Alison Wise

Obesity and diabetes genetic variants associated with gestational weight gain

OBJECTIVE We sought to determine whether genetic variants associated with diabetes and obesity predict gestational weight gain. STUDY DESIGN A total of 960 participants in the Pregnancy, Infection, and Nutrition cohorts were genotyped for 27 single-nucleotide polymorphisms (SNPs) associated with diabetes and obesity. RESULTS Among Caucasian and African American women (n = 960), KCNQ1 risk allele carriage was directly associated with weight gain (P < .01). In Bayesian hierarchical models among Caucasian women (n = 628), we found posterior odds ratios >3 for inclusion of TCF2 and THADA SNPs in our models. Among African American women (n = 332), we found associations between risk allele carriage and weight gain for the THADA and INSIG2 SNPs. In Bayesian variable selection models, we found an interaction between the TSPAN8 risk allele and pregravid obesity, with lower weight gain among obese risk allele carriers. CONCLUSION We found evidence that diabetes and obesity risk alleles interact with maternal pregravid body mass index to predict gestational weight gain.

Facilitators of Transforming Primary Care: A Look Under the Hood at Practice Leadership

PURPOSE This study examined how characteristics of practice leadership affect the change process in a statewide initiative to improve the quality of diabetes and asthma care. METHODS We used a mixed methods approach, involving analyses of existing quality improvement data on 76 practices with at least 1 year of participation and focus groups with clinicians and staff in a 12-practice subsample. Existing data included monthly diabetes or asthma measures (clinical measures) and monthly practice implementation, leadership, and practice engagement scores rated by an external practice coach. RESULTS Of the 76 practices, 51 focused on diabetes and 25 on asthma. In aggregate, 50% to 78% made improvements within in each clinical measure in the first year. The odds of making practice changes were greater for practices with higher leadership scores (odds ratios = 2.41–4.20). Among practices focused on diabetes, those with higher leadership scores had higher odds of performing nephropathy screening (odds ratio = 1.37, 95% CI, 1.08–1.74); no significant associations were seen for the intermediate outcome measures of hemoglobin A1c, blood pressure, and cholesterol. Focus groups revealed the importance of a leader, typically a physician, who believed in the transformation work (ie, a visionary leader) and promoted practice engagement through education and cross-training. Practices with greater change implementation also mentioned the importance of a midlevel operational leader who helped to create and sustain practice changes. This person communicated and interacted well with, and was respected by both clinicians and staff. CONCLUSIONS In the presence of a vision for transformation, operational leaders within practices can facilitate practice changes that are associated with clinical improvement.

More extensive implementation of the chronic care model is associated with better lipid control in diabetes

Objective: Chronic disease collaboratives help practices redesign care delivery. The North Carolina Improving Performance in Practice program provides coaches to guide implementation of 4 key practice changes: registries, planned care templates, protocols, and self-management support. Coaches rate progress using the Key Drivers Implementation Scales (KDIS). This study examines whether higher KDIS scores are associated with improved diabetes outcomes. Methods: We analyzed clinical and KDIS data from 42 practices. We modeled whether higher implementation scores at year 1 of participation were associated with improved diabetes measures during year 2. Improvement was defined as an increase in the proportion of patients with hemoglobin A1C values <9%, blood pressure values <130/80 mmHg, and low-density lipoprotein (LDL) levels <100 mg/dL. Results: Statistically significant improvements in the proportion of patients who met the LDL threshold were noted with higher “registry” and “protocol” KDIS scores. For hemoglobin A1C and blood pressure values, none of the odds ratios were statistically significant. Conclusions: Practices that implement key changes may achieve improved patient outcomes in LDL control among their patients with diabetes. Our data confirm the importance of registry implementation and protocol use as key elements of improving patient care. The KDIS tool is a pragmatic option for measuring practice changes that are rooted in the Chronic Care Model.

Maternal genotype and gestational diabetes.

OBJECTIVE To determine whether genetic variants associated with glucose homeostasis are associated with gestational diabetes (GDM). STUDY DESIGN We genotyped 899 self-identified Caucasian women and 386 self-identified African-American women in the Pregnancy, Infection and Nutrition (PIN) Studies cohorts for 38 single-nucleotide polymorphisms (SNPs) associated with type II diabetes (T2DM) and/or glucose homeostasis in European populations. RESULTS GDM was diagnosed in 56 of 899 (6.2%) Caucasian and 24 of 386 (6.2%) African-American women. Among Caucasian women, GDM was associated with carriage of TCF7L2 rs7901695, MTNR1B rs10830963 and GCKR rs780094 alleles that are associated with T2DM and fasting glucose in nonpregnant populations. Among African-American participants, we found an increased risk among TSPAN8 rs7961581 C allele homozygotes and reduced risk among carriers of the JAZF1 rs864745 T allele. CONCLUSION We found several SNPs that are associated with GDM risk in the PIN cohorts. Maternal genotyping may identify women at risk for impaired gestational glucose tolerance.

Adrenomedullin signaling pathway polymorphisms and adverse pregnancy outcomes.

OBJECTIVE Reduced maternal plasma levels of the peptide vasodilator adrenomedullin have been associated with adverse pregnancy outcomes. We measured the extent to which genetic polymorphisms in the adrenomedullin signaling pathway are associated with birth weight, glycemic regulation, and preeclampsia risk. STUDY DESIGN We genotyped 1,353 women in the Pregnancy, Infection, and Nutrition Postpartum Study for 37 ancestry-informative markers and for single-nucleotide polymorphisms in adrenomedullin (ADM), complement factor H variant (CFH), and calcitonin receptor-like receptor (CALCRL). We used linear and logistic regression to model the association between genotype and birth weight, glucose loading test (GLT) results, preeclampsia, and gestational diabetes (GDM). All models were adjusted for pregravid body mass index, maternal age, and probability of Yoruban ancestry. p values of < 0.05 were considered statistically significant. RESULTS Among Caucasian women, ADM rs57153895, a proxy for rs11042725, was associated with reduced birth weight z-score. Among African-American women, ADM rs57153895 was associated with increased birth weight z-score. Two CALCRL variants were associated with GDM risk. CFH rs1061170 was associated with higher GLT results and increased preeclampsia risk. CONCLUSION Consistent with studies of plasma adrenomedullin and adverse pregnancy outcomes, we found associations between variants in the adrenomedullin signaling pathway and birth weight, glycemic regulation, and preeclampsia.

Learning about the X from our parents

The X chromosome is generally understudied in association studies, in part because the analyst has had limited methodological options. For nuclear-family-based association studies, most current methods extend the transmission disequilibrium test (TDT) to the X chromosome. We present a new method to study association in case-parent triads: the parent-informed likelihood ratio test for the X chromosome (PIX-LRT). Our method enables estimation of relative risks and takes advantage of parental genotype information and the sex of the affected offspring to increase statistical power to detect an effect. Under a parental exchangeability assumption for the X, if case-parent triads are complete, the parents of affected offspring provide an independent replication sample for estimates based on transmission distortion to their affected offspring. For each offspring sex we combine the parent-level and the offspring-level information to form a likelihood ratio test statistic; we then combine the two to form a combined test statistic. Our method can estimate relative risks under different modes of inheritance or a more general co-dominant model. In triads with missing parental genotypes, the method accounts for missingness with the Expectation-Maximization algorithm. We calculate non-centrality parameters to assess the power gain and robustness of our method compared to alternative methods. We apply PIX-LRT to publically available data from an international consortium of genotyped families affected by the birth defect oral cleft and find a strong, internally-replicated signal for a SNP marker related to cleft lip with or without cleft palate.

A family-based, genome-wide association study of young-onset breast cancer: inherited variants and maternally mediated effects

Young-onset breast cancer shows certain phenotypic and etiologic differences from older-onset breast cancer and may be influenced by some distinct genetic variants. Few genetic studies of breast cancer have targeted young women and no studies have examined whether maternal variants influence disease in their adult daughters through prenatal effects. We conducted a family-based, genome-wide association study of young-onset breast cancer (age at diagnosis <50 years). A total of 602 188 single-nucleotide polymorphisms (SNPs) were genotyped for 1279 non-Hispanic white cases and their parents or sisters. We used likelihood-based log-linear models to test for transmission asymmetry within families and for maternally mediated genetic effects. Three autosomal SNPs (rs28373882, P=2.8 × 10−7; rs879162, P=9.2 × 10−7; rs12606061, P=9.1 × 10−7) were associated with risk of young-onset breast cancer at a false-discovery rate below 0.20. None of these loci has been previously linked with young-onset or overall breast cancer risk, and their functional roles are unknown. There was no evidence of maternally mediated, X-linked, or mitochondrial genetic effects, and no notable findings within cancer subcategories defined by menopausal status, estrogen receptor status, or by tumor invasiveness. Further investigations are needed to explore other potential genetic, epigenetic, or epistatic mechanisms and to confirm the association between these three novel loci and young-onset breast cancer.