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Correlation of genetic mutations with inflammatory markers and micronutrient status in familial Mediterranean fever

Year 2025, Volume: 7 Issue: 4, 396 - 403, 28.07.2025

Canan Emiroğlu , Neslihan Düzkale

Abstract

Aims: Familial Mediterranean fever (FMF) is a monogenic autoinflammatory disorder characterized by recurrent febrile episodes and serosal inflammation. This study aimed to investigate the association between CRP levels, MEFV genotypes, and serum levels of vitamin D, vitamin B12, and iron in adult FMF patients.
Methods: This retrospective cross-sectional study included 392 adult FMF patients. Laboratory parameters evaluated in the analysis included erythrocyte sedimentation rate, C-reactive protein (CRP), fibrinogen, hemoglobin, white blood cell count, serum iron, total iron-binding capacity, ferritin, vitamin B12, vitamin D, and genetic findings.
Results: CRP and other acute phase reactants were significantly higher in the homozygous (p<0.001) and compound heterozygous (p=0.002) FMF groups, and significantly lower in carriers (p<0.001). Univariate logistic regression showed compatibility between CRP and other markers (fibrinogen and WBC), with significant associations in the two FMF genotype groups. Carriers had a significantly lower risk of elevated CRP (p<0.001). In multivariate analysis, male sex and homozygous mutation remained significant predictors of high CRP levels. No significant differences were found in vitamin D and ferritin levels, while vitamin B12 levels were significantly lower in carriers (p=0.04).
Conclusion: This study demonstrates that CRP levels were elevated at the time of diagnosis, particularly in FMF patients with a homozygous genotype. Given the high prevalence of FMF in the region, clinicians—especially primary care providers—should consider FMF in the differential diagnosis and pursue genetic testing when appropriate.

Keywords

Familial Mediterranean fever C-reactive protein genotype inflammation MEFV vitamin D vitamin B12

References

  • Bouomrani S, Masmoudi I, Teber SB. Familial Mediterranean fever: what associations to screen for? Reumatologia. 2020;58(3):150-154. doi: 10.5114/reum.2020.96688
  • Alesh MB, Keti DB, Kısaarslan AP, Muhtaroğlu S, Taşkın SN. Hidden threat in familial Mediterranean fever: subclinical inflammation, oxidative stress and their relationship with vitamin D status. Turk J Med Sci. 2022;52(1):67-75. doi:10.3906/sag-2103-235
  • Tufan A, Lachmann HJ. Familial Mediterranean fever, from pathogenesis to treatment: a contemporary review. Turk J Med Sci. 2020; 50(SI-2):1591-1610. doi:10.3906/sag-2008-11
  • Ocak T, Görünen A, Coşkun BN, et al. Pan-immune-inflammation value could be a new marker to predict amyloidosis and disease severity in familial Mediterranean fever. Diagnostics (Basel). 2024;14(6):634. doi: 10.3390/diagnostics14060634
  • Elhani I, Backes S, Kallinich T, et al. Inflammatory biomarker analysis confirms reduced disease severity in heterozygous patients with familial Mediterranean fever. RMD Open. 2024;10(4):e004677. doi:10.1136/rmdopen-2024-004677
  • Chen M, Li W, Li L, Chai Y, Yang Y, Pu X. Ankylosing spondylitis disease activity and serum vitamin D levels: a systematic review and meta-analysis. Medicine (Baltimore). 2022;101(46):e31764. doi:10.1097/MD.0000000000031764
  • Aronen M, Viikari L, Langen H, et al. The long-term prognostic value of serum 25(OH)D, albumin, and LL-37 levels in acute respiratory diseases among older adults. BMC Geriatr. 2022;22(1):146. doi:10.1186/s12877-022-02836-8
  • Sadeghi M, Momeni A, Mirsaeidi FS, et al. The effect of vitamin D deficiency treatment on lipid profile and C-reactive protein in patients with ischemic heart disease: double-blind randomized clinical trial. Adv Biomed Res. 2024;13(1):79. doi:10.4103/abr.abr_380_23
  • Zhang X, Chen Z, Xiang Y, et al. The association between serum level of vitamin D and inflammatory biomarkers in hospitalized adult patients: a cross-sectional study based on real-world data. Mediators Inflamm. 2024;2024:8360538. doi:10.1155/2024/8360538
  • Sutherland JP, Zhou A, Hyppönen E. Vitamin D, C-reactive protein, and increased fall risk: a genetic epidemiological study. Nutrients. 2024; 17(1):38. doi:10.3390/nu17010038
  • Zhou A, Hyppönen E. Vitamin D deficiency and C-reactive protein: a bidirectional Mendelian randomization study. Int J Epidemiol. 2023; 52(1):260-271. doi:10.1093/ije/dyac087
  • Mu Q, Chen L, Gao X, et al. The role of iron homeostasis in remodeling immune function and regulating inflammatory disease. Sci Bull (Beijing). 2021;66(17):1806-1816. doi:10.1016/j.scib.2021.02.010
  • Weyh C, Krüger K, Peeling P, Castell L. The role of minerals in the optimal functioning of the immune system. Nutrients. 2022;14(3):644. doi:10.3390/nu14030644
  • Poles J, Karhu E, McGill M, McDaniel HR, Lewis JE. The effects of twenty-four nutrients and phytonutrients on immune system function and inflammation: a narrative review. J Clin Transl Res. 2021;7(3):333-376.
  • Tetik Dincer B, Ozcelik G, Urganci N. Comparison of vitamin D, B12, and folic acid levels according to attack frequency in familial Mediterranean fever cases. Sisli Etfal Hastan Tip Bul. 2024;58(3):359-362. doi:10.14744/SEMB.2024.86461
  • Grant WB, Wimalawansa SJ, Pludowski P, Cheng RZ. Vitamin D: evidence-based health benefits and recommendations for population guidelines. Nutrients. 2025;17(2):277. doi:10.3390/nu17020277
  • Wolffenbuttel BHR, McCaddon A, Ahmadi KR, Green R. A brief overview of the diagnosis and treatment of cobalamin (B12) deficiency. Food Nutr Bull. 2024;45(1_suppl):S40-S49. doi:10.1177/03795721241229500
  • Martens K, DeLoughery TG. Sex, lies, and iron deficiency: a call to change ferritin reference ranges. Hematology Am Soc Hematol Educ Program. 2023;2023(1):617-621. doi:10.1182/hematology.2023000494
  • Kisaoglu H, Baba O, Kalyoncu M. Genotype-phenotype associations of children with familial Mediterranean fever in a cohort consisting of M694V mutation and implications for colchicine-resistant disease. J Clin Rheumatol. 2023;29(4):207-213. doi:10.1097/RHU.0000000000001953
  • Barut K, Sahin S, Adrovic A, et al. Familial Mediterranean fever in childhood: a single-center experience. Rheumatol Int. 2018;38(1):67-74. doi:10.1007/s00296-017-3796-0
  • Lancieri M, Bustaffa M, Palmeri S, et al. An update on familial Mediterranean fever. Int J Mol Sci. 2023;24(11):9584. doi:10.3390/ijms 24119584
  • Federici S, Sormani MP, Ozen S, et al. Evidence-based provisional clinical classification criteria for autoinflammatory periodic fevers. Ann Rheum Dis. 2015;74(5):799-805. doi:10.1136/annrheumdis-2014-206580
  • Gattorno M, Hofer M, Federici S, et al. Classification criteria for autoinflammatory recurrent fevers. Ann Rheum Dis. 2019;78(8):1025-1032. doi:10.1136/annrheumdis-2019-215048
  • Börekçi NÖ. D vitamini eksikliği ile ilgili güncel bilgiler. Jour Turk Fam Phy. 2019;10(1):35-42. doi:10.15511/jtfp.19.00135
  • Ates B, Sazak S, Turkmenoglu Y, Irdem A, Dursun H. Relationship of serum vitamin D, D-dimer and uric acid levels with attacks in children with familial Mediterranean fever. The Egyptian Rheumatologist. 2022; 44(4):301-305 doi:10.1016/j.ejr.2022.03.004
  • Dağdeviren-Çakır A, Arvas A, Barut K, Gür E, Kasapçopur Ö. Serum vitamin D levels during activation and remission periods of patients with juvenile idiopathic arthritis and familial Mediterranean fever. Turk J Pediatr. 2016;58(2):125-131. doi:10.24953/turkjped.2016.02.001
  • Onur H, Aral H, Arica V, Bercem GA, Kasapcopur O. Vitamin D levels in children with familial Mediterranean fever. Pediatr Rheumatol Online J. 2016;14(1):28. doi:10.1186/s12969-016-0089-1
  • Erten S, Altunoğlu A, Ceylan GG, Maraş Y, Koca C, Yüksel A. Low plasma vitamin D levels in patients with familial Mediterranean fever. Rheumatol Int. 2012;32(12):3845-3849. doi:10.1007/s00296-011-2281-4
  • Anık A, Catlı G, Makay B, et al. Decreased vitamin D levels in children with familial Mediterranean fever. Int J Rheum Dis. 2014;17(3):321-326. doi:10.1111/1756-185X.12253
  • Başaran Ö, Uncu N. Kolşisin tedavisi altındaki ailevi akdeniz ateşi tanısı ile takip edilen çocuk hastalarda vitamin B12 düzeylerinin değerlendirilmesi. Güncel Pediatri. 2018;16(2):86-92.
  • Ural Ulucan H, Özdemir F, Yılmaz D, Acar EB, Keçeci E. Comparison of vitamin B12 values and kidney function tests in patients diagnosed with FMF and Gout under colchicine treatment. Van Saglık Bilimleri Dergisi. 2023;16(1):94-99. doi:10.52976/vansaglik.1146462
  • Gemici AI, Sevindik ÖG, Akar S, Tunca M. Vitamin B12 levels in familial Mediterranean fever patients treated with colchicine. Clin Exp Rheumatol. 2013;31(3 Suppl 77):57-59.
  • Parrish CR, Wentworth BJ, Copland AP. Revisiting vitamin B12 Deficiency: A Clinician’s Guide for the 21st Century. Nutrition Issues in Gastroenterology, Series #182. Practical Gastroenterology, December 2018. (http://med.virginia.edu/ginutrition/wp-content/uploads/sites/199/2020/ 09/B12-Deficiency-December-18.pdf) (Accessed on June 3,2025).
  • Vitamin B12 deficiency in over 16s: diagnosis and management. NICE guideline/NG/ Published: 06 March 2024. (http://nice.org.uk/guidance/ng239/chapter/recommendatitions) (Accessed on June 3,2025)

Correlation of genetic mutations with inflammatory markers and micronutrient status in familial Mediterranean fever

Year 2025, Volume: 7 Issue: 4, 396 - 403, 28.07.2025

Canan Emiroğlu , Neslihan Düzkale

Abstract

Aims: Familial Mediterranean fever (FMF) is a monogenic autoinflammatory disorder characterized by recurrent febrile episodes and serosal inflammation. This study aimed to investigate the association between CRP levels, MEFV genotypes, and serum levels of vitamin D, vitamin B12, and iron in adult FMF patients.
Methods: This retrospective cross-sectional study included 392 adult FMF patients. Laboratory parameters evaluated in the analysis included erythrocyte sedimentation rate, C-reactive protein (CRP), fibrinogen, hemoglobin, white blood cell count, serum iron, total iron-binding capacity, ferritin, vitamin B12, vitamin D, and genetic findings.
Results: CRP and other acute phase reactants were significantly higher in the homozygous (p<0.001) and compound heterozygous (p=0.002) FMF groups, and significantly lower in carriers (p<0.001). Univariate logistic regression showed compatibility between CRP and other markers (fibrinogen and WBC), with significant associations in the two FMF genotype groups. Carriers had a significantly lower risk of elevated CRP (p<0.001). In multivariate analysis, male sex and homozygous mutation remained significant predictors of high CRP levels. No significant differences were found in vitamin D and ferritin levels, while vitamin B12 levels were significantly lower in carriers (p=0.04).
Conclusion: This study demonstrates that CRP levels were elevated at the time of diagnosis, particularly in FMF patients with a homozygous genotype. Given the high prevalence of FMF in the region, clinicians—especially primary care providers—should consider FMF in the differential diagnosis and pursue genetic testing when appropriate.

Keywords

Familial Mediterranean fever C-reactive protein genotype inflammation MEFV vitamin D vitamin B12

References

  • Bouomrani S, Masmoudi I, Teber SB. Familial Mediterranean fever: what associations to screen for? Reumatologia. 2020;58(3):150-154. doi: 10.5114/reum.2020.96688
  • Alesh MB, Keti DB, Kısaarslan AP, Muhtaroğlu S, Taşkın SN. Hidden threat in familial Mediterranean fever: subclinical inflammation, oxidative stress and their relationship with vitamin D status. Turk J Med Sci. 2022;52(1):67-75. doi:10.3906/sag-2103-235
  • Tufan A, Lachmann HJ. Familial Mediterranean fever, from pathogenesis to treatment: a contemporary review. Turk J Med Sci. 2020; 50(SI-2):1591-1610. doi:10.3906/sag-2008-11
  • Ocak T, Görünen A, Coşkun BN, et al. Pan-immune-inflammation value could be a new marker to predict amyloidosis and disease severity in familial Mediterranean fever. Diagnostics (Basel). 2024;14(6):634. doi: 10.3390/diagnostics14060634
  • Elhani I, Backes S, Kallinich T, et al. Inflammatory biomarker analysis confirms reduced disease severity in heterozygous patients with familial Mediterranean fever. RMD Open. 2024;10(4):e004677. doi:10.1136/rmdopen-2024-004677
  • Chen M, Li W, Li L, Chai Y, Yang Y, Pu X. Ankylosing spondylitis disease activity and serum vitamin D levels: a systematic review and meta-analysis. Medicine (Baltimore). 2022;101(46):e31764. doi:10.1097/MD.0000000000031764
  • Aronen M, Viikari L, Langen H, et al. The long-term prognostic value of serum 25(OH)D, albumin, and LL-37 levels in acute respiratory diseases among older adults. BMC Geriatr. 2022;22(1):146. doi:10.1186/s12877-022-02836-8
  • Sadeghi M, Momeni A, Mirsaeidi FS, et al. The effect of vitamin D deficiency treatment on lipid profile and C-reactive protein in patients with ischemic heart disease: double-blind randomized clinical trial. Adv Biomed Res. 2024;13(1):79. doi:10.4103/abr.abr_380_23
  • Zhang X, Chen Z, Xiang Y, et al. The association between serum level of vitamin D and inflammatory biomarkers in hospitalized adult patients: a cross-sectional study based on real-world data. Mediators Inflamm. 2024;2024:8360538. doi:10.1155/2024/8360538
  • Sutherland JP, Zhou A, Hyppönen E. Vitamin D, C-reactive protein, and increased fall risk: a genetic epidemiological study. Nutrients. 2024; 17(1):38. doi:10.3390/nu17010038
  • Zhou A, Hyppönen E. Vitamin D deficiency and C-reactive protein: a bidirectional Mendelian randomization study. Int J Epidemiol. 2023; 52(1):260-271. doi:10.1093/ije/dyac087
  • Mu Q, Chen L, Gao X, et al. The role of iron homeostasis in remodeling immune function and regulating inflammatory disease. Sci Bull (Beijing). 2021;66(17):1806-1816. doi:10.1016/j.scib.2021.02.010
  • Weyh C, Krüger K, Peeling P, Castell L. The role of minerals in the optimal functioning of the immune system. Nutrients. 2022;14(3):644. doi:10.3390/nu14030644
  • Poles J, Karhu E, McGill M, McDaniel HR, Lewis JE. The effects of twenty-four nutrients and phytonutrients on immune system function and inflammation: a narrative review. J Clin Transl Res. 2021;7(3):333-376.
  • Tetik Dincer B, Ozcelik G, Urganci N. Comparison of vitamin D, B12, and folic acid levels according to attack frequency in familial Mediterranean fever cases. Sisli Etfal Hastan Tip Bul. 2024;58(3):359-362. doi:10.14744/SEMB.2024.86461
  • Grant WB, Wimalawansa SJ, Pludowski P, Cheng RZ. Vitamin D: evidence-based health benefits and recommendations for population guidelines. Nutrients. 2025;17(2):277. doi:10.3390/nu17020277
  • Wolffenbuttel BHR, McCaddon A, Ahmadi KR, Green R. A brief overview of the diagnosis and treatment of cobalamin (B12) deficiency. Food Nutr Bull. 2024;45(1_suppl):S40-S49. doi:10.1177/03795721241229500
  • Martens K, DeLoughery TG. Sex, lies, and iron deficiency: a call to change ferritin reference ranges. Hematology Am Soc Hematol Educ Program. 2023;2023(1):617-621. doi:10.1182/hematology.2023000494
  • Kisaoglu H, Baba O, Kalyoncu M. Genotype-phenotype associations of children with familial Mediterranean fever in a cohort consisting of M694V mutation and implications for colchicine-resistant disease. J Clin Rheumatol. 2023;29(4):207-213. doi:10.1097/RHU.0000000000001953
  • Barut K, Sahin S, Adrovic A, et al. Familial Mediterranean fever in childhood: a single-center experience. Rheumatol Int. 2018;38(1):67-74. doi:10.1007/s00296-017-3796-0
  • Lancieri M, Bustaffa M, Palmeri S, et al. An update on familial Mediterranean fever. Int J Mol Sci. 2023;24(11):9584. doi:10.3390/ijms 24119584
  • Federici S, Sormani MP, Ozen S, et al. Evidence-based provisional clinical classification criteria for autoinflammatory periodic fevers. Ann Rheum Dis. 2015;74(5):799-805. doi:10.1136/annrheumdis-2014-206580
  • Gattorno M, Hofer M, Federici S, et al. Classification criteria for autoinflammatory recurrent fevers. Ann Rheum Dis. 2019;78(8):1025-1032. doi:10.1136/annrheumdis-2019-215048
  • Börekçi NÖ. D vitamini eksikliği ile ilgili güncel bilgiler. Jour Turk Fam Phy. 2019;10(1):35-42. doi:10.15511/jtfp.19.00135
  • Ates B, Sazak S, Turkmenoglu Y, Irdem A, Dursun H. Relationship of serum vitamin D, D-dimer and uric acid levels with attacks in children with familial Mediterranean fever. The Egyptian Rheumatologist. 2022; 44(4):301-305 doi:10.1016/j.ejr.2022.03.004
  • Dağdeviren-Çakır A, Arvas A, Barut K, Gür E, Kasapçopur Ö. Serum vitamin D levels during activation and remission periods of patients with juvenile idiopathic arthritis and familial Mediterranean fever. Turk J Pediatr. 2016;58(2):125-131. doi:10.24953/turkjped.2016.02.001
  • Onur H, Aral H, Arica V, Bercem GA, Kasapcopur O. Vitamin D levels in children with familial Mediterranean fever. Pediatr Rheumatol Online J. 2016;14(1):28. doi:10.1186/s12969-016-0089-1
  • Erten S, Altunoğlu A, Ceylan GG, Maraş Y, Koca C, Yüksel A. Low plasma vitamin D levels in patients with familial Mediterranean fever. Rheumatol Int. 2012;32(12):3845-3849. doi:10.1007/s00296-011-2281-4
  • Anık A, Catlı G, Makay B, et al. Decreased vitamin D levels in children with familial Mediterranean fever. Int J Rheum Dis. 2014;17(3):321-326. doi:10.1111/1756-185X.12253
  • Başaran Ö, Uncu N. Kolşisin tedavisi altındaki ailevi akdeniz ateşi tanısı ile takip edilen çocuk hastalarda vitamin B12 düzeylerinin değerlendirilmesi. Güncel Pediatri. 2018;16(2):86-92.
  • Ural Ulucan H, Özdemir F, Yılmaz D, Acar EB, Keçeci E. Comparison of vitamin B12 values and kidney function tests in patients diagnosed with FMF and Gout under colchicine treatment. Van Saglık Bilimleri Dergisi. 2023;16(1):94-99. doi:10.52976/vansaglik.1146462
  • Gemici AI, Sevindik ÖG, Akar S, Tunca M. Vitamin B12 levels in familial Mediterranean fever patients treated with colchicine. Clin Exp Rheumatol. 2013;31(3 Suppl 77):57-59.
  • Parrish CR, Wentworth BJ, Copland AP. Revisiting vitamin B12 Deficiency: A Clinician’s Guide for the 21st Century. Nutrition Issues in Gastroenterology, Series #182. Practical Gastroenterology, December 2018. (http://med.virginia.edu/ginutrition/wp-content/uploads/sites/199/2020/ 09/B12-Deficiency-December-18.pdf) (Accessed on June 3,2025).
  • Vitamin B12 deficiency in over 16s: diagnosis and management. NICE guideline/NG/ Published: 06 March 2024. (http://nice.org.uk/guidance/ng239/chapter/recommendatitions) (Accessed on June 3,2025)
There are 34 citations in total.

Details

Primary Language English
Subjects ​Internal Diseases, Medical Genetics (Excl. Cancer Genetics)
Journal Section Research Articles
Authors

Canan Emiroğlu 0000-0003-2543-4246

Neslihan Düzkale 0000-0001-6122-5316

Publication Date July 28, 2025
Submission Date May 9, 2025
Acceptance Date June 6, 2025
Published in Issue Year 2025 Volume: 7 Issue: 4

Cite

AMA Emiroğlu C, Düzkale N. Correlation of genetic mutations with inflammatory markers and micronutrient status in familial Mediterranean fever. Anatolian Curr Med J / ACMJ / acmj. July 2025;7(4):396-403.
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