Chunyan He

A Genome-Wide Association Meta-Analysis of Circulating Sex Hormone–Binding Globulin Reveals Multiple Loci Implicated in Sex Steroid Hormone Regulation

Sex hormone-binding globulin (SHBG) is a glycoprotein responsible for the transport and biologic availability of sex steroid hormones, primarily testosterone and estradiol. SHBG has been associated with chronic diseases including type 2 diabetes (T2D) and with hormone-sensitive cancers such as breast and prostate cancer. We performed a genome-wide association study (GWAS) meta-analysis of 21,791 individuals from 10 epidemiologic studies and validated these findings in 7,046 individuals in an additional six studies. We identified twelve genomic regions (SNPs) associated with circulating SHBG concentrations. Loci near the identified SNPs included SHBG (rs12150660, 17p13.1, p = 1.8×10−106), PRMT6 (rs17496332, 1p13.3, p = 1.4×10−11), GCKR (rs780093, 2p23.3, p = 2.2×10−16), ZBTB10 (rs440837, 8q21.13, p = 3.4×10−09), JMJD1C (rs7910927, 10q21.3, p = 6.1×10−35), SLCO1B1 (rs4149056, 12p12.1, p = 1.9×10−08), NR2F2 (rs8023580, 15q26.2, p = 8.3×10−12), ZNF652 (rs2411984, 17q21.32, p = 3.5×10−14), TDGF3 (rs1573036, Xq22.3, p = 4.1×10−14), LHCGR (rs10454142, 2p16.3, p = 1.3×10−07), BAIAP2L1 (rs3779195, 7q21.3, p = 2.7×10−08), and UGT2B15 (rs293428, 4q13.2, p = 5.5×10−06). These genes encompass multiple biologic pathways, including hepatic function, lipid metabolism, carbohydrate metabolism and T2D, androgen and estrogen receptor function, epigenetic effects, and the biology of sex steroid hormone-responsive cancers including breast and prostate cancer. We found evidence of sex-differentiated genetic influences on SHBG. In a sex-specific GWAS, the loci 4q13.2-UGT2B15 was significant in men only (men p = 2.5×10−08, women p = 0.66, heterogeneity p = 0.003). Additionally, three loci showed strong sex-differentiated effects: 17p13.1-SHBG and Xq22.3-TDGF3 were stronger in men, whereas 8q21.12-ZBTB10 was stronger in women. Conditional analyses identified additional signals at the SHBG gene that together almost double the proportion of variance explained at the locus. Using an independent study of 1,129 individuals, all SNPs identified in the overall or sex-differentiated or conditional analyses explained ∼15.6% and ∼8.4% of the genetic variation of SHBG concentrations in men and women, respectively. The evidence for sex-differentiated effects and allelic heterogeneity highlight the importance of considering these features when estimating complex trait variance.

B-aggressive Lymphoma Family Proteins Have Unique Domains That Modulate Transcription and Exhibit Poly(ADP-ribose) Polymerase Activity

BAL1 (B-aggressive lymphoma 1) was originally identified as a risk-related gene in diffuse large B-cell lymphoma. BAL1 encodes a nuclear protein with N-terminal macro domains and a putative C-terminal poly(ADP-ribose) polymerase (PARP) active site. Macro domains are sequences homologous to the non-histone region of histone macroH2A. Several lines of evidence suggest that these domains may modulate transcription, including a high concentration of histone macroH2A in the inactive X chromosome, direct interference with transcription factor binding in a positioned nucleosome, and structural similarity to DNA binding domains. Poly(ADP-ribosyl)ation is a critical post-translational modification that regulates chromatin configuration and transcription. In this report we describe two additional BAL family members, BAL2 and BAL3, with N-terminal macro domains and putative C-terminal PARP active sites and assess the function of these specific regions in BAL family members. Herein, we demonstrate that BAL macro domains repress transcription when tethered to a promoter. In addition, we show that BAL2 and BAL3, but not BAL1, exhibit PARP activity. In agreement with these data, BAL1 lacks several critical donor and acceptor residues that are conserved in the BAL2 and -3 PARP active sites. Of interest, BAL family members with inactive or functional PARP domains differed in their ability to repress transcription. BAL family members are the only described proteins with both PARP and macro domains, underscoring the potential functional significance of this unique combination.

A genome-wide association study of early menopause and the combined impact of identified variants

Early menopause (EM) affects up to 10% of the female population, reducing reproductive lifespan considerably. Currently, it constitutes the leading cause of infertility in the western world, affecting mainly those women who postpone their first pregnancy beyond the age of 30 years. The genetic aetiology of EM is largely unknown in the majority of cases. We have undertaken a meta-analysis of genome-wide association studies (GWASs) in 3493 EM cases and 13 598 controls from 10 independent studies. No novel genetic variants were discovered, but the 17 variants previously associated with normal age at natural menopause as a quantitative trait (QT) were also associated with EM and primary ovarian insufficiency (POI). Thus, EM has a genetic aetiology which overlaps variation in normal age at menopause and is at least partly explained by the additive effects of the same polygenic variants. The combined effect of the common variants captured by the single nucleotide polymorphism arrays was estimated to account for ∼30% of the variance in EM. The association between the combined 17 variants and the risk of EM was greater than the best validated non-genetic risk factor, smoking.

Association Studies of Common Variants in 10 Hypogonadotropic Hypogonadism Genes with Age at Menarche

CONTEXT Although the timing of puberty is a highly heritable trait, little is known about the genes that regulate pubertal timing in the general population. Several genes have been identified that, when mutated, cause disorders of delayed or absent puberty such as hypogonadotropic hypogonadism (HH). OBJECTIVE Because severe variants in HH-related genes cause a severe puberty phenotype, we hypothesized that common subtle variation in these genes could contribute to the population variation in pubertal timing. DESIGN We assessed common genetic variation in 10 HH-related genes in 1801 women from the Hawaii and Los Angeles Multiethnic Cohort with either early (age<11 yr) or late (age>14 yr) menarche and in other replication samples. In addition to these common variants, we also studied the most frequently reported HH mutations to assess their role in the population variation in pubertal timing. SETTING AND PATIENTS/OTHER PARTICIPANTS: Within the general community, 1801 women from the Hawaii and Los Angeles Multiethnic Cohort participated. MAIN OUTCOME MEASURES We assessed the association of genetic variation with age at menarche. RESULTS We found no significant association between any of the variants tested and age at menarche, although we cannot rule out modest effects of these variants or of other variants at long distances from the coding region. In several self-reported racial/ethnic groups represented in our study, we observed an association between estimated genetic ancestry and age at menarche. CONCLUSIONS Our results suggest that common variants near 10 HH-related loci do not play a substantial role in the regulation of age at menarche in the general population.

Genome-wide association studies of age at menarche and age at natural menopause

Genome-wide association studies (GWAS) have been successful in uncovering genetic determinants of age at menarche and age at natural menopause. To date, more than 30 novel genetic loci have been identified in GWAS for age at menarche and 17 for age at natural menopause. These findings have stimulated a plethora of follow-up studies particularly with respect to the functional characterization of these novel loci and how these results can be translated into risk prediction. However, the genetic loci identified so far account for only a small fraction of the overall heritability. This review provides an overview of the current state of our knowledge of the genetic basis of menarche and menopause timing. It emphasizes recent GWAS results and outlines strategies for discovering the missing heritability and strategies to further our understanding of the underlying molecular mechanisms of the observed genetic associations.

Regulation of nuclear-cytoplasmic shuttling and function of Family with sequence similarity 13, member A (Fam13a) by B56-containing PP2As and Akt

FAM13A is a novel human lung disease–associated gene. Fam13a is dispensable but is capable of inducing Wnt signaling. Nuclear localization of Fam13a is important for its function in the Wnt pathway. Akt/PP2A-dependent reversible phosphorylation on Ser-322 is a molecular switch that controls nuclear–cytoplasmic shuttling of Fam13a.

Traumatic Brain Injury Causes Aberrant Migration of Adult-Born Neurons in the Hippocampus

Traumatic brain injury (TBI) promotes neural stem/progenitor cell (NSC) proliferation in an attempt to initiate innate repair mechanisms. However, all immature neurons in the CNS are required to migrate from their birthplace to their final destination to develop into functional neurons. Here we assessed the destination of adult-born neurons following TBI. We found that a large percentage of immature neurons migrated past their normal stopping site at the inner granular cell layer (GCL), and became misplaced in the outer GCL of the hippocampal dentate gyrus. The aberrant migration of adult-born neurons in the hippocampus occurred 48 hours after TBI, and lasted for 8 weeks, resulting in a great number of newly generated neurons misplaced in the outer GCL in the hippocampus. Those misplaced neurons were able to become mature and differentiate into granular neurons, but located ectopically in the outer GCL with reduced dendritic complexity after TBI. The adult-born neurons at the misplaced position may make wrong connections with inappropriate nearby targets in the pre-existing neural network. These results suggest that although stimulation of endogenous NSCs following TBI might offer new avenues for cell-based therapy, additional intervention is required to further enhance successful neurogenesis for repairing the damaged brain.

Reproductive aging-associated common genetic variants and the risk of breast cancer

IntroductionA younger age at menarche and an older age at menopause are well established risk factors for breast cancer. Recent genome-wide association studies have identified several novel genetic loci associated with these two traits. However, the association between these loci and breast cancer risk is unknown.MethodsIn this study, we investigated 19 and 17 newly identified single nucleotide polymorphisms (SNPs) from the ReproGen Consortium that have been associated with age at menarche and age at natural menopause, respectively, and assessed their associations with breast cancer risk in 6 population-based studies among up to 3,683 breast cancer cases and 34,174 controls in white women of European ancestry. In addition, we used these SNPs to calculate genetic risk scores (GRSs) based on their associations with each trait.ResultsAfter adjusting for age and potential population stratification, two age at menarche associated SNPs (rs1079866 and rs7821178) and one age at natural menopause associated SNP (rs2517388) were associated with breast cancer risk (p values, 0.003, 0.009 and 0.023, respectively). The odds ratios for breast cancer corresponding to per-risk-allele were 1.14 (95% CI, 1.05 to 1.24), 1.08 (95% CI, 1.02 to 1.15) and 1.10 (95% CI, 1.01 to 1.20), respectively, and were in the direction predicted by their associations with age at menarche or age at natural menopause. These associations did not appear to be attenuated by further controlling for self-reported age at menarche, age at natural menopause, or known breast cancer susceptibility loci. Although we did not observe a statistically significant association between any GRS for reproductive aging and breast cancer risk, the 4th and 5th highest quintiles of the younger age at menarche GRS had odds ratios of 1.14 (95% CI, 1.01 to 1.28) and 1.13 (95% CI, 1.00 to 1.27), respectively, compared to the lowest quintile.ConclusionsOur study suggests that three genetic variants, independent of their associations with age at menarche or age at natural menopause, were associated with breast cancer risk and may contribute modestly to breast cancer risk prediction; however, the combination of the 19 age at menarche or the 17 age at natural menopause associated SNPs did not appear to be useful for identifying a high risk subgroup for breast cancer.

Polymorphisms in genes involved in oxidative stress and their interactions with lifestyle factors on skin cancer risk

Ultraviolet (UV)-induced oxidative stress has been implicated in skin carcinogenesis [1]. Several antioxidant enzymes, such as glutathione peroxidase (GPX) and catalase (CAT), counteract oxidative damage and constitute a primary defense against oxidative stress. GPX is a soluble selenoprotein that reduces H2O2 and organic hydroperoxides to H2O, and GPX1 is the most abundant and ubiquitous intracellular isoform [1]. GPX1 activity is not strongly affected by UV and is considered to be the most important antioxidant enzyme defense mechanism in the skin [2]. CAT is a heme enzyme that neutralizes reactive oxygen species by converting H2O2 to H2O and O2. CAT activity in the skin is significantly reduced after exposure to UV [2], which suggests its effect may be prone to effect modification by environmental factors. Inherited variants in the encoding genes that affect the activity or expression of these antioxidant enzymes are hypothesized to modulate oxidative stress and thus influence skin cancer risk. A polymorphism in the GPX1 gene (Pro198Leu, rs1050450) and a polymorphism in the promoter region of the CAT gene (C-262T, rs1001179) have been shown to be associated with lower enzyme activities of their encoded enzymes [3, 4]. To test our main hypothesis that these two genetic polymorphisms are associated with skin cancer risk, we conducted a nested case-control study of Caucasians (218 melanoma, 285 squamous cell carcinoma (SCC), and 300 basal cell carcinoma (BCC) cases, and 870 age-matched controls) within the Nurses’ Health Study. We further investigated potential gene-environment interactions between these polymorphisms and lifestyle factors such as dietary antioxidant intake and sun exposure related risk factors. A detailed description of the characteristics of cases and controls was published previously [5]. Information on dietary intake was collected prospectively by food-frequency questionnaires, and total-energy-adjusted cumulative average of dietary intake was used to reduce within-person variation and represent long-term dietary intake [6]. We genotyped the two single nuclear polymorphisms (SNPs) (rs1050450 and rs1001179) by the 5′ nuclease assay (TaqMan®) in 384-well format, using the ABI PRISM 7900HT Sequence Detection System (Applied Biosystems, Foster City, CA). The distributions of genotypes for the two SNPs were in Hardy-Weinberg equilibrium among controls (p=0.94, 0.83, respectively). We compared the cases of each type of skin cancer to the common control series. We used unconditional multivariate logistic regression to model the association between genetic polymorphisms and skin cancer risk and to estimate multivariate Odds Ratios (ORs) and 95% Confidence Intervals (CIs). To test statistical significance of gene-environmental interactions, we used dominant model for genotypes and dichotomized environmental exposures as low versus high based on median values among controls. We tested the statistical significance of a single multiplicative interaction term. In the main effect analysis (Table 1), we observed that the GPX1 198 Leu/Leu genotype was significantly associated with a two-fold increased risk of melanoma (OR, 2.14; 95% CI, 1.22–3.72), after adjustment for age and other covariates. No association was found between this polymorphism and SCC or BCC risk, which was consistent with one previous study [7]. This polymorphism has been shown to be associated with lung cancer [8] and breast cancer [3] previously. We did not observe significant association between the CAT C-262T polymorphism and the risk of any type of skin cancer. Table 1 Association between GPX Pro198Leu and CAT C-262T genetic polymorphisms and skin cancer risk a As exploratory analyses, we further tested gene-environment interactions between the genetic variants and lifestyle factors that modulate oxidative stress. We found the association between the CAT C-262T polymorphism and melanoma risk was significantly modified by history of severe sunburns (p for interaction, 0.008, Table 2), a variable combining exposure intensity and biological response to sun exposure. The positive association between history of severe sunburns and melanoma risk was restricted to T carriers (OR, 1.73; 95% CI, 1.02–2.92), compared to women with CC genotype (OR, 1.03; 95% CI, 0.63–1.69). We also observed a significant gene-diet interaction between the CAT C-262T polymorphism and total carotenoid intake on melanoma risk (p for interaction, 0.01). The inverse association of total carotenoid intake with melanoma risk was limited among women with CC genotype (OR, 0.63; 95% CI, 0.41–0.97), whereas no association was observed among T carriers (OR, 1.23; 95% CI, 0.77–1.97). Inconsistent results were reported on the relationship between dietary carotenoid intake and melanoma risk in several previous case-control studies. An inverse association between the intake and the risk of melanoma was observed in some studies [9], but not in other studies [10]. Our results suggest that the inconsistency in the literature may reflect a potential gene-diet interaction. As we tested different genetic polymorphisms, multiple environmental exposures and dietary factors, and three types of skin cancer, multiple testing in our study may lead to false positive results. Replications in independent studies are needed to validate these results. No significant interactions were observed between the GPX1 polymorphism and these lifestyle factors on melanoma risk. We did not observe any significant interaction between these genetic variants and environmental exposures on the risk of SCC or BCC. Table 2 Interaction between the CAT C-262T genetic polymorphism and history of severe sunburns and total carotenoid intake on melanoma risk In summary, we first observed the GPX1 198 Leu/Leu genotype was significantly associated with a two-fold increased risk of melanoma, and the association between the CAT C-262T polymorphism and melanoma risk was significantly modified by history of severe sunburns and total carotenoid intake. Further research is needed to confirm these possible associations and illustrate the underlying molecular mechanisms.

Age at Menarche and Risk of Gestational Diabetes Mellitus: A Prospective Cohort Study Among 27,482 Women

OBJECTIVE To examine the association between age at menarche and risk of gestational diabetes mellitus (GDM). RESEARCH DESIGN AND METHODS A prospective cohort study of 42,109 eligible pregnancies from 27,482 women in the Nurses’ Health Study II. RESULTS The adjusted risk ratios for GDM across the age at menarche categories (≤11, 12, 13, and ≥14 years) were 1.34 (95% CI 1.14–1.58), 1.13 (0.97–1.31), 1.11 (0.95–1.29), and 1.00 (referent; P for trend = 0.0005), respectively. Analysis of the mediating effect indicated that 42.1% (P = 0.0007) of the association was mediated through prepregnancy BMI. CONCLUSIONS These findings suggested that earlier menarche was significantly associated with an increased risk of GDM. This association was largely mediated through prepregnancy excessive body adiposity.