The rate and nature of mitochondrial DNA mutations in human pedigrees.

We examined the rate and nature of mitochondrial DNA (mtDNA) mutations in humans using sequence data from 64,806 contemporary Icelanders from 2,548 matrilines. Based on 116,663 mother-child transmissions, 8,199 mutations were detected, providing robust rate estimates by nucleotide type, functional impact, position, and different alleles at the same position. We thoroughly document the true extent of hypermutability in mtDNA, mainly affecting the control region but also some coding-region variants. The results reveal the impact of negative selection on viable deleterious mutations, including rapidly mutating disease-associated 3243A>G and 1555A>G and pre-natal selection that most likely occurs during the development of oocytes. Finally, we show that the fate of new mutations is determined by a drastic germline bottleneck, amounting to an average of 3 mtDNA units effectively transmitted from mother to child.

Cohort profile update: Tehran cardiometabolic genetic study.

The Tehran cardiometabolic genetic study (TCGS) is a large population-based cohort study that conducts periodic follow-ups. TCGS has created a comprehensive database comprising 20,367 participants born between 1911 and 2015 selected from four main ongoing studies in a family-based longitudinal framework. The study's primary goal is to identify the potential targets for prevention and intervention for non-communicable diseases that may develop in mid-life and late life. TCGS cohort focuses on cardiovascular, endocrine, metabolic abnormalities, cancers, and some inherited diseases. Since 2017, the TCGS cohort has augmented by encoding all health-related complications, including hospitalization outcomes and self-reports according to ICD11 coding, and verifying consanguineous marriage using genetic markers. This research provides an update on the rationale and design of the study, summarizes its findings, and outlines the objectives for precision medicine.

Familial genetic and environmental risk profile and high blood pressure event: a prospective cohort of cardio-metabolic and genetic study.

BACKGROUND AND AIMS: High blood pressure is the heritable risk factor for cardiovascular diseases. We investigated whether the presence of familial genetic and environmental risk factors are associated with increased risk of high blood pressure. METHODS: A total of 4,559 individuals from 401 families were included in this study. Familial aggregation analysis was carried out on systolic blood pressure (SBP), diastolic blood pressure (DBP), body mass index (BMI) and waist circumference (WC), and heritability was estimated for SBP and DBP. The association between familial risk factors and blood pressure traits including, incidence of hypertension, SBP and DBP was estimated separately using regression-based two-level Haseman-Elston (HE) method, with individual and familial BMI and WC as environmental exposures and familial genetic profile of known variants as genetic risk factors in 210 index families (≥2 hypertensive cases). Models were adjusted for the two nested sets of covariates. RESULTS: During a follow-up of 15 years, the SBP, DBP, BMI and WC were highly correlated in inter class of mother-offspring and intraclass of sister-sister with heritability of 30 and 25% for DBP and SBP, respectively. Among index families, those whose members with higher familial BMI or WC had significantly increased risk of hypertension and consistent, strong signals of rs2493134 (AGT) linked with SBP and DBP, rs976683 (NLGN1) linked with SBP and HTN, and epistasis of rs2021783 (TNXB) and known genetic variants linked with all blood pressure traits. CONCLUSIONS: Findings from this study show that familial genetic and environmental risk profile increase risk for high blood pressure beyond the effect of the individuals' own risk factors.

The role of childhood BMI in predicting early adulthood dysglycemia: Tehran lipid and glucose study.

BACKGROUND AND AIM: Increased adiposity is associated with insulin resistance and glycemic disturbances. We aimed to determine whether childhood overweight or obesity are independent factors in predicting adulthood dysglycemia (prediabetes or type 2 diabetes). METHODS AND RESULTS: In this population-based cohort study, 1290 normoglycemic subjects aged 3-11 years were followed for incidence of dysglycemia. Cox-proportional hazard models were employed to evaluate the association of obesity and overweight with incidence of dysglycemia by adjustments for age, sex, parental risk factors and baseline individual risk factors. The participants, with a mean age of 7.7 ± 2.5 years, were followed for a median of 14.9 years. During follow up, 158 subjects developed dysglycemia (18 type 2 diabetes, 140 prediabetes), contributing to a total cumulative incidence of 24.7%. The unadjusted HR for developing adult dysglycemia were 1.6 (95% CI; 1.0-2.4) and 1.7 (95% CI; 1.0-3.0) in overweight and obese children, respectively. Further adjustments for age, sex, parental risk factors and baseline individual risk factors changed the results in both overweight and obese children. CONCLUSION: These findings show that overweight or obesity in childhood have no independent role for developing adulthood dysglycemia.

Lack of association between FTO gene variations and metabolic healthy obese (MHO) phenotype: Tehran Cardio-metabolic Genetic Study (TCGS).

BACKGROUND: Obesity is currently an international epidemic and metabolic derangements pose these individuals at greater risk for future morbidity and mortality. Genetics and environmental factors have undeniable effects and among genetic risk factors, FTO/CETP genes are important. The current study examines the interaction between obesity phenotypes and FTO/CETP SNPs and their effects on lipid profile changes. MATERIALS AND METHODS: We selected 954 adult subjects from TCGS (47.9% male). Participants were stratified according to their BMI and presence of metabolic syndrome according to the Joint Interim Statement (JIS) definition. Nine selected polymorphisms from FTO/CETP genes were genotyped using Tetra ARMS-PCR method. After age and sex adjustment the interaction of 9 markers with lipid profiles among phenotypes were tested by PASW. RESULTS: In three main groups, HDL_C level had a strong significant association with CETP markers: (rs3764261, ß(95% CI) - 0.48(- 0.61 to - 0.35), P = 1.0 × 10-11), (rs1800775, ß(95% CI) 0.5(0.36;0.65), P = 1.0 × 10-6) and (rs1864163, ß(95% CI) 0.3(0.16;0.43), P = 9.1 × 10-5). This association was also seen in rs7202116 within the total population. In only unhealthy metabolic obese (MUHO) subgroups four new FTO markers (rs1421085, rs1121980, rs1558902 and rs8050136) (P value < 0.01) demonstrated significant association, even after lipid profile adjustment. CONCLUSION: In the present study, we investigated the association between obesity phenotypes and some variations in FTO/CETP genes for the first time. Our study showed that four markers in the first intron of the FTO gene should be the risk marker in MUHO participants. LEVEL OF EVIDENCE: Level III, case-control study.

Generality of genomic findings on blood pressure traits and its usefulness in precision medicine in diverse populations: A systematic review.

Remarkable findings from genome-wide association studies (GWAS) on blood pressure (BP) traits have made new insights for developing precision medicine toward more effective screening measures. However, generality of GWAS findings in diverse populations is hampered by some technical limitations. There is no comprehensive study to evaluate source(s) of the non-generality of GWAS results on BP traits, so to fill the gap, this systematic review study was carried out. Using MeSH terms, 1545 records were detected through searching in five databases and 49 relevant full-text articles were included in our review. Overall, 749 unique variants were reported, of those, majority of variants have been detected in Europeans and were associated to systolic and diastolic BP traits. Frequency of genetic variants with same position was low in European and non-European populations (n = 38). However, more than 200 (>25%) single nucleotide polymorphisms were found on same loci or linkage disequilibrium blocks (r2 ≥ 80%). Investigating for locus position and linkage disequilibrium of infrequent unique variants showed modest to high reproducibility of findings in Europeans that in some extent was generalizable in other populations. Beyond theoretical limitations, our study addressed other possible sources of non-generality of GWAS findings for BP traits in the same and different origins.

Incidence and predictors of early adulthood pre-diabetes/type 2 diabetes, among Iranian adolescents: the Tehran Lipid and Glucose Study.

PURPOSE: To evaluate the incidence and predictors of early adulthood pre-diabetes/type 2 diabetes (T2D) among Iranian adolescents during a median follow-up of 9.2 yr. METHOD: A total of 2563 subjects aged 10-19 yr, without pre-diabetes/T2D at baseline, were entered in the study. Pre-diabetes was defined as those with fasting plasma glucose (FPG) 5.6 to <7 mmol/L. T2D was defined as anti-T2D drug consumption or FPG ≥7 mmol/L. Multivariate Cox-proportional analysis was applied to examine the association between different risk factors that showed attained statistical significance < 0.2 in univariate analysis, with incident pre-diabetes/T2D. Same method was repeated on 1803 subjects with complete parental data to find the relation between parental risk factors and pre-diabetes/T2D. RESULT: The mean age of participants was 14.45 ± 2.78 yr, and 53.6% were female. During follow-up 208 cases of pre-diabetes/T2D occurred, resulting in an incidence rate of 9.61 per 1000 person-years. Multivariate-adjusted hazard ratios (HRs) for incident pre-diabetes/T2D showed significant risk for 1 standard deviation increase in FPG and body mass index with corresponding HR of 1.89 (1.6-2.23) and 1.435 (1.080-1.905), respectively. Among parental potential risk factors, the paternal history of T2D was independently associated with increased risk for pre-diabetes/T2D in the adolescence (HR = 1.63(1.02-2.60)). CONCLUSION: About 1% of Iranian adolescents developed pre-diabetes/T2D each year. Among the non-modifiable risk factors paternal history of T2D and, among modifiable risk factors, the presence of general adiposity as well as the higher level of FPG should be considered among adolescents for development of pre-diabetes/T2D later in the young adulthood.

The Tehran longitudinal family-based cardiometabolic cohort study sheds new light on dyslipidemia transmission patterns.

Dyslipidemia, as a metabolic risk factor, with the strongest and most heritable independent cause of cardiovascular diseases worldwide. We investigated the familial transmission patterns of dyslipidemia through a longitudinal family-based cohort, the Tehran Cardiometabolic Genetic Study (TCGS) in Iran. We enrolled 18,729 individuals (45% were males) aged > 18 years (mean: 38.15 (15.82)) and observed them over five 3-year follow-up periods. We evaluated the serum concentrations of total cholesterol, triglyceride, high-density lipoprotein cholesterol, and low-density lipoprotein cholesterol with the first measurement among longitudinal measures and the average measurements (AM) of the five periods. Heritability analysis was conducted using a mixed-effect framework with likelihood-based and Bayesian approaches. The periodic prevalence and heritability of dyslipidemia were estimated to be 65.7 and 42%, respectively. The likelihood of an individual having at least one dyslipidemic parent reveals an OR = 6.94 (CI 5.28-9.30) compared to those who do not have dyslipidemic parents. The most considerable intraclass correlation of family members was for the same-sex siblings, with ICC ~ 25.5%. For serum concentrations, heritability ranged from 33.64 to 60.95%. Taken together, these findings demonstrate that familial transmission of dyslipidemia in the Tehran population is strong, especially within the same-gender siblings. According to previous reports, the heritability of dyslipidemia in this population is considerably higher than the global average.

Heritability of the metabolic syndrome and its components in the Tehran Lipid and Glucose Study (TLGS).

Growing evidence suggests that metabolic syndrome (MetS) has both genetic and environmental bases. We estimated the heritability of the MetS and its components in the families from the Tehran Lipid and Glucose Study (TLGS). We investigated 904 nuclear families in TLGS with two biological parents and at least one offspring (1565 parents and 2448 children), aged 3-90 years, for whom MetS information was available and had at least two members of family with MetS. Variance component methods were used to estimate age and sex adjusted heritability of metabolic syndrome score (MSS) and MetS components using SOLAR software. The heritability of waist circumference (WC), HDL-cholesterol (HDL-C), triglycerides (TGs), fasting blood sugar (FBS), systolic blood pressure (SBP) and diastolic blood pressure (DBP) as continuous traits after adjusting for age and gender were 27, 46, 36, 29, 25, 26 and 15%, respectively, and MSS had a heritability of 15%. When MetS components were analysed as discrete traits, the estimates of age and gender adjusted heritability for MetS, abdominal obesity, low HDL-C, high TG, high FBS and high blood pressure (BP) were 22, 40, 34, 38 and 23%, respectively (P < 0·05). Three factors were extracted from the six continuous traits of the MetS including factor I (BP), factor II (lipids) and factor III (obesity and FBS). Heritability estimation for these three factors were 7, 13 (P < 0·05) and 2%, respectively. The highest heritability was for HDL-C and TG. The results strongly encourage efforts to identify the underlying susceptibility genes.

Parental Transmission Plays the Major Role in High Aggregation of Type 2 Diabetes in Iranian Families: Tehran Lipid and Glucose Study.

BACKGROUND: This study is the first to evaluate familial aggregation, heritability and inheritance mode of type 2 diabetes (T2D) in Tehran Lipid Glucose Study (TLGS) participants as a representative sample of the Iranian population. METHODS: From the ongoing family-based TLGS cohort, 13,741 individuals at least 20 years of age (mean ± standard deviation, 39.71±16.56) were assessed. After correcting family structures using genomic information from the Tehran Cardiometabolic Genetic Study, 2,594 constituent pedigrees were constructed. Familial aggregation was assessed based on genealogic index testing, familial intraclass correlation and positive family history. Family-based heritability was checked with 2 linear mixed models, including 2 different random components: the kinship matrix and the genomic relationship matrix. The mode of inheritance of T2D was investigated by complex segregation analysis (CSA). RESULTS: Familial aggregation of T2D was significant (p<0.05), and family-based heritability showed a high degree of genetic variation in T2D between individuals at 65% (standard error, 0.034). Within first-degree relatives (parent/offspring and siblings), the likelihood of a parental affect was higher than in siblings (odds ratio, 4.11 vs 1.65). Family history of T2D among first-degree relatives was more noteworthy than for second-degree relatives (odds ratio, 3.84 vs 0.59). CSA revealed that the polygenic model is best to illustrate the mode of inheritance of T2D for TLGS participants. CONCLUSIONS: Our findings demonstrate that the heritability of T2D with polygenic mode in the Iranian population is higher than the global average. We also found that T2D is transmitted equally into siblings, with parental affect the leading risk factor. These data suggest that policymakers should change individual-level to family-level prevention.

SARS-CoV-2 infection susceptibility influenced by ACE2 genetic polymorphisms: insights from Tehran Cardio-Metabolic Genetic Study.

The genetic variations among individuals are one of the notable factors determining disease severity and drug response. Nowadays, COVID-19 pandemic has been adversely affecting many aspects of human life. We used the Tehran Cardio-Metabolic Genetic Study (TCGS) data that is an ongoing genetic study including the whole-genome sequencing of 1200 individuals and chip genotyping of more than 15,000 participants. Here, the effect of ACE2 variations by focusing on the receptor-binding site of SARS-CoV-2 and ACE2 cleavage by TMPRSS2 protease were investigated through simulations study. After analyzing TCGS data, 570 genetic variations on the ACE2 gene, including single nucleotide polymorphisms (SNP) and insertion/deletion (INDEL) were detected. Interestingly, two observed missense variants, K26R and S331F, which only the first one was previously reported, can reduce the receptor affinity for the viral Spike protein. Moreover, our bioinformatics simulation of 3D structures and docking of proteins explains important details of ACE2-Spike and ACE2-TMPRSS2 interactions, especially the critical role of Arg652 of ACE2 for protease function of TMPRSS2 was uncovered. As our results show that the genetic variation of ACE2 can at least influence the affinity of this receptor to its partners, we need to consider the genetic variations on ACE2 as well as other genes in the pathways that contribute to the pathogenesis of COVID-19 for designing efficient drugs and vaccines.

Adolescent metabolic syndrome and its components associations with incidence of type 2 diabetes in early adulthood: Tehran lipid and glucose study.

AIM: To investigate the association of youth metabolic syndrome (MetS) and its components, individually and in combination with early adulthood incident type 2 diabetes (T2DM). METHODS: A total of 2798 adolescents aged 11-19 years enrolled in the study. At baseline, MetS, its components including blood pressure (BP), waist circumference (WC), triglycerides (TGs), fasting plasma glucose, and low HDL-C, and different combinations of MetS components were defined. After a mean 11.3 years of follow-up, T2DM was determined. Multivariable Cox proportional hazard regression analysis adjusted for age, sex, family history of T2DM, and adult BMI was used for data analysis. The hazard ratio (HR) and 95% confidence interval (CI) were reported. RESULTS: During the follow-up, 44 incidents T2DM were developed. Among different individual components, only high WC [HR = 2.63, 95% CI (1.39-4.97)] and high TGs [HR = 1.82, 95% CI (1.00-3.34)] remained as significant predictors only in the age and sex adjusted model. Regarding combinations of MetS components, 'high TGs and high WC' [HR = 2.70, 95% CI (1.27-5.77)], 'high BP and high WC' [HR = 2.52, 95% CI (1.00-6.33)], 'high TGs and high BP' [HR = 2.27, 95% CI (1.02-5.05)] as well as MetS per se [HR = 2.82, 95% CI (1.41-5.64)] had a significant relationship with incident T2DM in the multivariable adjusted model. Among different confounders, being female and having family history of T2DM were consistently associated with higher risk of T2DM, in different combinations of MetS components. CONCLUSIONS: Adolescence MetS and some combinations of MetS components predicted early adulthood T2DM. Thus, adolescents, particularly female ones, with combinations of MetS components as well as those with family history of T2DM could be targeted for lifestyle intervention.

GWAS findings improved genomic prediction accuracy of lipid profile traits: Tehran Cardiometabolic Genetic Study.

In recent decades, ongoing GWAS findings discovered novel therapeutic modifications such as whole-genome risk prediction in particular. Here, we proposed a method based on integrating the traditional genomic best linear unbiased prediction (gBLUP) approach with GWAS information to boost genetic prediction accuracy and gene-based heritability estimation. This study was conducted in the framework of the Tehran Cardio-metabolic Genetic study (TCGS) containing 14,827 individuals and 649,932 SNP markers. Five SNP subsets were selected based on GWAS results: top 1%, 5%, 10%, 50% significant SNPs, and reported associated SNPs in previous studies. Furthermore, we randomly selected subsets as large as every five subsets. Prediction accuracy has been investigated on lipid profile traits with a tenfold and 10-repeat cross-validation algorithm by the gBLUP method. Our results revealed that genetic prediction based on selected subsets of SNPs obtained from the dataset outperformed the subsets from previously reported SNPs. Selected SNPs' subsets acquired a more precise prediction than whole SNPs and much higher than randomly selected SNPs. Also, common SNPs with the most captured prediction accuracy in the selected sets caught the highest gene-based heritability. However, it is better to be mindful of the fact that a small number of SNPs obtained from GWAS results could capture a highly notable proportion of variance and prediction accuracy.

Genome-wide association study on blood pressure traits in the Iranian population suggests ZBED9 as a new locus for hypertension.

High blood pressure is the heritable risk factor for cardiovascular and kidney diseases. Genome-wide association studies(GWAS) on blood pressure traits increase our understanding of its underlying genetic basis. However, a large proportion of GWAS was conducted in Europeans, and some roadblocks deprive other populations to benefit from their results. Iranians population with a high degree of genomic specificity has not been represented in international databases to date, so to fill the gap, we explored the effects of 652,919 genomic variants on Systolic Blood Pressure (SBP), Diastolic Blood Pressure (DBP), and Hypertension (HTN) in 7694 Iranian adults aged 18 and over from Tehran Cardiometabolic Genetic Study (TCGS). We identified consistent signals on ZBED9 associated with HTN in the genome-wide borderline threshold after adjusting for different sets of environmental predictors. Moreover, strong signals on ABHD17C and suggestive signals on FBN1 were detected for DBP and SBP, respectively, while these signals were not consistent in different GWA analysis. Our finding on ZBED9 was confirmed for all BP traits by linkage analysis in an independent sample. We found significant associations with similar direction of effects and allele frequency of genetic variants on ZBED9 with DBP (genome-wide threshold) and HTN (nominal threshold) in GWAS summary data of UK Biobank. Although there is no strong evidence to support the function of ZBED9 in blood pressure regulation, it provides new insight into the pleiotropic effects of hypertension and other cardiovascular diseases.

Spousal metabolic risk factors and future cardiovascular events: A prospective cohort study.

BACKGROUND AND AIMS: We investigated whether the presence of metabolic risk factors in one spouse is associated with increased risk of cardiovascular disease (CVD) in the other spouse. METHODS: A total of 4390 married participants (2152 men and 2238 women free of CVD at baseline) aged ≥20 years were included in this study. The association between spousal risk factors and incident CVD was estimated separately for men and women (as index individuals) using Cox regression models, with spousal risk factors as exposures and CVD event in the index individuals as the outcome. Exposures included spousal body mass index (BMI), waist circumference, systolic and diastolic blood pressure, total cholesterol, high density lipoprotein cholesterol, fasting plasma glucose (all in both continuous and categorical forms) and smoking. Models were adjusted for the three nested sets of covariates. RESULTS: During a median follow-up of 16.1 years, 588 (419 men) cases of CVD were recorded. Among men, those whose wives were overweight and obese had significantly increased risk of CVD, compared with men whose spouses had normal weight, after adjusting for men risk factors. Hazard ratios (HR) with 95% confidence intervals (95% CI) were 1.41 (1.07-1.87) and 1.38 (1.03-1.85), respectively. Among women, no significant associations were observed between spousal metabolic risk factors and incidence of CVD, after controlling for their own risk factors. CONCLUSION: Findings from this study show that overweight and obesity in women increase their spouses' risk for CVD beyond the effect of the spouses' own risk factors.

Spousal metabolic risk factors and incident hypertension: A longitudinal cohort study in Iran.

We investigated the association between metabolic risk factors in one spouse with incident hypertension in the other. Study sample included 1528 men and 1649 women aged ≥20 years from the Tehran lipid and glucose study with information on body mass index (BMI), waist circumference (WC), hypertension, type 2 diabetes mellitus (DM), and dyslipidemia. The hazard ratio (HR) and 95% confidence interval (95% CI) were estimated for the association of spousal metabolic factors and incident hypertension among men and women separately. A total of 604 and 566 cases of incident hypertension were observed in men and women, respectively. Among men, spousal DM was associated with a 40% (CI: 1.07-1.83) excess risk of hypertension after adjusting for the men's own and their spouse's risk factors including BMI, DM, smoking, and physical activity level. Among women, spousal DM was associated with more than two times (2.11, 1.69-2.63) higher risk of hypertension. After further adjustment for the women's own and their spouse's risk factors, the association was attenuated and remained marginally significant (1.25, 0.99-1.58; P value = .053). Having a spouse with DM increases an individual's risk of hypertension, which raises the possibility of using preexisting information of one partner to guide the screening of the other partner.

Presence of CC Genotype for rs17773430 Could Affect the Percentage of Excess Weight Loss 1 Year After Bariatric Surgery: Tehran Obesity Treatment Study (TOTS).

BACKGROUND: Morbid obesity could last for a long period of life and increase the risk of morbidity as well as premature mortality. Although bariatric surgery benefits patients by quick weight loss, not all bariatric patients lose the same percentage of weight after a long time from surgery, which may be the result of diet, physical activity, and genetic components. OBJECTIVES: In this study, we evaluated the association between the MC4R gene and both excess weight loss percentage (EWL%) and excess BMI loss percentage (EBMIL%) in a cohort of bariatric surgery patients after 6 and 12 months from surgery. METHODS: A total of 424 bariatric surgery patients who had participated in the Tehran Obesity Treatment Study and had weight measurements after 6 and 12 months from surgery were included in the study. Four SNPs in the MC4R gene were selected for evaluating the associations. RESULTS: We found that rs17773430 had a significant effect on both EWL% and EBMIL%, especially after 12 months of bariatric surgery. Furthermore, three other SNPs, rs17782313, rs476828, and rs11152213, did not show any significant association with EWL% and EBMIL%. CONCLUSION: This study was the first to report on the association of rs17773430 with both EWL% and EBMIL% in a cohort of patients after bariatric surgery. We found that weight loss after surgery is influenced by genetic factors, and there were significant differences between the distribution of EWL% and EBMIL% in morbid obese bariatric patients who have two minor alleles of the rs17773430 and other SNPs.

Sex differences in the association between spousal metabolic risk factors with incidence of type 2 diabetes: a longitudinal study of the Iranian population.

BACKGROUND: We investigated whether metabolic risk factors in one spouse were associated with an excessive risk of type 2 diabetes in the other. METHODS: The study cohort (1999-2018) included 1833 men and 1952 women, aged ≥ 20 years with information on both their own and their spouse's diabetes status and metabolic risk factors including body mass index (BMI), waist circumference, systolic and diastolic blood pressure, triglyceride to high-density lipoprotein cholesterol ratio, and type 2 diabetes. The associations between spousal metabolic risk factors and type 2 diabetes were estimated using Cox regression models adjusted for the three nested sets of covariates. RESULTS: We found 714 (360 men and 354 women) incident cases of type 2 diabetes, after more than 15 years of follow-up. Among women, having a husband with diabetes was associated with a 38% (hazard ratio (HR) 1.38; 95% confidence interval (CI) 1.03, 1. 84) increased risk of type 2 diabetes, adjusted for age, socioeconomic status, individual's own value of the respective spousal exposure variable, family history of diabetes, and physical activity level. After further adjustment for the woman's own BMI level, the husband's diabetes was associated with 23% (HR 1.23; 0.92, 1.64) higher risk of type 2 diabetes in wives, values which did not reach statistical significance. No significant associations were found between spousal metabolic risk factors and incidence of type 2 diabetes among index men. CONCLUSION: We found a sex-specific effect of spousal diabetes on the risk of type 2 diabetes. Having a husband with diabetes increased an individual's risk of type 2 diabetes. Our results might contribute to the early detection of individuals at high risk of developing type 2 diabetes, particularly, in women adversely affected by their partner's diabetes.

Gestational diabetes mellitus in mothers and long term cardiovascular disease in both parents: Results of over a decade follow-up of the Iranian population.

BACKGROUND AND AIMS: We aimed at evaluating whether the presence of gestational diabetes mellitus (GDM) in mothers is associated with increased risk of incident cardiovascular disease (CVD) in both mothers and fathers. METHODS: In this population-based study, 4308 Iranian women, aged 18-64 years, with at least 1 live-birth delivery, and free of CVD at baseline, were followed. Corresponding spouses were identified in 2547 cases. The association between history of GDM and incident CVD was assessed using multivariate Cox's proportional hazard in 3 models: model 1, unadjusted; model 2, adjusted for age, body mass index, smoking (for men), maternal parity, miscarriage, physical activity, hypertension and hypercholesterolemia, and model 3, further adjusted for diabetes mellitus. RESULTS: After a median follow-up of 14.1 years, 314 mothers and 424 fathers experienced CVD. Women with history of GDM had an adjusted hazard ratio (HR), 95% CI of 1.85 (1.38-2.48) and 1.29 (0.96-1.75) for CVD in models 1 and 2, respectively. Furthermore, an independent association with CVD was observed in fathers with an adjusted HR of 1.35 (1.02-1.79) in the confounder adjusted model and even after further controlling for diabetes [1.36 (1.03-1.80)]. Moreover, all traditional risk factors, excluding BMI, showed an independent risk for CVD in both genders. CONCLUSIONS: Women with prior GDM showed an increased risk of CVD that was not independent of important CVD risk factors. However, among men, spousal history of GDM was an independent risk factor for incident CVD, even after considering important traditional risk factors, including diabetes.

Identifying new associated pleiotropic SNPs with lipids by simultaneous test of multiple longitudinal traits: An Iranian family-based study.

A number of genome-wide association studies (GWASs) have identified several genetic determinants of plasma lipids in European populations, in which analytical approaches have often been based on the linear regression models and the association test between a SNP and each lipid component individually in cross-sectional designs. Since lipid variations are correlated, the consideration of pleiotropy is necessary and using methods that can perform simultaneous association test of multiple longitudinal traits provides more information about the recognition of the pleiotropic variants. To identify new pleiotropic variants and to determine whether loci identified in previous GWASs can also exert the same effect on lipid concentrations in Iranian population, longitudinal measurements of lipid variations were used in a sample of Iranian population (16,353 individuals within 3100 families) that followed up every 3 years and using a two-step model, the associations of 20,036 available SNPs on chromosome 16 were assessed. Twenty variants within the AC009035.1, SLC12A3, CETP, NLRC5, ESRP2 and, C16orf95 genes showed strong evidence for association with HDL-C, cholesterol, and triglycerides with p-values ranging from 1.7 × 10-102 to 6.6 × 10-5. Since many genetic variants associated with lipids still remain to be determined, the results of the present study may provide valuable information on identifying the associations of new genetic loci with lipid variations in other populations.