The ENPP1 K121Q polymorphism is associated with obesity-related parameters in Iranian normoglycemic male subjects
Abstract
Objectives: The K121Q polymorphism of the Ectoenzyme Nucleotide Pyrophosphate Phosphodiesterase 1 (ENPP1) gene has been variably associated with obesity in several populations. However, this association has not been studied in Iranian subjects. It was hypothesized that the K121Q variant might be associated with obesity and related risk factors in subjects with normal glucose tolerance and normal fasting glucose.
Methods: The K121Q genotypes were determined by PCR-restriction fragment length polymorphism in 377 non-diabetic subjects.
Results: In males, the frequency of the Q allele was 20.8% and 15.9% (p=0.269) in obese and non-obese subjects, respectively. The ENPP1 genotype (KQ+QQ) was not associated with systolic and diastolic blood pressure, triglyceride, cholesterol, LDL-C, HDL-C, HOMA-IR, or insulin levels in both genders. Male carriers of the KQ+QQ genotype had significantly higher values for BMI (p=0.079), waist (p=0.01), and WHR (p=0.006) than subjects with the KK genotype. Obesity-related parameters were not significantly different between obese and non-obese female subjects.
Conclusion: Our results suggest that the ENPP1 121Q allele might be associated with obesity and related parameters only among Iranian normoglycemic male subjects.
1. Meshkani R, Adeli K. Hepatic insulin resistance, metabolic syndrome and cardiovascular disease. Clin Biochem. 2009;42(13-14):1331-46.
2. Meshkani R, Taghikhani M, Larijani B, Khatami S, Khoshbin E, Adeli K. The relationship between homeostasis model assessment and cardiovascular risk factors in Iranian subjects with normal fasting glucose and normal glucose tolerance. Clin Chim Acta. 2006;371(1-2):169-75.
3. Hosseinpanah F, Barzin M, Eskandary PS, Mirmiran P, Azizi F. Trends of obesity and abdominal obesity in Tehranian adults: a cohort study. BMC Public Health. 2009;9:426.
4. Herbert A, Gerry NP, McQueen MB, Heid IM, Pfeufer A, Illig T, et al. A common genetic variant is associated with adult and childhood obesity. Science. 2006;312(5771):279-83.
5. Meyre D, Bouatia-Naji N, Tounian A, Samson C, Lecoeur C, Vatin V, et al. Variants of ENPP1 are associated with childhood and adult obesity and increase the risk of glucose intolerance and type 2 diabetes. Nat Genet. 2005;37(8):863-7.
6. Qi L, Corella D, Sorli JV, Portoles O, Shen H, Coltell O, et al. Genetic variation at the perilipin (PLIN) locus is associated with obesity-related phenotypes in White women. Clin Genet. 2004;66(4):299-310.7.
7. Dong H, Maddux BA, Altomonte J, Meseck M, Accili D, Terkeltaub R, et al. Increased hepatic levels of the insulin receptor inhibitor, PC-1/NPP1, induce insulin resistance and glucose intolerance. Diabetes. 2005;54(2):367-72.
8. Maddux BA, Sbraccia P, Kumakura S, Sasson S, Youngren J, Fisher A, et al. Membrane glycoprotein PC-1 and insulin resistance in non-insulin-dependent diabetes mellitus. Nature. 1995;373(6513):448-51.
9. Arya R, Blangero J, Williams K, Almasy L, Dyer TD, Leach RJ, et al. Factors of insulin resistance syndrome–related phenotypes are linked to genetic locations on chromosomes 6 and 7 in nondiabetic Mexican-Americans. Diabetes. 2002;51(3):841-847.
10. Duggirala R, Blangero J, Almasy L, Arya R, Dyer TD, Williams KL, et al. A major locus for fasting insulin concentrations and insulin resistance on chromosome 6q with strong pleiotropic effects on obesity-related phenotypes in nondiabetic Mexican Americans. Am J Hum Genet. 2001;68(5):1149-1164.
11. Goding JW, Terkeltaub R, Maurice M, Deterre P, Sali A, Belli SI. Ecto‐phosphodiesterase/pyrophosphatase of lymphocytes and non‐lymphoid cells: structure and function of the PC‐1 family. Immunol Rev. 1998;161(1):11-26.
12. Funakoshi I, Kato H, Horie K, Yano T, Hori Y, Kobayashi H, et al. Molecular cloning of cDNAs for human fibroblast nucleotide pyrophosphatase. Arch Biochem Biophys. 1992;295(1):180-187.
13. Frittitta L, Youngren J, Vigneri R, Maddux B, Trischitta V, Goldfine I. PC-1 content in skeletal muscle of non-obese, non-diabetic subjects: relationship to insulin receptor tyrosine kinase and whole body insulin sensitivity. Diabetologia. 1996;39:1190-1195.
14. 14. Pizzuti A, Frittitta L, Argiolas A, Baratta R, Goldfine ID, Bozzali M, et al. A polymorphism (K121Q) of the human glycoprotein PC-1 gene coding region is strongly associated with insulin resistance. Diabetes. 1999;48(9):1881-1884.
15. Gu HF, Almgren P, Lindholm E, Frittitta L, Pizzuti A, Trischitta V, et al. Association between the human glycoprotein PC-1 gene and elevated glucose and insulin levels in a paired-sibling analysis. Diabetes. 2000;49(9):1601-1603.
16. Costanzo BV, Trischitta V, Di Paola R, Spampinato D, Pizzuti A, Vigneri R, et al. The Q allele variant (GLN121) of membrane glycoprotein PC-1 interacts with the insulin receptor and inhibits insulin signaling more effectively than the common K allele variant (LYS121). Diabetes. 2001;50(4):831-836.
17. Diagnosis ECot and CoDM. Report of the expert committee on the diagnosis and classification of diabetes mellitus. Diabetes Care. 2003;26(suppl_1):s5-s20.
18. Matthews DR, Hosker JP, Rudenski AS, Naylor BA, Treacher DF, Turner RC. Homeostasis model assessment: insulin resistance and β-cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia. 1985;28:412-419.
19. Grarup N, Urhammer S, Ek J, Albrechtsen A, Glümer C, Borch-Johnsen K, et al. Studies of the relationship between the ENPP1 K121Q polymorphism and type 2 diabetes, insulin resistance and obesity in 7,333 Danish white subjects. Diabetologia. 2006;49:2097-2104.
20. Weedon MN, Shields B, Hitman G, Walker M, McCarthy MI, Hattersley AT, et al. No evidence of association of ENPP1 variants with type 2 diabetes or obesity in a study of 8,089 UK Caucasians. Diabetes. 2006;55(11):3175-3179.
21. González‐Sánchez JL, Martínez‐Larrad MT, Fernández‐Pérez C, Kubaszek A, Laakso M, Serrano‐Ríos M. K121Q PC‐1 gene polymorphism is not associated with insulin resistance in a Spanish population. Obes Res. 2003;11(5):603-605.
22. Seo HJ, Kim SG, Kwon OJ. The K121Q polymorphism in ENPP1 (PC-1) is not associated with type 2 diabetes or obesity in Korean male workers. J Korean Med Sci. 2008;23(3):459-464.
23. Matsuoka N, Patki A, Tiwari H, Allison D, Johnson S, Gregersen P, et al. Association of K121Q polymorphism in ENPP1 (PC-1) with BMI in Caucasian and African-American adults. Int J Obes (Lond). 2006;30(2):233-237.
24. Prudente S, Chandalia M, Morini E, Baratta R, Dallapiccola B, Abate N, et al. The Q121/Q121 genotype of ENPP1/PC‐1 is associated with lower BMI in non‐diabetic whites. Obesity (Silver Spring). 2007;15(1):1-4.
25. Wan C, Zhang T, Wang B, Han Y, Zhang C, Zhang Y, et al. Obesity risk associated with the K121Q polymorphism of the glycoprotein PC‐1 gene. Diabetes Obes Metab. 2006;8(6):703-708.
26. Böttcher Y, Körner A, Reinehr T, Enigk B, Kiess W, Stumvoll M, et al. ENPP1 variants and haplotypes predispose to early onset obesity and impaired glucose and insulin metabolism in German obese children. J Clin Endocrinol Metab. 2006;91(12):4948-4952.
27. Tanyolaç S, Mahley RW, Hodoglugil U, Goldfine ID. Gender Differences in the Relationship of ENPP1/PC‐1 Variants to Obesity in a Turkish Population. Obesity (Silver Spring). 2008;16(11):2468-2471.
28. 28. Bruning JC, Gautam D, Burks DJ, Gillette J, Schubert M, Orban PC, et al. Role of brain insulin receptor in control of body weight and reproduction. Science. 2000;289(5487):2122-2125.
29. Kubaszek A, PIHLAJAMaki J, KARHAPaa P, Vauhkonen I, Laakso M. The K121Q polymorphism of the PC-1 gene is associated with insulin resistance but not with dyslipidemia. Diabetes Care. 2003;26(2):464-467.
30. Frittitta L, Baratta R, Spampinato D, Di Paola R, Pizzuti A, Vigneri R, et al. The Q121 PC-1 variant and obesity have additive and independent effects in causing insulin resistance. J Clin Endocrinol Metab. 2001;86(12):5888-5891.
31. Hamaguchi K, Terao H, Kusuda Y, Yamashita T, Hazoury Bahles J, Cruz LL, et al. The PC-1 Q121 allele is exceptionally prevalent in the Dominican Republic and is associated with type 2 diabetes. J Clin Endocrinol Metab. 2004;89(3):1359-1364.
32. Goldfine ID, Maddux BA, Youngren JF, Reaven G, Accili D, Trischitta V, et al. The role of membrane glycoprotein plasma cell antigen 1/ectonucleotide pyrophosphatase phosphodiesterase 1 in the pathogenesis of insulin resistance and related abnormalities. Endocr Rev. 2008;29(1):62-75.
33. Horikoshi M, Hara K, Ito C, Shojima N, Nagai R, Ueki K, et al. Variations in the HHEX gene are associated with increased risk of type 2 diabetes in the Japanese population. Diabetologia. 2007;50:2461-2466.
34. Rasmussen SK, Urhammer SA, Pizzuti A, Echwald SM, Ekstrøm CT, Hansen L, et al. The K121Q variant of the human PC-1 gene is not associated with insulin resistance or type 2 diabetes among Danish Caucasians. Diabetes. 2000;49(9):1608-1611.
35. Chandalia M, Grundy SM, Adams-Huet B, Abate N. Ethnic differences in the frequency of ENPP1/PC1 121Q genetic variant in the Dallas Heart Study cohort. J Diabetes Complications. 2007;21(3):143-148..
2. Meshkani R, Taghikhani M, Larijani B, Khatami S, Khoshbin E, Adeli K. The relationship between homeostasis model assessment and cardiovascular risk factors in Iranian subjects with normal fasting glucose and normal glucose tolerance. Clin Chim Acta. 2006;371(1-2):169-75.
3. Hosseinpanah F, Barzin M, Eskandary PS, Mirmiran P, Azizi F. Trends of obesity and abdominal obesity in Tehranian adults: a cohort study. BMC Public Health. 2009;9:426.
4. Herbert A, Gerry NP, McQueen MB, Heid IM, Pfeufer A, Illig T, et al. A common genetic variant is associated with adult and childhood obesity. Science. 2006;312(5771):279-83.
5. Meyre D, Bouatia-Naji N, Tounian A, Samson C, Lecoeur C, Vatin V, et al. Variants of ENPP1 are associated with childhood and adult obesity and increase the risk of glucose intolerance and type 2 diabetes. Nat Genet. 2005;37(8):863-7.
6. Qi L, Corella D, Sorli JV, Portoles O, Shen H, Coltell O, et al. Genetic variation at the perilipin (PLIN) locus is associated with obesity-related phenotypes in White women. Clin Genet. 2004;66(4):299-310.7.
7. Dong H, Maddux BA, Altomonte J, Meseck M, Accili D, Terkeltaub R, et al. Increased hepatic levels of the insulin receptor inhibitor, PC-1/NPP1, induce insulin resistance and glucose intolerance. Diabetes. 2005;54(2):367-72.
8. Maddux BA, Sbraccia P, Kumakura S, Sasson S, Youngren J, Fisher A, et al. Membrane glycoprotein PC-1 and insulin resistance in non-insulin-dependent diabetes mellitus. Nature. 1995;373(6513):448-51.
9. Arya R, Blangero J, Williams K, Almasy L, Dyer TD, Leach RJ, et al. Factors of insulin resistance syndrome–related phenotypes are linked to genetic locations on chromosomes 6 and 7 in nondiabetic Mexican-Americans. Diabetes. 2002;51(3):841-847.
10. Duggirala R, Blangero J, Almasy L, Arya R, Dyer TD, Williams KL, et al. A major locus for fasting insulin concentrations and insulin resistance on chromosome 6q with strong pleiotropic effects on obesity-related phenotypes in nondiabetic Mexican Americans. Am J Hum Genet. 2001;68(5):1149-1164.
11. Goding JW, Terkeltaub R, Maurice M, Deterre P, Sali A, Belli SI. Ecto‐phosphodiesterase/pyrophosphatase of lymphocytes and non‐lymphoid cells: structure and function of the PC‐1 family. Immunol Rev. 1998;161(1):11-26.
12. Funakoshi I, Kato H, Horie K, Yano T, Hori Y, Kobayashi H, et al. Molecular cloning of cDNAs for human fibroblast nucleotide pyrophosphatase. Arch Biochem Biophys. 1992;295(1):180-187.
13. Frittitta L, Youngren J, Vigneri R, Maddux B, Trischitta V, Goldfine I. PC-1 content in skeletal muscle of non-obese, non-diabetic subjects: relationship to insulin receptor tyrosine kinase and whole body insulin sensitivity. Diabetologia. 1996;39:1190-1195.
14. 14. Pizzuti A, Frittitta L, Argiolas A, Baratta R, Goldfine ID, Bozzali M, et al. A polymorphism (K121Q) of the human glycoprotein PC-1 gene coding region is strongly associated with insulin resistance. Diabetes. 1999;48(9):1881-1884.
15. Gu HF, Almgren P, Lindholm E, Frittitta L, Pizzuti A, Trischitta V, et al. Association between the human glycoprotein PC-1 gene and elevated glucose and insulin levels in a paired-sibling analysis. Diabetes. 2000;49(9):1601-1603.
16. Costanzo BV, Trischitta V, Di Paola R, Spampinato D, Pizzuti A, Vigneri R, et al. The Q allele variant (GLN121) of membrane glycoprotein PC-1 interacts with the insulin receptor and inhibits insulin signaling more effectively than the common K allele variant (LYS121). Diabetes. 2001;50(4):831-836.
17. Diagnosis ECot and CoDM. Report of the expert committee on the diagnosis and classification of diabetes mellitus. Diabetes Care. 2003;26(suppl_1):s5-s20.
18. Matthews DR, Hosker JP, Rudenski AS, Naylor BA, Treacher DF, Turner RC. Homeostasis model assessment: insulin resistance and β-cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia. 1985;28:412-419.
19. Grarup N, Urhammer S, Ek J, Albrechtsen A, Glümer C, Borch-Johnsen K, et al. Studies of the relationship between the ENPP1 K121Q polymorphism and type 2 diabetes, insulin resistance and obesity in 7,333 Danish white subjects. Diabetologia. 2006;49:2097-2104.
20. Weedon MN, Shields B, Hitman G, Walker M, McCarthy MI, Hattersley AT, et al. No evidence of association of ENPP1 variants with type 2 diabetes or obesity in a study of 8,089 UK Caucasians. Diabetes. 2006;55(11):3175-3179.
21. González‐Sánchez JL, Martínez‐Larrad MT, Fernández‐Pérez C, Kubaszek A, Laakso M, Serrano‐Ríos M. K121Q PC‐1 gene polymorphism is not associated with insulin resistance in a Spanish population. Obes Res. 2003;11(5):603-605.
22. Seo HJ, Kim SG, Kwon OJ. The K121Q polymorphism in ENPP1 (PC-1) is not associated with type 2 diabetes or obesity in Korean male workers. J Korean Med Sci. 2008;23(3):459-464.
23. Matsuoka N, Patki A, Tiwari H, Allison D, Johnson S, Gregersen P, et al. Association of K121Q polymorphism in ENPP1 (PC-1) with BMI in Caucasian and African-American adults. Int J Obes (Lond). 2006;30(2):233-237.
24. Prudente S, Chandalia M, Morini E, Baratta R, Dallapiccola B, Abate N, et al. The Q121/Q121 genotype of ENPP1/PC‐1 is associated with lower BMI in non‐diabetic whites. Obesity (Silver Spring). 2007;15(1):1-4.
25. Wan C, Zhang T, Wang B, Han Y, Zhang C, Zhang Y, et al. Obesity risk associated with the K121Q polymorphism of the glycoprotein PC‐1 gene. Diabetes Obes Metab. 2006;8(6):703-708.
26. Böttcher Y, Körner A, Reinehr T, Enigk B, Kiess W, Stumvoll M, et al. ENPP1 variants and haplotypes predispose to early onset obesity and impaired glucose and insulin metabolism in German obese children. J Clin Endocrinol Metab. 2006;91(12):4948-4952.
27. Tanyolaç S, Mahley RW, Hodoglugil U, Goldfine ID. Gender Differences in the Relationship of ENPP1/PC‐1 Variants to Obesity in a Turkish Population. Obesity (Silver Spring). 2008;16(11):2468-2471.
28. 28. Bruning JC, Gautam D, Burks DJ, Gillette J, Schubert M, Orban PC, et al. Role of brain insulin receptor in control of body weight and reproduction. Science. 2000;289(5487):2122-2125.
29. Kubaszek A, PIHLAJAMaki J, KARHAPaa P, Vauhkonen I, Laakso M. The K121Q polymorphism of the PC-1 gene is associated with insulin resistance but not with dyslipidemia. Diabetes Care. 2003;26(2):464-467.
30. Frittitta L, Baratta R, Spampinato D, Di Paola R, Pizzuti A, Vigneri R, et al. The Q121 PC-1 variant and obesity have additive and independent effects in causing insulin resistance. J Clin Endocrinol Metab. 2001;86(12):5888-5891.
31. Hamaguchi K, Terao H, Kusuda Y, Yamashita T, Hazoury Bahles J, Cruz LL, et al. The PC-1 Q121 allele is exceptionally prevalent in the Dominican Republic and is associated with type 2 diabetes. J Clin Endocrinol Metab. 2004;89(3):1359-1364.
32. Goldfine ID, Maddux BA, Youngren JF, Reaven G, Accili D, Trischitta V, et al. The role of membrane glycoprotein plasma cell antigen 1/ectonucleotide pyrophosphatase phosphodiesterase 1 in the pathogenesis of insulin resistance and related abnormalities. Endocr Rev. 2008;29(1):62-75.
33. Horikoshi M, Hara K, Ito C, Shojima N, Nagai R, Ueki K, et al. Variations in the HHEX gene are associated with increased risk of type 2 diabetes in the Japanese population. Diabetologia. 2007;50:2461-2466.
34. Rasmussen SK, Urhammer SA, Pizzuti A, Echwald SM, Ekstrøm CT, Hansen L, et al. The K121Q variant of the human PC-1 gene is not associated with insulin resistance or type 2 diabetes among Danish Caucasians. Diabetes. 2000;49(9):1608-1611.
35. Chandalia M, Grundy SM, Adams-Huet B, Abate N. Ethnic differences in the frequency of ENPP1/PC1 121Q genetic variant in the Dallas Heart Study cohort. J Diabetes Complications. 2007;21(3):143-148..
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| Issue | Vol 1 No 1 (2023) | |
| Section | Original Articles | |
| DOI | https://doi.org/10.18502/abi.v1i1.14061 | |
| Keywords | ||
| Iranian population Obesity K121Q ENPP1 | ||
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How to Cite
1.
Saberi H, Taheripak G, Meshkani R. The ENPP1 K121Q polymorphism is associated with obesity-related parameters in Iranian normoglycemic male subjects. ABI. 2023;1(1):20-25.
