrosis. To the contrary, genotype GG with respect to SNP rs6961 161 is not deleterious for the patient.

The invention provides a method for detecting a predisposition to and/or prognosing fibrosis progression of a subject in need thereof, comprising detecting at least one single nucleotide polymorphism (SNP) in WNTI OA gene, in a biological sample of said subject, wherein the presence of at least one SNP in WNT10A gene is indicative of a predisposition to fibrosis or of fibrosis progression.

WNT10A gene is the gene encoding for the Wnt family member 10A. The human gene ID in the NCBI database is 80326.

The invention also relates to a method for detecting a predisposition and/or prognosing fibrosis progression of a subject in need thereof, comprising detecting, in a biological sample of said subject the presence of at least the following genotype in WNT10A gene locus:

- genotype GG or AG with respect to SNP rs45741 13,

wherein the presence of said at least one genotype in or around WNT10A gene locus is indicative of a predisposition to fibrosis or of fibrosis progression.

In an embodiment, the presence of a G allele, such as a GG or AG genotype, with respect to SNP rs45741 13, is deleterious for the patient, i.e. it is indicative of a patient being likely to develop abnormal deposit of ECMP, or fibrosis, especially hepatic fibrosis.

To the contrary, genotype AA with respect to SNP rs45741 13 is not deleterious for the patient.

The invention provides a method for detecting a predisposition to and/or prognosing fibrosis progression of a subject in need thereof, comprising detecting at least one single nucleotide polymorphism (SNP) in IL17RD gene, in a biological sample of said subject, wherein the presence of at least one SNP in IL17RD gene is indicative of a predisposition to fibrosis or of fibrosis progression.

IL17RD gene is the gene encoding for the interleukin 17 receptor D. The human gene ID in the NCBI database is 54756.

The invention also relates to a method for detecting a predisposition and/or prognosing fibrosis progression of a subject in need thereof, comprising detecting, in a biological sample of said subject the presence of at least the following genotype in IL17RD gene locus:

- genotype AA or AG with respect to SNP rs34313207,

wherein the presence of said at least one genotype in IL17RD gene locus is indicative of a predisposition to fibrosis or of fibrosis progression.

In an embodiment, the presence of an A allele, such as a AA or AG genotype, with respect to SNP rs34313207, is deleterious for the patient, i.e. it is indicative of a patient being likely to develop abnormal deposit of ECMP, or fibrosis, especially hepatic fibrosis. To the contrary, genotype GG with respect to SNP rs34313207 is not deleterious for the patient. The invention provides a method for detecting a predisposition to and/or prognosing fibrosis progression of a subject in need thereof, comprising detecting at least one single nucleotide polymorphism (SNP) near JADE1 gene, in a biological sample of said subject, wherein the presence of at least one SNP near or in JADE1 gene is indicative of a predisposition to fibrosis or of fibrosis progression.

JADE1 gene is the gene encoding for the jade family PHD finger 1. The human gene ID in the NCBI database is 79960.

The invention also relates to a method for detecting a predisposition and/or prognosing fibrosis progression of a subject in need thereof, comprising detecting, in a biological sample of said subject the presence of at least the following genotype near or in JADE1 gene locus:

- genotype GG or AG with respect to SNP rs2288606,

wherein the presence of said at least one genotype near or in JADE1 gene locus is indicative of a predisposition to fibrosis or of fibrosis progression.

In an embodiment, the presence of a GG or AG genotype with respect to SNP rs2088606, is deleterious for the patient, i.e. it is indicative of a patient being likely to develop abnormal deposit of ECMP, or fibrosis, especially hepatic fibrosis.

To the contrary, genotype AA with respect to SNP rs2288606 is not deleterious for the patient.

The invention provides a method for detecting a predisposition to and/or prognosing fibrosis progression of a subject in need thereof, comprising detecting at least one single nucleotide polymorphism (SNP) in FGF1 gene, in a biological sample of said subject, wherein the presence of at least one SNP in FGF1 gene is indicative of a predisposition to fibrosis or of fibrosis progression.

FGF1 gene is the gene encoding for the fibroblast growth factor 1. The human gene ID in the NCBI database is 2246.

The invention also relates to a method for detecting a predisposition and/or prognosing fibrosis progression of a subject in need thereof, comprising detecting, in a biological sample of said subject the presence of at least the following genotype in FGF1 gene locus:

- genotype GG with respect to SNP rs72796624, wherein the presence of said genotype in FGF1 gene locus is indicative of a predisposition to fibrosis or of fibrosis progression.

In an embodiment, the presence of a GG genotype allele with respect to SNP rs72796624, is deleterious for the patient, i.e. it is indicative of a patient being likely to develop abnormal deposit of ECMP, or fibrosis, especially hepatic fibrosis.

To the contrary, genotype AA or AG with respect to SNP rs72796624 is not deleterious for the patient.

The invention provides a method for detecting a predisposition to and/or prognosing fibrosis progression of a subject in need thereof, comprising detecting at least one single nucleotide polymorphism (SNP) in IL2RA gene, in a biological sample of said subject, wherein the presence of at least one SNP in IL2RA gene is indicative of a predisposition to fibrosis or of fibrosis progression.

IL2RA gene is the gene encoding for the interleukin 2 receptor subunit alpha. The human gene ID in the NCBI database is 3559.

The invention also relates to a method for detecting a predisposition and/or prognosing fibrosis progression of a subject in need thereof, comprising detecting, in a biological sample of said subject the presence of at least the following genotype in IL2RA gene locus:

- genotype TT with respect to SNP rs706778,

wherein the presence of said genotype in IL2RA gene locus is indicative of a predisposition to fibrosis or of fibrosis progression.

In an embodiment, the presence of a TT genotype with respect to SNP rs706778, is deleterious for the patient, i.e. it is indicative of a patient being likely to develop abnormal deposit of ECMP, or fibrosis, especially hepatic fibrosis.

To the contrary, genotype CC or CT with respect to SNP rs706778 is not deleterious for the patient.

The invention provides a method for detecting a predisposition to and/or prognosing fibrosis progression of a subject in need thereof, comprising detecting at least one single nucleotide polymorphism (SNP) in IL22RA2 gene, in a biological sample of said subject, wherein the presence of at least one SNP in IL22RA2 gene is indicative of a predisposition to fibrosis or of fibrosis progression. IL22RA2 gene is the gene encoding for the interleukin 22 receptor subunit alpha 2. The human gene ID in the NCBI database is 1 16379.

The invention also relates to a method for detecting a predisposition and/or prognosing fibrosis progression of a subject in need thereof, comprising detecting, in a biological sample of said subject the presence of at least the following genotype in IL22RA2 gene locus:

- genotype TT with respect to SNP rs2064501 ,

wherein the presence of said genotype in IL22RA2 gene locus is indicative of a predisposition to fibrosis or of fibrosis progression.

In an embodiment, the presence of a TT genotype with respect to SNP rs2064501 , is deleterious for the patient, i.e. it is indicative of a patient being likely to develop abnormal deposit of ECMP, or fibrosis, especially hepatic fibrosis.

To the contrary, genotype CC or CT with respect to SNP rs2064501 is not deleterious for the patient.

The invention provides a method for detecting a predisposition to and/or prognosing fibrosis progression of a subject in need thereof, comprising detecting at least one single nucleotide polymorphism (SNP) in RAC1 gene, in a biological sample of said subject, wherein the presence of at least one SNP in RAC1 gene is indicative of a predisposition to fibrosis or of fibrosis progression.

RAC1 gene is the gene encoding for the Rac family small GTPase 1. The human gene ID in the NCBI database is 5879.

The invention also relates to a method for detecting a predisposition and/or prognosing fibrosis progression of a subject in need thereof, comprising detecting, in a biological sample of said subject the presence of at least the following genotype in RAC1 gene locus:

- genotype AA or AG with respect to SNP rs836560,

wherein the presence of said at least one genotype in RAC1 gene locus is indicative of a predisposition to fibrosis or of fibrosis progression.

In an embodiment, the presence of an A allele, such as a AA or AG genotype, with respect to SNP rs836560, is deleterious for the patient, i.e. it is indicative of a patient being likely to develop abnormal deposit of ECMP, or fibrosis, especially hepatic fibrosis. To the contrary, genotype GG with respect to SNP rs836560 is not deleterious for the patient.

The invention provides a method for detecting a predisposition to and/or prognosing fibrosis progression of a subject in need thereof, comprising detecting at least one single nucleotide polymorphism (SNP) in SEMA6D gene, in a biological sample of said subject, wherein the presence of at least one SNP in SEMA6D gene is indicative of a predisposition to fibrosis or of fibrosis progression.

SEMA6D gene is the gene encoding for the semaphoring 6D. The human gene ID in the NCBI database is 80031.

The invention also relates to a method for detecting a predisposition and/or prognosing fibrosis progression of a subject in need thereof, comprising detecting, in a biological sample of said subject the presence of at least the following genotype in SEMA6D gene locus:

- genotype GG with respect to SNP rs1559677,

wherein the presence of said genotype in SEMA6D gene locus is indicative of a predisposition to fibrosis or of fibrosis progression.

In an embodiment, the presence of a GG genotype with respect to SNP rs1559677, is deleterious for the patient, i.e. it is indicative of a patient being likely to develop abnormal deposit of ECMP, or fibrosis, especially hepatic fibrosis.

To the contrary, genotype AA or GA with respect to SNP rs1559677 is not deleterious for the patient.

Preferably, the method of the invention comprises the detection of SNP in at least 2 of the following genes, preferably at least 3, preferably at least 4, preferably at least 5, preferably at least 6, preferably at least 7, preferably at least 8, preferably at least 9, preferably at least 10, preferably at least 1 1 , preferably at least 12, preferably all 13 genes, in a biological sample of said subject: IL17D, IL17RD, IL2RA, IL22RA2, SFRP4, NLRP3, TLE1 , NXPH1 , WNT10A, JADE1 , FGF1 , RAC1 and SEMA6D.

Preferably, the SNP which is detected by the method of the invention is as follows:

the SNP in RAC1 is rs836560, and/or

the SNP in IL17D is rs2282047, and/or

the SNP in SFRP4 is chosen from rs1717739 and rs2044831 , and/or

the SNP in NLRP3 is rs10925015, and/or the SNP in TLE1 is rs60259878, and/or

the SNP near or in NXPH1 is rs6961 161 , and/or

the SNP in WNT 10A is rs45741 13, and/or

the SNP in IL17RD is rs34313207, and/or

the SNP near or in JADE1 is rs2088606, and/or

the SNP in FGF1 is rs72796624, and/or

the SNP in IL2RA is rs706778, and/or

the SNP in IL22RA2 is rs2064501 , and/or

the SNP in SEMA6D is rs1559677.

The invention also relates to a method for detecting a predisposition and/or prognosing fibrosis progression of a subject in need thereof, comprising detecting, in a biological sample of said subject:

a) the presence of at least one of the following genotypes in RAC1 gene locus:

- genotype AA or AG with respect to SNP rs836560, and/or

b) the presence of at least one of the following genotypes in IL17D gene locus:

- genotype CC or CG with respect to SNP rs2282047, and/or

c) the presence of at least one of the following genotypes in SFRP4 gene locus:

- genotype CC with respect to SNP rs1717739, or

- genotype CC or CT with respect to SNP rs2044831 , and/or

d) the presence of at least the following genotype in NLRP3 gene locus:

- genotype GG with respect to SNP rs10925015, and/or

e) the presence of at least the following genotype in TLE1 gene locus:

- genotype CC with respect to SNP rs60259878, and/or

f) the presence of at least one of the following genotypes near or in NXPH1 gene locus:

- genotype GT or TT with respect to SNP rs6961 161 , and/or

g) the presence of at least one of the following genotypes in WNT 10A gene locus:

- genotype GG or AG with respect to SNP rs45741 13, and/or

h) the presence of at least one of the following genotypes in IL17RD gene locus:

- genotype AG or AA with respect to SNP rs34313207, and/or

i) the presence of at least one of the following genotypes near or in JADE1 gene locus:

- genotype GG or AG with respect to SNP rs2088606, and/or

j) the presence of at least the following genotype in FGF1 gene locus:

- genotype GG with respect to SNP rs72796624, and/or

k) the presence of at least the following genotype in IL2RA gene locus:

- genotype TT with respect to SNP rs706778, and/or L) the presence of at least the following genotype in IL22RA2 gene locus:

- genotype TT with respect to SNP rs2064501 , and/or

m) the presence of at least the following genotype in SEMA6D gene locus:

- genotype GG with respect to SNP rs1559677,

wherein a) the presence of said at least one genotype in RAC1 gene locus, and/or b) the presence of said at least one genotype in IL17D gene locus, and/or c) the presence of said at least one genotype in SFRP4 gene locus, and/or d) the presence of said genotype in NLRP3 gene locus, and/or e) the presence of said genotype in TLE1 gene locus, and/or f) the presence of said at least one genotype near or in NXPH1 gene locus, and/or g) the presence of said at least one genotype in WNT10A gene locus, and/or h) the presence of said at least one genotype in IL17RD gene locus, and/or i) the presence of said at least one genotype near or in JADE1 gene locus, and/or j) the presence of said genotype in FGF1 gene locus, and/or k) the presence of said genotype in IL2RA gene locus, and/or I) the presence of said genotype in IL22RA2 gene locus, and/or m) the presence of said genotype in SEMA6D gene locus, are indicative of a predisposition to fibrosis or of fibrosis progression.

Preferably, the invention relates to a method for detecting a predisposition to and/or prognosing keloid progression of a subject in need thereof, comprising detecting in a biological sample of said subject:

a) the presence of at least one of the following genotypes in RAC1 gene locus:

- genotype AA or AG with respect to SNP rs836560, and/or

b) the presence of at least one of the following genotypes in IL17D gene locus:

- genotype CC or CG with respect to SNP rs2282047, and/or

c) the presence of at least one of the following genotypes in SFRP4 gene locus:

- genotype CC with respect to SNP rs1717739, or

- genotype CC or CT with respect to SNP rs2044831 , and/or

d) the presence of at least the following genotype in NLRP3 gene locus:

- genotype GG with respect to SNP rs10925015, and/or

e) the presence of at least the following genotype in TLE1 gene locus:

- genotype CC with respect to SNP rs60259878, and/or

- genotype GT or TT with respect to SNP rs6961 161 , and/or

- genotype GG or AG with respect to SNP rs45741 13, and/or

h) the presence of at least one of the following genotypes in IL17RD gene locus: - genotype AG or AA with respect to SNP rs34313207, and/or

- genotype GG or AG with respect to SNP rs2088606, and/or

j) the presence of at least the following genotype in FGF1 gene locus:

- genotype GG with respect to SNP rs72796624, and/or

k) the presence of at least the following genotype in IL2RA gene locus:

- genotype TT with respect to SNP rs706778, and/or

L) the presence of at least the following genotype in IL22RA2 gene locus:

- genotype TT with respect to SNP rs2064501 , and/or

m) the presence of at least the following genotype in SEMA6D gene locus:

- genotype GG with respect to SNP rs1559677,

wherein a) the presence of said at least one genotype in RAC1 gene locus, and/or b) the presence of said at least one genotype in IL17D gene locus, and/or c) the presence of said at least one genotype in SFRP4 gene locus, and/or d) the presence of said genotype in NLRP3 gene locus, and/or e) the presence of said genotype in TLE1 gene locus, and/or f) the presence of said at least one genotype near or in NXPH1 gene locus, and/or g) the presence of said at least one genotype in WNT10A gene locus, and/or h) the presence of said at least one genotype in IL17RD gene locus, and/or i) the presence of said at least one genotype near or in JADE1 gene locus, and/or j) the presence of said genotype in FGF1 gene locus, and/or k) the presence of said genotype in IL2RA gene locus, and/or I) the presence of said genotype in IL22RA2 gene locus, and/or m) the presence of said genotype in SEMA6D gene locus, are indicative of a predisposition to keloid or of keloid progression.

Preferably, the invention relates to a method for detecting a predisposition and/or prognosing fibrosis progression of a subject in need thereof, comprising detecting, in a biological sample of said subject:

a) the presence of at least one of the following genotypes in RAC1 gene locus:

- genotype AA or AG with respect to SNP rs836560, and

b) the presence of at least one of the following genotypes in IL17D gene locus:

- genotype CC or CG with respect to SNP rs2282047, and

c) the presence of at least one of the following genotypes in SFRP4 gene locus:

- genotype CC with respect to SNP rs1717739, or

- genotype CC or CT with respect to SNP rs2044831 , and

d) the presence of at least the following genotype in NLRP3 gene locus:

- genotype GG with respect to SNP rs10925015, and e) the presence of at least the following genotype in TLE1 gene locus:

- genotype CC with respect to SNP rs60259878, and

- genotype GT or TT with respect to SNP rs6961 161 , and

- genotype GG or AG with respect to SNP rs45741 13, and

- genotype AG or AA with respect to SNP rs34313207, and

- genotype GG or AG with respect to SNP rs2088606, and

j) the presence of at least the following genotype in FGF1 gene locus:

- genotype GG with respect to SNP rs72796624, and

k) the presence of at least the following genotype in IL2RA gene locus:

- genotype TT with respect to SNP rs706778, and

L) the presence of at least the following genotype in IL22RA2 gene locus:

- genotype TT with respect to SNP rs2064501 , and

m) the presence of at least the following genotype in SEMA6D gene locus:

- genotype GG with respect to SNP rs1559677,

wherein a) the presence of said at least one genotype in RAC1 gene locus, b) the presence of said at least one genotype in IL17D gene locus, c) the presence of said at least one genotype in SFRP4 gene locus, d) the presence of said genotype in NLRP3 gene locus, e) the presence of said genotype in TLE1 gene locus, f) the presence of said at least one genotype near or in NXPH1 gene locus, g) the presence of said at least one genotype in WNT10A gene locus, h) the presence of said at least one genotype in IL17RD gene locus, i) the presence of said at least one genotype near or in JADE1 gene locus, j) the presence of said genotype in FGF1 gene locus, k) the presence of said genotype in IL2RA gene locus, I) the presence of said genotype in IL22RA2 gene locus, and m) the presence of said genotype in SEMA6D gene locus, are all indicative of a predisposition to fibrosis or of fibrosis progression.

By“SNP” or "single nucleotide polymorphism", it is meant a single nucleotide variation in a genetic sequence that occurs at appreciable frequency in the population. There are millions of SNPs in the human genome. Most commonly, these variations are found in the DNA between genes. When SNPs occur within a gene or in a regulatory region near a gene, they may play a more direct role in disease by affecting the gene’s function. Linkage disequilibrium (LD) is defined as the non-random association of alleles at different loci across the genome. Alleles at two or more loci are in LD if their combination occurs more or less frequently than expected by chance in the population. When there is a causal locus in a DNA region, due to LD, one or more SNPs nearby are likely associated with the trait too. Therefore, any SNPs in strong LD (yielding a r²>0.04) with a given SNP associated with an abnormal ECMP deposit will be associated with this trait.

Identification of additional SNPs in linkage disequilibrium with a given SNP involves: (a) amplifying a fragment from the genomic region comprising or surrounding a first SNP from a plurality of individuals; (b) identifying second SNPs in the genomic region harboring or surrounding said first SNP; (c) conducting a linkage disequilibrium analysis between said first SNP and second SNPs; and (d) selecting said second SNPs as being in linkage disequilibrium with said first marker. Sub-combinations comprising steps (b) and (c) are also contemplated.

Methods to identify SNPs and to conduct linkage disequilibrium analysis can be carried out by the skilled person without undue experimentation by using well-known methods.

The SNPs of interest in the present invention are summarized in the Table 1 below:

_

The sequence listing enclosed quotes the variable nucleotides of the above sequences according to the IUPAC nucleotide code, i.e.:

r = a or g;

s = g or c;

d = a or g or t;

v = a or c or g;

b = c or g or t;

y = c or t.

Moreover, in the present application, the wording“genotype X1X2 with respect to SNP Y”, means that for the given SNP Y, one allele is X1 and the other allele is X2.

The term“gene” is to be understood in its meaning known in the art, and comprises coding and non-coding sequences, as well as regulating sequences.

The term “subject” as used herein refers to a mammalian, preferably a human. Preferably, the subject may be infected with a virus, preferably a virus selected from the Flaviviridae, such as Hepatitis A or C or B Virus. According to another embodiment, preferably, the subject may be infected by schistosoma, such as Schistosoma mansoni, Schistosoma haematobium , Schistosoma japonicum, Schistosoma mekongi or Schistosoma intercalatum. These schistosoma are responsible for bilharzia (or schistosomiasis). According to another embodiment, preferably, the subject has a diet which is fat-rich, and/or alcohol-rich. Preferably, in such cases, the subject is afflicted by obesity and/or alcoholism.

Within the context of this invention, "fibrosis" designates all types of human fibrosis, i.e. abnormal ECMP depot, occurring in a human fibrotic disease. Such a human fibrotic disease may be chosen from hepatic fibrosis (notably of various grades, including cirrhosis), cutaneous keloid, hypertrophic scars, scleroderma, fibrosis due to obesity and/or alcoholism. Preferably, fibrosis is chosen from:

- hepatic fibrosis, comprising hepatic fibrosis of various grades including cirrhosis, alcoholic and non-alcoholic, fibrosis caused by Hepatitis viruses,

- fibrosis of the skin tissue, particularly due to cutaneous keloid, hypertrophic scars or scleroderma, - fibrosis of the adipose tissue, such as fibrosis due to obesity (such as non alcoholic fatty liver disease (NAFLD) or non-alcoholic steatohepatitis (NASH)) and

- pulmonary fibrosis.

Very preferably, fibrosis is fibrosis of the skin tissue, preferably cutaneous keloid.

Within the context of this invention, "hepatic fibrosis" or "HF" designates all types of fibrosis occurring in a liver, tissue thereof or any part of tissue thereof. Hepatic fibrosis occurs especially in response to an injury. Hepatic fibrosis can be the common response to chronic liver injury, ultimately leading to cirrhosis and its complications, portal hypertension, liver failure, and hepatocellular carcinoma. Various types of chronic liver injury can cause hepatic fibrosis, such as:

- hepatic fibrosis due to a chemical agent (such as an hepato-toxic drug or alcohol),

- hepatic fibrosis due to fat (such as NAFLD or NASH),

- hepatic fibrosis due to a bacterial infection (such as brucellosis),

- hepatic fibrosis due to a parasitic infection (such as bilharzia), or

- hepatic fibrosis due to viral infections (such as hepatic A virus (HAV), hepatic B virus (HBC) or hepatic C virus (HCV) infections).

“Fibrosis of the skin tissue” may be chosen from cutaneous keloid, hypertrophic scars and scleroderma.

A cutaneous keloid is an excessive growth of scar tissue on the skin. A hypertrophic scar is a cutaneous condition characterized by excessive collagen depot which gives rise to a raised scar, and which, contrary to keloid, does not grow beyond the boundaries of the original wound.

Keloids and hypertrophic scars often occur following trauma, inflammation, surgery, burns and sometimes spontaneously. These disorders represent aberrations in the fundamental processes of wound healing.

Within the context of the present invention, the term "prognosis" includes the detection, monitoring, dosing and/or comparison, at various stages, including early, pre-symptomatic stages, and late stages, in adults, children and pre-birth. Prognosis typically includes the prediction of the progression of fibrosis and the characterization of a subject to define the most appropriate treatment.

The biological sample of the monitoring method of the invention is isolated from a subject and can include, by way of example and not limitation, bodily fluids and/or tissue extracts such as homogenates or solubilized tissue obtained from said subject. Bodily fluids useful in the present invention include blood, urine, saliva or any other bodily secretion or derivative thereof. As used herein "blood" includes whole blood, plasma, serum, circulating epithelial cells, constituents, or any derivative of blood.

Preferably the biological sample used in the invention is a biopsy, a blood sample, a saliva sample or a urine sample, more preferably a biopsy or a blood sample. The blood sample may be a freshly isolated blood sample (<48h) or a blood sample which has been obtained previously and kept frozen until use.

The detections of at least one SNP in at least one of the genes of the invention (target gene(s)) may independently be performed by selective hybridization assay, sequencing assay or microsequencing assay. Other suitable methods include allele-specific oligonucleotide (ASO), allele-specific amplification, Southern blot (for DNAs), Northern blot (for RNAs), single-stranded conformation analysis (SSCA), fluorescent in situ hybridization (FISH), gel migration, clamped denaturing gel electrophoresis, heteroduplex analysis, chemical mismatch cleavage, ELISA, radio-immunoassays (RIA) and immuno- enzymatic assays (IEMA). Some of these approaches (such as SSCA) are based on a change in electrophoretic mobility of the nucleic acids, as a result of the presence of an altered sequence. According to these techniques, the altered sequence is visualized by a shift in mobility on gels. The fragments may then be sequenced to confirm the alteration. Some others are based on specific hybridization between nucleic acids from the subject and a probe specific for wild-type or altered target gene or RNA. The probe may be in suspension or immobilized on a substrate. The probe is typically labelled to facilitate detection of hybrids. Some of these approaches are particularly suited for assessing a polypeptide sequence or expression level, such as Northern blot, ELISA and RIA. These latter require the use of a ligand specific for the polypeptide, more preferably of a specific antibody.

The present invention also relates to a kit for detecting a predisposition and/or prognosing fibrosis progression of a subject.

Said kit allows detecting at least one SNP in at least one of the following genes, in a biological sample: IL17D, IL17RD, IL2RA, IL22RA2, SFRP4, NLRP3, TLE1 , NXPH1 , WNT10A, JADE1 , FGF1 , RAC1 and SEMA6D or near NXPH1 or JADE1 .

Preferably, said kit allows detecting SNP in at least 2 of the following genes, preferably at least 3, preferably at least 4, preferably at least 5, preferably at least 6, preferably at least 7, preferably at least 8, preferably at least 9, preferably at least 10, preferably at least 1 1 , preferably at least 12, preferably all 13 genes, in a biological sample of said subject: IL17D, IL17RD, IL2RA, IL22RA2, SFRP4, NLRP3, TLE1 , NXPH1 , WNT10A, JADE1 , FGF1 , RAC1 and SEMA6D or near NXPH1 or JADE1 .

Preferably, the kit allows detecting the following SNP:

the SNP in RAC1 rs836560, and/or

the SNP in IL17D rs2282047, and/or

the SNP in SFRP4 chosen from rs1717739 and rs2044831 , and/or

the SNP in NLRP3 rs10925015, and/or

the SNP in TLE1 rs60259878, and/or

the SNP near or in NXPH1 rs6961 161 , and/or

the SNP in WNT 10A rs45741 13, and/or

the SNP in IL17RD rs34313207, and/or

the SNP near or in JADE1 rs2088606, and/or

the SNP in FGF1 rs72796624, and/or

the SNP in IL2RA rs706778, and/or

the SNP in IL22RA2 rs2064501 , and/or

the SNP in SEMA6D rs1559677.

Thus, according to the invention, said kit comprises at least the different primers useful for detecting the relevant gene(s).

Finally, the present invention also relates to a method for treating fibrosis in a subject in need thereof, comprising the following steps:

i) detecting at least one single nucleotide polymorphism (SNP) in at least one of the following genes, preferably at least 2 of the following genes, preferably at least 3, preferably at least 4, preferably at least 5, preferably at least 6, preferably at least 7, preferably at least 8, preferably at least 9, preferably at least 10, preferably at least 1 1 , preferably at least 12, preferably all 13 genes, in a biological sample of said subject: IL17D, IL17RD, IL2RA, IL22RA2, SFRP4, NLRP3, TLE1 , NXPH1 , WNT10A, JADE1 , FGF1 , RAC1 and SEMA6D, or near NXPH1 or JADE1 ,

wherein if at least one SNP is detected, preferably at least 2, preferably at least 3, preferably at least 4, preferably at least 5, preferably at least 6, preferably at least 7, preferably at least 8, preferably at least 9, preferably at least 10, preferably at least 1 1 , preferably at least 12, preferably at least 13 SNPs are detected, and each in one of the above genes, then said subject is a rapid or slow progressor; and

ii) subsequently treating said rapid or slow progressor subject with a treatment. Preferably, the SNP are the ones as described above, and preferably the genotypes are the ones as described above.

The treatment of step ii) above may be chosen from antiviral drugs (antiviral agent and/or interferons).

The method of treatment of the invention allows an efficient prognosis of fibrosis progression, and thus, a better treatment. Indeed, as there is no treatment for curing severe fibrosis cases, the method of the invention allows an earlier prognosis of severe fibrosis cases, increasing the chance of a better outcome.

Example 1 : Association tests between each of the SNPs of the invention and the keloid phenotype

Each SNP according to the invention has been evaluated for its presence in a control group (line“TE”) or in a keloid group (line“CHEL”).

The total number of individuals (control and keloid) is 1481 , which includes 1276 controls and 205 keloid patients; except for rs1559677 (gene SEMA6D), where the SNP has been tested for a part of said cohort only.

The population of individuals comes from keloid patients recruited in France (Marseille and Paris), and controls recruited in France and Africa by monitoring the ethnic diversity of patients with keloids.

As keloids present the risk of being mixed with hypertrophic scars, only the scars with a score greater than 15 on the scale established by the Japanese dermatology society were considered as keloids. This scale allowed eliminating doubtful cases.

The criteria used for scoring are particularly (i.e. those who weigh the most in the score): the etiological cause (often unknown), heredity (in 50% of cases), the age at onset (patient aged of less than 30 years in general), the horizontal growth of the lesion, the ethnicity, the clinical signs (pain and pruritus), the localization on the body and the number of lesions.

This classification is described in details in Ogawa et al, Medical hypotheses 96, 2016, 51 - 60.

The results are presented below for each SNP, and for each genotype (deleterious and non-deleterious). SNP rs836560

Chi-Square Tests

a. 0 cells (,0%) have expected count less than 5. The minimum expected count is 12,32. SNP rs2282047

Chi-Square Tests

a. 0 cells (,0%) have expected count less than 5. The minimum expected count

is 43,33.

SNP rs1717739

Chi-Square Tests

a. 0 cells (,0%) have expected count less than 5. The minimum expected count is 51 ,49.

b. Computed only for a 2x2 table SNP rs2044831

Chi-Square Tests

a. 0 cells (,0%) have expected count less than 5. The minimum expected count is 22,84.

SNP rs10925015

Chi-Square Tests

a. 0 cells (,0%) have expected count less than 5. The minimum expected count is 17,03.

SNP rs60259878

Chi-Square Tests

a. 1 cells (16,7%) have expected count less than 5. The minimum expected count is 2,63. SNP rs6961 161

Chi-Square Tests

a. 0 cells (,0%) have expected count less than 5. The minimum expected count is 5,54.

SNP rs45741 13

Chi-Square Tests

a. 0 cells (,0%) have expected count less than 5. The minimum expected count is 60,07.

SNP rs34313207

Chi-Square Tests

a. 0 cells (,0%) have expected count less than 5. The minimum expected count is 98,97. b. Computed only for a 2x2 table

SNP rs2088606

Chi-Square Tests

a. 0 cells (,0%) have expected count less than 5. The minimum expected count is 17,30.

SNP rs72796624

Chi-Square Tests

a. 1 cells (16,7%) have expected count less than 5. The minimum expected count is 2,49. SNP rs706778

Chi-Square Tests

a. 0 cells (,0%) have expected count less than 5. The minimum expected count is 47,34. b. Computed only for a 2x2 table

SNP rs2064501

Chi-Square Tests

a. 0 cells (,0%) have expected count less than 5. The minimum expected count is 25,05.

SNP rs1559677

Chi-Square Tests

The results clearly show that each one of the SNPs rs2282047 (for IL17D), rs836560 (RAC1 ), rs1717739 (for SFRP4), rs2044831 (for SFRP4), rs10925015 (NLRP3), rs60259878 (for TLE1 ), rs6961 161 (NXPH1 ), rs45741 13 (for WNT10A), rs34313207

(IL17RD), rs2088606 (JADE1 ), rs72796624 (for FGF1 ), rs706778 (IL2RA), rs2064501 (for IL22RA2) and rs1559677 (SEMA6D) is correlated, and for some SNPs highly correlated, to keloid.

Thus, these SNPs are, at least alone, and much better in combination, useful for detecting a predisposition to keloid and/or prognosing keloid progression.

Claims

1. Method for detecting a predisposition to and/or prognosing fibrosis progression of a subject in need thereof, comprising detecting at least one single nucleotide polymorphism (SNP) in at least one the following genes, in a biological sample of said subject: IL17D, IL17RD, IL2RA, IL22RA2, SFRP4, NLRP3, TLE1 , NXPH1 , WNT10A, JADE1 , FGF1 , RAC1 and SEMA6D,

wherein the presence of at least one SNP in at least one of said genes is indicative of a predisposition to fibrosis or of fibrosis progression.

2. Method according to claim 1 , wherein it comprises detecting, in a biological sample of said subject, at least one SNP in IL17D gene, and at least one SNP in at least one of the following genes: IL17RD, IL2RA, IL22RA2, SFRP4, NLRP3, TLE1 , NXPH1 , WNT10A, JADE1 , FGF1 , RAC1 and SEMA6D.

3. Method according to claim 1 or 2, wherein it comprises the detection of SNP in at least 2 genes, preferably at least 3, preferably at least 4, preferably at least 5, preferably at least 6, preferably at least 7, preferably at least 8, preferably at least 9, preferably at least 10, preferably at least 1 1 , preferably at least 12, preferably all 13 genes, in a biological sample of said subject.

4. Method according to any one of claims 1 to 3, wherein said fibrosis is chosen from:

- hepatic fibrosis, comprising hepatic fibrosis of various grades including cirrhosis, alcoholic and non-alcoholic,

- fibrosis of the skin tissue, particularly due to cutaneous keloid, hypertrophic scars or scleroderma,

- fibrosis of the adipose tissue, such as fibrosis due to obesity, such as non alcoholic fatty liver disease or non-alcoholic steatohepatitis, and

- pulmonary fibrosis.

5. Method according to any one of claims 1 to 4, wherein said fibrosis is chosen from fibrosis of the skin tissue, particularly a keloid.

6. Method according to any one of claims 1 to 5, wherein said fibrosis is hepatic fibrosis, particularly due to a chemical agent, such as an hepato-toxic drug or alcohol; due to fat, such as non-alcoholic fatty liver disease or non-alcoholic steatohepatitis; due to a bacterial infection, such as brucellosis; due to a parasitic infection, such as bilharzia; or due to viral infections, such as hepatic A virus, hepatic B virus or hepatic C virus infections.

7. Method according to any one of claims 1 to 6, wherein said biological sample is a biopsy, a blood sample, a saliva sample or a urine sample.

8. Method according to any one of claims 1 to 7, wherein the subject is infected with a virus, preferably a virus selected from the Flaviviridae, such as Hepatitis A or C or B Virus; or the subject is infected by schistosoma, such as Schistosoma mansoni, Schistosoma haematobium , Schistosoma japonicum, Schistosoma mekongi or Schistosoma intercalatum·, or the subject has a diet which is fat-rich, and/or alcohol-rich, preferably is afflicted by obesity and/or alcoholism.

9. Method according to any one of claims 1 to 8, wherein:

the SNP in RAC1 is rs836560, and/or

the SNP in IL17D is rs2282047, and/or

the SNP in SFRP4 is chosen from rs1717739 and rs2044831 , and/or

the SNP in NLRP3 is rs10925015, and/or

the SNP in TLE1 is rs60259878, and/or

the SNP near or in NXPH1 is rs6961 161 , and/or

the SNP in WNT 10A is rs45741 13, and/or

the SNP in IL17RD is rs34313207, and/or

the SNP near or in JADE1 is rs2088606, and/or

the SNP in FGF1 is rs72796624, and/or

the SNP in IL2RA is rs706778, and/or

the SNP in IL22RA2 is rs2064501 , and/or

the SNP in SEMA6D is rs1559677.

10. Method according to any one of claims 1 to 9, wherein it comprises detecting, in a biological sample of said subject:

a) the presence of at least one of the following genotypes in RAC1 gene locus:

- genotype AA or AG with respect to SNP rs836560, and/or

b) the presence of at least one of the following genotypes in IL17D gene locus:

- genotype CC or CG with respect to SNP rs2282047, and/or

c) the presence of at least one of the following genotypes in SFRP4 gene locus:

- genotype CC with respect to SNP rs1717739, or - genotype CC or CT with respect to SNP rs2044831 , and/or

d) the presence of at least the following genotype in NLRP3 gene locus:

- genotype GG with respect to SNP rs10925015, and/or

e) the presence of at least the following genotype in TLE1 gene locus:

- genotype CC with respect to SNP rs60259878, and/or

- genotype GT or TT with respect to SNP rs6961 161 , and/or

- genotype GG or AG with respect to SNP rs45741 13, and/or

- genotype AG or AA with respect to SNP rs34313207, and/or

- genotype GG or AG with respect to SNP rs2088606, and/or

j) the presence of at least the following genotype in FGF1 gene locus:

- genotype GG with respect to SNP rs72796624, and/or

k) the presence of at least the following genotype in IL2RA gene locus:

- genotype TT with respect to SNP rs706778, and/or

L) the presence of at least the following genotype in IL22RA2 gene locus:

- genotype TT with respect to SNP rs2064501 , and/or

m) the presence of at least the following genotype in SEMA6D gene locus:

- genotype GG with respect to SNP rs1559677,

1 1. Method according to any one of claims 1 to 10, wherein it comprises detecting, in a biological sample of said subject: a) the presence of at least one of the following genotypes in RAC1 gene locus:

- genotype AA or AG with respect to SNP rs836560, and

b) the presence of at least one of the following genotypes in IL17D gene locus:

- genotype CC or CG with respect to SNP rs2282047, and

c) the presence of at least one of the following genotypes in SFRP4 gene locus:

- genotype CC with respect to SNP rs1717739, or

- genotype CC or CT with respect to SNP rs2044831 , and

d) the presence of at least the following genotype in NLRP3 gene locus:

- genotype GG with respect to SNP rs10925015, and

e) the presence of at least the following genotype in TLE1 gene locus:

- genotype CC with respect to SNP rs60259878, and

- genotype GT or TT with respect to SNP rs6961 161 , and

- genotype GG or AG with respect to SNP rs45741 13, and

- genotype AG or AA with respect to SNP rs34313207, and

- genotype GG or AG with respect to SNP rs2088606, and

j) the presence of at least the following genotype in FGF1 gene locus:

- genotype GG with respect to SNP rs72796624, and

k) the presence of at least the following genotype in IL2RA gene locus:

- genotype TT with respect to SNP rs706778, and

L) the presence of at least the following genotype in IL22RA2 gene locus:

- genotype TT with respect to SNP rs2064501 , and

m) the presence of at least the following genotype in SEMA6D gene locus:

- genotype GG with respect to SNP rs1559677,

12. Method according to any one of claims 1 to 1 1 , wherein it is for detecting a predisposition to and/or prognosing keloid or keloid progression of a subject in need thereof, comprising detecting at least one SNP in at least one of the following genes, in a biological sample of said subject: IL17D, IL17RD, IL2RA, IL22RA2, SFRP4, NLRP3, TLE1 , NXPH1 , WNT10A, JADE1 , FGF1 , RAC1 and SEMA6D,

wherein the presence of at least one SNP in at least one of said genes is indicative of a predisposition to keloid or keloid progression.

13. Method according to any one of claims 1 to 12, wherein it is for detecting a predisposition to and/or prognosing keloid or keloid progression of a subject in need thereof, comprising detecting at least one SNP in all of the following genes, in a biological sample of said subject: IL17D, IL17RD, IL2RA, IL22RA2, SFRP4, NLRP3, TLE1 , NXPH1 , WNT10A, JADE1 , FGF1 , RAC1 and SEMA6D,

wherein the presence of at least one SNP in all of said genes is indicative of a predisposition to keloid or keloid progression.