(2010) Unraveling the directional link between adiposity and inflammation: a bidirectional mendelian randomization approach. Context: Associations between adiposity and circulating inflammation markers are assumed to be causal, although the direction of the relationship has not been proven. Objective: The aim of the study was to explore the causal direction of the relationship between adiposity and inflammation using a bidirectional Mendelian randomization approach. Methods: In the PROSPER study of 5804 elderly patients, we related C-reactive protein (CRP) single nucleotide polymorphisms (SNPs) (rs1800947 and rs1205) and adiposity SNPs (FTO and MC4R) to body mass index (BMI) as well as circulating levels of CRP and leptin. We gave each individual two allele scores ranging from zero to 4, counting each pair of alleles related to CRP levels or BMI. Results: With increasing CRP allele score, there was a stepwise decrease in CRP levels (P for trend 0.0001) and a 1.98 mg/liter difference between extremes of the allele score distribution, but there was no associated change in BMI or leptin levels (P 0.89). By contrast, adiposity allele score was associated with 1) an increase in BMI (1.2 kg/m 2 difference between extremes; P for trend 0.002); 2) an increase in circulating leptin (5.77 ng/ml difference between extremes; P for trend 0.0027); and 3) increased CRP levels (1.24 mg/liter difference between extremes; P for trend 0.002). Conclusions: Greater adiposity conferred by FTO and MC4R SNPs led to higher CRP levels, with no evidence for any reverse pathway. Future studies should extend our findings to other circulating inflammatory parameters. This study illustrates the potential power of Mendelian randomization to dissect directions of causality between intercorrelated metabolic factors. (J Clin Endocrinol Metab 95: 93-99, 2010) Abbreviations: BMI, Body mass index; CRP, C-reactive protein; HWE, Hardy-Weinberg equilibrium; MR, Mendelian randomization; SNP, single nucleotide polymorphism. O R I G I N A L A R T I C L E E n d o c r i n e C a r e J Clin Endocrinol Metab, January 2010, 95(1):93-99 jcem.endojournals.org 93 at Glasgow Univ Library on April 26, 2010 jcem.endojournals.org Downloaded from 94 Welsh et al. Fat and Inflammation: Causality by MR J Clin Endocrinol Metab, January 2010, 95(1):93-99 Welsh et al. Fat and Inflammation: Causality by MR J Clin Endocrinol Metab, January 2010, 95(1):93-99 at Glasgow Univ Library on April 26, 2010 jcem.endojournals.org Downloaded from Welsh et al. Fat and Inflammation: Causality by MR J Clin Endocrinol Metab, January 2010, 95(1):93-99 at Glasgow Univ Library on April 26, 2010 jcem.endojournals.org Downloaded from

Our purpose is to provide a framework for diagnosing the inherited causes of marked high-density lipoprotein (HDL) deficiency (HDL cholesterol levels <10 mg/dL in the absence of severe hypertriglyceridemia or liver disease) and to provide information about coronary heart disease (CHD) risk for such cases. Published articles in the literature on severe HDL deficiencies were used as sources. If apolipoprotein (Apo) A-I is not present in plasma, then three forms of ApoA-I deficiency, all with premature CHD,and normal low-density lipoprotein (LDL) cholesterol levels have been described: ApoA-I/C-III/A-IV deficiency with fat malabsorption, ApoA-I/C-III deficiency with planar xanthomas, and ApoA-I deficiency with planar and tubero-eruptive xanthomas (pictured in this review for the first time). If ApoA-I is present in plasma at a concentration <10 mg/dL, with LDL cholesterol that is about 50% of normal and mild hypertriglyceridemia, a possible diagnosis is Tangier disease due to mutations at the adenosine triphosphate binding cassette protein A1 (ABCA1) gene locus. These patients may develop premature CHD and peripheral neuropathy, and have evidence of cholesteryl ester-laden macrophages in their liver, spleen, tonsils, and Schwann cells, as well as other tissues. The third form of severe HDL deficiency is characterized by plasma ApoA-I levels <40 mg/dL, moderate hypertriglyceridemia, and decreased LDL cholesterol, and the finding that most of the cholesterol in plasma is in the free rather than the esterified form, due to a deficiency in lecithin:cholesterol acyltransferase activity. These patients have marked corneal opacification and splenomegaly, and are at increased risk of developing renal failure, but have no clear evidence of premature CHD. Marked HDL deficiency has different etiologies and is generally associated with early CHD risk.

Low serum high density lipoprotein cholesterol level (HDL-C) < 40 mg/dL in men and < 50 mg/dL in women are a significant independent risk factor for cardiovascular disease (CVD), and are often observed in patients with hypertriglyceridemia, obesity, insulin resistance, and diabetes. Patients with marked deficiency of HDL-C (< 20 mg/dL) in the absence of secondary causes are much less common (< 1% of the population). These patients may have homozygous, compound heterozygous, or heterozygous defects involving the apolipoprotein (APO)AI, ABCA1, or lecithin:cholesterol acyl transferase genes, associated with Apo A-I Deficiency, ApoA-I Variants, Tangier Disease, Familial Lecithin:Cholesteryl Ester Acyltransferase Deficiency, and Fish Eye Disease. There is marked variability in laboratory and clinical presentation, and DNA analysis is necessary for diagnosis. These patients can develop premature CVD, neuropathy, kidney failure, neuropathy, hepatosplenomegaly and anemia. Treatment should be directed at optimizing all non-HDL risk factors.