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1.  Sugar-Sweetened Beverages and Genetic Risk of Obesity 
The New England journal of medicine  2012;367(15):1387-1396.
BACKGROUND
Temporal increases in the consumption of sugar-sweetened beverages have paralleled the rise in obesity prevalence, but whether the intake of such beverages interacts with the genetic predisposition to adiposity is unknown.
METHODS
We analyzed the interaction between genetic predisposition and the intake of sugar-sweetened beverages in relation to body-mass index (BMI; the weight in kilograms divided by the square of the height in meters) and obesity risk in 6934 women from the Nurses’ Health Study (NHS) and in 4423 men from the Health Professionals Follow-up Study (HPFS) and also in a replication cohort of 21,740 women from the Women’s Genome Health Study (WGHS). The genetic-predisposition score was calculated on the basis of 32 BMI-associated loci. The intake of sugar-sweetened beverages was examined prospectively in relation to BMI.
RESULTS
In the NHS and HPFS cohorts, the genetic association with BMI was stronger among participants with higher intake of sugar-sweetened beverages than among those with lower intake. In the combined cohorts, the increases in BMI per increment of 10 risk alleles were 1.00 for an intake of less than one serving per month, 1.12 for one to four servings per month, 1.38 for two to six servings per week, and 1.78 for one or more servings per day (P<0.001 for interaction). For the same categories of intake, the relative risks of incident obesity per increment of 10 risk alleles were 1.19 (95% confidence interval [CI], 0.90 to 1.59), 1.67 (95% CI, 1.28 to 2.16), 1.58 (95% CI, 1.01 to 2.47), and 5.06 (95% CI, 1.66 to 15.5) (P = 0.02 for interaction). In the WGHS cohort, the increases in BMI per increment of 10 risk alleles were 1.39, 1.64, 1.90, and 2.53 across the four categories of intake (P = 0.001 for interaction); the relative risks for incident obesity were 1.40 (95% CI, 1.19 to 1.64), 1.50 (95% CI, 1.16 to 1.93), 1.54 (95% CI, 1.21 to 1.94), and 3.16 (95% CI, 2.03 to 4.92), respectively (P = 0.007 for interaction).
CONCLUSIONS
The genetic association with adiposity appeared to be more pronounced with greater intake of sugar-sweetened beverages.
doi:10.1056/NEJMoa1203039
PMCID: PMC3518794  PMID: 22998338
2.  Sex Hormone–Binding Globulin and Risk of Type 2 Diabetes in Women and Men 
The New England journal of medicine  2009;361(12):1152-1163.
BACKGROUND
Circulating sex hormone–binding globulin levels are inversely associated with insulin resistance, but whether these levels can predict the risk of developing type 2 diabetes is uncertain.
METHODS
We performed a nested case–control study of postmenopausal women in the Women’s Health Study who were not using hormone therapy (359 with newly diagnosed type 2 diabetes and 359 controls). Plasma levels of sex hormone–binding globulin were measured; two polymorphisms of the gene encoding sex hormone–binding globulin, SHBG, that were robustly associated with the protein levels were genotyped and applied in mendelian randomization analyses. We then conducted a replication study in an independent cohort of men from the Physicians’ Health Study II (170 with newly diagnosed type 2 diabetes and 170 controls).
RESULTS
Among women, higher plasma levels of sex hormone–binding globulin were prospectively associated with a lower risk of type 2 diabetes: multivariable odds ratios were 1.00 for the first (lowest) quartile of plasma levels, 0.16 (95% confidence interval [CI], 0.08 to 0.33) for the second quartile, 0.04 (95% CI, 0.01 to 0.12) for the third quartile, and 0.09 (95% CI, 0.03 to 0.21) for the fourth (highest) quartile (P<0.001 for trend). These prospective associations were replicated among men (odds ratio for the highest quartile of plasma levels vs. the lowest quartile, 0.10; 95% CI, 0.03 to 0.36; P<0.001 for trend). As compared with homozygotes of the respective wild-type allele, carriers of a variant allele of the SHBG single-nucleotide polymorphism (SNP) rs6259 had 10% higher sex hormone–binding globulin levels (P = 0.005), and carriers of an rs6257 variant had 10% lower plasma levels (P = 0.004); variants of both SNPs were also associated with a risk of type 2 diabetes in directions corresponding to their associated sex hormone–binding globulin levels. In mendelian randomization analyses, the predicted odds ratio of type 2 diabetes per standard-deviation increase in the plasma level of sex hormone–binding globulin was 0.28 (95% CI, 0.13 to 0.58) among women and 0.29 (95% CI, 0.15 to 0.58) among men, a finding that suggests that sex hormone–binding globulin may have a causal role in the risk of type 2 diabetes.
CONCLUSIONS
Low circulating levels of sex hormone–binding globulin are a strong predictor of the risk of type 2 diabetes in women and men. The clinical usefulness of both SHBG genotypes and plasma levels in stratification and intervention for the risk of type 2 diabetes warrants further examination.
doi:10.1056/NEJMoa0804381
PMCID: PMC2774225  PMID: 19657112
3.  Performance of Common Genetic Variants in Breast-Cancer Risk Models 
The New England journal of medicine  2010;362(11):986-993.
BACKGROUND
Genomewide association studies have identified multiple genetic variants associated with breast cancer. The extent to which these variants add to existing risk-assessment models is unknown.
METHODS
We used information on traditional risk factors and 10 common genetic variants associated with breast cancer in 5590 case subjects and 5998 control subjects, 50 to 79 years of age, from four U.S. cohort studies and one case–control study from Poland to fit models of the absolute risk of breast cancer. With the use of receiveroperating- characteristic curve analysis, we calculated the area under the curve (AUC) as a measure of discrimination. By definition, random classification of case and control subjects provides an AUC of 50%; perfect classification provides an AUC of 100%. We calculated the fraction of case subjects in quintiles of estimated absolute risk after the addition of genetic variants to the traditional risk model.
RESULTS
The AUC for a risk model with age, study and entry year, and four traditional risk factors was 58.0%; with the addition of 10 genetic variants, the AUC was 61.8%. About half the case subjects (47.2%) were in the same quintile of risk as in a model without genetic variants; 32.5% were in a higher quintile, and 20.4% were in a lower quintile.
CONCLUSIONS
The inclusion of newly discovered genetic factors modestly improved the performance of risk models for breast cancer. The level of predicted breast-cancer risk among most women changed little after the addition of currently available genetic information.
doi:10.1056/NEJMoa0907727
PMCID: PMC2921181  PMID: 20237344
4.  Incidental Meniscal Findings on Knee MRI in Middle-Aged and Elderly Persons 
The New England journal of medicine  2008;359(11):1108-1115.
BACKGROUND
Magnetic resonance imaging (MRI) of the knee is often performed in patients who have knee symptoms of unclear cause. When meniscal tears are found, it is commonly assumed that the symptoms are attributable to them. However, there is a paucity of data regarding the prevalence of meniscal damage in the general population and the association of meniscal tears with knee symptoms and with radiographic evidence of osteoarthritis.
METHODS
We studied persons from Framingham, Massachusetts, who were drawn from census-tract data and random-digit telephone dialing. Subjects were 50 to 90 years of age and ambulatory; selection was not made on the basis of knee or other joint problems. We assessed the integrity of the menisci in the right knee on 1.5-tesla MRI scans obtained from 991 subjects (57% of whom were women). Symptoms involving the right knee were evaluated by questionnaire.
RESULTS
The prevalence of a meniscal tear or of meniscal destruction in the right knee as detected on MRI ranged from 19% (95% confidence interval [CI], 15 to 24) among women 50 to 59 years of age to 56% (95% CI, 46 to 66) among men 70 to 90 years of age; prevalences were not materially lower when subjects who had had previous knee surgery were excluded. Among persons with radiographic evidence of osteoarthritis (Kellgren–Lawrence grade 2 or higher, on a scale of 0 to 4, with higher numbers indicating more definite signs of osteoarthritis), the prevalence of a meniscal tear was 63% among those with knee pain, aching, or stiffness on most days and 60% among those without these symptoms. The corresponding prevalences among persons without radiographic evidence of osteoarthritis were 32% and 23%. Sixty-one percent of the subjects who had meniscal tears in their knees had not had any pain, aching, or stiffness during the previous month.
CONCLUSIONS
Incidental meniscal findings on MRI of the knee are common in the general population and increase with increasing age.
doi:10.1056/NEJMoa0800777
PMCID: PMC2897006  PMID: 18784100

Results 1-4 (4)