Maternal cardiovascular disease risk factors as predictors of preterm birth in California: a case-control study.

OBJECTIVE: To determine whether maternal cardiovascular disease (CVD) risk factors predict preterm birth. DESIGN: Case control. SETTING: California hospitals. PARTICIPANTS: 868 mothers with linked demographic information and biospecimens who delivered singleton births from July 2009 to December 2010. METHODS: Logistic regression analysis was employed to calculate odds ratios for the associations between maternal CVD risk factors before and during pregnancy (including diabetes, hypertensive disorders and cholesterol levels) and preterm birth outcomes. PRIMARY OUTCOME: Preterm delivery status. RESULTS: Adjusting for the other maternal CVD risk factors of interest, all categories of hypertension led to increased odds of preterm birth, with the strongest magnitude observed in the pre-eclampsia group (adjusted OR (aOR), 13.49; 95% CI 6.01 to 30.27 for preterm birth; aOR, 10.62; 95% CI 4.58 to 24.60 for late preterm birth; aOR, 17.98; 95% CI 7.55 to 42.82 for early preterm birth) and chronic hypertension alone for early preterm birth (aOR, 4.58; 95% CI 1.40 to 15.05). Diabetes (types 1 and 2 and gestational) was also associated with threefold increased risk for preterm birth (aOR, 3.06; 95% CI 1.12 to 8.41). A significant and linear dose response was found between total and low-density lipoprotein (LDL) cholesterol and aORs for late and early preterm birth, with increasing cholesterol values associated with increased risk (likelihood χ2 differences of 8.422 and 8.019 for total cholesterol for late and early, and 9.169 and 10.896 for LDL for late and early, respectively). Receiver operating characteristic curves using these risk factors to predict late and early preterm birth produced C statistics of 0.601 and 0.686. CONCLUSION: Traditional CVD risk factors are significantly associated with an increased risk of preterm birth; these findings reinforce the clinical importance of integrating obstetric and cardiovascular risk assessment across the healthcare continuum in women.

Exposures to structural racism and racial discrimination among pregnant and early post-partum Black women living in Oakland, California.

Research supports that exposure to stressors (e.g., perceived stress and racism) during pregnancy can negatively impact the immune system, which may lead to infection and ultimately increases the risk for having a preterm or low-birthweight infant. It is well known that Black women report higher levels of stressors at multiple timepoints across pregnancy compared with women of all other racial and ethnic groups. This study addresses gaps in the literature by describing pregnant and early post-partum Black women's exposures to structural racism and self-reported experiences of racial discrimination, and the extent to which these factors are related. We used a cross-sectional study design to collect data related to exposures to racism from pregnant and early post-partum Black women residing in Oakland, California, from January 2016 to December 2017. Comparative analysis revealed that living in highly deprived race + income neighborhoods was associated with experiencing racial discrimination in three or more situational domains (p = .01). Findings show that Black women are exposed to high levels of racism that may have negative impacts on maternal health outcomes.

Genetic Risk Scores for Maternal Lipid Levels and Their Association with Preterm Birth.

Maternal lipid profiles are associated with risk for preterm birth (PTB), although the lipid component and effect size are inconsistent between studies. It is also unclear whether these associations are the result of excessive changes in lipid metabolism during pregnancy or genetic variability in genes controlling basal lipid metabolism. This study investigates the association between genetic risk scores (GRS) for four lipid components (high-density lipoprotein [HDL-C], low-density lipoprotein [LDL-C], triacylglycerols [TAG], and total cholesterol [TC]) with risk for PTB. Subjects included 954 pregnant women from California for whom second trimester serum samples were available, of which 479 gave birth preterm and 475 gave birth at term. We genotyped 96 single-nucleotide polymorphisms, which were selected from genome-wide association studies of lipid levels in adult populations. Lipid-specific GRS were constructed for HDL-C, LDL-C, TAG, and TC. The associations between GRS and PTB were analyzed using logistic regression. A higher HDL-C GRS was associated with increased risk for PTB overall and spontaneous PTB. Higher TAG and TC GRS were associated with decreased risk for PTB overall and spontaneous PTB. This study identifies counter-intuitive associations between lipid GRS and spontaneous PTB. Further replication studies are needed to confirm these findings, but they suggest that our current scientific understanding of the relationship between lipid metabolism, PTB, and genetics is incomplete.

Socioeconomic Status, Preeclampsia Risk and Gestational Length in Black and White Women.

BACKGROUND: Higher socioeconomic status (SES) has less impact on cardio-metabolic disease and preterm birth risk among Black women compared to White women, an effect called "diminishing returns." No studies have tested whether this also occurs for pregnancy cardio-metabolic disease, specifically preeclampsia, or whether preeclampsia risk could account for race-by-SES disparities in birth timing. METHODS: A sample of 718,604 Black and White women was drawn from a population-based California cohort of singleton births. Education, public health insurance status, gestational length, and preeclampsia diagnosis were extracted from a State-maintained birth cohort database. Age, prenatal care, diabetes diagnosis, smoking during pregnancy, and pre-pregnancy body mass index were covariates. RESULTS: In logistic regression models predicting preeclampsia risk, the race-by-SES interaction (for both education and insurance status) was significant. White women were at lower risk for preeclampsia, and higher SES further reduced risk. Black women were at higher risk for preeclampsia, and SES did not attenuate risk. In pathway analyses predicting gestational length, an indirect effect of the race-by-SES interaction was observed. Among White women, higher SES predicted lower preeclampsia risk, which in turn predicted longer gestation. The same was not observed for Black women. CONCLUSIONS: Compared to White women, Black women had increased preeclampsia risk. Higher SES attenuated risk for preeclampsia among White women, but not for Black women. Similarly, higher SES indirectly predicted longer gestational length via reduced preeclampsia risk among White women, but not for Black women. These findings are consistent with diminishing returns of higher SES for Black women with respect to preeclampsia.

Impact of autoimmune rheumatic diseases on birth outcomes: a population-based study.

Objectives: Autoimmune rheumatic diseases (ARDs) affect women of childbearing age and have been associated with adverse birth outcomes. The impact of diseases like ankylosing spondylitis and psoriatic arthritis (PsA) on birth outcomes remains less studied to date. Our objective was to evaluate the impact of ARDs on preterm birth (PTB), congenital anomalies, low birth weight (LBW) and small for gestational age (SGA), in a large cohort of women. Methods: We conducted a propensity score-matched analysis to predict ARD from a retrospective birth cohort of all live, singleton births in California occurring between 2007 and 2012. Data were derived from birth certificate records linked to hospital discharge International Classification of Diseases, ninth revision codes. Results: We matched 10 244 women with a recorded ARD diagnosis (rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), antiphospholipid syndrome, PsA); ankylosing spondylitis and juvenile idiopathic arthritis (JIA) to those without an ARD diagnosis. The adjusted OR (aOR) of PTB was increased for women with any ARD (aOR 1.93, 95% CI 1.78 to 2.10) and remained significant for those with RA, SLE, PsA and JIA. The odds of LBW and SGA were also significantly increased among women with an ARD diagnosis. ARDs were not associated with increased odds of congenital anomalies. Conclusion: Consistent with prior literature, we found that women with ARDs are more likely to have PTB or deliver an SGA infant. Some reassurance is provided that an increase in congenital anomalies was not found even in this large cohort.

Effect of Fetal Growth on 1-Year Mortality in Neonates With Critical Congenital Heart Disease.

Background Infants with critical congenital heart disease ( CCHD ) are more likely to be small for gestational age (GA). It is unclear how this affects mortality. The authors investigated the effect of birth weight Z score on 1-year mortality separately in preterm (GA <37 weeks), early-term (GA 37-38 weeks), and full-term (GA 39-42 weeks) infants with CCHD . Methods and Results Live-born infants with CCHD and GA 22 to 42 weeks born in California 2007-2012 were included in the analysis. The primary predictor was Z score for birth weight and the primary outcome was 1-year mortality. Multivariable logistic regression was used. Results are presented as adjusted odds ratios and 95% confidence intervals ( CIs ). The authors identified 6903 infants with CCHD . For preterm and full-term infants, only a Z score for birth weight <-2 was associated with increased mortality compared with the reference group ( Z score 0-0.5, adjusted odds ratio, 2.15 [95% CI , 1.1-4.21] and adjusted odds ratio, 3.93 [95% CI , 2.32-6.68], respectively). In contrast, in early-term infants, the adjusted odds ratios for Z scores <-2, -2 to -1, and -1 to -0.5 were 3.42 (95% CI , 1.93-6.04), 1.78 (95% CI , 1.12-2.83), and 2.03 (95% CI , 1.27-3.23), respectively, versus the reference group. Conclusions GA seems to modify the effect of birth weight Z score on mortality in infants with CCHD . In preterm and full-term infants, only the most severe small-for-GA infants ( Z score <-2) were at increased risk for mortality, while, in early-term infants, the risk extended to mild to moderate small-for-GA infants ( Z score <-0.5). This information helps to identify high-risk infants and is useful for surgical planning.

Altered metabolites in newborns with persistent pulmonary hypertension.

BACKGROUND: There is an emerging evidence that pulmonary hypertension is associated with amino acid, carnitine, and thyroid hormone aberrations. We aimed to characterize metabolic profiles measured by the newborn screen (NBS) in infants with persistent pulmonary hypertension of the newborn (PPHN) METHODS: Nested case-control study from population-based database. Cases were infants with ICD-9 code for PPHN receiving mechanical ventilation. Controls receiving mechanical ventilation were matched 2:1 for gestational age, sex, birth weight, parenteral nutrition administration, and age at NBS collection. Infants were divided into derivation and validation datasets. A multivariable logistic regression model was derived from candidate metabolites, and the area under the receiver operator characteristic curve (AUROC) was generated from the validation dataset. RESULTS: We identified 1076 cases and 2152 controls. Four metabolites remained in the final model. Ornithine (OR 0.32, CI 0.26-0.41), tyrosine (OR 0.48, CI 0.40-0.58), and TSH 0.50 (0.45-0.55) were associated with decreased odds of PPHN; phenylalanine was associated with increased odds of PPHN (OR 4.74, CI 3.25-6.90). The AUROC was 0.772 (CI 0.737-0.807). CONCLUSIONS: In a large, population-based dataset, infants with PPHN have distinct, early metabolic profiles. These data provide insight into the pathophysiology of PPHN, identifying potential therapeutic targets and novel biomarkers to assess the response.

Second trimester serum cortisol and preterm birth: an analysis by timing and subtype.

OBJECTIVE: We hypothesized second trimester serum cortisol would be higher in spontaneous preterm births compared to provider-initiated (previously termed 'medically indicated') preterm births. STUDY DESIGN: We used a nested case-control design with a sample of 993 women with live births. Cortisol was measured from serum samples collected as part of routine prenatal screening. We tested whether mean-adjusted cortisol fold-change differed by gestational age at delivery or preterm birth subtype using multivariable linear regression. RESULT: An inverse association between cortisol and gestational age category (trend p = 0.09) was observed. Among deliveries prior to 37 weeks, the mean-adjusted cortisol fold-change values were highest for preterm premature rupture of the membranes (1.10), followed by premature labor (1.03) and provider-initiated preterm birth (1.01), although they did not differ statistically. CONCLUSION: Cortisol continues to be of interest as a marker of future preterm birth. Augmentation with additional biomarkers should be explored.

Racial and Ethnic Disparities in Preterm Infant Mortality and Severe Morbidity: A Population-Based Study.

BACKGROUND: Disparities exist in the rates of preterm birth and infant mortality across different racial/ethnic groups. However, only a few studies have examined the impact of race/ethnicity on the outcomes of premature infants. OBJECTIVE: To report the rates of mortality and severe neonatal morbidity among multiple gestational age (GA) groups stratified by race/ethnicity. METHODS: A retrospective cohort study utilizing linked birth certificate, hospital discharge, readmission, and death records up to 1 year of life. Live-born infants ≤36 weeks born in the period 2007-2012 were included. Maternal self-identified race/ethnicity, as recorded on the birth certificate, was used. ICD-9 diagnostic and procedure codes captured neonatal morbidities (intraventricular hemorrhage, retinopathy of prematurity, periventricular leukomalacia, bronchopulmonary dysplasia, and necrotizing enterocolitis). Multiple logistic regression was performed to evaluate the impact of race/ethnicity on mortality and morbidity, adjusting for GA, birth weight, sex, and multiple gestation. RESULTS: Our cohort totaled 245,242 preterm infants; 26% were white, 46% Hispanic, 8% black, and 12% Asian. At 22-25 weeks, black infants were less likely to die than white infants (odds ratio [OR] 0.76; 95% confidence interval [CI] 0.62-0.94). However, black infants born at 32-34 weeks (OR 1.64; 95% CI 1.15-2.32) or 35-36 weeks (OR 1.57; 95% CI 1.00-2.24) were more likely to die. Hispanic infants born at 35-36 weeks were less likely to die than white infants (OR 0.66; 95% CI 0.50-0.87). Racial disparities at different GAs were also detected for severe morbidities. CONCLUSIONS: The impact of race/ethnicity on mortality and severe morbidity varied across GA categories in preterm infants. Disparities persisted even after adjusting for important potential confounders.

Chemokine polymorphisms and lymphoma: a pooled analysis.

Polymorphisms in chemokine genes have been associated with human immunodeficiency virus (HIV)-related non-Hodgkin lymphoma (NHL) but are understudied in non-HIV-related NHL. Associations of NHL and NHL subtypes with polymorphisms and haplotypes in CCR5, CCR2, CCL5, CXCL12, and CX(3)CR(1) were explored in a pooled analysis of three case-control studies (San Francisco Bay Area, California; United Kingdom; total: cases N = 1610, controls N = 1992). Adjusted unconditional logistic regression was used to estimate relative risks among HIV-negative non-Hispanic Caucasians. The CCR5 Delta32 deletion reduced the risk of NHL (odds ratio = 0.56, 95% confidence interval = 0.38-0.83) in men but not women with similar effects observed for diffuse large-cell and follicular lymphoma (FL). NHL risk also was reduced in men with the CCR2/CCR5 haplotype characterized by the CCR5 Delta32 deletion. The CCL5 -403A allele conferred reduced risks of FL and chronic lymphocytic leukemia/small lymphocytic lymphoma. Results should be interpreted conservatively. Continued investigation is warranted to confirm these findings.

Polymorphisms in the estrogen receptor 1 and vitamin C and matrix metalloproteinase gene families are associated with susceptibility to lymphoma.

BACKGROUND: Non-Hodgkin lymphoma (NHL) is the fifth most common cancer in the U.S. and few causes have been identified. Genetic association studies may help identify environmental risk factors and enhance our understanding of disease mechanisms. METHODOLOGY/PRINCIPAL FINDINGS: 768 coding and haplotype tagging SNPs in 146 genes were examined using Illumina GoldenGate technology in a large population-based case-control study of NHL in the San Francisco Bay Area (1,292 cases 1,375 controls are included here). Statistical analyses were restricted to HIV- participants of white non-Hispanic origin. Genes involved in steroidogenesis, immune function, cell signaling, sunlight exposure, xenobiotic metabolism/oxidative stress, energy balance, and uptake and metabolism of cholesterol, folate and vitamin C were investigated. Sixteen SNPs in eight pathways and nine haplotypes were associated with NHL after correction for multiple testing at the adjusted q<0.10 level. Eight SNPs were tested in an independent case-control study of lymphoma in Germany (494 NHL cases and 494 matched controls). Novel associations with common variants in estrogen receptor 1 (ESR1) and in the vitamin C receptor and matrix metalloproteinase gene families were observed. Four ESR1 SNPs were associated with follicular lymphoma (FL) in the U.S. study, with rs3020314 remaining associated with reduced risk of FL after multiple testing adjustments [odds ratio (OR) = 0.42, 95% confidence interval (CI) = 0.23-0.77) and replication in the German study (OR = 0.24, 95% CI = 0.06-0.94). Several SNPs and haplotypes in the matrix metalloproteinase-3 (MMP3) and MMP9 genes and in the vitamin C receptor genes, solute carrier family 23 member 1 (SLC23A1) and SLC23A2, showed associations with NHL risk. CONCLUSIONS/SIGNIFICANCE: Our findings suggest a role for estrogen, vitamin C and matrix metalloproteinases in the pathogenesis of NHL that will require further validation.

Accuracy of multiplexed Illumina platform-based single-nucleotide polymorphism genotyping compared between genomic and whole genome amplified DNA collected from multiple sources.

Association studies designed to identify the genetic determinants underlying complex disease increasingly require sustainable high-quality DNA resources for large-scale single-nucleotide polymorphism (SNP) genotyping. Recent studies have shown that genomic DNA (gDNA) suitable for SNP genotyping can be obtained from buccal cells and from dried blood spots on Guthrie cards. Further, successful SNP genotyping has been done using the reaction product of multiple displacement amplification of gDNA. We evaluated genotype consistency on the Illumina genotyping platform for 717 to 1,744 SNP loci between replicate samples of gDNA and whole genome amplified DNA (wgaDNA) from a variety of sources. Nine healthy adults provided peripheral blood via venipuncture and buccal cells by mouth rinse. DNA was also obtained from urothelial cells in urine samples from five of the nine subjects. gDNA was extracted from all samples, wgaDNA was generated from each gDNA, and all samples were genotyped. To assess SNP genotyping accuracy of DNA obtained from dried blood spots, gDNA was extracted, amplified, and genotyped from peripheral blood samples and paired Guthrie card samples were obtained from eight childhood leukemia patients. Call rates and replicate concordances for all sample types, regardless of amplification, were >97%, with most sample types having call rates and replicate concordances >99%. Using the gDNA from blood samples as the reference for concordances calculated for all other sample types, we observed concordances >98% regardless of sample type or amplification. We conclude that highly multiplexed Illumina genotyping may be done on gDNA and wgaDNA obtained from whole blood, buccal samples, dried blood spots on Guthrie cards, and possibly even urine samples, with minimal misclassification.

Polymorphisms and haplotypes in the cytochrome P450 17A1, prolactin, and catechol-O-methyltransferase genes and non-Hodgkin lymphoma risk.

Expression of prolactin and of prolactin and estrogen receptors in lymphocytes, bone marrow, and lymphoma cell lines suggests that hormonal modulation may influence lymphoma risk. Prolactin and estrogen promote the proliferation and survival of B cells, factors that may increase non-Hodgkin lymphoma risk, and effects of estrogen may be modified by catechol-O-methyltransferase (COMT), an enzyme that alters estrogenic activity. Cytochrome P450 17A1 (CYP17A1), a key enzyme in estrogen biosynthesis, has been associated with increased cancer risk and may affect lymphoma susceptibility. We studied the polymorphisms prolactin (PRL) -1149G>T, CYP17A1 -34T>C, and COMT 108/158Val>Met, and predicted haplotypes among a subset of participants (n = 308 cases, n = 684 controls) in a San Francisco Bay Area population-based non-Hodgkin lymphoma study (n = 1,593 cases, n = 2,515 controls) conducted from 1988 to 1995. Oral contraceptive and other hormone use also was analyzed. Odds ratios (OR) for non-Hodgkin lymphoma and follicular lymphoma were reduced for carriers of the PRL -1149TT genotype [OR, 0.64; 95% confidence interval (95% CI), 0.41-1.0; OR, 0.53; 95% CI, 0.26-1.0, respectively]. Diffuse large-cell lymphoma risk was increased for those with CYP17A1 polymorphisms including CYP17A1 -34CC (OR, 2.0; 95% CI, 1.1-3.5). ORs for all non-Hodgkin lymphoma and follicular lymphoma among women were decreased for COMT IVS1 701A>G [rs737865; variant allele: OR, 0.53; 95% CI, 0.34-0.82; OR, 0.42; 95% CI, 0.23-0.78, respectively]. Compared with never users of oral contraceptives, a 35% reduced risk was observed among oral contraceptive users in the total population. Reduced ORs for all non-Hodgkin lymphoma were observed with use of exogenous estrogens among genotyped women although 95% CIs included unity. These results suggest that PRL, CYP17A1, and COMT may be relevant genetic loci for non-Hodgkin lymphoma and indicate a possible role for prolactin and estrogen in lymphoma pathogenesis.

CYP19 (aromatase) haplotypes and endometrial cancer risk.

Endogenous estrogen exposure is an important determinant of endometrial cancer risk. Aromatase, encoded by CYP19, catalyzes the aromatization of androstenedione and testosterone to estrone and estradiol, respectively. Several common genetic polymorphisms in CYP19 have been identified, including a TCT insertion/deletion and a (TTTA)(n) repeat polymorphism in intron IV as well as a 3'UTR C/T polymorphism. We evaluated these 3 polymorphisms plus an additional 9 noncoding polymorphisms as individual genotypes and predicted haplotypes as risk factors for endometrial cancer using a nested case-control study design. Invasive endometrial cancer cases (n = 222) and matched controls (n = 666) were identified among participants in the Nurses' Health Study who had provided a blood sample in 1989-1990 (n = 32,826). We estimated haplotypes from unphased genotype data spanning > 123 kb of CYP19. Six haplotypes constructed from 10 SNPs were estimated with a frequency > or = 5%. The highest prevalence haplotype (33% among cases, 28% among controls) was significantly associated with endometrial cancer risk (p = 0.03). Loci with variant alleles that comprise the risk haplotype were independently associated with endometrial cancer, with relative risk estimates ranging from 1.68 (95% CI 1.13-2.48) to 2.07 (95% CI 1.33-3.23), comparing variant allele carriers to wild-type homozygotes. We observed significant interactions between menopausal status and 2 of the high-risk loci (p = 0.03 and p < 0.01), with > 2-fold increased risk for variant allele carriers who were postmenopausal but no association between genotype and endometrial cancer among premenopausal women. We evaluated associations between CYP19 haplotypes and plasma steroid hormone levels. The haplotype associated with endometrial cancer risk is also significantly associated with the ratios of estrone to androstenedione and estradiol to testosterone, the products and substrates of the enzyme aromatase, encoded by CYP19. Our data suggest that there is a high-frequency CYP19 haplotype related to higher estrogen to androgen ratios and increased risk of endometrial cancer and that this association may primarily pertain to postmenopausal women.

Accounting for haplotype uncertainty in matched association studies: a comparison of simple and flexible techniques.

Population-based case-control studies measuring associations between haplotypes of single nucleotide polymorphisms (SNPs) are increasingly popular, in part because haplotypes of a few "tagging" SNPs may serve as surrogates for variation in relatively large sections of the genome. Due to current technological limitations, haplotypes in cases and controls must be inferred from unphased genotypic data. Using individual-specific inferred haplotypes as covariates in standard epidemiologic analyses (e.g., conditional logistic regression) is an attractive analysis strategy, as it allows adjustment for nongenetic covariates, provides omnibus and haplotype-specific tests of association, and can estimate haplotype and haplotype x environment interaction effects. In principle, some adjustment for the uncertainty in inferred haplotypes should be made. Via simulation, we compare the performance (bias and mean squared error of haplotype and haplotype x environment interaction effect estimates) of several analytic strategies using inferred haplotypes in the context of matched case-control data. These strategies include using only the most likely haplotype assignment, the expectation substitution approach described by Stram et al. ([2003b] Hum. Hered. 55:179-190) and others, and an improper version of multiple imputation. For relatively uncomplicated haplotype structures and moderate haplotype relative risks (/=5). An application to progesterone-receptor haplotypes and endometrial cancer further illustrates that the performance of all these methods depends on how well the observed haplotypes "tag" the unobserved causal variant.

No evidence of a role for PPARgamma Pro12Ala polymorphism in endometrial cancer susceptibility.

Endogenous oestrogens play a crucial role in endometrial cancer pathogenesis, with most endometrial cancer risk factors causing an increase in oestrogens. Adipose tissue, where androgens are converted to oestrogens by the enzyme aromatase, is an important source of endogenous oestrogen production in the postmenopausal woman. The peroxisome proliferator-activated receptor-gamma (PPARgamma), a key transcriptional regulator of adipogenesis, may also play a role in the regulation of aromatase expression in adipose tissue. We hypothesized that the functional PPARgamma ProAla polymorphism may alter aromatase expression, ultimately affecting endometrial cancer susceptibility. We genotyped the PPARgamma ProAla polymorphism in a study of invasive endometrial cancer cases (n = 222) and matched controls (n = 666) nested within the Nurses' Health Study Cohort. We found little or no evidence of an association between the Ala allele of the PPARgamma codon 12 polymorphism and endometrial cancer risk (adjusted odds ratio = 1.18, 95% confidence interval = 0.80-1.76). Furthermore, we found no association with the PPARgamma ProAla polymorphism and the ratio of oestrone to androstenedione or oestradiol to testosterone plasma hormone levels, measures of aromatase activity. Consistent with previous findings for breast cancer, these results suggest that the PPARgamma ProAla polymorphism does not play a major role in mediating circulating oestrogen levels or endometrial cancer susceptibility.