Did grandmothers enhance reproductive success in historic populations? : Testing evolutionary theories on historical demographic data in Scandinavia and North America

Human reproductive success requires both producing children and making investments in the development of offspring. To a large extent these investments are made by the parents of the child, but researchers are now looking beyond the nuclear family to understand how extended kin, notably grandmothers, enhance reproductive success by making transfers to progeny of different kinds. The extent to which kin influence fertility and mortality outcomes may vary across different socio-economic and geographic contexts; as a result, an international comparative framework is used here to sharpen our understanding of the role of kin in reproduction. This chapter assesses the role of grandmothers in fertility outcomes in a comparative historical demographic study based on data from Scandinavia and North America. The individual-level data used are all longitudinal and multigenerational, allowing us to address the impact of maternal and paternal grandmothers on the fertility of their daughters and daughters-in-law, while attending to heterogeneous effects across space and time as well as within-family differences via the use of fixed effects models. We discover broader associations of the paternal grandmother with higher fertility across the four regions. We also find a general fertility advantage associated with the post-reproductive availability or recent death of the maternal grandmother in the four populations. Important variations across regions nevertheless exist in terms of the strength of the association, the importance of the grandmother’s proximity, and the results derived by using fixed effects models. Our interpretation is that grandmothers were generally associated with high-fertility outcomes, but that the mechanism for this effect was co-determined by family configurations, resource allocation and the advent of fertility control

BRCA2 polymorphic stop codon K3326X and the risk of breast, prostate, and ovarian cancers

Background: The K3326X variant in BRCA2 (BRCA2*c.9976A>T; p.Lys3326*; rs11571833) has been found to be associated with small increased risks of breast cancer. However, it is not clear to what extent linkage disequilibrium with fully pathogenic mutations might account for this association. There is scant information about the effect of K3326X in other hormone-related cancers. Methods: Using weighted logistic regression, we analyzed data from the large iCOGS study including 76 637 cancer case patients and 83 796 control patients to estimate odds ratios (ORw) and 95% confidence intervals (CIs) for K3326X variant carriers in relation to breast, ovarian, and prostate cancer risks, with weights defined as probability of not having a pathogenic BRCA2 variant. Using Cox proportional hazards modeling, we also examined the associations of K3326X with breast and ovarian cancer risks among 7183 BRCA1 variant carriers. All statistical tests were two-sided. Results: The K3326X variant was associated with breast (ORw = 1.28, 95% CI = 1.17 to 1.40, P = 5.9x10- 6) and invasive ovarian cancer (ORw = 1.26, 95% CI = 1.10 to 1.43, P = 3.8x10-3). These associations were stronger for serous ovarian cancer and for estrogen receptor–negative breast cancer (ORw = 1.46, 95% CI = 1.2 to 1.70, P = 3.4x10-5 and ORw = 1.50, 95% CI = 1.28 to 1.76, P = 4.1x10-5, respectively). For BRCA1 mutation carriers, there was a statistically significant inverse association of the K3326X variant with risk of ovarian cancer (HR = 0.43, 95% CI = 0.22 to 0.84, P = .013) but no association with breast cancer. No association with prostate cancer was observed. Conclusions: Our study provides evidence that the K3326X variant is associated with risk of developing breast and ovarian cancers independent of other pathogenic variants in BRCA2. Further studies are needed to determine the biological mechanism of action responsible for these associations

The BRCA2 c.68-7T > A variant is not pathogenic: A model for clinical calibration of spliceogenicity.

Although the spliceogenic nature of the BRCA2 c.68-7T>A variant has been demonstrated, its association with cancer risk remains ontroversial. In this study, we accurately quantified by real-time PCR and digital PCR the BRCA2 isoforms retaining or missing exon 3. In addition, the combined odds ratio for causality of the variant was estimated using genetic and clinical data, and its associated cancer risk was estimated by case-control analysis in 83,636 individuals. Co-occurrence in trans with pathogenic BRCA2 variants was assessed in 5,382 families. Exon 3 exclusion rate was 4.5-fold higher in variant carriers (13%) than controls (3%), indicating an exclusion rate for the c.68-7T>A allele of approximately 20%. The posterior probability of pathogenicity was 7.44 x 10-115. There was neither evidence for increased risk of breast cancer (OR 1.03; 95% CI 0.86-1.24), nor for a deleterious effect of the variant when co-occurring with pathogenic variants. Our data provide for the first time robust evidence of the non-pathogenicity of the BRCA2 c.68-7T>A. Genetic and quantitative transcript analyses together inform the threshold for the ratio between functional and altered BRCA2 isoforms compatible with normal cell function. These findings might be exploited to assess the relevance for cancer risk of other BRCA2 spliceogenic variants

Investigation of parental transmission of GABBR2 Single Nucleotide Polymorphisms and its association with nonsyndromic cleft lip with or without cleft palate

Background and Objectives: Genetic factors and maternal smoking status have been suggested to be a strong cause in the risk of cleft. GABBR2 has been found to be associated with plasma vitamin B12 (Hazra, 2009). Expression of GABBR2 may be regulated by nicotine. We investigated the association between 189 SNPs of GABBR2 and non-syndromic cleft lip with or without cleft palate in 165 Utah case-parent trios. Methods: Minor allele and chi-square test for Hardy-Weinberg equilibrium at each SNP were computed between parents. Pairwise linkage disequilibrium was computed as D\u27 and r2 for all SNPs. Both allelic and genotypic transmission disequilibrium tests (TDTs) were performed for individual SNPs using package TRIO in R. The results were confirmed in PLINK. Sliding windows of haplotypes consisting of two SNPs were tested. Haplotype analysis was performed using PBAT. Results: The family-based genotypic and allelic TDT showed significant evidence of linkage and association at rs375828 at a nominal value of p\u3c0.05. This SNP remained significant after maxT permutation allelic TDT test with p-value = 0.02. All haplotypes including rs375828 also showed nominally significant p values, possibly reflecting effects of this single SNP. No significant genotype-environment interaction was found. Conclusions: These findings suggest the possible involvement of GABBR2-rs375828 in the etiology of CL/P in Utah cleft-parent trios without excess parental transmission

Nutrition and Genes Associated With Orofacial Cleft Birth Defects in Utah

Orofacial clefts (OFCs) are facial malformations that happen during early pregnancy and have a complex and heterogeneous etiology, involving both genetic and environmental risk factors. This project examined the association between maternal nutrition, folaterelated biomarkers, candidate genes involved in one-carbon metabolism (OCM), and OFCs in order to achieve more comprehensive knowledge of how nutrition and genetics influence OFC risk. First, the association between maternal periconceptional multivitamin (PCMV) use, maternal dietary patterns during the periconceptional period, and OFC risk was examined. This study showed that neither PCMV use nor healthy dietary pattern score alone was individually associated with OFC risk. However, the combination of PCMV use and a higher score reflecting the ideal Dietary Approach to Stop Hypertension diet was associated with 55% reduction in the risk of isolated OFCs, evidence that the prevention of OFCs may require attention to both PCMV use and improving maternal diets. Second, the association between maternal multivitamin use, folic acid supplemental intake, and measured blood folate levels in case mothers of OFC children and control mothers was examined. Mothers who had an OFC-affected pregnancy compared with control mothers had lower mean levels of plasma folate in both multivitamin users and non-users. At levels of folic acid intake \u3e400µg/day, the difference in plasma folate between case mothers and control mothers narrowed, evidence that higher folate intake levels may be required for mothers with a history of OFC-affected pregnancy. The ability to utilize supplement folic acid might be modified by MTHFR C677T genotype. In mothers with 677CC genotype, both case and control mothers’ plasma folate concentrations responded to increased levels of folic acid supplemental intake, although case mothers’ plasma folate concentrations were always significantly lower than control mothers’ until folate supplemental intake reached 400µg. In mothers with 677CT genotype, control but not case mothers’ plasma folate concentrations responded to increased levels of folic acid supplemental intake. In mothers with 677TT genotype, case but not control mothers’ plasma folate concentrations responded to increased levels of folic acid supplemental intake. Lastly, variations in folate-related OCM genes were examined in association with risk of OFCs using GWAS data and the case-parent trio approach. Several genes in the OCM pathway were associated with isolated, non-syndromic OFCs with some through genetic effects alone but most through gene-environment interaction effects with maternal multivitamin supplementation during periconceptional period and maternal biomarker concentrations for OCM-related nutrients. These results emphasize the need to consider gene-environment interactions when searching for genes influencing isolated OFCs. Reduction in the prevalence of OFCs could have tremendous importance. The results of this dissertation may help identify factors important to OFCs etiology and in turn, provide valuable targets for preventive intervention. Children born with an OFC require medical care from birth until adulthood and encounter a higher mortality rate. The costs incurred from caring for children born with OFCs not only include the clinical care of many disciplines but also involve the emotional disturbance and social and employment exclusion for affected individuals. Reducing the risk of OFCs would lessen considerable financial and emotional burdens to families and societies

Examining validity of body mass index calculated using height and weight data from the US driver license

Abstract Background Driver license departments in many US states collect data on individuals’ height and weight. These data can be useful to researchers in epidemiological and public health studies. As height and weight on driver license are self-reported, they may be prone to reporting bias. We compare height and weight obtained from driver license records and clinically measured height and weight, as well as body mass index (BMI) values calculated using the two data sources for the same individual. Methods We linked individual height and weight records obtained from the Driver License Division (DLD) in the Utah Department of Public Safety to clinical records from one of the largest healthcare providers in the state of Utah. We then calculated average differences between height, weight and BMI values separately for women and men in the sample, as well as discrepancies between the two sets of measures by age and BMI category. We examined how well self-reported height and weight from the driver licenses classify individuals into specific BMI categories based on clinical measures. Finally, we used two sets of BMI values to estimate individuals’ relative risk of type II diabetes. Results Individuals, on average, tend to overestimate their height and underestimate their weight. Consequently, the value of BMI calculated using driver license records is lower than BMI calculated using clinical measurements. The discrepancy varies by age and by BMI category. Despite the discrepancy, BMI based on self-reported height and weight allows for accurate categorization of individuals at the higher end of the BMI scale, such as the obese. When used as predictors of relative risk of type II diabetes, both sets of BMI values yield similar risk estimates. Conclusions Data on height and weight from driver license data can be a useful asset for monitoring population health in states where such information is collected, despite the degree of misreporting associated with self-report

The changing food environment and neighborhood prevalence of type 2 diabetes

In this ecological study, we used longitudinal data to assess if changes in neighborhood food environments were associated with type 2 diabetes mellitus (T2DM) prevalence, controlling for a host of neighborhood characteristics and spatial error correlation. We found that the population-adjusted prevalence of fast-food and pizza restaurants, grocery stores, and full-service restaurants along with changes in their numbers from 1990 to 2010 were associated with 2015 T2DM prevalence. The results suggested that neighborhoods where fast-food restaurants have increased and neighborhoods where full-service restaurants have decreased over time may be especially important targets for educational campaigns or other public health-related T2DM interventions

The BRCA1 c. 5096G > A p.Arg1699Gln (R1699Q) intermediate risk variant: breast and ovarian cancer risk estimation and recommendations for clinical management from the ENIGMA consortium

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