Paul McKeigue

Lighter variations of pigmentation in humans are associated with diminished number, size, and density of melanosomes, the pigmented organelles of melanocytes. Here we show that zebrafish golden mutants share these melanosomal changes and that golden encodes a putative cation exchanger slc24a5 (nckx5) that localizes to an intracellular membrane, likely the melanosome or its precursor. The human ortholog is highly similar in sequence and functional in zebrafish. The evolutionarily conserved ancestral allele of a human coding polymorphism predominates in African and East Asian populations. In contrast, the variant allele is nearly fixed in European populations, is associated with a substantial reduction in regional heterozygosity, and correlates with lighter skin pigmentation in admixed populations, suggesting a key role for the SLC24A5 gene in human pigmentation.

OBJECTIVE: Polycystic ovary syndrome (PCOS) is associated with higher prevalence of cardiovascular risk factors but the relative prevalence of cardiovascular disease in women with PCOS has not previously been reported. We have compared cardiovascular mortality and morbidity in middle-aged women previously diagnosed with PCOS and age-matched control women. DESIGN: A retrospective cohort study of women diagnosed with PCOS in the United Kingdom before 1979. PATIENTS: Seventy cohort members died before 31 March 1999. Morbidity data were collected from 319 women with PCOS and 1060 age-matched control women. Sixty-one women with PCOS and 63 control women attended a clinical examination. MEASUREMENTS: Data were collected from death certificates, general practitioners' records and questionnaires with measurement of cardiovascular risk factors in a subsample of questionnaire respondents. RESULTS: All-cause and cardiovascular mortality in the cohort were similar to women in the general population (standardized mortality ratios (95% CI): 93 (72-117) and 78 (45-124), respectively). Women with PCOS had higher levels of several cardiovascular risk factors: diabetes (P = 0.002) hypertension (P = 0.04), hypercholesterolaemia (P < 0.001), hypertriglyceridaemia (P = 0.02) and increased waist:hip ratio (P = 0.004). After adjustment for BMI, odds ratios (OR) were 2.2 (0.9-5. 2) for diabetes, 1.4 (0.9-2.0) for hypertension and 3.2 (1.7-6.0) for hypercholesterolaemia. A history of coronary heart disease (CHD) was not significantly more common in women with PCOS (crude OR (95%CI) 1.5 (0.7-2.9)) but the crude OR for cerebrovascular disease was 2.8 (1.1-7.1). CONCLUSION: At long-term follow-up, a history of nonfatal cerebrovascular disease and cardiovascular risk factors including diabetes are more prevalent among women with polycystic ovary syndrome. Morbidity and mortality from of coronary heart disease among women with polycystic ovary syndrome is not as high as previously predicted. This finding challenges our understanding of the aetiology of coronary heart disease in women.

OBJECTIVE: To establish whether fetal growth rate (as distinct from size at birth) is associated with mortality from ischaemic heart disease. DESIGN: Cohort study based on uniquely detailed obstetric records with 97% follow up over the entire life course and linkage to census data in adult life. SUBJECTS: All 14 611 babies delivered at the Uppsala Academic Hospital, Sweden, during 1915-29 followed up to end of 1995. MAIN OUTCOME MEASURES: Mortality from ischaemic heart disease and other causes. RESULTS: Cardiovascular disease showed an inverse association with birth weight for both men and women, although this was significant only for men. In men a 1000 g increase in birth weight was associated with a proportional reduction in the rate of ischaemic heart disease of 0.77 (95% confidence interval 0.67 to 0.90). Adjustment for socioeconomic circumstances at birth and in adult life led to slight attenuation of this effect. Relative to the lowest fourth of birth weight for gestational age, mortality from ischaemic heart disease in men in the second, third, and fourth fourths was 0.81 (0.66 to 0.98), 0.63 (0.50 to 0.78), and 0.67 (0.54 to 0.82), respectively. The inclusion of birth weight per se and birth weight for gestational age in the same model strengthened the association with birth weight for gestational age but removed the association with birth weight. CONCLUSION: This study provides by far the most persuasive evidence of a real association between size at birth and mortality from ischaemic heart disease in men, which cannot be explained by methodological artefact or socioeconomic confounding. It strongly suggests that it is variation in fetal growth rate rather than size at birth that is aetiologically important.