Women Transmits Type 2 Diabetes Mellitus (T2DM) More Than Men: Evidences from Parental Inheritance of T2DM Among Bahrainis

Abstract

Introduction: Heritability in type 2 diabetes mellitus (T2DM) is observed but not well understood.

Methods: In this study, family history and clinical/biochemical data from 789 Bahrainis (418 T2DM, 371 controls) was analyzed. Fasting blood glucose (FBG) and HbA1c were measured and angiotensin-converting enzyme (ACE) and methylene tetrahydrofolate reductase (MTHFR) polymorphisms (SNPs) were analyzed.

Results: Patients compared to controls have higher proportions of diabetic mothers (50.2% vs. 32.7%, p=0.005), fathers (35.2% vs. 12.1%, p<0.001) and siblings (56% vs. 15.3%, p<0.001). The proportions of diabetic mothers was higher than the proportions of diabetic fathers among the patients (50.2% vs. 35.2%, p<0.001) and the controls (32.7% vs. 12.1%, p<0.001). Patients born to diabetic mothers compared to the other patients were smaller in age at the time of enrollment in this study (p=0.005), and at onset of T2DM (p<0.001), and also had higher FBG (p=0.033). Interestingly, the prevalence of T1DM was highest amongst the siblings of the controls compared to patients (p=0.04). Finally, the heterozygote I/D genotype of the ACE gene was over expressed in patients born to diabetic mothers when compared to patients born to diabetic fathers, p=0.007.

Conclusions: there was strong clustering of T2DM in families, with significant dominant maternal role in transmission of T2DM and associated severity markers. Patients (T2DM) born to diabetic mothers were genetically and phenotypically different from the other patients.

Key words

T2DM - inheritance - parents - maternal - angiotensin converting enzyme

• References

• 1 Chen L, Magliano DJ, Zimmet PZ. The worldwide epidemiology of type 2 diabetes mellitus – present and future perspectives. Nat Rev Endocrinol 2011; 8: 228-236
• 2 Doria A, Patti M-E, Kahn CR. The emerging genetic architecture of type 2 diabetes. Cell Metabolism 2008; 8: 186-200
• 3 Kahn CR. Insulin action, diabetogenes, and the cause of type II diabetes (Banting Lecture). Diabetes 1994; 43: 1066-1084
• 4 Weir GC, Leahy JL. Pathogenesis of non-insulin-dependent (type II) diabetes mellitus. In: Kahn CR, Weir GC. (eds.) Joslin’s diabetes mellitus. Philadelphia: Lea & Febiger: 1994: 240-264
• 5 Hansen L, Pedersen O. Genetics of type 2 diabetes mellitus: status and perspectives. Diabetes Obes Metab. 2005; 7: 122-35
• 6 Cheţa D, Dumitrescu C, Georgescu M et al. A study on the types of diabetes mellitus in first degree relatives of diabetic patients. Diabete Metab 1990; 16: 11-15
• 7 Shera AS, Rafique G, Khawaja IA et al. Pakistan National Diabetes Survey: prevalence of glucose intolerance and associated factors in Baluchistan province. Diabetes Res Clin Pract 1999; 44: 49-58
• 8 Erasmus RT, Blanco E, Okesina AB et al. Importance of family history in type 2 black South African diabetic patients. Postgrad Med J 2001; 77: 323-325
• 9 Arfa I, Abid A, Malouche D et al. Familial aggregation and excess maternal transmission of type 2 diabetes in Tunisia. Postgrad Med J 2007; 83: 348-351
• 10 Bener A, Yousafzai MT, Al-Hamaq AO et al. Parental transmission of type 2 diabetes mellitus in a highly endogamous population. World J Diabetes 2013; 15: 40-46
• 11 Ma XJ, Jia WP, Hu C et al. Genetic characteristics of familial type 2 diabetes pedigrees: a preliminary analysis of 4468 persons from 715 pedigrees. Zhonghua Yi Xue Za Zhi 2008; 23: 2541-2543
• 12 Lee SC, Pu YB, Chow CC et al. Diabetes in Hong Kong Chinese: evidence for familial clustering and parental effects. Diabetes Care 2000; 23: 1365-1368
• 13 Rigoli L, Salpietro DC, Caruso RA et al. Mitochondrial DNA mutation at np 3243 in a family with maternally inherited diabetes mellitus. Acta Diabetol 1999; 36: 163-167
• 14 Liao WQ, Pang Y, Yu CA et al. Novel mutations of mitochondrial DNA associated with type 2 diabetes in Chinese Han population. Tohoku J Exp Med 2008; 215: 377-384
• 15 Neel JV. Diabetes mellitus: a ‘thrifty’ genotype rendered detrimental by ‘progress’?. Am J Hum Genet 1962; 14: 353-362
• 16 Speakman JR. A nonadaptive scenario explaining the genetic predisposition to obesity: the ‘predation release’ hypothesis. Cell Metab 2007; 6: 5-12
• 17 Al-Mahroos F, McKeigue PM. High prevalence of diabetes in Bahrainis. Associations with ethnicity and raised plasma cholesterol. Diabetes Care 1998; 21: 936-942
• 18 Rigat B, Hubert C, Corvol P et al. PCR detection of the insertion/deletion polymorphism of the human angiotensin converting enzyme gene (DCP1) (dipeptidylcarboxypeptidase 1). Nucleic Acids Res 1999; 20: 1433
• 19 Al-Harbi EM, Farid EM, Gumaa KA et al. Genotypes and allele frequencies of angiotensin-converting enzyme (ACE) insertion/deletion polymorphism among Bahraini population with type 2 diabetes mellitus and related diseases. Mol Cell Biochem 2012; 362: 219-223
• 20 Frosst P, Zhang Z, Pai A et al. The methylenetetrahydrofolate reductase (Mthfr) gene maps to distal mouse chromosome 4. Mamm Genome 1996; 7: 864-865
• 21 Al-Harbi EM, Farid EM, Gumaa KA et al. Genetic combination of angiotensin-converting enzyme with methylene tetrahydrofolate reductase polymorphisms and the risk of type 2 diabetes mellitus in Bahrain. J Renin Angiotensin Aldosterone Syst 2015; 16: 172-177
• 22 Benrahma H, Arfa I, Charif M et al. Maternal effect and familial aggregation in a type 2 diabetic Moroccan population. J Community Health 2011; 36: 943-948
• 23 Karter AJ, Rowell SE, Ackerson LM et al. Excess maternal transmission of type 2 diabetes. The Northern California Kaiser Permanente Diabetes Registry. Diabetes Care 1999; 22: 938-43
• 24 Otabe S, Nakayama H, Fukutani T et al. Excessive maternal transmission of diabetes in Japanese families with young-onset type 2 diabetes and insulin secretion defect according to clinical features. Acta Diabetol 2010; 1: 133-138
• 25 Viswanathan M, McCarthy MI, Snehalatha C et al. Familial aggregation of type 2 (non-insulin-dependent) diabetes mellitus in south India; absence of excess maternal transmission. Diabet Med 1996; 13: 232-237
• 26 Kim DJ, Cho NH, Noh JH et al. Lack of excess maternal transmission of type 2 diabetes in a Korean population. Diabetes Res Clin Pract 2004; 65: 117-124
• 27 Mohlke KL, Jackson AU, Scott LJ et al. Mitochondrial polymorphisms and susceptibility to type 2 diabetes-related traits in Finns. Hum Genet 2005; 118: 245-254
• 28 Bo S, Cavallo-Perin P, Gentile L et al. Influence of a familial history of diabetes on the clinical characteristics of patients with Type 2 diabetes mellitus. Diabet Med 2000; 17: 538-542
• 29 Papazafiropoulou A, Sotiropoulos A, Skliros E et al. Familial history of diabetes and clinical characteristics in Greek subjects with type 2 diabetes. BMC Endocr Disord. 2009; 27: 12
• 30 Lee SC, Ko GT, Li JK et al. Factors predicting the age when type 2 diabetes is diagnosed in Hong Kong Chinese subjects. Diabetes Care 2001; 24: 646-649
• 31 Crispim D, Canani LH, Gross JL et al. Familial history of type 2 diabetes in patients from Southern Brazil and its influence on the clinical characteristics of this disease. Arch Bras Endocrinol Metabol 2006; 50: 862-868
• 32 Molyneaux L, Constantino M, Yue D. Strong family history predicts a younger age of onset for subjects diagnosed with type 2 diabetes. Diabetes Obes Metab 2004; 6: 187-194
• 33 Alcolado JC, Alcolado R. Importance of maternal history of non-insulin dependent diabetic patients. BMJ 1991; 18: 1178-1180
• 34 Thomas F, Balkau B, Vauzelle-Kervroedan F et al. Maternal effect and familial aggregation in NIDDM. The CODIAB Study. CODIAB-INSERM-ZENECA Study Group. Diabetes 1994; 43: 63-67
• 35 Tusié Luna MT. Genes and type 2 diabetes mellitus. Arch Med Res 2005; 36: 210-222
• 36 Yang M, Qiu CC, Xu Q et al. Association of angiotensin converting enzyme gene I/D polymorphism with type 2 diabetes mellitus. Biomed Environ Sci 2006; 19: 323-327
• 37 Park KS, Chan JC, Chuang LM et al. A mitochondrial DNA variant at position 16189 is associated with type 2 diabetes mellitus in Asians. Diabetologia 2008; 51: 602-608
• 38 Murphy R, Turnbull DM, Walker M et al. Clinical features, diagnosis and management of maternally inherited diabetes and deafness (MIDD) associated with the 3243A>G mitochondrial point mutation. Diabet Med 2008; 25: 383-399
• 39 Malecki MT. Genetics of type 2 diabetes mellitus. Diabetes Res Clin Pract 2005; 68 (Suppl1) S10-S21
• 40 Neel JV, Weder AB, Julius S. Type II diabetes, essential hypertension, and obesity as ‘syndromes of impaired genetic homeostasis’: the ‘thrifty genotype’ hypothesis enters the 21^st century. Perspect Biol Med 1998; 42: 44-74
• 41 Alhyas L, McKay A, Balasanthiran A et al. Prevalences of overweight, obesity, hyperglycaemia, hypertension and dyslipidaemia in the Gulf: systematic review. JRSM Short Rep 2011; 2: 55