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Genes and metabolic pathway of sarcoidosis: identification of key players and risk modifiers.

ABSTRACT: Introduction:Sarcoidosis is a rare multisystem granulomatous disease with unknown etiology. The interplay of vitamin D deficiency and genetic polymorphisms in genes coding for the proteins relevant for metabolism of vitamin D is an important, but unexplored area. The aim of this study was to investigate the association between single nucleotide polymorphisms (SNPs) in CYP2R1 (rs10741657), CYP27B1 (rs10877012), DBP (rs7041; rs4588), and VDR (rs2228570) genes and sarcoidosis, as well as the association between these SNPs and 25(OH)D levels in sarcoidosis patients. Material and methods:For that purpose we genotyped 86 sarcoidosis patients and 50 healthy controls using the PCR-RFLP method. Results:Subjects carrying the CC genotype of CYP27B1 rs10877012 have 10 times lower odds of suffering from sarcoidosis. Moreover, DBP rs4588 AA genotype was shown to be a susceptibility factor, where carriers of this genotype had eight times higher odds for developing sarcoidosis. In addition, the A allele of the DBP gene (rs4588) was associated with lower levels of 25(OH)D in sarcoidosis patients. Conclusions:These results suggest that patients with vitamin D deficiency should be regularly tested for genetic modifiers that are related to sarcoidosis in order to prevent development of serious forms of sarcoidosis.

SUBMITTER: Stjepanovic MI

PROVIDER: S-EPMC6764301 | biostudies-literature | 2019 Sep

REPOSITORIES: biostudies-literature

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Genes and metabolic pathway of sarcoidosis: identification of key players and risk modifiers.

Stjepanovic Mihailo I MI Mihailovic-Vucinic Violeta V Spasovski Vesna V Milin-Lazovic Jelena J Skodric-Trifunovic Vesna V Stankovic Sanja S Andjelkovic Marina M Komazec Jovana J Momcilovic Ana A Santric-Milicevic Milena M Pavlovic Sonja S

Archives of medical science : AMS 20181123 5

<h4>Introduction</h4>Sarcoidosis is a rare multisystem granulomatous disease with unknown etiology. The interplay of vitamin D deficiency and genetic polymorphisms in genes coding for the proteins relevant for metabolism of vitamin D is an important, but unexplored area. The aim of this study was to investigate the association between single nucleotide polymorphisms (SNPs) in CYP2R1 (rs10741657), CYP27B1 (rs10877012), DBP (rs7041; rs4588), and VDR (rs2228570) g ...[more]

PMID: 31572458

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Project description:Although recent studies have shown that human genomes contain hundreds of loci that exhibit signatures of positive selection, variants that are associated with adaptation in energy-balance regulation remain elusive. We reasoned that the difficulty in identifying such variants could be due to heterogeneity in selection pressure and that an integrative approach that incorporated experiment-based evidence and population genetics-based statistical judgments would be needed to reveal important metabolic modifiers in humans.To identify common metabolic modifiers that underlie phenotypic variation in diabetes-associated or obesity-associated traits in humans, or both, we screened 207 candidate loci for regulatory single nucleotide polymorphisms (SNPs) that exhibited evidence of gene-environmental interactions.Three SNPs (rs3895874, rs3848460, and rs937301) at the 5' gene region of human GIP were identified as prime metabolic-modifier candidates at the enteroinsular axis. Functional studies have shown that GIP promoter reporters carrying derived alleles of these three SNPs (haplotype GIP(-1920A)) have significantly lower transcriptional activities than those with ancestral alleles at corresponding positions (haplotype GIP(-1920G)). Consistently, studies of pregnant women who have undergone a screening test for gestational diabetes have shown that patients with a homozygous GIP(-1920A/A) genotype have significantly lower serum concentrations of glucose-dependent insulinotropic polypeptide (GIP) than those carrying an ancestral GIP(-1920G) haplotype. After controlling for a GIPR variation, we showed that serum glucose concentrations of patients carrying GIP(-1920A/A) homozygotes are significantly higher than that of those carrying an ancestral GIP(-1920G) haplotype (odds ratio 3.53).Our proof-of-concept study indicates that common regulatory GIP variants impart a difference in GIP and glucose metabolism. The study also provides a rare example that identified the common variant-common phenotypic variation pattern based on evidence of moderate gene-environmental interactions.

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Genes and metabolic pathway of sarcoidosis: identification of key players and risk modifiers.

Publications

Genes and metabolic pathway of sarcoidosis: identification of key players and risk modifiers.

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