Mitochondrial Genetics and Cancer

The first modern human, the Mitochondrial Eve, was traced back to Africa about 200,000 years ago, based on the variation in the mitochondrial DNA (mtDNA). An eruption of a super volcano, Mount Toba, in Sumatra 70,000 years ago may have led to a 'nuclear winter', followed by a 1,000-year ice age. This cold snap would have made life difficult; genetic evidence indicated a sharp reduction in population size around this time, reaching approximately 10,000 individuals. Once the climate started to improve, our ancestors recovered from this near-extinction event. The population expanded, and some courageous explorers ventured beyond Africa. Around 50,000 years ago some of these brave ancestors had successfully crossed the globe to South East Asia and Australia. Some of them settled in the Indonesian archipelago, forming the first settlement of prehistoric Indonesia. The second migration happened around 10,000 years ago, where a group of hunter-gatherers followed the now-submerged river systems that once ran from mainland Asia between the modern islands of Sumatera, Java, and Borneo. Then, around 4,000 years ago the third group of ancestors arrived. This agricultural community brought along their culture of pottery, plant cultivation, and animal domestication, co-inciding with the vast spread of Austronesian languages. Therefore, it is likely that the Indonesian archipelago hosts a wide range of linguistic, ethnic and genetic diversity.1 Nowadays, the modern Indonesia is home to around 700 ethnic populations, each with distinct cultural and linguistic characteristics, representing vast genome diversity.Our ancestors’ decision to embark on a sea travel and take on its related lifestyle has influenced the development of susceptibility and resistance to various diseases observed today. During the prolonged travel, our ancestors were subjected to changes in global climate and geographic dynamic, which strongly influenced and shaped the genetic background of modern humans, including the mtDNA genome. Mitochondria, a well-adapted endosymbiotic intracellular organelles, became efficient for energy production through-out the course of evolution. They are critical for survival and proliferation of living organisms under aerobic conditions and produce ATP through oxidative phosphorylation (OXPHOS). Adaptation to new environments that favor beneficial traits may have caused genetic risk differences that influence the crucial function of the mitochondria, consequently affecting many function in the cell.2 The altered function of the mitochondria might act as an important factor for disease susceptibility across many human populations, i.e. mtDNA variation that grouped together forming a certain type/group (the mtDNA haplogroup) was reported to modulate cancer susceptibility3-5 and resistance6 in Chinese population.Cancer cells are characterized in general by a decrease of mitochondrial respiration and OXPHOS, a consequence of disruptive mtDNA mutations commonly found in cancer cells, and thus one could say that the growth of cancer cells is directly limited by energetics.7 In order to survive, cancer cells must modify their mitochondrial physiology to optimize energy production to their changing environments. There are two types of advantageous mtDNA mutation in cancer cells: mutations that impair OXPHOS and serve to stimulate neoplastic transformation, and those that facilitate cancer cell adaption to changing bioenergetics environments.8 These mtDNA mutations would eventually lead to an enhanced generation of reactive oxygen species (ROS), which can act both as mutagens and cellular mitogens, and contribute directly to cancer progression.7 Therefore, it can be concluded that mitochondrial alterations are critical for cancer initiation, promotion, and metastasis (Fig 1).     Figure 1. Integrated mitochondrial paradigm to explain genetic and phenotypic complexities of metabolic and degenerative disease, aging, and cancer.Top three arrows: factors that have impact on mitochondrial OXPHOS robustness, risk for developing disease symptoms. Central oval arrows: pathophysiological basis of disease processes and the basis of disease progression. Lower five arrows: summarized disease categories and phenotypic outcomes of disturbed mitochondrial energy transformation. Bottom arrow: effect of the problematic accumulation of somatic mtDNA mutations resulting in delayed onset and a progressive course of diseases and aging. Right arrow: clinical problems that can result from reduced energy production in the most energetic tissues: the brain, heart, muscle, and kidney. Left arrow: indicates the metabolic effects of mitochondrial dysfunction, which result in the perturbation of the body’s energy balance. Lower right arrow: mitochondrial alterations are critical for cancer initiation, promotion, and metastasis. Lower left arrow: the hypothesized inflammatory and autoimmune responses that may result from chronic introduction of mitochondria’s bacteria-like DNA and N-formylmethionine proteins into the bloodstream.9 

Prevalence of anemia and factors associated with pregnant women in West Sumatra, Indonesia: Findings from VDPM Cohort Study

ABSTRAKLatar belakang: Anemia kehamilan masih menjadi masalah kesehatan masyarakat di negara berkembang yang berkontribusi terhadap risiko tinggi komplikasi kehamilan. Indonesia sebagai negara berkembang memiliki risiko anemia yang lebih tinggi yang bisa disebabkan oleh kekurangan asupan zat gizi mikro, infeksi, atau faktor sosial-demografis lainnya.Tujuan: Identifikasi prevalensi dan faktor risiko anemia pada ibu hamil yang tinggal di Sumatera Barat, Indonesia.Metode: Penelitian ini adalah analisis data sekunder dari studi kohort prospektif yaitu "“Vitamin D Pregnant Mother (VDPM) di Sumatera Barat". Subyek ibu hamil trimester diperoleh dari Puskesmas di Provinsi Sumatera Barat. Waktu penelitian dilakukan pada Januari-Maret 2017. Data demografi, sosial ekonomi, antropometri, dan Riwayat kesehatan ibu diteliti. Regresi logistik biner multivariatdigunakan untuk menentukan faktor-faktor terkait anemia. Dalam semua kasus, nilai p kurang dari 0,05 dianggap signifikan secara statistik.Hasil: 176 ibu hamil yang memenuhi kriteria inklusi diambil dalam penelitian ini. Prevalensi anemia ditemukan sebesar 61,90%. Rerata konsentrasi hemoglobin adalah 10,56 ± 1,41 g / dL. Prevalensi anemia sedang dan ringan masing-masing adalah 34% dan 27%. Status anemia ibu hamil trimester ketiga berhubungan dengan wanita yang memiliki <upah minimum/bulan (AOR: 5.15; 95% CI: 1.30-20.47), pengetahuan gizi ibu yang rendah (AOR: 15.88; 95% CI: 3.82- 66.02), IMT sebelum kehamilan <25 kg/m2 (AOR: 11.82; 95% CI: 2.70-51.69), dan tidak patuh konsumsi suplemen zat besi (AOR: 29.69; 95% CI: 6.58-133.91).Kesimpulan: Terdapat masih tingginya prevalensi anemia pada wanita hamil di Sumatera Barat. Oleh karena itu, meningkatkan kesadaran akan suplementasi zat besi dan kesehatan yang berkaitan dengan nutrisi selama kehamilan perlu dipertimbangkan untuk meningkatkan status kesehatan ibu untuk mengurangi anemia. Namun, penelitian lebih lanjut diperlukan dengan ukuran sampel yang besar untuk mengkonfirmasi temuan ini.KATA KUNCI: anemia; faktor risiko; kehamilan; trimester ketiga; Sumatra Barat ABSTRACTBackground: Anemia during pregnancy remain to be a public health problem in developing countries which contributes to the high risk of adverse pregnancy outcomes. Indonesia as developing country has a higher risk of anemia that could be due to high of deficiencies of micronutrients intake, infection, or other socio-demographic factors.Objectives: The aim of this study was to determine the prevalence and risk factors anemia among pregnant women living in West Sumatra, Indonesia.Methods: The study is a secondary data analysis of prospective cohort study named “Vitamin D Pregnant Mother (VDPM) study in West Sumatra”. The third trimester pregnant women were enrolled from the public health centers in West Sumatra Province from January to March 2017. Structured questionnaires were used to collect data of demographic, socio-economic, anthropometry, and maternal health from all the study subjects. A multivariate binary logistic regression had been used to determine the associated factors of anemia. In all cases, P value less than 0.05 was considered statistically significant.Results: 176 pregnant women who fulfilled the inclusion criteria were enrolled this study. The prevalence of anemia was 61.90%. The mean of hemoglobin concentration was 10.56±1.41 g/dL. Moderate and mild anemia prevalence were 34% and 27%, respectively. The third trimester of pregnant women anemia status were associated with women who had <minimum wage/month (AOR: 5.15; 95%CI: 1.30-20.47), low-moderate maternal nutrition knowledge (AOR: 15.88; 95%CI: 3.82-66.02), pre-pregnancy BMI <25 kg/m2 (AOR: 11.82; 95%CI: 2.70-51.69), and no adherence iron supplement intake status (AOR: 29.69; 95%CI: 6.58-133.91).Conclusions: There was a high prevalence of anemia status in the third pregnant women in West Sumatra. Therefore, raise awareness of iron supplementation and health related to nutrition during pregnancy need to be considered to improve maternal health status to reduce anemia. However, further studies required with large sample size to confirm this finding.KEYWORDS: anemia; risk factors; third trimester; pregnancy; West Sumatr

A genetic approach to study the relationship between maternal Vitamin D status and newborn anthropometry measurements: the Vitamin D pregnant mother (VDPM) cohort study

Purpose Adverse effects of maternal vitamin D deficiency have been linked to adverse pregnancy outcomes. We investigated the relationship between maternal vitamin D status and newborn anthropometry measurements using a genetic approach and examined the interaction between genetic variations in involved in vitamin D synthesis and metabolism and maternal vitamin D concentrations on newborn anthropometry. Methods The study was conducted in 183 pregnant Indonesian Minangkabau women. Genetic risk scores (GRSs) were created using six vitamin D–related single nucleotide polymorphisms and their association with 25-hydroxyvitamin D [25(OH)D] levels and newborn anthropometry (183 infants) were investigated. Results There was no significant association between maternal 25(OH)D concentrations and newborn anthropometry measurements (P > 0.05, for all comparisons). After correction for multiple testing using Bonferroni correction, GRS was significantly associated with 25(OH)D in the third trimester (P = 0.004). There was no association between GRS and newborn anthropometric measurements; however, there was an interaction between GRS and 25(OH)D on head circumference (P = 0.030), where mothers of neonates with head circumference < 35 cm had significantly lower 25(OH)D if they carried ≥4 risk alleles compared to those who carried ≤3 risk alleles. Conclusion Our findings demonstrate the impact of vitamin D-related GRS on 25(OH)D and provides evidence for the effect of vitamin D-related GRS on newborn anthropometry through the influence of serum 25(OH)D levels among Indonesian pregnant women. Even though our study is a prospective cohort, before the implementation of vitamin D supplementation programs in Indonesia to prevent adverse pregnancy outcomes, further large studies are required to confirm our findings

TCF7L2 gene polymorphisms rs12255372, rs7903146, rs10885406 and the association with type 2 diabetes in a population of Legian Village, Kuta, Bali.

Background: Polymorphisms in the transcription factor 7 like-2 (TCF7L2) gene have been consistently reported to be associated with increased risk of type 2 diabetes mellitus in various populations, in particular, the rs7903146, rs12255372, and rs10885406 polymorphism. Objective: The aim of this study was to investigate whether these polymorphisms in the Balinese population of Legian village. Methods: A cross-sectional study enrolling 286 participants (178 male, 108 female), mean age was 46.0±10.0 (range 20–83) years. PCR-RFLP conducted genotyping for rs7903146, rs12255372, and rs10885406 polymorphism, fasting and two hours after meal blood glucose were measured. Student’s t-test and analysis of variance (ANOVA) and chi-square test were employed.  Results: The frequencies of the CC and CT genotypes of the rs7903146 polymorphism were 93.4% and 6.6%. The GG and GT genotypes of the rs12255372 polymorphism were 94.8% and 5.2%, while in the rs10885406 they were 87.1%, 12.2%, and 0.7% for the AA, AG, and GG genotypes. The TT genotypes of the rs7903146 and rs12255372 not found. The prevalence of type 2 diabetes in this population were 9.0%. The frequency of the CT genotype of the rs7903146 was higher in diabetes compare to the non-diabetes group (7.6% vs. 6.5%, p=0.822), while GT genotype in rs12255372 was lower (3.8% vs. 5.3%, p=0.737). The AG genotype of the rs10885406 also lower in diabetes group (7.6% vs. 12.6%, p=0.679). In the CT genotype of rs7903146, the two hours after meal blood glucose were significantly higher (141.15 ± 125.06 vs. 107.50 ± 46.94, p=0.012). Interestingly, although not statistically significant, individuals with the GG genotype showed the lowest blood glucose. Conclusion: Rs7903146, rs12255372, and rs10885406 polymorphisms in the TCF7L2 genes did not show association with type 2 diabetes in the Balinese population of Legian Village. However, two hours after meal blood glucose level was found to be significantly higher in the CT genotype of the rs7903146.</p

The Role of Serum Expression Levels of Microrna-21 on Bone Mineral Density in Hypostrogenic Postmenopausal Women with Osteoporosis: Study on Level of RANKL, OPG, TGFβ-1, Sclerostin, RANKL/OPG Ratio, and Physical Activity

Background: MiR-21 is known to play a role in osteoclast proliferation and differentiation, but the role of serum miR-21 expression in osteoporosis remains unclear. Previous research found that serum miR-21 expression was positively correlated with bone mineral density in postmenopausal osteoporosis patients, but other factors involved in postmenopausal osteoporosis still unknown. This study aimed to determine the role of serum miR-21 expression, concentration of RANKL, OPG, TGF-β1, sclerostin and serum calcium, RANKL/OPG ratio, and physical activity on bone mineral density of spine in hypoestrogenic postmenopausal women with osteoporosis (PMOP) compared with no osteoporosis (PMNOP), with point of interest on the expression of serum miR-21. Methods: this study was conducted by comparative cross-sectional design. The subjects were divided into 2 groups of PMOP and PMNOP. We used an absolute quantification real-time PCR method to determine serum miR-21 expressions level. Results: Median of serum miR-21 expression at the PMOP group was significantly higher compared to PMNOP group (p = 0.001). Serum miR-21 expression, RANKL, RANKL/OPG ratio, and physical activity were significantly correlated with BMD values in the PMOP group. Moderate physical activity was significantly negatively correlated with serum miR-21 expression. We also obtained a linear regression equation BMD = 1.373-0.085*Ln.miR-21-0.176*Log10.RANKL (R2 = 52.5%). Conclusion: serum miR-21 expression in PMOP was higher compared with PMNOP. Serum miR-21 expression proved to have a negative effect on spinal BMD values in hypoestrogenic postmenopausal women with osteoporosis of 8.5%. Obtained equation of BMD = 1.373-0.085*Ln.miR-21-0.176*Log10.RANKL can explain the value of spinal BMD by 52.5%

SUPPLEMENTATION WITH 2:1 RATIO OF N-6:N-3 POLYUNSATURATED FATTY ACID IMPROVES LIVER STEATOSIS AND SERUM CYTOKINE LEVELS IN YOUNG OBESE BALINESE WOMEN: A RANDOMIZED CLINICAL TRIAL

  Objectives: In addition to the rise in obesity prevalence globally, morbidity due to nonalcoholic fatty liver disease is increasing. Primary modalities for preventing and managing this problem include dietary modification and improved physical activities. A daily diet with a low n-6:n-3 polyunsaturated fatty acid (PUFA) ratio is suspected to contribute to ameliorating liver steatosis (LS). The present study was conducted to elucidate the effects of an n-6:n-3 PUFA ratio of 2:1 in alleviating LS.Methods: Twenty-four young obese women with LS were recruited from Denpasar, Bali, Indonesia. They were randomly allocated to an intervention or control group. Both groups were given linoleic acid:α-linolenic acid at ratios of 2035:970 and 240:100 g, respectively, for 12 weeks. Baseline and end-line data were obtained. All patients were advised to maintain their daily energy intake no more than 1500 kcal and to perform structured physical exercises once a week.Results: The intervention significantly decreased the body fat (body mass index, p=0.040; triglyceride, p=0.008) and serum tumor necrosis factor-α (TNF-α) levels (p=0.002) and increased serum interleukin-10 (IL-10) levels (p=0.004). The severity of LS was reduced through the intervention (odds ratio=0.064; 95% confidence interval=0.013-0.310; p=0.001).Conclusion: An increased intake of 2:1 n-6:n-3 PUFA ratio alleviated LS, decreased body fat composition and serum TNF-α levels, and increased serum IL-10 levels

Sex-linked genetic diversity originates from persistent sociocultural processes at microgeographic scales.

Population genetics has been successful at identifying the relationships between human groups and their interconnected histories. However, the link between genetic demography inferred at large scales and the individual human behaviours that ultimately generate that demography is not always clear. While anthropological and historical context are routinely presented as adjuncts in population genetic studies to help describe the past, determining how underlying patterns of human sociocultural behaviour impact genetics still remains challenging. Here, we analyse patterns of genetic variation in village-scale samples from two islands in eastern Indonesia, patrilocal Sumba and a matrilocal region of Timor. Adopting a 'process modelling' approach, we iteratively explore combinations of structurally different models as a thinking tool. We find interconnected socio-genetic interactions involving sex-biased migration, lineage-focused founder effects, and on Sumba, heritable social dominance. Strikingly, founder ideology, a cultural model derived from anthropological and archaeological studies at larger regional scales, has both its origins and impact at the scale of villages. Process modelling lets us explore these complex interactions, first by circumventing the complexity of formal inference when studying large datasets with many interacting parts, and then by explicitly testing complex anthropological hypotheses about sociocultural behaviour from a more familiar population genetic standpoint

Association between pre-pregnancy body mass index and gestational weight gain on pregnancy outcomes: a cohort study in Indonesian pregnant women

Background: Pre-pregnancy BMI (PP BMI) and gestational weight gain (GWG) are prominent anthropometric indicators for maternal nutritional status and are related to an increased risk of adverse pregnancy outcomes. This study aimed to determine the factors afecting total GWG, PP BMI and pregnancy outcomes among pregnant women in West Sumatra, Indonesia. Methods: This observational analysis was conducted among healthy women in the Vitamin D Pregnant Mother (VDPM) cohort study. A total of 195 pregnant women and their newborn babies were enrolled, and information regarding their socio-demographic characteristics, obstetric history, dietary intake and anthropometric data were assessed through direct interviews. Furthermore, the Institute of Medicine (IOM) 2009 guidelines were used to obtain the total GWG. Results: PP BMI was used to categorise the 195 pregnant women as overweight/obese (43.1%), normal (46.7%) and underweight (10.2%). There were 53.3%, 34.4% and 12.3% of women who had inadequate, adequate and excessive GWG, respectively. The multinomial logistic regression model indicated that overweight or obese women at the pre-pregnancy stage were 4.09 times more likely to have an excessive rate of GWG (AOR=4.09, 95% CI: 1.38–12.12, p=0.011) than those whose weight was normal. Furthermore, women with excessive GWG were 27.11 times more likely to have a baby with macrosomia (AOR=27.11, 95% CI: 2.99–245.14) (p=0.001) and those with inadequate GWG were 9.6 times more likely to give birth to a baby with low birth weight (LBW) (AOR=9.60, 95% CI; 0.88–105.2) (p=0.002). Conclusions: This study demonstrates that the malnutrition status prior to pregnancy and inadequate or excessive GWG status during pregnancy as signifcant risk factors for developing adverse pregnancy outcomes. These fndings highlight the importance of providing information, preconception counselling and health education on weight management for healthy pregnancies