Polymorphisms in the SUMO4 Gene Region and Type 1 Diabetes Mellitus in Non-Asian Populations: A Scoping Review

Lopes, Mateus Santana; Silva, Paula Rothbarth; Lopes, Maria Luiza Clarindo; Valdameri, Glaucio; Moure, Vivian Rotuno; Alves, Alexessander Couto; Manica, Graciele Cristiane More; Picheth, Geraldo; Rego, Fabiane Gomes de Moraes; Sari, Marcel Henrique Marcondes

doi:10.1590/1678-4324-2025250025

Review - Human and Animal Health • Braz. arch. biol. technol. 68 • 2025 • https://doi.org/10.1590/1678-4324-2025250025 linkcopy

Polymorphisms in the SUMO4 Gene Region and Type 1 Diabetes Mellitus in Non-Asian Populations: A Scoping Review

Authorship SCIMAGO INSTITUTIONS RANKINGS

Type 1 diabetes mellitus (T1D) is a complex autoimmune disease resulting from pancreatic insulin-producing cell destruction. Numerous studies have investigated the association between the Small Ubiquitin-like Modifier 4 (SUMO4) gene and the risk of T1D development. However, these findings are not consistent, particularly in non-Asian populations. This scoping review aims to comprehensively assess the association between the SUMO4 gene and TD1 in individuals of non-Asian origin. A systematic search of electronic databases was performed, including Web of Science, PubMed, Embase and Scopus. Case-control studies and prospective cohorts that provided relevant information for the association analysis were included. 6,841 articles were initially identified through database searches. After removing duplicates, 3,835 articles remained for screening. Twenty-five studies underwent full-text analysis, with nine being included in the scoping review after 16 were excluded. These studies utilized various genotyping methods, including PCR-ARMS, SSCP, RFLP, and genotyping platforms such as ILMN and SQMN. While some studies reported the male/female ratio, others focused on family studies or diabetic probands. The research was predominantly conducted in North America, Europe, Oceania, and Argentina. Across these studies, no significant evidence linking SUMO4 SNPs to T1D was found, except for marginal associations or those dependent on high-risk HLA genotype positivity. No significant association was detected between the SUMO4 gene and T1D in non-asian individuals. This finding suggests that polymorphisms in this gene might not play a substantial role in susceptibility to T1D in the investigated population.

Keywords:
Diabetes mellitus; insulin-dependent diabetes; SNPs; Euro-descendant; rs237025.

This scoping review evaluated the SUMO4 and T1D association in non-Asians.

It is the first study that investigates SUMO4 and T1D association in non-Asians.

SUMO4 does not appear to affect the risk of T1D in non-Asian populations.

Database	Queries
PubMed	((((((((((polymorphism, genetic[MeSH Terms]) OR (SUMO4[Title/Abstract])) OR ("Small ubiquitin-like modifier 4"[Title/Abstract])) OR (rs237025[Title/Abstract])) OR (A163G[Title/Abstract])) OR (m55v[Title/Abstract])) OR (met55val[Title/Abstract])) OR (SNP[Title/Abstract])) OR ("single nucleotide polymorphism"[Title/Abstract])) OR (polymorphism[Title/Abstract])) AND (((((Diabetes Mellitus, Type 1[MeSH Terms]) OR ("Diabetes Mellitus, Type 1"[Title/Abstract])) OR (T1D[Title/Abstract])) OR (LADA[Title/Abstract])) OR ("Latent autoimmune diabetes of adults"[Title/Abstract]))
Scopus	( ( TITLE-ABS-KEY ( “Diabetes Mellitus, Type 1” ) OR TITLE-ABS-KEY ( t1d ) OR TITLE-ABS-KEY ( lada ) OR TITLE-ABS-KEY ( “Latent autoimmune diabetes of adults” ) ) ) AND ( ( TITLE-ABS-KEY ( sumo4 ) OR TITLE-ABS-KEY ( “Small ubiquitin-like modifier 4” ) OR TITLE-ABS-KEY ( rs237025 ) OR TITLE-ABS-KEY ( a163g ) OR TITLE-ABS-KEY ( m55v ) OR TITLE-ABS-KEY ( met55val ) OR TITLE-ABS-KEY ( snp ) OR TITLE-ABS-KEY ( “single nucleotide polymorphism” ) OR TITLE-ABS-KEY ( polymorphism ) ) )
Web of Science	SUMO4 (Topic) or “Small ubiquitin-like modifier 4” (Topic) or rs237025 (Topic) or A163G (Topic) or m55v (Topic) or met55val (Topic) or SNP (Topic) or “single nucleotide polymorphism” (Topic) or polymorphism (Topic) AND “Diabetes Mellitus, Type 1” (Topic) or T1D (Topic) or LADA (Topic) or “Latent autoimmune diabetes of adults” (Topic)
Embase	('diabetes mellitus, type 1':ti,ab,kw OR t1d:ti,ab,kw OR lada:ti,ab,kw) AND 'latent autoimmune diabetes of adults':ti,ab,kw AND sumo4:ti,ab,kw OR 'small ubiquitin-like modifier 4':ti,ab,kw OR rs237025:ti,ab,kw OR a163g:ti,ab,kw OR m55v:ti,ab,kw OR met55val:ti,ab,kw OR snp:ti,ab,kw OR 'single nucleotide polymorphism':ti,ab,kw OR polymorphism:ti,ab,kw

Reference	Design	Volunteers	Country/ Region	SNP	Methods	Results
Caputo et al. (2007) [⁴³]	Case-control	n = 62 volunteers with LADA n = 112 volunteers with T1D n = 129 non-diabetic volunteers	Argentina	rs237025	PCR-SSCP	The frequencies of the AA and AG genotypes were similar in the three groups and the frequency of the GG genotype was slightly higher in the control group; however, no significant association was observed in this study**
Howson et al. (2009) [⁴⁴]	Cohort	n = 2300 families, representing a total of 9682 people.	Europe, North America, and Oceania	- -	ILMN and SQMN	No association of SUMO4 with T1D was observed among the 15 genotyped SNPs (minimum P=0.09).
Julier et al. (2009) [⁴⁵]	Cohort	n = 2298 families, representing a total of 11159 people.	Europe, USA, and Oceania	rs237025	ILMN and SQMN	No association of SUMO4 alleles with T1D was observed in the study population. Genotypic and allelic frequencies were similar among volunteers in this cohort.**
Kosoy and Concannon (2005) [⁴⁶]	Cohort	There were 554 families totaling 2604 people, with 1458 of them having T1D.	Europe, and USA	rs237025 rs237027 rs6942381	MGB-eclipse system	No significant evidence of association with T1D was observed for alleles of SNPs rs6942381 (P=0.498), rs237027 (P=0.657) and rs237025 (P=0.778).
Owerbach, Pina and Gabbay (2004) [⁴⁷]	Cohort	n= 478 families, 256 from USA and 222 from UK.	USA, and United Kingdon	rs237025 rs237027 rs237034 rs237037 rs6942381 rs7896	PCR-SBE	SNPs alleles rs237025 (P≤0.006), rs237027 (P≤0.05), rs237034 (P≤0.006), rs6942381 (P≤0.006) and rs7896 (P≤0.01) were significantly more transmitted to probands with T1D.
Podolsky, Prasad linga-reddy e She (2009) [⁴⁸]	Cohort	n = 2317 families, with 11250 people in total, of which 5047 had T1D.	Europe, and Oceania	rs12204461 rs7742990 rs9373589 rs9404034 rs2789490 rs237032 rs237025 rs2789488 rs2789489 rs652921 rs366905 rs480034 rs236999 rs513923 rs9485389	ILMN and SQNM	Only rs236999 showed marginally significant association with T1D in both SNP genotyping platforms, ILMN (P=0.020) and SQMN (P=0.072). SNPs rs366905 and rs480034 showed marginally significant association (P<0.05), in both platforms, with T1D dependent on the positive HLA-DR4 genotype.
Sedimbi et al. (2007) [⁴⁹]	Case-control	n = 673 diabetic volunteers n = 535 non-diabetic volunteers	Sweden	rs237025	PCR-RFLP	The GG genotype was associated with high-risk T1D in HLA-DR3/DR4 positive patients P≤0.0001
Sedimbi et al. (2006) [⁵⁰]	Case-control	n = 46 volunteers with LADA n = 95 volunteers with T1D n = 100 non-diabetic volunteers	Latvia	rs237025	PCR-RFLP	There was no statistically significant difference for the frequencies of the G allele in the control, LADA (P=0.06) and T1D (P=0.09) groups. The comparison of SUMO4 polymorphism with HLA-DR3 or DR4 positive and negative patients also did not identify any significant association.
Wägner et al. (2008) [⁵¹]	Cohort	n= 253 families, representing a total of 1097 people.	Denmark	rs237025	ARMS-PCR	The SUMO4 functional variant was transmitted to 50.9% of affected offspring and 50.5% of unaffected offspring (P=0.767). No association was observed between SUMO4 SNPs and transmission frequency among affected probands.

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[1] PCR-RFLP (Polymerase Chain Reaction - Restriction Fragment Length Polymorphism); PCR-SSCP (Polymerase Chain Reaction - single-strand conformation polymorphism); MGB (Minor Groove Binding); ILMN (Illumina); SQMN (Sequenom); SNP (Single Nucleotide Polymorphism); USA (United States of America); UK (United Kingdom);

[TFN1] ^**
Did not demonstrate P value.